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    Interictal intracranial EEG for predicting surgical success: the importance of space and time. (arXiv:1909.07932v1 [q-bio.NC])

    Predicting post-operative seizure freedom using functional correlation networks derived from interictal intracranial EEG has shown some success. However, there are important challenges to consider. 1: electrodes physically closer to each other naturally tend to be more correlated causing a spatial bias. 2: implantation location and number of electrodes differ between patients, making cross-subject comparisons difficult. 3: functional correlation networks can vary over time but are currently assumed as static. In this study we address these three substantial challenges using intracranial EEG data from 55 patients with intractable focal epilepsy. Patients additionally underwent preoperative MR imaging, intra-operative CT, and post-operative MRI allowing accurate localisation of electrodes and delineation of removed tissue. We show that normalising for spatial proximity between nearby electrodes improves prediction of post-surgery seizure outcomes. Moreover, patients with more extensive electrode coverage were more likely to have their outcome predicted correctly (ROC-AUC >0.9, p<<0.05), but not necessarily more likely to have a better outcome. Finally, our predictions are robust regardless of the time segment. Future studies should account for the spatial proximity of electrodes in functional network construction to improve prediction of post-surgical seizure outcomes. Greater coverage of both removed and spared tissue allows for predictions with higher accuracy.

    in q-bio.NC updates on arXiv.org on September 18, 2019 01:30 AM.

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    Topological stability of the hippocampal spatial map and synaptic transience. (arXiv:1909.07540v1 [q-bio.NC])

    Spatial awareness in mammals is based on internalized representations of the environment---cognitive maps---encoded by networks of spiking neurons. Although behavioral studies suggest that these maps can remain stable for long periods, it is also well-known that the underlying networks of synaptic connections constantly change their architecture due to various forms of neuronal plasticity. This raises a principal question: how can a dynamic network encode a stable map of space? In the following, we discuss some recent results obtained in this direction using an algebro-topological modeling approach, which demonstrate that emergence of stable cognitive maps produced by networks with transient architectures is not only possible, but may be a generic phenomenon.

    in q-bio.NC updates on arXiv.org on September 18, 2019 01:30 AM.

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    From topological analyses to functional modeling: the case of hippocampus. (arXiv:1909.07536v1 [q-bio.NC])

    Topological data analyses are rapidly turning into key tools for quantifying large volumes of neurobiological data, e.g., for organizing the spiking outputs of large neuronal ensembles and thus gaining insights into the information produced by various networks. Below we discuss a case in which several convergent topological analyses not only provide a description of the data structure, but also produce insights into how these data may be processed in the hippocampus---a brain part that plays a key role in learning and memory. The resulting functional model provides a unifying framework for integrating spiking information at different timescales and understanding the course of spatial learning at different levels of spatiotemporal granularity. In particular, the model allows quantifying contributions of various physiological phenomena---brain waves, synaptic strengths, synaptic architectures, etc., into spatial cognition.

    in q-bio.NC updates on arXiv.org on September 18, 2019 01:30 AM.

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    Meta-analysis of Gene Expression in Neurodegenerative Diseases Reveals Patterns in GABA Synthesis and Heat Stress Pathways. (arXiv:1909.07469v1 [q-bio.MN])

    Neurodegenerative diseases are characterized as the progressive loss of neural cells, e.g. neurons, glial cells. Ageing, monogenic variations, viral infections, and many other factors are determined and speculated as causes for them. While many individual genes, such as APP for Alzheimer disease and HTT for Huntington disease, and biological pathways are studied for neurodegenerative diseases, system-wide pathogenesis studies are limited. In this study, we carried out a meta-analysis of RNA-Seq studies for three neurodegenerative diseases, namely Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS) to minimize the batch effect derived differences and identify the similarly altered factors among studies. Our main assumption is that these three diseases share some pathological pathway pattern. For this purpose, we downloaded publicly available Alzheimer's disease (84 patients + 33 controls = 117 individuals), Parkinson's disease (28 patients + 43 controls = 71 individuals) and ALS (2 studies: 46 patients + 25 control = 71 individuals) RNA-Seq data from Sequence Read Archive (SRA) database. The significantly differentially expressed genes common to these studies were first identified and analyzed for the patterns in their pathways and variations. Our meta-analysis revealed the shared nature of differential gene expression and mutation load of the cellular heat stress response and GABA synthesis in neurodegenerative diseases. The downregulated GABA synthesis-related genes (e.g. GAD1 and GAD2) and the upregulated cellular heat stress response-related genes (e.g. DNAJB6 and HSP90AA1), in addition to their expression patterns, contain unique variations in samples from patients with neurodegenerative diseases. The significance of genes and pathways we identified in this study corroborated by the recent literature on neurodegenerative diseases.

    in q-bio.NC updates on arXiv.org on September 18, 2019 01:30 AM.

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    Decoding and mapping task states of the human brain via deep learning. (arXiv:1801.09858v2 [q-bio.NC] UPDATED)

    Multivariate pattern analysis (MVPA) has delivered promising performance in decoding specific task states based on functional magnetic resonance imaging (fMRI) of the human brain. However, the number of dimensions of fMRI signals are too large (hundreds of thousands of voxels in one volume) to be efficiently learnt by the MVPA. Researchers thus need to reduce the features to tens or hundreds of dimensions through feature selection/extraction that requires expert knowledge and may lead to a selection bias. In this study, we propose a deep neural network (DNN) for directly decoding multiple brain task states from fMRI signals of the brain without any burden for feature handcrafts. We trained and tested the DNN classifier using task fMRI data from the Human Connectome Project's S1200 dataset (N=1034). In tests to verify its performance, the proposed classification method identified seven tasks with an average accuracy of 93.7%. We also showed the general applicability of the DNN for transfer learning to small datasets (N=43), a situation encountered in typical neuroscience research. The proposed method achieved an average accuracy of 89% and 94.7% on a working memory task and a motor classification task, respectively, higher than the accuracy of 69.2% and 68.6% obtained by the MVPA. A visualization analysis showed that the DNN automatically detected features from areas of the brain related to each task. Without incurring the burden of handcrafting the features, the proposed deep decoding method can classify brain task states highly accurately, and is a powerful tool for fMRI researchers.

    in q-bio.NC updates on arXiv.org on September 18, 2019 01:30 AM.

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    Dichloroacetate Stabilizes Mitochondrial Fusion Dynamics in Models of Neurodegeneration

    Mitochondrial dysfunction is a recognized hallmark of neurodegenerative diseases and abnormal mitochondrial fusion-fission dynamics have been implicated in the pathogenesis of neurodegenerative disorders. This study characterizes the effects of metabolic flux inhibitors and activators on mitochondrial fusion dynamics in the neuronal cell culture model of differentiated PC12 cells. Using a real time confocal microscopy assay, it was found that the carnitine palmitoyltransferase I (CPTI) inhibitor, etomoxir, reduced mitochondrial fusion dynamics in a time-dependent manner. Etomoxir also decreased JO2, ΔΨm and reactive oxygen species (ROS) production rates. The mitochondrial pyruvate carrier (MPC) inhibitor, UK5099, reduced fusion dynamics and in combination with etomoxir these inhibitory effects were amplified. Use of the pyruvate dehydrogenase (PDH) kinase inhibitor dichloroacetate, which is known to increase metabolic flux through PDH, reversed the etomoxir-induced effects on fusion dynamics, JO2, ΔΨm but not ROS production rates. Dichloroacetate also partially reversed inhibition of mitochondrial fusion dynamics caused by the parkinsonian-inducing neurotoxin, MPP+. These results suggest that dichloroacetate-induced activation of metabolic flux in the mitochondrion may be a mechanism to restore normal mitochondrial fusion-fission dynamics in metabolically challenged cells.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    Brain Senescence Caused by Elevated Levels of Reactive Metabolite Methylglyoxal on D-Galactose-Induced Aging Mice

    Aging is a complex natural phenomenon that is manifested by degenerative changes in the structure and function of cells and tissues. D-Galactose-induced aging mice are an artificial accelerated aging model that causes memory and learning impairment, oxidative stress, and neuroinflammation. In this study, we examined the underlying mechanism of an aging mouse model induced by D-galactose. Our behavioral Morris water maze results revealed that D-galactose administration for 2 months significantly induced memory and learning impairment in C57BL/6J mice. High performance liquid chromatography (HPLC) results showed elevated levels of the metabolite methylglyoxal (MG) in D-galactose-induced aging mice. Whether and how D-galactose induces senescence by elevated levels of reactive metabolite MG remain unclear. In our study, MG mainly accumulated through the following two aspects: to increase its source, namely, the triose phosphate produced by the glycolysis pathway, and to reduce its detoxification system, namely, the glyoxalase system. Therefore, elevated MG levels may be one of the causes of brain senescence in D-galactose-induced mice. However, the molecular mechanism of the increased level of the reaction metabolite methylglyoxal requires further exploration.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 18, 2019 12:00 AM.

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    Rejuvenating the Brain With Chronic Exercise Through Adult Neurogenesis

    The aging brain presents a general decline in plasticity that also affects hippocampal neurogenesis. Besides the well-known reduction in the rate of neuronal generation, development of new neurons is largely delayed in the aging brain. We have recently shown that this slow development is accelerated when middle-aged mice perform voluntary exercise in a running wheel. It is unclear whether the effects of exercise on neurogenic plasticity are persistent in time in a manner that might influence neuronal cohorts generated over an extended time span. To clarify these issues, we examined the effects of exercise length in 3-week-old neurons and found that their development is accelerated only when running occurs for long (3–4 weeks) but not short periods (1 week). Furthermore, chronic running acted with similar efficiency on neurons that were born at the onset, within, or at the end of the exercise period, lasting until 3 months. Interestingly, no effects were observed on neurons born 1 month after exercise had ended. Our results indicate that multiple neuronal cohorts born throughout the exercise span integrate very rapidly in the aging brain, such that the effects of running will accumulate and expand network assembly promoted by neurogenesis. These networks are likely to be more complex than those assembled in a sedentary mouse due to the faster and more efficient integration of new neurons.

    in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on September 18, 2019 12:00 AM.

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    Receptor-Mediated Delivery of Astaxanthin-Loaded Nanoparticles to Neurons: An Enhanced Potential for Subarachnoid Hemorrhage Treatment

    Astaxanthin (ATX) is a carotenoid that exerts strong anti-oxidant and anti-inflammatory property deriving from its highly unsaturated molecular structures. However, the low stability and solubility of ATX results in poor bioavailability, which markedly hampers its application as therapeutic agent in clinic advancement. This study investigated a promising way of transferrin conjugated to poly (ethylene glycol) (PEG)-encapsulated ATX nanoparticles (ATX-NPs) on targeted delivery and evaluated the possible mechanism underlying neuroprotection capability. As a result, the ATX integrated into nanocarrier presented both well water-dispersible and biocompatible, primely conquering its limitations. More than that, the transferrin-containing ATX-NPs exhibited enhanced cellular uptake efficiency than that of ATX-NPs without transferrin conjugated in primary cortical neurons. Additionally, compared to free ATX, transferrin-containing ATX-NPs with lower ATX concentration showed powerful neuroprotective effects on OxyHb-induced neuronal damage. Taken together, the improved bioavailability and enhanced neuroprotective effects enabled ATX-NPs as favorable candidates for targeted delivery and absorption of ATX. We believe that these in vitro findings will provide insights for advancement of subarachnoid hemorrhage therapy.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on September 18, 2019 12:00 AM.

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    Mapping BOLD Activation by Pharmacologically Evoked Tremor in Swine

    Harmaline-induced tremor is one of the most commonly utilized disease models for essential tremor (ET). However, the underlying neural networks involved in harmaline-induced tremor and the degree to which these are a representative model of the pathophysiologic mechanism of ET are incompletely understood. In this study, we evaluated the functional brain network effects induced by systemic injection of harmaline using pharmacological functional magnetic resonance imaging (ph-fMRI) in the swine model. With harmaline administration, we observed significant activation changes in cerebellum, thalamus, and inferior olivary nucleus (ION). In addition, inter-regional correlations in activity between cerebellum and deep cerebellar nuclei and between cerebellum and thalamus were significantly enhanced. These harmaline-induced effects gradually decreased with repeated administration of drug, replicating the previously demonstrated ‘tolerance’ effect. This study demonstrates that harmaline-induced tremor is associated with activity changes in brain regions previously implicated in humans with ET. Thus, harmaline-induction of tremor in the swine may be a useful model to explore the neurological effects of novel therapeutic agents and/or neuromodulation techniques for ET.

    in Frontiers in Neuroscience | Systems Biology section | New and Recent Articles on September 18, 2019 12:00 AM.

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    Bringing Psychological Strategies to Robot-Assisted Physiotherapy for Enhanced Treatment Efficacy

    Robotic technologies offer a range of functions to augment clinical rehabilitation practice. However, compliance with robot-assisted rehabilitation techniques has not been optimally achieved. Traditional approaches to improving the treatment efficacy are focusing more on the system function, while psychological factors have not been integrated comprehensively. In this perspective paper, eight key factors reflecting three conceptions-robot design, function design, and patients’ expectations have been evaluated and analyzed. Clinical results with 28 therapists and 84 patients indicate that integrating psychological strategies into robot-assisted physiotherapy may promote better trust and acceptance of rehabilitation robots.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on September 18, 2019 12:00 AM.

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    fMRI in Non-human Primate: A Review on Factors That Can Affect Interpretation and Dynamic Causal Modeling Application

    Dynamic causal modeling (DCM)—a framework for inferring hidden neuronal states from brain activity measurements (e. g., fMRI) and their context-dependent modulation—was developed for human neuroimaging, and has not been optimized for non-human primate (NHP) studies, which are usually done under anesthesia. Animal neuroimaging studies offer the potential to improve effective connectivity modeling using DCM through combining functional imaging with invasive procedures such as in vivo optogenetic or electrical stimulation. Employing a Bayesian approach, model parameters are estimated based on prior knowledge of conditions that might be related to neural and BOLD dynamics (e.g., requires empirical knowledge about the range of plausible parameter values). As such, we address the following questions in this review: What factors need to be considered when applying DCM to NHP data? What differences in functional networks, cerebrovascular architecture and physiology exist between human and NHPs that are relevant for DCM application? How do anesthetics affect vascular physiology, BOLD contrast, and neural dynamics—particularly, effective communication within, and between networks? Considering the factors that are relevant for DCM application to NHP neuroimaging, we propose a strategy for modeling effective connectivity under anesthesia using an integrated physiologic-stochastic DCM (IPS-DCM).

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 18, 2019 12:00 AM.

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    Brain Networks Underlying Eye’s Pupil Dynamics

    Phasic changes in eye’s pupil diameter have been repeatedly observed during cognitive, emotional and behavioral activity in mammals. Although pupil diameter is known to be associated with noradrenergic firing in the pontine Locus Coeruleus (LC), thus far the causal chain coupling spontaneous pupil dynamics to specific cortical brain networks remains unknown. In the present study, we acquired steady-state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) data combined with eye-tracking pupillometry from fifteen healthy subjects that were trained to maintain a constant attentional load. Regression analysis revealed widespread visual and sensorimotor BOLD-fMRI deactivations correlated with pupil diameter. Furthermore, we found BOLD-fMRI activations correlated with pupil diameter change rate within a set of brain regions known to be implicated in selective attention, salience, error-detection and decision-making. These regions included LC, thalamus, posterior cingulate cortex (PCC), dorsal anterior cingulate and paracingulate cortex (dACC/PaCC), orbitofrontal cortex (OFC), and right anterior insular cortex (rAIC). Granger-causality analysis performed on these regions yielded a complex pattern of interdependence, wherein LC and pupil dynamics were far apart in the network and separated by several cortical stages. Functional connectivity (FC) analysis revealed the ubiquitous presence of the superior frontal gyrus (SFG) in the networks identified by the brain regions correlated to the pupil diameter change rate. No significant correlations were observed between pupil dynamics, regional activation and behavioral performance. Based on the involved brain regions, we speculate that pupil dynamics reflects brain processing implicated in changes between self- and environment-directed awareness.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 18, 2019 12:00 AM.

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    Intracellular and Intercellular Mitochondrial Dynamics in Parkinson’s Disease

    The appearance of alpha-synuclein-positive inclusion bodies (Lewy bodies) and the loss of catecholaminergic neurons are the primary pathological hallmarks of Parkinson’s disease (PD). However, the dysfunction of mitochondria has long been recognized as a key component in the progression of the disease. Dysfunctional mitochondria can in turn lead to dysregulation of calcium homeostasis and, especially in dopaminergic neurons, raised mean intracellular calcium concentration. As calcium binding to alpha-synuclein is one of the important triggers of alpha-synuclein aggregation, mitochondrial dysfunction will promote inclusion body formation and disease progression. Increased reactive oxygen species (ROS) resulting from inefficiencies in the electron transport chain also contribute to the formation of alpha-synuclein aggregates and neuronal loss. Recent studies have also highlighted defects in mitochondrial clearance that lead to the accumulation of depolarized mitochondria. Transaxonal and intracytoplasmic translocation of mitochondria along the microtubule cytoskeleton may also be affected in diseased neurons. Furthermore, nanotube-mediated intercellular transfer of mitochondria has recently been reported between different cell types and may have relevance to the spread of PD pathology between adjacent brain regions. In the current review, the contributions of both intracellular and intercellular mitochondrial dynamics to the etiology of PD will be discussed.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 18, 2019 12:00 AM.

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    Editorial: Physiological Computing of Social Cognition

    in Frontiers in Human Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    Prediction of Gait Impairment in Toddlers Born Preterm From Near-Term Brain Microstructure Assessed With DTI, Using Exhaustive Feature Selection and Cross-Validation

    Aim

    To predict gait impairment in toddlers born preterm with very-low-birth-weight (VLBW), from near-term white-matter microstructure assessed with diffusion tensor imaging (DTI), using exhaustive feature selection, and cross-validation.

    Methods

    Near-term MRI and DTI of 48 bilateral and corpus callosum regions were assessed in 66 VLBW preterm infants; at 18–22 months adjusted-age, 52/66 participants completed follow-up gait assessment of velocity, step length, step width, single-limb support and the Toddle Temporal-spatial Deviation Index (TDI). Multiple linear models with exhaustive feature selection and leave-one-out cross-validation were employed in this prospective cohort study: linear and logistic regression identified three brain regions most correlated with gait outcome.

    Results

    Logistic regression of near-term DTI correctly classified infants high-risk for impaired gait velocity (93% sensitivity, 79% specificity), right and left step length (91% and 93% sensitivity, 85% and 76% specificity), single-limb support (100% and 100% sensitivity, 100% and 100% specificity), step width (85% sensitivity, 80% specificity), and Toddle TDI (85% sensitivity, 75% specificity). Linear regression of near-term brain DTI and toddler gait explained 32%–49% variance in gait temporal-spatial parameters. Traditional MRI methods did not predict gait in toddlers.

    Interpretation

    Near-term brain microstructure assessed with DTI and statistical learning methods predicted gait impairment, explaining substantial variance in toddler gait. Results indicate that at near term age, analysis of a set of brain regions using statistical learning methods may offer more accurate prediction of outcome at toddler age. Infants high risk for single-limb support impairment were most accurately predicted. As a fundamental element of biped gait, single-limb support may be a sensitive marker of gait impairment, influenced by early neural correlates that are evolutionarily and developmentally conserved. For infants born preterm, early prediction of gait impairment can help guide early, more effective intervention to improve quality of life.

    What This Paper Adds:

    • Accurate prediction of toddler gait from near-term brain microstructure on DTI.

    • Use of machine learning analysis of neonatal neuroimaging to predict gait.

    • Early prediction of gait impairment to guide early treatment for children born preterm.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    Music-Evoked Reward and Emotion: Relative Strengths and Response to Intervention of People With ASD

    This review presents research findings showing that music is a unique domain to assess perception, reward, emotion, and associated physiological reactions and neural circuitry of people with autism spectrum disorder (ASD). There is growing evidence, reported in several studies in this review article, indicating that music is a relative strength of people with ASD including musical pitch perception, musical memory, and identification of music-evoked emotions. Listening to music activates neural circuits of reward and emotion response, which are described. Research presented shows adults with ASD also activate these systems when listening to music, although there may be developmental differences in the physiological and neural response to music in childhood and adolescence alongside typical behavioral response. Nonetheless, studies reviewed lend support to the use of music therapy and education for people with ASD, specifically to improve social skills and communication. Neural correlates of response to music therapy and education are also discussed. Taken together, findings reviewed provide evidence for music as a strength-based approach for ASD to assess reward and emotion response and as a powerful tool for intervention.

    in Frontiers in Neural Circuits | New and Recent Articles on September 18, 2019 12:00 AM.

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    The Endocannabinoid System as a Window Into Microglial Biology and Its Relationship to Autism

    Microglia are the resident, innate immune cells of the central nervous system (CNS) and are critical in managing CNS injuries and infections. Microglia also maintain CNS homeostasis by influencing neuronal development, viability, and function. However, aberrant microglial activity and phenotypes are associated with CNS pathology, including autism spectrum disorder (ASD). Thus, improving our knowledge of microglial regulation could provide insights into the maintenance of CNS homeostasis as well as the prevention and treatment of ASD. Control of microglial activity is in part overseen by small, lipid-derived molecules known as endogenous cannabinoids (endocannabinoids). Endocannabinoids are one component of the endocannabinoid system (ECS), which also includes the enzymes that metabolize these ligands, in addition to cannabinoid receptor 1 (CB1) and 2 (CB2). Interestingly, increased ECS signaling leads to an anti-inflammatory, neuroprotective phenotype in microglia. Here, we review the literature and propose that ECS signaling represents a largely untapped area for understanding microglial biology and its relationship to ASD, with special attention paid to issues surrounding the use of recreational cannabis (marijuana). We also discuss major questions within the field and suggest directions for future research.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    Rod Bipolar Cells Require Horizontal Cells for Invagination Into the Terminals of Rod Photoreceptors

    In the central nervous system, neuronal processing relies on the precisely orchestrated formation of synapses during development. The first synapse of the visual system is a triad synapse, comprising photoreceptors, horizontal cells and bipolar cells. During the second postnatal week, the axon terminal processes of horizontal cells invaginate rod spherules, followed by rod bipolar cell dendrites. Both elements finally oppose the synaptic ribbon (the release site of glutamate). However, it has not been fully elucidated whether horizontal cells are essential for rod bipolar cell dendrites to find their way into the rod terminal. In the present study, we investigated this question by specifically ablating horizontal cells from the early postnatal mouse retina. We monitored the formation of the rod-to-rod bipolar cell synapse during retinal maturation until postnatal day 21. Based on quantitative electron microscopy, we found that without horizontal cells, the dendrites of rod bipolar cells never entered rod terminals. Furthermore, rods displayed significantly fewer and shorter presynaptic ribbons, suggesting that glutamate release is decreased, which coincided with significantly reduced expression of postsynaptic proteins (mGluR6, GPR179) in rod bipolar cells. Collectively, our findings uncover that horizontal cells are indeed necessary guideposts for rod bipolar cells. Whether horizontal cells release diffusible guidance cues or provide structural guidance by expressing specific cell adhesion molecules remains to be seen.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    Mast Cells and Sensory Nerves Contribute to Neurogenic Inflammation and Pruritus in Chronic Skin Inflammation

    The intimate interaction between mast cells and sensory nerves can be illustrated by the wheal and surrounding flare in an urticarial reaction in human skin. This reaction is typically associated with an intense itch at the reaction site. Upon activation, cutaneous mast cells release powerful mediators, such as histamine, tryptase, cytokines, and growth factors that can directly stimulate corresponding receptors on itch-mediating sensory nerves. These include, e.g., H1- and H4-receptors, protease-activated receptor-2, IL-31 receptor, and the high-affinity receptor of nerve growth factor (TrkA). On the other hand, sensory nerves can release neuropeptides, including substance P and vasoactive intestinal peptide, that are able to stimulate mast cells to release mediators leading to potentiation of the reciprocal interaction, inflammation, and itch. Even though mast cells are well recognized for their role in allergic skin whealing and urticaria, increasing evidence supports the reciprocal function between mast cells and sensory nerves in neurogenic inflammation in chronic skin diseases, such as psoriasis and atopic dermatitis, which are often characterized by distressing itch, and exacerbated by psychological stress. Increased morphological contacts between mast cells and sensory nerves in the lesional skin in psoriasis and atopic dermatitis as well as experimental models in mice and rats support the essential role for mast cell-sensory nerve communication in consequent pruritus. Therefore, we summarize here the present literature pointing to a close association between mast cells and sensory nerves in pruritic skin diseases as well as review the essential supporting findings on pruritic models in mice and rats.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson’s Disease

    A paradigm shift has emerged in Parkinson’s disease (PD) highlighting the prominent role of CD4+ Tregs in pathogenesis and treatment. Bench to bedside research, conducted by others and our own laboratories, advanced a neuroprotective role for Tregs making pharmacologic transformation of immediate need. Herein, a vasoactive intestinal peptide receptor-2 (VIPR2) peptide agonist, LBT-3627, was developed as a neuroprotectant for PD-associated dopaminergic neurodegeneration. Employing both 6-hydroxydopamine (6-OHDA) and α-synuclein (α-Syn) overexpression models in rats, the sequential administration of LBT-3627 increased Treg activity without altering cell numbers both in naïve animals and during progressive nigrostriatal degeneration. LBT-3627 administration was linked to reductions of inflammatory microglia, increased survival of dopaminergic neurons, and improved striatal densities. While α-Syn overexpression resulted in reduced Treg activity, LBT-3627 rescued these functional deficits. This occurred in a dose-dependent manner closely mimicking neuroprotection. Taken together, these data provide the basis for the use of VIPR2 agonists as potent therapeutic immune modulating agents to restore Treg activity, attenuate neuroinflammation, and interdict dopaminergic neurodegeneration in PD. The data underscore an important role of immunity in PD pathogenesis.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    Axonal Computations

    Axons functionally link the somato-dendritic compartment to synaptic terminals. Structurally and functionally diverse, they accomplish a central role in determining the delays and reliability with which neuronal ensembles communicate. By combining their active and passive biophysical properties, they ensure a plethora of physiological computations. In this review, we revisit the biophysics of generation and propagation of electrical signals in the axon and their dynamics. We further place the computational abilities of axons in the context of intracellular and intercellular coupling. We discuss how, by means of sophisticated biophysical mechanisms, axons expand the repertoire of axonal computation, and thereby, of neural computation.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    Editorial: Organization of the White Matter Anatomy in the Human Brain

    in Frontiers in Neuroanatomy | New and Recent Articles on September 18, 2019 12:00 AM.

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    Transduction of Craniofacial Motoneurons Following Intramuscular Injections of Canine Adenovirus Type-2 (CAV-2) in Rhesus Macaques

    Reliable viral vector-mediated transgene expression in primate motoneurons would improve our ability to anatomically and physiologically interrogate motor systems. We therefore investigated the efficacy of replication defective, early region 1-deleted canine adenovirus type-2 (CAV-2) vectors for mediating transgene expression of fluorescent proteins into brainstem motoneurons following craniofacial intramuscular injections in four rhesus monkeys (Macaca mulatta). Vector injections were placed into surgically identified and isolated craniofacial muscles. After a 1- to 2-month survival time, animals were sacrificed and transgene expression was assessed with immunohistochemistry in the corresponding motoneuronal populations. We found that injections of CAV-2 into individual craniofacial muscles at doses in the range of ∼1010 to 1011 physical particles/muscle resulted in robust motoneuronal transduction and expression of immunohistochemically identified fluorescent proteins across multiple animals. By using different titers in separate muscles, with the resulting transduction patterns tracked via fluorophore expression and labeled motoneuron location, we established qualitative dose-response relationships in two animals. In one animal that received an atypically high titer (5.7 × 1011 total CAV-2 physical particles) distributed across numerous injection sites, no transduction was detected, likely due to a retaliatory immune response. We conclude that CAV-2 vectors show promise for genetic modification of primate motoneurons following craniofacial intramuscular injections. Our findings warrant focused attention toward the use of CAV-2 vectors to deliver opsins, DREADDs, and other molecular probes to improve genetics-based methods for primate research. Further work is required to optimize CAV-2 transduction parameters. CAV-2 vectors encoding proteins could provide a new, reliable route for modifying activity in targeted neuronal populations of the primate central nervous system.

    in Frontiers in Neuroanatomy | New and Recent Articles on September 18, 2019 12:00 AM.

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    Study Protocol: Does an Acute Intervention of High-Intensity Physical Exercise Followed by a Brain Training Video Game Have Immediate Effects on Brain Activity of Older People During Stroop Task in fMRI?—A Randomized Controlled Trial With Crossover Design

    Background: Elderly people are affected by processes leading to decline in various aspects of daily living that impair their quality of life. Regarding neurological aspects, executive functions have been shown to be valuable for daily life and to slow decline during aging. Most intervention studies intended to improve cognitive functions during aging specifically address long-term destructive processes and countermeasures. However, to an increasing degree, studies also investigate the acute benefits that prove to be useful for daily life, such as physical exercise or video games in the form of exercise video gaming (“exergaming”). Because little is known about the change in cognitive ability following acute intervention of a combination of physical exercise and video gaming, especially for older people, this work is designed as an attempt to address this matter.

    Methods: This study is a randomized crossover controlled trial to test the response to an acute bout of high-intensity physical exercise followed by a short session with a brain training (Brain Age) video game in physically active and cognitively healthy older adults (60–70 years). The response is measured using Stroop task performance (cognitive task for executive function) and related brain activity assessed with functional magnetic resonance imaging (fMRI). The control conditions are low-intensity physical exercise and Tetris for video gaming.

    Discussion: This study is intended to provide insight into the alteration of executive function and its related brain activity from an acute intervention with a combination of physical exercise and video gaming in older people. The protocol might not be implementable in daily life to improve cognitive abilities. However, the results can support future studies that investigate cognition and the combination of physical exercise and video gaming. Moreover, it can provide real-life implications.

    Trial registration: This trial was registered in The University Hospital Medical Information Network Clinical Trials Registry (UMIN000033054). Registered 19 July 2018, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000037687.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    The Evolution of Tau Phosphorylation and Interactions

    Tau is a neuronal microtubule-associated protein (MAP) that is involved in the regulation of axonal microtubule assembly. However, as a protein with intrinsically disordered regions (IDRs), tau also interacts with many other partners in addition to microtubules. Phosphorylation at selected sites modulates tau’s various intracellular interactions and regulates the properties of IDRs. In Alzheimer’s disease (AD) and other tauopathies, tau exhibits pathologically increased phosphorylation (hyperphosphorylation) at selected sites and aggregates into neurofibrillary tangles (NFTs). By bioinformatics means, we tested the hypothesis that the sequence of tau has changed during the vertebrate evolution in a way that novel interactions developed and also the phosphorylation pattern was affected, which made tau prone to the development of tauopathies. We report that distinct regions of tau show functional specialization in their molecular interactions. We found that tau’s amino-terminal region, which is involved in biological processes related to “membrane organization” and “regulation of apoptosis,” exhibited a strong evolutionary increase in protein disorder providing the basis for the development of novel interactions. We observed that the predicted phosphorylation sites have changed during evolution in a region-specific manner, and in some cases the overall number of phosphorylation sites increased owing to the formation of clusters of phosphorylatable residues. In contrast, disease-specific hyperphosphorylated sites remained highly conserved. The data indicate that novel, non-microtubule related tau interactions developed during evolution and suggest that the biological processes, which are mediated by these interactions, are of pathological relevance. Furthermore, the data indicate that predicted phosphorylation sites in some regions of tau, including a cluster of phosphorylatable residues in the alternatively spliced exon 2, have changed during evolution. In view of the “antagonistic pleiotropy hypothesis” it may be worth to take disease-associated phosphosites with low evolutionary conservation as relevant biomarkers into consideration.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    High Frequency Repetitive Transcranial Magnetic Stimulation Alleviates Cognitive Impairment and Modulates Hippocampal Synaptic Structural Plasticity in Aged Mice

    Normal aging is accompanied by hippocampus-dependent cognitive impairment, which is a risk factor of Alzheimer’s disease. This study aims to investigate the effect of high frequency-repetitive transcranial magnetic stimulation (HF-rTMS) on hippocampus-dependent learning and memory in aged mice and explore its underlying mechanisms. Forty-five male Kunming mice (15 months old) were randomly divided into three groups: aged sham, 5 Hz rTMS, and 25 Hz rTMS. Two sessions of 5 Hz or 25 Hz rTMS comprising 1,000 pulses in 10 trains were delivered once a day for 14 consecutive days. The aged sham group was treated by the reverse side of the coil. In the adult sham group, 15 male Kunming mice (3 months old) were treated the same way as the aged sham group. A Morris water maze (MWM) was conducted following the stimulation, and synaptic ultrastructure was observed through a transmission electron microscope. HF-rTMS improved spatial learning and memory impairment in the aged mice, and 5 Hz was more significant than 25 Hz. Synaptic plasticity-associated gene profiles were modified by HF-rTMS, especially neurotrophin signaling pathways and cyclic adenosine monophosphate response element binding protein (CREB) cofactors. Compared to the aged sham group, synaptic plasticity-associated proteins, i.e., synaptophysin (SYN) and postsynaptic density (PSD)-95 were increased; brain-derived neurotrophic factor (BDNF) and phosphorylated CREB (pCREB) significantly increased after the 5 Hz HF-rTMS treatment. Collectively, our results suggest that HF-rTMS ameliorated cognitive deficits in naturally aged mice. The 5 Hz rTMS treatment significantly enhanced synaptic structural plasticity and activated the BDNF/CREB pathway in the hippocampus.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 18, 2019 12:00 AM.

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    Complex genetic and epigenetic regulation deviates gene expression from a unifying global transcriptional program

    by Mónica Chagoyen, Juan F. Poyatos

    Environmental or genetic perturbations lead to gene expression changes. While most analyses of these changes emphasize the presence of qualitative differences on just a few genes, we now know that changes are widespread. This large-scale variation has been linked to the exclusive influence of a global transcriptional program determined by the new physiological state of the cell. However, given the sophistication of eukaryotic regulation, we expect to have a complex architecture of specific control affecting this program. Here, we examine this architecture. Using data of Saccharomyces cerevisiae expression in different nutrient conditions, we first propose a five-sector genome partition, which integrates earlier models of resource allocation, as a framework to examine the deviations from the global control. In this scheme, we recognize invariant genes, whose regulation is dominated by physiology, specific genes, which substantially depart from it, and two additional classes that contain the frequently assumed growth-dependent genes. Whereas the invariant class shows a considerable absence of specific regulation, the rest is enriched by regulation at the level of transcription factors (TFs) and epigenetic modulators. We nevertheless find markedly different strategies in how these classes deviate. On the one hand, there are TFs that act in a unique way between partition constituents, and on the other, the action of chromatin modifiers is significantly diverse. The balance between regulatory strategies ultimately modulates the action of the general transcription machinery and therefore limits the possibility of establishing a unifying program of expression change at a genomic scale.

    in PLOS Computational Biology: New Articles on September 17, 2019 09:00 PM.

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    Predicting gene regulatory interactions based on spatial gene expression data and deep learning

    by Yang Yang, Qingwei Fang, Hong-Bin Shen

    Reverse engineering of gene regulatory networks (GRNs) is a central task in systems biology. Most of the existing methods for GRN inference rely on gene co-expression analysis or TF-target binding information, where the determination of co-expression is often unreliable merely based on gene expression levels, and the TF-target binding data from high-throughput experiments may be noisy, leading to a high ratio of false links and missed links, especially for large-scale networks. In recent years, the microscopy images recording spatial gene expression have become a new resource in GRN reconstruction, as the spatial and temporal expression patterns contain much abundant gene interaction information. Till now, the spatial expression resources have been largely underexploited, and only a few traditional image processing methods have been employed in the image-based GRN reconstruction. Moreover, co-expression analysis using conventional measurements based on image similarity may be inaccurate, because it is the local-pattern consistency rather than global-image-similarity that determines gene-gene interactions. Here we present GripDL (Gene regulatory interaction prediction via Deep Learning), which incorporates high-confidence TF-gene regulation knowledge from previous studies, and constructs GRNs for Drosophila eye development based on Drosophila embryonic gene expression images. Benefitting from the powerful representation ability of deep neural networks and the supervision information of known interactions, the new method outperforms traditional methods with a large margin and reveals new intriguing knowledge about Drosophila eye development.

    in PLOS Computational Biology: New Articles on September 17, 2019 09:00 PM.

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    Unified feature association networks through integration of transcriptomic and proteomic data

    by Ryan S. McClure, Jason P. Wendler, Joshua N. Adkins, Jesica Swanstrom, Ralph Baric, Brooke L. Deatherage Kaiser, Kristie L. Oxford, Katrina M. Waters, Jason E. McDermott

    High-throughput multi-omics studies and corresponding network analyses of multi-omic data have rapidly expanded their impact over the last 10 years. As biological features of different types (e.g. transcripts, proteins, metabolites) interact within cellular systems, the greatest amount of knowledge can be gained from networks that incorporate multiple types of -omic data. However, biological and technical sources of variation diminish the ability to detect cross-type associations, yielding networks dominated by communities comprised of nodes of the same type. We describe here network building methods that can maximize edges between nodes of different data types leading to integrated networks, networks that have a large number of edges that link nodes of different–omic types (transcripts, proteins, lipids etc). We systematically rank several network inference methods and demonstrate that, in many cases, using a random forest method, GENIE3, produces the most integrated networks. This increase in integration does not come at the cost of accuracy as GENIE3 produces networks of approximately the same quality as the other network inference methods tested here. Using GENIE3, we also infer networks representing antibody-mediated Dengue virus cell invasion and receptor-mediated Dengue virus invasion. A number of functional pathways showed centrality differences between the two networks including genes responding to both GM-CSF and IL-4, which had a higher centrality value in an antibody-mediated vs. receptor-mediated Dengue network. Because a biological system involves the interplay of many different types of molecules, incorporating multiple data types into networks will improve their use as models of biological systems. The methods explored here are some of the first to specifically highlight and address the challenges associated with how such multi-omic networks can be assembled and how the greatest number of interactions can be inferred from different data types. The resulting networks can lead to the discovery of new host response patterns and interactions during viral infection, generate new hypotheses of pathogenic mechanisms and confirm mechanisms of disease.

    in PLOS Computational Biology: New Articles on September 17, 2019 09:00 PM.

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    3D spatial organization and network-guided comparison of mutation profiles in Glioblastoma reveals similarities across patients

    by Cansu Dincer, Tugba Kaya, Ozlem Keskin, Attila Gursoy, Nurcan Tuncbag

    Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor. Molecular heterogeneity is a hallmark of GBM tumors that is a barrier in developing treatment strategies. In this study, we used the nonsynonymous mutations of GBM tumors deposited in The Cancer Genome Atlas (TCGA) and applied a systems level approach based on biophysical characteristics of mutations and their organization in patient-specific subnetworks to reduce inter-patient heterogeneity and to gain potential clinically relevant insights. Approximately 10% of the mutations are located in “patches” which are defined as the set of residues spatially in close proximity that are mutated across multiple patients. Grouping mutations as 3D patches reduces the heterogeneity across patients. There are multiple patches that are relatively small in oncogenes, whereas there are a small number of very large patches in tumor suppressors. Additionally, different patches in the same protein are often located at different domains that can mediate different functions. We stratified the patients into five groups based on their potentially affected pathways, revealed from the patient-specific subnetworks. These subnetworks were constructed by integrating mutation profiles of the patients with the interactome data. Network-guided clustering showed significant association between each group and patient survival (P-value = 0.0408). Also, each group carries a set of signature 3D mutation patches that affect predominant pathways. We integrated drug sensitivity data of GBM cell lines with the mutation patches and the patient groups to analyze the therapeutic outcome of these patches. We found that Pazopanib might be effective in Group 3 by targeting CSF1R. Additionally, inhibiting ATM that is a mediator of PTEN phosphorylation may be ineffective in Group 2. We believe that from mutations to networks and eventually to clinical and therapeutic data, this study provides a novel perspective in the network-guided precision medicine.

    in PLOS Computational Biology: New Articles on September 17, 2019 09:00 PM.

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    Correction to Supporting Information for Caro et al., Analysis of lipoprotein transport depletion in Vibrio cholerae using CRISPRi [SI Correction]

    MICROBIOLOGY Correction to Supporting Information for “Analysis of lipoprotein transport depletion in Vibrio cholerae using CRISPRi,” by Florence Caro, Nicole M. Place, and John J. Mekalanos, which was first published August 1, 2019; 10.1073/pnas.1906158116 (Proc. Natl. Acad. Sci. U.S.A. 116, 17013–17022). The authors note that Fig. S14 in the SI...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Correction for Miehlbradt et al., Data-driven body-machine interface for the accurate control of drones [Corrections]

    ENGINEERING, NEUROSCIENCE Correction for “Data-driven body–machine interface for the accurate control of drones,” by Jenifer Miehlbradt, Alexandre Cherpillod, Stefano Mintchev, Martina Coscia, Fiorenzo Artoni, Dario Floreano, and Silvestro Micera, which was first published July 16, 2018; 10.1073/pnas.1718648115 (Proc. Natl. Acad. Sci. U.S.A. 115, 7913–7918). The authors note that the following...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Extracellular RNA in a single droplet of human serum reflects physiologic and disease states [Systems Biology]

    Extracellular RNAs (exRNAs) are present in human serum. It remains unclear to what extent these circulating exRNAs may reflect human physiologic and disease states. Here, we developed SILVER-seq (Small Input Liquid Volume Extracellular RNA Sequencing) to efficiently sequence both integral and fragmented exRNAs from a small droplet (5 μL to...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Market-mediated responses confound policies to limit deforestation from oil palm expansion in Malaysia and Indonesia [Sustainability Science]

    The global demand for palm oil has grown rapidly over the past several decades. Much of the output expansion has occurred in carbon- and biodiversity-rich forest lands of Malaysia and Indonesia (M&I), contributing to record levels of terrestrial carbon emissions and biodiversity loss. This has led to a variety of...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Autophagy controls reactive oxygen species homeostasis in guard cells that is essential for stomatal opening [Plant Biology]

    Reactive oxygen species (ROS) function as key signaling molecules to inhibit stomatal opening and promote stomatal closure in response to diverse environmental stresses. However, how guard cells maintain basal intracellular ROS levels is not yet known. This study aimed to determine the role of autophagy in the maintenance of basal...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Phosphorylated claudin-16 interacts with Trpv5 and regulates transcellular calcium transport in the kidney [Physiology]

    Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) was previously considered to be a paracellular channelopathy caused by mutations in the claudin-16 and claudin-19 genes. Here, we provide evidence that a missense FHHNC mutation c.908C>G (p.T303R) in the claudin-16 gene interferes with the phosphorylation in the claudin-16 protein. The claudin-16 protein...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Nmnat restores neuronal integrity by neutralizing mutant Huntingtin aggregate-induced progressive toxicity [Neuroscience]

    Accumulative aggregation of mutant Huntingtin (Htt) is a primary neuropathological hallmark of Huntington’s disease (HD). Currently, mechanistic understanding of the cytotoxicity of mutant Htt aggregates remains limited, and neuroprotective strategies combating mutant Htt-induced neurodegeneration are lacking. Here, we show that in Drosophila models of HD, neuronal compartment-specific accumulation of mutant...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    The default-mode network represents aesthetic appeal that generalizes across visual domains [Neuroscience]

    Visual aesthetic evaluations, which impact decision-making and well-being, recruit the ventral visual pathway, subcortical reward circuitry, and parts of the medial prefrontal cortex overlapping with the default-mode network (DMN). However, it is unknown whether these networks represent aesthetic appeal in a domain-general fashion, independent of domain-specific representations of stimulus content...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Oxidative stress drives the selection of quorum sensing mutants in the Staphylococcus aureus population [Microbiology]

    Quorum sensing (QS) is the central mechanism by which social interactions within the bacterial community control bacterial behavior. QS-negative cells benefit by exploiting public goods produced by the QS-proficient population. Mechanisms to keep the balance between producers and nonproducers within the population are expected but have not been elucidated for...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Subgenomic flavivirus RNA binds the mosquito DEAD/H-box helicase ME31B and determines Zika virus transmission by Aedes aegypti [Microbiology]

    Zika virus (ZIKV) is an arthropod-borne flavivirus predominantly transmitted by Aedes aegypti mosquitoes and poses a global human health threat. All flaviviruses, including those that exclusively replicate in mosquitoes, produce a highly abundant, noncoding subgenomic flavivirus RNA (sfRNA) in infected cells, which implies an important function of sfRNA during mosquito...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Discovery of novel bacterial queuine salvage enzymes and pathways in human pathogens [Microbiology]

    Queuosine (Q) is a complex tRNA modification widespread in eukaryotes and bacteria that contributes to the efficiency and accuracy of protein synthesis. Eukaryotes are not capable of Q synthesis and rely on salvage of the queuine base (q) as a Q precursor. While many bacteria are capable of Q de...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    On the evolution and physiology of cable bacteria [Microbiology]

    Cable bacteria of the family Desulfobulbaceae form centimeter-long filaments comprising thousands of cells. They occur worldwide in the surface of aquatic sediments, where they connect sulfide oxidation with oxygen or nitrate reduction via long-distance electron transport. In the absence of pure cultures, we used single-filament genomics and metagenomics to retrieve...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site [Microbiology]

    Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed pyrazolopyrimidines inhibit pleconaril-resistant...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Comprehensive genomic profiling of glioblastoma tumors, BTICs, and xenografts reveals stability and adaptation to growth environments [Medical Sciences]

    Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Medullary thymic epithelial NF-kB-inducing kinase (NIK)/IKK{alpha} pathway shapes autoimmunity and liver and lung homeostasis in mice [Immunology and Inflammation]

    Aberrant T cell development is a pivotal risk factor for autoimmune disease; however, the underlying molecular mechanism of T cell overactivation is poorly understood. Here, we identified NF–κB-inducing kinase (NIK) and IkB kinase α (IKKα) in thymic epithelial cells (TECs) as essential regulators of T cell development. Mouse TEC-specific ablation...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Phenotypically distinct neutrophils patrol uninfected human and mouse lymph nodes [Immunology and Inflammation]

    Neutrophils play a key role in innate immunity. As the dominant circulating phagocyte, they are rapidly recruited from the bloodstream to sites of infection or injury to internalize and destroy microbes. More recently, neutrophils have been identified in uninfected organs, challenging the classical view of their function. Here we show...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Molecular basis for retinol binding by serum amyloid A during infection [Immunology and Inflammation]

    Serum amyloid A (SAA) proteins are strongly induced in the liver by systemic infection and in the intestine by bacterial colonization. In infected mice, SAA proteins circulate in association with the vitamin A derivative retinol, suggesting that SAAs transport retinol during infection. Here we illuminate a structural basis for the...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Decreased humoral immunity to mumps in young adults immunized with MMR vaccine in childhood [Immunology and Inflammation]

    In the past decade, multiple mumps outbreaks have occurred in the United States, primarily in close-contact, high-density settings such as colleges, with a high attack rate among young adults, many of whom had the recommended 2 doses of mumps-measles-rubella (MMR) vaccine. Waning humoral immunity and the circulation of divergent wild-type...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    The genetic landscape of Scotland and the Isles [Genetics]

    Britain and Ireland are known to show population genetic structure; however, large swathes of Scotland, in particular, have yet to be described. Delineating the structure and ancestry of these populations will allow variant discovery efforts to focus efficiently on areas not represented in existing cohorts. Thus, we assembled genotype data...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis [Genetics]

    Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop...

    in Proceedings of the National Academy of Sciences Recent Issues on September 17, 2019 04:01 PM.

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    Graph learning: How humans infer and represent networks. (arXiv:1909.07186v1 [physics.soc-ph])

    Humans communicate, receive, and store information using sequences of items -- from words in a sentence or notes in music to abstract concepts in lectures and books. The networks formed by these items (nodes) and the sequential transitions between them (edges) encode important structural features of human communication and knowledge. But how do humans learn the networks of probabilistic transitions that underlie sequences of items? Moreover, what do people's internal maps of these networks look like? Here, we introduce graph learning, a growing and interdisciplinary field focused on studying how humans learn and represent networks in the world around them. We begin by describing established results from statistical learning showing that humans are adept at detecting differences in the transition probabilities between items in a sequence. We next present recent experiments that directly control for differences in transition probabilities, demonstrating that human behavior also depends critically on the abstract network structure of transitions. Finally, we present computational models that researchers have proposed to explain the effects of network structure on human behavior and cognition. Throughout, we highlight a number of exciting open questions in the study of graph learning that will require creative insights from cognitive scientists and network scientists alike.

    in q-bio.NC updates on arXiv.org on September 17, 2019 01:30 AM.

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    Human Language: A Boson Gas of Quantum Entangled Cognitons. (arXiv:1909.06845v1 [q-bio.NC])

    We model a piece of text of human language telling a story by means of the quantum structure describing a Bose gas in a temperature close to a Bose-Einstein condensate near absolute zero. For this we introduce energy levels for the concepts (words) used in the story and we also introduce the new notion of 'cogniton' as the quantum of human language. Concepts (words) are then cognitons in different energy states as it is the case for photons in different energy states, states of different frequency radiation, when the considered boson gas would be light. We show that Bose-Einstein statistics delivers a very good model for these pieces of texts telling stories, as well for short stories as for long stories of the size of novels. We analyze an unexpected connection with Zipf's law in human language, the Zipf ranking relating to the energy levels of the words, and the Bose-Einstein graph coinciding with the Zipf graph. We investigate the issue of 'identity and indistinguishability' from this new perspective and conjecture that the way one can easily understand how two 'the same concepts' are 'absolutely identical and indistinguishable' in human language is also the way in which quantum particles are absolutely identical and indistinguishable in physical reality, providing new evidence for our conceptuality interpretation of quantum theory.

    in q-bio.NC updates on arXiv.org on September 17, 2019 01:30 AM.

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    Unifying criticality and the neutral theory of neural avalanches. (arXiv:1909.06813v1 [physics.bio-ph])

    The distribution of collective firing of neurons, known as a neural avalanche, obeys a power law. Three proposed explanations of this emergent scale-free behavior are criticality, neutral theory, and self-organized criticality. We show that the neutral theory of neural avalanches can be unified with criticality, which requires fine tuning of control parameters, and rule out self-organized criticality. We study a model of the brain for which the dynamics are governed by neutral theory. We identify the tuning parameters, which are consistent with experiments, and show that scale-free neural avalanches occur only at the critical point. The scaling hypothesis provides a unified explanation of the power laws which characterize the critical point. The critical exponents characterizing the avalanche distributions and divergence of the response functions are shown to be consistent with the predictions of the scaling hypothesis. We use an universal scaling function for the avalanche profile to find that the firing rate for avalanches of different sizes shows data collapse after appropriate rescaling. Critical slowing-down and algebraic relaxation of avalanches demonstrate that the dynamics are also consistent with the system being at a critical point. We discuss how our results can motivate future empirical studies of criticality in the brain.

    in q-bio.NC updates on arXiv.org on September 17, 2019 01:30 AM.

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    Cognitive swarming in complex environments with attractor dynamics and oscillatory computing. (arXiv:1909.06711v1 [cs.MA])

    Neurobiological theories of spatial cognition developed with respect to recording data from relatively small and/or simplistic environments compared to animals' natural habitats. It has been unclear how to extend theoretical models to large or complex spaces. Complementarily, in autonomous systems technology, applications have been growing for distributed control methods that scale to large numbers of low-footprint mobile platforms. Animals and many-robot groups must solve common problems of navigating complex and uncertain environments. Here, we introduce the 'NeuroSwarms' control framework to investigate whether adaptive, autonomous swarm control of minimal artificial agents can be achieved by direct analogy to neural circuits of rodent spatial cognition. NeuroSwarms analogizes agents to neurons and swarming groups to recurrent networks. We implemented neuron-like agent interactions in which mutually visible agents operate as if they were reciprocally-connected place cells in an attractor network. We attributed a phase state to agents to enable patterns of oscillatory synchronization similar to hippocampal models of theta-rhythmic (5-12 Hz) sequence generation. We demonstrate that multi-agent swarming and reward-approach dynamics can be expressed as a mobile form of Hebbian learning and that NeuroSwarms supports a single-entity paradigm that directly informs theoretical models of animal cognition. We present emergent behaviors including phase-organized rings and trajectory sequences that interact with environmental cues and geometry in large, fragmented mazes. Thus, NeuroSwarms is a model artificial spatial system that integrates autonomous control and theoretical neuroscience to potentially uncover common principles to advance both domains.

    in q-bio.NC updates on arXiv.org on September 17, 2019 01:30 AM.

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    Carbogen inhalation during Non-Convulsive Status Epilepticus: A quantitative analysis of EEG recordings. (arXiv:1909.06683v1 [q-bio.NC])

    Objective: To quantify the effect of inhaled 5% carbon-dioxide/95% oxygen on EEG recordings from patients in non-convulsive status epilepticus (NCSE). Methods: Five children of mixed aetiology in NCSE were given high flow of inhaled carbogen (5% carbon dioxide/95% oxygen) using a face mask for maximum 120s. EEG was recorded concurrently in all patients. The effects of inhaled carbogen on patient EEG recordings were investigated using band-power, functional connectivity and graph theory measures. Carbogen effect was quantified by measuring effect size (Cohen's d) between "before", "during" and "after" carbogen delivery states. Results: Carbogen's apparent effect on EEG band-power and network metrics across all patients for "before-during" and "before-after" inhalation comparisons was inconsistent across the five patients. Conclusion: The changes in different measures suggest a potentially non-homogeneous effect of carbogen on the patients' EEG. Different aetiology and duration of the inhalation may underlie these non-homogeneous effects. Tuning the carbogen parameters (such as ratio between CO2 and O2, duration of inhalation) on a personalised basis may improve seizure suppression in future.

    in q-bio.NC updates on arXiv.org on September 17, 2019 01:30 AM.

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    Structure Learning in Coupled Dynamical Systems and Dynamic Causal Modelling. (arXiv:1904.03093v2 [q-bio.NC] UPDATED)

    Identifying a coupled dynamical system out of many plausible candidates, each of which could serve as the underlying generator of some observed measurements, is a profoundly ill posed problem that commonly arises when modelling real world phenomena. In this review, we detail a set of statistical procedures for inferring the structure of nonlinear coupled dynamical systems (structure learning), which has proved useful in neuroscience research. A key focus here is the comparison of competing models of (ie, hypotheses about) network architectures and implicit coupling functions in terms of their Bayesian model evidence. These methods are collectively referred to as dynamical casual modelling (DCM). We focus on a relatively new approach that is proving remarkably useful; namely, Bayesian model reduction (BMR), which enables rapid evaluation and comparison of models that differ in their network architecture. We illustrate the usefulness of these techniques through modelling neurovascular coupling (cellular pathways linking neuronal and vascular systems), whose function is an active focus of research in neurobiology and the imaging of coupled neuronal systems.

    in q-bio.NC updates on arXiv.org on September 17, 2019 01:30 AM.

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    Looking inside an injection system

    The proteins injected by bacteria into eukaryotic organisms can lead to fates as diverse as death and metamorphosis

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    Single molecule mechanics resolves the earliest events in force generation by cardiac myosin

    Key steps of cardiac mechanochemistry, including the force-generating working stroke and the release of phosphate (Pi), occur rapidly after myosin-actin attachment. An ultra-high-speed optical trap enabled direct observation of the timing and amplitude of the working stroke, which can occur within <200 μs of actin binding by β-cardiac myosin. The initial actomyosin state can sustain loads of at least 4.5 pN and proceeds directly to the stroke or detaches before releasing ATP hydrolysis products. The rates of these processes depend on the force. The time between binding and stroke is unaffected by 10 mM Pi which, along with other findings, indicates the stroke precedes phosphate release. After Pi release, Pi can rebind enabling reversal of the working stroke. Detecting these rapid events under physiological loads provides definitive indication of the dynamics by which actomyosin converts biochemical energy into mechanical work.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    A critical role of VMP1 in lipoprotein secretion

    Lipoproteins are lipid-protein complexes that are primarily generated and secreted from the intestine, liver, and visceral endoderm and delivered to peripheral tissues. Lipoproteins, which are assembled in the endoplasmic reticulum (ER) membrane, are released into the ER lumen for secretion, but its mechanism remains largely unknown. Here, we show that the release of lipoproteins from the ER membrane requires VMP1, an ER transmembrane protein essential for autophagy and certain types of secretion. Loss of vmp1, but not other autophagy-related genes, in zebrafish causes lipoprotein accumulation in the intestine and liver. Vmp1 deficiency in mice also leads to lipid accumulation in the visceral endoderm and intestine. In VMP1-depleted cells, neutral lipids accumulate within lipid bilayers of the ER membrane, thus affecting lipoprotein secretion. These results suggest that VMP1 is important for the release of lipoproteins from the ER membrane to the ER lumen in addition to its previously known functions.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

    Epithelial homeostasis and regeneration require a pool of quiescent cells. How the quiescent cells are established and maintained is poorly understood. Here we report that Trpv6, a cation channel responsible for epithelial Ca2+ absorption, functions as a key regulator of cellular quiescence. Genetic deletion and pharmacological blockade of Trpv6 promoted zebrafish epithelial cells to exit from quiescence and re-enter the cell cycle. Reintroducing Trpv6, but not its channel dead mutant, restored the quiescent state. Ca2+ imaging showed that Trpv6 is constitutively open in vivo. Mechanistically, Trpv6-mediated Ca2+ influx maintained the quiescent state by suppressing insulin-like growth factor (IGF)-mediated Akt-Tor and Erk signaling. In zebrafish epithelia and human colon carcinoma cells, Trpv6/TRPV6 elevated intracellular Ca2+ levels and activated PP2A, which down-regulated IGF signaling and promoted the quiescent state. Our findings suggest that Trpv6 mediates constitutive Ca2+ influx into epithelial cells to continuously suppress growth factor signaling and maintain the quiescent state.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    Self-organization of modular network architecture by activity-dependent neuronal migration and outgrowth

    The spatial distribution of neurons and activity-dependent neurite outgrowth shape long-range interaction, recurrent local connectivity and the modularity in neuronal networks. We investigated how this mesoscale architecture develops by interaction of neurite outgrowth, cell migration and activity in cultured networks of rat cortical neurons and show that simple rules can explain variations of network modularity. In contrast to theoretical studies on activity-dependent outgrowth but consistent with predictions for modular networks, spontaneous activity and the rate of synchronized bursts increased with clustering, whereas peak firing rates in bursts increased in highly interconnected homogeneous networks. As Ca2+ influx increased exponentially with increasing network recruitment during bursts, its modulation was highly correlated to peak firing rates. During network maturation, long-term estimates of Ca2+ influx showed convergence, even for highly different mesoscale architectures, neurite extent, connectivity, modularity and average activity levels, indicating homeostatic regulation towards a common set-point of Ca2+ influx.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    Mechanisms of iron- and O2-sensing by the [4Fe-4S] cluster of the global iron regulator RirA

    RirA is a global regulator of iron homeostasis in Rhizobium and related α-proteobacteria. In its [4Fe-4S] cluster-bound form it represses iron uptake by binding to IRO Box sequences upstream of RirA-regulated genes. Under low iron and/or aerobic conditions, [4Fe-4S] RirA undergoes cluster conversion/degradation to apo-RirA, which can no longer bind IRO Box sequences. Here, we apply time-resolved mass spectrometry and electron paramagnetic resonance spectroscopy to determine how the RirA cluster senses iron and O2. The data indicate that the key iron-sensing step is the O2-independent, reversible dissociation of Fe2+ from [4Fe-4S]2+ to form [3Fe-4S]0. The dissociation constant for this process was determined as Kd = ~3 µM, which is consistent with the sensing of ‘free’ iron in the cytoplasm. O2-sensing occurs through enhanced cluster degradation under aerobic conditions, via O2-mediated oxidation of the [3Fe-4S]0 intermediate to form [3Fe-4S]1+. This work provides a detailed mechanistic/functional view of an iron-responsive regulator.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    Learning is enhanced by tailoring instruction to individual genetic differences

    It is widely argued that personalized instruction based on individual differences in learning styles or genetic predispositions could improve learning outcomes. However, this proposition has resisted clear demonstration in human studies, where it is difficult to control experience and quantify outcomes. Here, we take advantage of the tractable nature of vocal learning in songbirds (Lonchura striata domestica) to test the idea that matching instruction to individual genetic predispositions can enhance learning. We use both cross-fostering and computerized instruction with synthetic songs to demonstrate that matching the tutor song to individual predispositions can improve learning across genetic backgrounds. Moreover, we find that optimizing instruction in this fashion can equalize learning differences across individuals that might otherwise be construed as genetically determined. Our results demonstrate potent, synergistic interactions between experience and genetics in shaping song, and indicate the likely importance of such interactions for other complex learned behaviors.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    Evolution of neuronal anatomy and circuitry in two highly divergent nematode species

    The nematodes C. elegans and P. pacificus populate diverse habitats and display distinct patterns of behavior. To understand how their nervous systems have diverged, we undertook a detailed examination of the neuroanatomy of the chemosensory system of P. pacificus. Using independent features such as cell body position, axon projections and lipophilic dye uptake, we have assigned homologies between the amphid neurons, their first-layer interneurons, and several internal receptor neurons of P. pacificus and C. elegans. We found that neuronal number and soma position are highly conserved. However, the morphological elaborations of several amphid cilia are different between them, most notably in the absence of ‘winged’ cilia morphology in P. pacificus. We established a synaptic wiring diagram of amphid sensory neurons and amphid interneurons in P. pacificus and found striking patterns of conservation and divergence in connectivity relative to C. elegans, but very little changes in relative neighborhood of neuronal processes. These findings demonstrate the existence of several constraints in patterning the nervous system and suggest that major substrates for evolutionary novelty lie in the alterations of dendritic structures and synaptic connectivity.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    A contractile injection system stimulates tubeworm metamorphosis by translocating a proteinaceous effector

    The swimming larvae of many marine animals identify a location on the sea floor to undergo metamorphosis based on the presence of specific bacteria. Although this microbe–animal interaction is critical for the life cycles of diverse marine animals, what types of biochemical cues from bacteria that induce metamorphosis has been a mystery. Metamorphosis of larvae of the tubeworm Hydroides elegans is induced by arrays of phage tail-like contractile injection systems, which are released by the bacterium Pseudoalteromonas luteoviolacea. Here we identify the novel effector protein Mif1. By cryo-electron tomography imaging and functional assays, we observe Mif1 as cargo inside the tube lumen of the contractile injection system and show that the mif1 gene is required for inducing metamorphosis. Purified Mif1 is sufficient for triggering metamorphosis when electroporated into tubeworm larvae. Our results indicate that the delivery of protein effectors by contractile injection systems may orchestrate microbe–animal interactions in diverse contexts.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    The Photorhabdus asymbiotica virulence cassettes deliver protein effectors directly into target eukaryotic cells

    Photorhabdus is a highly effective insect pathogen and symbiont of insecticidal nematodes. To exert its potent insecticidal effects, it elaborates a myriad of toxins and small molecule effectors. Among these, the Photorhabdus Virulence Cassettes (PVCs) represent an elegant self-contained delivery mechanism for diverse protein toxins. Importantly, these self-contained nanosyringes overcome host cell membrane barriers, and act independently, at a distance from the bacteria itself. In this study, we demonstrate that Pnf, a PVC needle complex associated toxin, is a Rho-GTPase, which acts via deamidation and transglutamination to disrupt the cytoskeleton. TEM and Western blots have shown a physical association between Pnf and its cognate PVC delivery mechanism. We demonstrate that for Pnf to exert its effect, translocation across the cell membrane is absolutely essential.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    Multivariable two-sample Mendelian randomization estimates of the effects of intelligence and education on health

    Intelligence and education are predictive of better physical and mental health, socioeconomic position (SEP), and longevity. However, these associations are insufficient to prove that intelligence and/or education cause these outcomes. Intelligence and education are phenotypically and genetically correlated, which makes it difficult to elucidate causal relationships. We used univariate and multivariable Mendelian randomization to estimate the total and direct effects of intelligence and educational attainment on mental and physical health, measures of socioeconomic position, and longevity. Both intelligence and education had beneficial total effects. Higher intelligence had positive direct effects on income and alcohol consumption, and negative direct effects on moderate and vigorous physical activity. Higher educational attainment had positive direct effects on income, alcohol consumption, and vigorous physical activity, and negative direct effects on smoking, BMI and sedentary behaviour. If the Mendelian randomization assumptions hold, these findings suggest that both intelligence and education affect health.

    in eLife: latest articles on September 17, 2019 12:00 AM.

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    17α Estradiol promotes plasticity of spared inputs in the adult amblyopic visual cortex

    The promotion of structural and functional plasticity by estrogens is a promising therapy to enhance central nervous system function in the aged. However, how the sensitivity to estrogens is regulated across brain regions, age and experience is poorly understood. To ask if estradiol treatment impacts structural and functional plasticity in sensory cortices, we examined the acute effect of 17 Estradiol in adult Long Evans (LE) rats following chronic monocular deprivation, a manipulation that reduces the strength and selectivity of deprived eye vision. Chronic monocular deprivation decreased thalamic input from the deprived eye to the binocular visual cortex and accelerated short-term depression of the deprived eye pathway, without changing the total density of excitatory synapses. Importantly, we found that the classical estrogen receptors ER and ER{beta} are robustly expressed in the adult visual cortex, and that a single dose of 17 Estradiol increased the size of excitatory postsynaptic densities, reduced the expression of parvalbumin and decreased the integrity of the extracellular matrix. Furthermore, 17 Estradiol enhanced experience dependent plasticity in the amblyopic visual cortex, and promoted response potentiation of the pathway served by the non-deprived eye. The promotion of plasticity at synapses serving the non-deprived eye may reflect selectivity for synapses with an initially low probability of neurotransmitter release, and may inform applications to remap spared inputs around a scotoma or a cortical infarct.

    in bioRxiv Subject Collection: Neuroscience on September 17, 2019 12:00 AM.

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    Regulation of expression site and generalizability of experience-dependent plasticity in visual cortex

    The experience-dependent decrease in stimulus detection thresholds that underly perceptual learning can be induced by repetitive exposure to a visual stimulus. Robust stimulus-selective potentiation of visual responses is induced in the primary mouse visual cortex by repetitive low frequency visual stimulation (LFVS). How the parameters of the repetitive visual stimulus impact the site and specificity of this experience-dependent plasticity is currently a subject of debate. Here we demonstrate that the stimulus selective response potentiation induced by repetitive low frequency (1 Hz) stimulation, which is typically limited to layer 4, shifts to superficial layers following manipulations that enhance plasticity in primary visual cortex. In contrast, repetitive high frequency (10 Hz) visual stimulation induces response potentiation that is expressed in layers 4 and 5/6, and generalizes to novel visual stimuli. Repetitive visual stimulation also induces changes in the magnitude and distribution of oscillatory activity in primary visual cortex, however changes in oscillatory power do not predict the locus or specificity of response potentiation. Instead we find that robust response potentiation is induced by visual stimulation that resets the phase of ongoing gamma oscillations. Furthermore, high frequency, but not low frequency, repetitive visual stimulation entrains oscillatory rhythms with enhanced sensitivity to phase reset, such that familiar and novel visual stimuli induce similar visual response potentiation.

    in bioRxiv Subject Collection: Neuroscience on September 17, 2019 12:00 AM.

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    Precision calcium imaging of dense neural populations via a cell body-targeted calcium indicator

    Methods for one-photon fluorescent imaging of calcium dynamics in vivo are popular due to their ability to simultaneously capture the dynamics of hundreds of neurons across large fields of view, at a low equipment complexity and cost. In contrast to two-photon methods, however, one-photon methods suffer from higher levels of crosstalk between cell bodies and the surrounding neuropil, resulting in decreased signal-to-noise and artifactual correlations of neural activity. Here, we address this problem by engineering cell body-targeted variants of the fluorescent calcium indicator GCaMP6f. We screened fusions of GCaMP6f to both natural as well as engineered peptides, and identified fusions that localized GCaMP6f to within approximately 50 microns of the cell body of neurons in live mice and larval zebrafish. One-photon imaging of soma-targeted GCaMP6f in dense neural circuits reported fewer artifactual spikes from neuropil, increased signal-to-noise ratio, and decreased artifactual correlation across neurons. Thus, soma-targeting of fluorescent calcium indicators increases neuronal signal fidelity and may facilitate even greater usage of simple, powerful, one-photon methods of population imaging of neural calcium dynamics.

    in bioRxiv Subject Collection: Neuroscience on September 17, 2019 12:00 AM.

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    Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula

    The habenula complex is appreciated as a critical regulator of motivated and pathological behavioral states via its output to midbrain nuclei. Despite this, transcriptional definition of cell populations that comprise both the medial (MHb) and lateral habenular (LHb) subregions in mammals remain undefined. To resolve this, we performed single-cell transcriptional profiling and highly multiplexed in situ hybridization experiments of the mouse habenula complex in naive mice and those exposed to an acute aversive stimulus. Transcriptionally distinct neuronal cell types identified within the MHb and LHb, were spatially defined, and differentially engaged by aversive stimuli. Cell types identified in mice, also displayed a high degree of transcriptional similarity to those previously described in zebrafish, highlighting the well conserved nature of habenular cell types across the phylum. These data identify key molecular targets within habenula cell types, and provide a critical resource for future studies.

    in bioRxiv Subject Collection: Neuroscience on September 17, 2019 12:00 AM.

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    A functionally conserved mechanism of modulation via a vestibule site in pentameric ligand-gated ion channels

    Pentameric ligand-gated ion channels (pLGICs) belong to a class of ion channels involved in fast synaptic signaling in the central and peripheral nervous systems. Molecules acting as allosteric modulators target binding sites that are remote from the neurotransmitter binding site, but functionally affect coupling of ligand binding to channel opening. Here, we investigated an allosteric binding site in the ion channel vestibule, which has converged from a series of studies on prokaryote and eukaryote channel homologs. We discovered single domain antibodies, called nanobodies, which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote channel ELIC bound either to a positive (PAM) or a negative (NAM) allosteric modulator. We extrapolate the functional importance of the vestibule binding site to eukaryote ion channels, suggesting a conserved mechanism of allosteric modulation. This work identifies key elements of allosteric binding sites and extends drug design possibilities in pLGICs using nanobodies.

    in bioRxiv Subject Collection: Neuroscience on September 17, 2019 12:00 AM.

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    Frequency spectrum of chemical fluctuation: A probe of reaction mechanism and dynamics

    by Sanggeun Song, Gil-Suk Yang, Seong Jun Park, Sungguan Hong, Ji-Hyun Kim, Jaeyoung Sung

    Even in the steady-state, the number of biomolecules in living cells fluctuates dynamically, and the frequency spectrum of this chemical fluctuation carries valuable information about the dynamics of the reactions creating these biomolecules. Recent advances in single-cell techniques enable direct monitoring of the time-traces of the protein number in each cell; however, it is not yet clear how the stochastic dynamics of these time-traces is related to the reaction mechanism and dynamics. Here, we derive a rigorous relation between the frequency-spectrum of the product number fluctuation and the reaction mechanism and dynamics, starting from a generalized master equation. This relation enables us to analyze the time-traces of the protein number and extract information about dynamics of mRNA number and transcriptional regulation, which cannot be directly observed by current experimental techniques. We demonstrate our frequency spectrum analysis of protein number fluctuation, using the gene network model of luciferase expression under the control of the Bmal 1a promoter in mouse fibroblast cells. We also discuss how the dynamic heterogeneity of transcription and translation rates affects the frequency-spectra of the mRNA and protein number.

    in PLOS Computational Biology: New Articles on September 16, 2019 09:00 PM.

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    A flexible and generalizable model of online latent-state learning

    by Amy L. Cochran, Josh M. Cisler

    Many models of classical conditioning fail to describe important phenomena, notably the rapid return of fear after extinction. To address this shortfall, evidence converged on the idea that learning agents rely on latent-state inferences, i.e. an ability to index disparate associations from cues to rewards (or penalties) and infer which index (i.e. latent state) is presently active. Our goal was to develop a model of latent-state inferences that uses latent states to predict rewards from cues efficiently and that can describe behavior in a diverse set of experiments. The resulting model combines a Rescorla-Wagner rule, for which updates to associations are proportional to prediction error, with an approximate Bayesian rule, for which beliefs in latent states are proportional to prior beliefs and an approximate likelihood based on current associations. In simulation, we demonstrate the model’s ability to reproduce learning effects both famously explained and not explained by the Rescorla-Wagner model, including rapid return of fear after extinction, the Hall-Pearce effect, partial reinforcement extinction effect, backwards blocking, and memory modification. Lastly, we derive our model as an online algorithm to maximum likelihood estimation, demonstrating it is an efficient approach to outcome prediction. Establishing such a framework is a key step towards quantifying normative and pathological ranges of latent-state inferences in various contexts.

    in PLOS Computational Biology: New Articles on September 16, 2019 09:00 PM.

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    Fast and near-optimal monitoring for healthcare acquired infection outbreaks

    by Bijaya Adhikari, Bryan Lewis, Anil Vullikanti, José Mauricio Jiménez, B. Aditya Prakash

    According to the Centers for Disease Control and Prevention (CDC), one in twenty five hospital patients are infected with at least one healthcare acquired infection (HAI) on any given day. Early detection of possible HAI outbreaks help practitioners implement countermeasures before the infection spreads extensively. Here, we develop an efficient data and model driven method to detect outbreaks with high accuracy. We leverage mechanistic modeling of C. difficile infection, a major HAI disease, to simulate its spread in a hospital wing and design efficient near-optimal algorithms to select people and locations to monitor using an optimization formulation. Results show that our strategy detects up to 95% of “future” C. difficile outbreaks. We design our method by incorporating specific hospital practices (like swabbing for infections) as well. As a result, our method outperforms state-of-the-art algorithms for outbreak detection. Finally, a qualitative study of our result shows that the people and locations we select to monitor as sensors are intuitive and meaningful.

    in PLOS Computational Biology: New Articles on September 16, 2019 09:00 PM.

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    Close spatial arrangement of mutants favors and disfavors fixation

    by Yunming Xiao, Bin Wu

    Cooperation is ubiquitous across all levels of biological systems ranging from microbial communities to human societies. It, however, seemingly contradicts the evolutionary theory, since cooperators are exploited by free-riders and thus are disfavored by natural selection. Many studies based on evolutionary game theory have tried to solve the puzzle and figure out the reason why cooperation exists and how it emerges. Network reciprocity is one of the mechanisms to promote cooperation, where nodes refer to individuals and links refer to social relationships. The spatial arrangement of mutant individuals, which refers to the clustering of mutants, plays a key role in network reciprocity. Besides, many other mechanisms supporting cooperation suggest that the clustering of mutants plays an important role in the expansion of mutants. However, the clustering of mutants and the game dynamics are typically coupled. It is still unclear how the clustering of mutants alone alters the evolutionary dynamics. To this end, we employ a minimal model with frequency independent fitness on a circle. It disentangles the clustering of mutants from game dynamics. The distance between two mutants on the circle is adopted as a natural indicator for the clustering of mutants or assortment. We find that the assortment is an amplifier of the selection for the connected mutants compared with the separated ones. Nevertheless, as mutants are separated, the more dispersed mutants are, the greater the chance of invasion is. It gives rise to the non-monotonic effect of clustering, which is counterintuitive. On the other hand, we find that less assortative mutants speed up fixation. Our model shows that the clustering of mutants plays a non-trivial role in fixation, which has emerged even if the game interaction is absent.

    in PLOS Computational Biology: New Articles on September 16, 2019 09:00 PM.

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    Optimizing spatial allocation of seasonal influenza vaccine under temporal constraints

    by Srinivasan Venkatramanan, Jiangzhuo Chen, Arindam Fadikar, Sandeep Gupta, Dave Higdon, Bryan Lewis, Madhav Marathe, Henning Mortveit, Anil Vullikanti

    Prophylactic interventions such as vaccine allocation are some of the most effective public health policy planning tools. The supply of vaccines, however, is limited and an important challenge is to optimally allocate the vaccines to minimize epidemic impact. This resource allocation question (which we refer to as VaccIntDesign) has multiple dimensions: when, where, to whom, etc. Most of the existing literature in this topic deals with the latter (to whom), proposing policies that prioritize individuals by age and disease risk. However, since seasonal influenza spread has a typical spatial trend, and due to the temporal constraints enforced by the availability schedule, the when and where problems become equally, if not more, relevant. In this paper, we study the VaccIntDesign problem in the context of seasonal influenza spread in the United States. We develop a national scale metapopulation model for influenza that integrates both short and long distance human mobility, along with realistic data on vaccine uptake. We also design GreedyAlloc, a greedy algorithm for allocating the vaccine supply at the state level under temporal constraints and show that such a strategy improves over the current baseline of pro-rata allocation, and the improvement is more pronounced for higher vaccine efficacy and moderate flu season intensity. Further, the resulting strategy resembles a ring vaccination applied spatiallyacross the US.

    in PLOS Computational Biology: New Articles on September 16, 2019 09:00 PM.

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    Deep learning as a tool for neural data analysis: Speech classification and cross-frequency coupling in human sensorimotor cortex

    by Jesse A. Livezey, Kristofer E. Bouchard, Edward F. Chang

    A fundamental challenge in neuroscience is to understand what structure in the world is represented in spatially distributed patterns of neural activity from multiple single-trial measurements. This is often accomplished by learning a simple, linear transformations between neural features and features of the sensory stimuli or motor task. While successful in some early sensory processing areas, linear mappings are unlikely to be ideal tools for elucidating nonlinear, hierarchical representations of higher-order brain areas during complex tasks, such as the production of speech by humans. Here, we apply deep networks to predict produced speech syllables from a dataset of high gamma cortical surface electric potentials recorded from human sensorimotor cortex. We find that deep networks had higher decoding prediction accuracy compared to baseline models. Having established that deep networks extract more task relevant information from neural data sets relative to linear models (i.e., higher predictive accuracy), we next sought to demonstrate their utility as a data analysis tool for neuroscience. We first show that deep network’s confusions revealed hierarchical latent structure in the neural data, which recapitulated the underlying articulatory nature of speech motor control. We next broadened the frequency features beyond high-gamma and identified a novel high-gamma-to-beta coupling during speech production. Finally, we used deep networks to compare task-relevant information in different neural frequency bands, and found that the high-gamma band contains the vast majority of information relevant for the speech prediction task, with little-to-no additional contribution from lower-frequency amplitudes. Together, these results demonstrate the utility of deep networks as a data analysis tool for basic and applied neuroscience.

    in PLOS Computational Biology: New Articles on September 16, 2019 09:00 PM.

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    Social isolation in adolescence disrupts cortical development and goal-dependent decision making in adulthood, despite social reintegration

    Abstract

    The social environment influences neurodevelopment. Investigations using rodents to study this phenomenon commonly isolate subjects, then assess neurobehavioral consequences while animals are still isolated. This approach precludes one from dissociating the effects of on-going vs. prior isolation, hindering our complete understanding of the consequences of social experience during particular developmental periods. Here we socially isolated adolescent mice from postnatal days 31-60, then re-housed them into social groups. We tested their ability to select actions based on expected outcomes using multiple reinforcer devaluation and instrumental contingency degradation techniques. Social isolation in adolescence (but not adulthood) weakened instrumental response updating, causing mice to defer to habit-like behaviors. Habit biases were associated with glucocorticoid insufficiency in adolescence, oligodendrocyte marker loss throughout cortico-striatal regions, and dendritic spine and synaptic marker excess in the adult orbitofrontal cortex (OFC). Artificial, chemogenetic stimulation of the ventrolateral OFC in typical, healthy mice recapitulated response biases following isolation, causing habit-like behaviors. Meanwhile, correcting dendritic architecture by inhibiting the cytoskeletal regulatory protein ROCK remedied instrumental response updating defects in socially-isolated mice. Our findings suggest that adolescence is a critical period during which social experience optimizes one’s ability to seek and attain goals later in life. Age-typical dendritic spine elimination appears to be an essential factor, and in its absence, organisms may defer to habit-based behaviors.

    Significance Humans and rodents who experience early-life traumas or adversities appear to be prone to habit-based behaviors, often occurring at the expense of goal-oriented actions. Despite consistencies across species, how adversity, particularly during specific developmental periods, causes long-term behavioral biases remains unclear. Compounding this issue, many rodent investigations using social isolation to model adversity test mice or rats while they are isolated, making it difficult to dissociate the consequences of current vs. developmental hardship. We reveal that mice with a history of social isolation during adolescence are biased towards habit-like behaviors, despite social reintegration in adulthood. Biases are linked with abnormalities in glucocorticoid tone and prefrontal cortical dendritic spine elimination during adolescence and were corrected by manipulating actin cytoskeletal regulatory factors.

    in RSS PAP on September 16, 2019 04:30 PM.

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    Genetic ablation of neural progenitor cells impairs acquisition of trace eyeblink conditioning

    Abstract

    Adult-born neurons are believed to play a role in memory formation by providing enhanced plasticity to the hippocampus. Past studies have demonstrated that reduction of neurogenesis impairs associative learning, but these experiments used irradiation or neurotoxic substances, which may have had unintended off-target effects. Therefore, to investigate the role of these adult-born neurons more precisely, we utilized C57BL/6-Tg(Nes-TK*,-EGFP)145Sker transgenic mice (Nes-TK) to selectively ablate newborn neurons. Nes-TK mice were fed a chow infused with valganciclovir to induce the ablation of neural progenitor cells. After being on this diet for four weeks, subjects were trained on trace eyeblink conditioning (tEBC), a hippocampus-dependent temporal associative memory task. Following the completion of training, brain sections from these animals were stained for doublecortin, a marker for immature neurons, to quantify levels of neurogenesis. We found that male transgenic mice on valganciclovir had significantly decreased amounts of doublecortin relative to male control animals, indicating a successful reduction in levels of neurogenesis. In conjunction with this reduction in neurogenesis, the male transgenic mice on valganciclovir learned at a significantly slower rate than male control mice. The female Nes-TK mice on valganciclovir showed no significant decrease in neurogenesis and no behavioral impairment relative to female control mice. Ultimately, the results are consistent with, and expand upon, prior studies that demonstrated that adult-born neurons are involved in the formation of associative memories. This study also provides a foundation to continue to explore the physiological role of newborn neurons with in vivo recordings during behavioral training.

    Significance Statement Newborn neurons in the adult brain have been shown to be involved in associative learning, but many prior studies illustrating this point used neurotoxins or irradiation to ablate newborn neurons, which may have had unintended off-target effects. Therefore, we utilized a transgenic mouse model to eliminate adult-born neurons in a more controlled, precise manner. Ultimately, we demonstrate that reduction of neurogenesis leads to an impairment in learning in males, and that levels of neurogenesis are associated with rate of learning and overall performance on trace eyeblink conditioning.

    in RSS PAP on September 16, 2019 04:30 PM.

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    Adversarial Feature Alignment: Avoid Catastrophic Forgetting in Incremental Task Lifelong Learning

    Neural Computation, Ahead of Print.

    in MIT Press: Neural Computation: Table of Contents on September 16, 2019 09:18 AM.

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    On Functions Computed on Trees

    Neural Computation, Ahead of Print.

    in MIT Press: Neural Computation: Table of Contents on September 16, 2019 09:18 AM.

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    Mutual Inhibition with Few Inhibitory Cells via Nonlinear Inhibitory Synaptic Interaction

    Neural Computation, Ahead of Print.

    in MIT Press: Neural Computation: Table of Contents on September 16, 2019 09:18 AM.

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    Capturing the Forest But Missing the Trees: Microstates Inadequate for Characterizing Shorter-Scale EEG Dynamics

    Neural Computation, Ahead of Print.

    in MIT Press: Neural Computation: Table of Contents on September 16, 2019 09:18 AM.

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    A Novel Predictive-Coding-Inspired Variational RNN Model for Online Prediction and Recognition

    Neural Computation, Ahead of Print.

    in MIT Press: Neural Computation: Table of Contents on September 16, 2019 09:17 AM.

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    Dynamic Integrative Synaptic Plasticity Explains the Spacing Effect in the Transition from Short- to Long-Term Memory

    Neural Computation, Ahead of Print.

    in MIT Press: Neural Computation: Table of Contents on September 16, 2019 09:17 AM.

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    Integrating Flexible Normalization into Midlevel Representations of Deep Convolutional Neural Networks

    Neural Computation, Ahead of Print.

    in MIT Press: Neural Computation: Table of Contents on September 16, 2019 09:17 AM.

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    Glymphatics visualization after focused ultrasound induced blood‐brain barrier opening in humans

    Abstract

    It is currently unclear whether the glymphatic system, a brain‐wide interstitial fluid‐cerebrospinal fluid exchange as described in rodents, exist in humans. Focal blood‐brain barrier disruption using MR‐guided focused ultrasound allows parenchymal penetration of gadobutrol contrast, creating an opportunity to study the glymphatics in vivo noninvasively. We describe patterns of contrast distribution in the perivascular space, subarachnoid space, and space surrounding large veins draining towards the dural sinuses on FLAIR in subjects with Alzheimer's disease and amyotrophic lateral sclerosis. This first evidence suggests glymphatic efflux persist in humans, and its relevance to proteinopathies and drug delivery is discussed.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on September 16, 2019 08:24 AM.

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    Regression of epileptogenesis by inhibiting TrkB signaling following a seizure

    Abstract

    Objective

    Temporal lobe epilepsy (TLE) is a devastating disease in which seizures persist in 35% of patients despite optimal use of antiseizure drugs. Clinical and preclinical evidence implicates seizures themselves as one factor promoting epilepsy progression. What is the molecular consequence of a seizure that promotes progression? Evidence from preclinical studies led us to hypothesize that activation of TrkB‐PLCγ1 signaling induced by a seizure promotes epileptogenesis.

    Methods

    To examine the effects of inhibiting TrkB signaling on epileptogenesis following an isolated seizure, we implemented a modified kindling model in which we induced a seizure through amygdala stimulation and then used either a chemical‐genetic strategy or pharmacologic methods to disrupt signaling for two days following the seizure. The severity of a subsequent seizure was assessed by behavioral and electrographic measures.

    Results

    Transient inhibition of TrkB‐PLCγ1 signaling initiated after an isolated seizure limited progression of epileptogenesis evidenced by the reduced severity and duration of subsequent seizures. Unexpectedly, transient inhibition of TrkB‐PLCγ1 signaling initiated following a seizure also reverted a subset of animals to an earlier state of epileptogenesis. Remarkably, inhibition of TrkB‐PLCγ1 signaling in the absence of a recent seizure did not reduce severity of subsequent seizures.

    Interpretation

    These results suggest a novel strategy for limiting progression or potentially ameliorating severity of TLE whereby transient inhibition of TrkB‐PLCγ1 signaling is initiated following a seizure.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on September 16, 2019 08:04 AM.

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    Brain-Like Object Recognition with High-Performing Shallow Recurrent ANNs. (arXiv:1909.06161v1 [cs.CV])

    Deep convolutional artificial neural networks (ANNs) are the leading class of candidate models of the mechanisms of visual processing in the primate ventral stream. While initially inspired by brain anatomy, over the past years, these ANNs have evolved from a simple eight-layer architecture in AlexNet to extremely deep and branching architectures, demonstrating increasingly better object categorization performance, yet bringing into question how brain-like they still are. In particular, typical deep models from the machine learning community are often hard to map onto the brain's anatomy due to their vast number of layers and missing biologically-important connections, such as recurrence. Here we demonstrate that better anatomical alignment to the brain and high performance on machine learning as well as neuroscience measures do not have to be in contradiction. We developed CORnet-S, a shallow ANN with four anatomically mapped areas and recurrent connectivity, guided by Brain-Score, a new large-scale composite of neural and behavioral benchmarks for quantifying the functional fidelity of models of the primate ventral visual stream. Despite being significantly shallower than most models, CORnet-S is the top model on Brain-Score and outperforms similarly compact models on ImageNet. Moreover, our extensive analyses of CORnet-S circuitry variants reveal that recurrence is the main predictive factor of both Brain-Score and ImageNet top-1 performance. Finally, we report that the temporal evolution of the CORnet-S "IT" neural population resembles the actual monkey IT population dynamics. Taken together, these results establish CORnet-S, a compact, recurrent ANN, as the current best model of the primate ventral visual stream.

    in q-bio.NC updates on arXiv.org on September 16, 2019 01:30 AM.

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    Brain Neurological Constructs: The Neuronal Computational Schemes for Resolution of Life's Complexities. (arXiv:1909.05910v1 [q-bio.NC])

    For complex life to evolve, a sophisticated nervous system for handling its complexities was fundamental. The demand resulted in the emergence of brain's computational facility, the neuronal network. This facet of the brain is attested solidly by its inspired scientific computational neural nets which (mathematically) resolve and solve many complex problems. The presumptive general semblance of the computational operation between the two systems allows for the inference that the process in brain's neural domain also renders complexities for solution, as sets of parametric equations, like the basic implicit algorithmic formalisms underlying the operations of the scientific neural nets. This parallel is based on the fact that such devices resolve complex problems for which no declarative logical formulation is deployed. The mathematically resolved neural net problem formalism also resembled that of any theoretically known and formulated complexities which are algorithmized, in their discretized solution domains, within the context of initial and boundary value problems for direct or iterative solution by computers. The brain neuronal net algorithmization of complexities delineate the governing equations of life and living, solutions of which are achieved by trial and error learning, deploying rest of the nervous system and other faculties of living beings. The computational operations of the brain delineate two mental states: consciousness and the unconscious; the aware and unaware states which describes the interactive living processes involved in charting life's path.

    in q-bio.NC updates on arXiv.org on September 16, 2019 01:30 AM.

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    Mental Stress: Source of Neurological Degeneration; Case of MS. (arXiv:1909.05909v1 [q-bio.NC])

    Mental stress is a vague though familiar concept that accounts for an agency of the good, the bad and the ugly, that operates in the brains of animated beings, in response to environmental stressors. In this work, we provide evidence for correlation of stressors with afflictions of MS throughout the world, and put forward arguments in support of the fact that stressors can render disruptions in the normal computational processes of the brain, defining the innards of the mental stress, which in turn may lead to the onset of physiologic adversities in the biologic systems, possibly rendering various diseases, even one as MS. While the real cause of the disease is still not known, major focus is put on the treatment of MS symptoms, aiming to slow down its progress and to reduce the frequency of attacks. In this effort we establish the link between MS and mental stress, through analyses of various aspects of statistics of prevalence and incidence, available in the literature [3-5], which lends itself to opening up of additional treatment possibilities that could be used separate of, or conjunctively with, the medical approaches. On a grander scale, publicizing the adverse workings of the mental stress and its evils can attain statistical gains, in the incidence reduction.

    in q-bio.NC updates on arXiv.org on September 16, 2019 01:30 AM.

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    Neurological Nature of Vision and Thought and Mechanisms of Perception Experiences. (arXiv:1909.05908v1 [q-bio.NC])

    Understanding of the phenomena of vision and thought require clarification of the general mechanism of perception. So far, philosophical inquiries and scientific investigations have not been able to address clearly the mysteries surrounding them. The present work is an attempt to unravel the essences of these phenomenal based on the presumption of computational brain. Within this context, the natures of thought is clarified, and the basis of the experience of perception is established. And by drawing from the successes of the developed tactile vision substitution systems (TVSS), which render some measure of vision,in vision handicapped persons, early or congenital blinds, the true nature of vision as cutaneous sensations is also divulged. The mechanism of perception involves sensing of the stimuli, and autonomous engagement of brain neuronal complexity resolution patterns; that is the brain implicit embedded computational instructions. Upon commencement of the triggers, brain computations, which aso involve engaging body's biophysical feedback system, are performed; and the results are outputted as motor signals that render the realization of perception. However, this requires deployment of a perception medium; an interface. Given the nature of efferent signals, there must be a (known) bio-mechanical system interface, other than the body muscle and skeletal system, which performs the needed function: Considering the fact that the vocal system performs such task for verbalization of brain's synthesis of language, the possibility of its further role in the experience of thought and vision, in the form of mostly quiet (inaudible) recital of the related motor signals, is suggested.

    in q-bio.NC updates on arXiv.org on September 16, 2019 01:30 AM.

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    A detailed study of recurrent neural networks used to model tasks in the cerebral cortex. (arXiv:1906.01094v2 [q-bio.NC] UPDATED)

    Recurrent Neural Networks or RNN are frequently used to model different aspects of brain regions. We studied the properties of RNN trained to perform temporal and flow control tasks with temporal stimuli. We present the results regarding three aspects: inner configuration sets, memory capacity with the scale and immunity to induced damage on trained networks. Our results allow us to quantify different aspects of these physical models, which are normally used as black boxes and must be understood previous to modeling the biological response of cerebral cortex.

    in q-bio.NC updates on arXiv.org on September 16, 2019 01:30 AM.

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    A repeated molecular architecture across thalamic pathways

    Nature Neuroscience, Published online: 16 September 2019; doi:10.1038/s41593-019-0483-3

    This work describes comprehensive transcriptomic sequencing from murine thalamic pathways. By integrating this molecular information with anatomical and functional features, this study reveals a repeated architecture across thalamocortical systems.

    in Nature Neuroscience - Issue - nature.com science feeds on September 16, 2019 12:00 AM.

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    Granulocyte-Colony Stimulating Factor-Induced Neutrophil Recruitment Provides Opioid-Mediated Endogenous Anti-nociception in Female Mice With Oral Squamous Cell Carcinoma

    Oral cancer patients report severe function-induced pain; severity is greater in females. We hypothesize that a neutrophil-mediated endogenous analgesic mechanism is responsible for sex differences in nociception secondary to oral squamous cell carcinoma (SCC). Neutrophils isolated from the cancer-induced inflammatory microenvironment contain β-endorphin protein and are identified by the Ly6G+ immune marker. We previously demonstrated that male mice with carcinogen-induced oral SCC exhibit less nociceptive behavior and a higher concentration of neutrophils in the cancer microenvironment compared to female mice with oral SCC. Oral cancer cells secrete granulocyte colony stimulating factor (G-CSF), a growth factor that recruits neutrophils from bone marrow to the cancer microenvironment. We found that recombinant G-CSF (rG-CSF, 5 μg/mouse, intraperitoneal) significantly increased circulating Ly6G+ neutrophils in the blood of male and female mice within 24 h of administration. In an oral cancer supernatant mouse model, rG-CSF treatment increased cancer-recruited Ly6G+ neutrophil infiltration and abolished orofacial nociceptive behavior evoked in response to oral cancer supernatant in both male and female mice. Local naloxone treatment restored the cancer mediator-induced nociceptive behavior. We infer that rG-CSF-induced Ly6G+ neutrophils drive an endogenous analgesic mechanism. We then evaluated the efficacy of chronic rG-CSF administration to attenuate oral cancer-induced nociception using a tongue xenograft cancer model with the HSC-3 human oral cancer cell line. Saline-treated male mice with HSC-3 tumors exhibited less oral cancer-induced nociceptive behavior and had more β-endorphin protein in the cancer microenvironment than saline-treated female mice with HSC-3 tumors. Chronic rG-CSF treatment (2.5 μg/mouse, every 72 h) increased the HSC-3 recruited Ly6G+ neutrophils, increased β-endorphin protein content in the tongue and attenuated nociceptive behavior in female mice with HSC-3 tumors. From these data, we conclude that neutrophil-mediated endogenous opioids warrant further investigation as a potential strategy for oral cancer pain treatment.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on September 16, 2019 12:00 AM.

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    Adult Goat Retinal Neuronal Culture: Applications in Modeling Hyperglycemia

    Culture of adult neurons of the central nervous system (CNS) can provide a unique model system to explore neurodegenerative diseases. The CNS includes neurons and glia of the brain, spinal cord and retina. Neurons in the retina have the advantage of being the most accessible cells of the CNS, and can serve as a reliable mirror to the brain. Typically, primary cultures utilize fetal rodent neurons, but very rarely adult neurons from larger mammals. Here, we cultured primary retinal neurons isolated from adult goat up to 10 days, and established an in vitro model of hyperglycemia for performing morphological and molecular characterization studies. Immunofluorescence staining revealed that approximately 30–40% of cultured cells expressed neuronal markers. Next, we examined the relative expression of cell adhesion molecules (CAMs) in adult goat brain and retina. We also studied the effect of different glucose concentrations and media composition on the growth and expression of CAMs in cultured retinal neurons. Hyperglycemia significantly enhances neurite outgrowth in adult retinal neurons in culture. Expression of CAMs such as Caspr1, Contactin1 and Prion is downregulated in the presence of high glucose. Hyperglycemia downregulates the expression of the transcription factor CCAAT/enhancer binding protein (C/EBP α), predicted to bind CAM gene promoters. Collectively, our study demonstrates that metabolic environment markedly affects transcriptional regulation of CAMs in adult retinal neurons in culture. The effect of hyperglycemia on CAM interactions, as well as related changes in intracellular signaling pathways in adult retinal neurons warrants further investigation.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 16, 2019 12:00 AM.

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    Dynamic turnover of centromeres drives karyotype evolution in Drosophila

    Centromeres are the basic unit for chromosome inheritance, but their evolutionary dynamics is poorly understood. We generate high-quality reference genomes for multiple Drosophila obscura group species to reconstruct karyotype evolution. All chromosomes in this lineage were ancestrally telocentric and the creation of metacentric chromosomes in some species was driven by de novo seeding of new centromeres at ancestrally gene-rich regions, independently of chromosomal rearrangements. The emergence of centromeres resulted in a drastic size increase due to repeat accumulation, and dozens of genes previously located in euchromatin are now embedded in pericentromeric heterochromatin. Metacentric chromosomes secondarily became telocentric in the pseudoobscura subgroup through centromere repositioning and a pericentric inversion. The former (peri)centric sequences left behind shrunk dramatically in size after their inactivation, yet contain remnants of their evolutionary past, including increased repeat-content and heterochromatic environment. Centromere movements are accompanied by rapid turnover of the major satellite DNA detected in (peri)centromeric regions.

    in eLife: latest articles on September 16, 2019 12:00 AM.

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    Self-assembling manifolds in single-cell RNA sequencing data

    Single-cell RNA sequencing has spurred the development of computational methods that enable researchers to classify cell types, delineate developmental trajectories, and measure molecular responses to external perturbations. Many of these technologies rely on their ability to detect genes whose cell-to-cell variations arise from the biological processes of interest rather than transcriptional or technical noise. However, for datasets in which the biologically relevant differences between cells are subtle, identifying these genes is challenging. We present the self-assembling manifold (SAM) algorithm, an iterative soft feature selection strategy to quantify gene relevance and improve dimensionality reduction. We demonstrate its advantages over other state-of-the-art methods with experimental validation in identifying novel stem cell populations of Schistosoma mansoni, a prevalent parasite that infects hundreds of millions of people. Extending our analysis to a total of 56 datasets, we show that SAM is generalizable and consistently outperforms other methods in a variety of biological and quantitative benchmarks.

    in eLife: latest articles on September 16, 2019 12:00 AM.

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    Neurexophilin4 is a selectively expressed α-neurexin ligand that modulates specific cerebellar synapses and motor functions

    Neurexophilins are secreted neuropeptide-like glycoproteins, and neurexophilin1 and neurexophilin3 are ligands for the presynaptic cell adhesion molecule α-neurexin. Neurexophilins are more selectively expressed in the brain than α-neurexins, however, which led us to ask whether neurexophilins modulate the function of α-neurexin in a context-specific manner. We characterized the expression and function of neurexophilin4 in mice and found it to be expressed in subsets of neurons responsible for feeding, emotion, balance, and movement. Deletion of Neurexophilin4 caused corresponding impairments, most notably in motor learning and coordination. We demonstrated that neurexophilin4 interacts with α-neurexin and GABAARs in the cerebellum. Loss of Neurexophilin4 impaired cerebellar Golgi-granule inhibitory neurotransmission and synapse number, providing a partial explanation for the motor learning and coordination deficits observed in the Neurexophilin4 null mice. Our data illustrate how selectively expressed Neurexophilin4, an α-neurexin ligand, regulates specific synapse function and modulates cerebellar motor control.

    in eLife: latest articles on September 16, 2019 12:00 AM.

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    Human motor fatigability as evoked by repetitive movements results from a gradual breakdown of surround inhibition

    Motor fatigability emerges when demanding tasks are executed over an extended period of time. Here, we used repetitive low-force movements that cause a gradual reduction in movement speed (or ‘motor slowing’) to study the central component of fatigability in healthy adults. We show that motor slowing is associated with a gradual increase of net excitability in the motor network and, specifically, in primary motor cortex (M1), which results from overall disinhibition. Importantly, we link performance decrements to a breakdown of surround inhibition in M1, which is associated with high coactivation of antagonistic muscle groups. This is consistent with the model that a loss of inhibitory control might broaden the tuning of population vectors such that movement patterns become more variable, ill-timed and effortful. We propose that the release of inhibition in M1 is an important mechanism underpinning motor fatigability and, potentially, also pathological fatigue as frequently observed in patients with brain disorders.

    in eLife: latest articles on September 16, 2019 12:00 AM.

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    Mechanically activated Piezo channels modulate outflow tract valve development through the Yap1 and Klf2-Notch signaling axis

    Mechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are important factors modulating these pathways. In addition, live reporters reveal that Piezo controls Klf2 and Notch activity in the endothelium and Yap1 localization in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.

    in eLife: latest articles on September 16, 2019 12:00 AM.

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    Anion channel SLAH3 is a regulatory target of chitin receptor-associated kinase PBL27 in microbial stomatal closure

    In plants, antimicrobial immune responses involve the cellular release of anions and are responsible for the closure of stomatal pores. Detection of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) induces currents mediated via slow-type (S-type) anion channels by a yet not understood mechanism. Here, we show that stomatal closure to fungal chitin is conferred by the major PRRs for chitin recognition, LYK5 and CERK1, the receptor-like cytoplasmic kinase PBL27, and the SLAH3 anion channel. PBL27 has the capacity to phosphorylate SLAH3, of which S127 and S189 are required to activate SLAH3. Full activation of the channel entails CERK1, depending on PBL27. Importantly, both S127 and S189 residues of SLAH3 are required for chitin-induced stomatal closure and anti-fungal immunity at the whole leaf level. Our results demonstrate a short signal transduction module from MAMP recognition to anion channel activation, and independent of ABA-induced SLAH3 activation.

    in eLife: latest articles on September 16, 2019 12:00 AM.

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    Motor behaviour selectively inhibits hair cells activated by forward motion in the lateral line of Zebrafish

    How do sensory systems disambiguate events in the external world from signals generated by the motor behaviour of the animal? One strategy is to suppress the sensory input whenever the motor system is active, but the cellular mechanisms remain unclear. We investigated how motor behaviour modulates signals transmitted by the lateral line of zebrafish, which senses pressure changes around the body of the animal. Activation of motor neurons during fictive swimming caused co-activation of efferent fibers and suppression of synaptic transmission from the primary mechanoreceptors, the hair cells. In some hair cells, a single motor spike inhibited glutamate release by about 50% and block was often complete within 50-100 ms of the start of swimming. All hair cells polarized to be activated by posterior deflections, as would occur during forward swimming, were suppressed by >90%, while only half of those polarized in the anterior direction were inhibited and by an average of just 45%. The selective inhibition of hair cells activated during motor behaviour provides a mechanism for the suppression of self-generated signals while maintaining sensitivity to stimuli originating in the external world.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    The impact of Relative Language Distance on Bilingual Language Control - a functional imaging study

    Cross-linguistic activation is unavoidable in bilinguals and they require language control to manage it. In this study, it is posited that Relative Language Distance (RLD; the extent of lexical feature-similarity between bilinguals languages) can affect the extent of cross-linguistic activation and hence influence bilingual language control. This was investigated via an er-fMRI word-translation task on three similar bilingual groups but with varying RLDs: Dutch-English (low-RLD), Hindi-English (intermediate-RLD) and Cantonese-English (high-RLD). Cross-linguistic conflict and the degree of conflict monitoring/control necessary to manage it were expected to increase with decreasing RLD across groups and be appropriately reflected in the activity of conflict monitoring/control neural regions, such as the ACC (anterior cingulate cortex). Analysis revealed a significantly differential ACC response across the groups, reflecting its adaptation to differential conflict monitoring/control demands generated by RLD. The findings provide emerging evidence for RLD as a dimension of bilingualism impacting bilingual language control processes and neurobiology.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Verbal thinking in rhythm: motor-to-sensory transformation network mediates imagined singing

    What enables us to think verbally? We hypothesized that the interaction between motor and sensory systems induced speech representation without external stimulation or overt articulation. This motor-to-sensory transformation formed the neural basis that enabled us to think verbally. Analogous to the frequency tracking of neural responses to auditory stimuli, we asked participants to imagine singing lyrics of famous songs rhythmically while their neural electro-magnetic signals were recorded using magnetoencephalography (MEG). We found that when participants imagined with less temporal variation, the neural oscillation at the delta band (same frequency band as the rhythm in the songs) showed more consistent phase coherence across trials. This neural phase tracking of imagined singing was observed in a frontal-parietal-temporal network - the proposed motor-to-sensory transformation pathway, including inferior frontal gyrus (IFG), insula, premotor, intra-parietal sulcus (IPS), temporal-parietal junction (TPJ), primary auditory cortex, and superior temporal gyrus and sulcus (STG & STS). These results suggest that neural oscillations can entrain the rhythm of our mental activity. The coherent activation in the motor-to-sensory transformation neural network mediates the internal construction of perceptual representation and forms the neural computation foundation for inner speech during verbal thinking.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Stochastic sampling provides a unifying account of working memory limits

    Attempts to characterize the limits of human working memory have differed on whether internal representations are discrete or continuous, with models of each type competing to best capture the errors observers make in delayed reproduction of elementary stimulus features. Here we show discretization only weakly discriminates between models; the critical distinction is instead between deterministic (fixed) and stochastic (randomly varying) limits, with only the latter compatible with observed human performance and the underlying biological system. Reconceptualizing existing models in terms of sampling reveals strong commonalities between seemingly opposing accounts: adding stochasticity to a discrete model brings it into closer correspondence with theories of neural coding, and puts its quality of fit on a par with continuous models, but also eliminates the stability and dependencies between items implied by a fixed set of "slots". A probabilistic limit on the number of items successfully retrieved is an emergent property of stochastic sampling, with no explicit mechanism required to enforce it. These findings resolve discrepancies between previous accounts and establish a unified computational framework for further investigating working memory.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Temporal complexity of fMRI is reproducible and correlates with higher order cognition

    In 2014, McDonough and Nashiro derived multiscale entropy --a marker of signal complexity-- from resting state functional MRI data (rsfMRI), and found that functional brain networks displayed unique multiscale entropy fingerprints. This is a finding with potential impact as an imaging-based marker of normal brain function, as well as pathological brain dysfunction. Nevertheless, a limitation of this study was that rsfMRI data from only 20 healthy individuals was used for analysis. To overcome this limitation, we aimed to replicate McDonough and Nashiro's finding in a large cohort of healthy subjects. We used rsfMRI from the Human Connectome Project (HCP) comprising 936 gender-matched healthy young adults aged 22-35, each with 4 x 14.4-minute rsfMRI data from 100 brain regions. We quantified multiscale entropy of rsfMRI time series averaged at different cortical and sub-cortical regions. We also performed a test-retest analysis on the data of four recording sessions in 10 previously reported resting state networks (RSNs). Given that the morphology of multiscale entropy patterns is affected by the choice of the tolerance parameter (r), we performed the analyses at two r values: 0.5, similar to the original study and 0.15, a commonly used option in the literature. Our results were similar to previous findings by McDonough and Nashiro emphasizing high temporal complexity in the default mode network and frontoparietal networks, and low temporal complexity in the cerebellum. We also investigated the effect of temporal resolution (determined by fMRI repetition time) by downsampling rsfMRI time series. At a low temporal resolution, we observed increased entropy and variance across datasets likely due to fewer data points in the multiscale entropy analysis. Test-retest analysis showed that findings were likely reproducible across individuals over four rsfMRI runs, especially for r = 0.5. We also showed a positive relationship between temporal complexity of RSNs and fluid intelligence (people's capacity to reason and think flexibly), suggesting that complex dynamics is an important attribute of optimized brain function.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Single-cell profiling and SCOPE-seq reveal the lineage dynamics of adult neurogenesis and NOTUM as a key V-SVZ regulator

    Neural stem cells (NSCs) and their progeny reside in specialized niches in the adult mammalian brain where they generate new neurons and glia throughout life. Adult NSCs of the ventricular-subventricular zone (V-SVZ) are prone to rapid exhaustion; thus timely, context-dependent neurogenesis demands adaptive signaling among the vast number of neighboring progenitors nestled between the ventricular surface and nearby blood vessels. To dissect adult neuronal lineage progression and regulation, we profiled >56,000 V-SVZ and olfactory bulb (OB) cells by single-cell RNA-sequencing (scRNA-seq). Our analyses revealed the diversity of V-SVZ-derived OB neurons, the temporal dynamics of lineage progression, and a key intermediate NSC population enriched for expression of Notum, which encodes a secreted WNT antagonist. Single Cell Optical Phenotyping and Expression (SCOPE-seq), a technology linking live cell imaging with scRNA-seq, uncovered dynamic control of cell size concomitant with NSC differentiation with Notum+ NSCs at a critical size poised for cell division, and a preference of NOTUM surface binding to neuronal precursors with active WNT signaling. Finally, in vivo pharmacological inhibition of NOTUM significantly expanded neuronal precursor pools in the V-SVZ. Our findings highlight a critical regulatory state during NSC activation marked by NOTUM, a secreted enzyme that ensures efficient neurogenesis by preventing WNT signaling activation in NSC progeny.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Saccade vigor as an implicit measure of subjective economic value

    Decisions are made based on the subjective value that the brain assigns to options. However, subjective value is a mathematical construct that cannot be measured directly, but only inferred from choices. Is there another aspect of behavior that directly reflects subjective valuation of an option? Recent results have demonstrated that movement vigor is modulated by reward, raising the possibility that there is a link between how the brain evaluates an option, and how it controls movements toward that option. Alternatively, vigor may reflect salience and not value of the stimulus, growing larger for both stimuli that promise gain as well as stimuli that foretell loss. To dissociate between these possibilities, we asked people to choose among risky options represented by abstract stimuli, some associated with gain, others with loss. From their choices we estimated the subjective value that they assigned to each stimulus. In probe trials, they viewed only one stimulus at a time, and we measured their saccade vigor. We found that vigor was lowest for stimuli that promised loss, highest for stimuli that promised gain. This implied that vigor corresponded to value not salience. Naturally, a given stimulus was valued more by some participants. Remarkably, those who valued a given stimulus more tended to move with greater vigor in response to that stimulus. Thus, subjective value of a stimulus monotonically modulated the vigor with which the eyes moved to acquire a stimulus, suggesting that subjective valuation may be inferred from movement vigor.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    The Tolman-Eichenbaum Machine: Unifying space and relational memory through generalisation in the hippocampal formation

    The hippocampal-entorhinal system is important for spatial and relational memory tasks. We formally link these domains; provide a mechanistic understanding of the hippocampal role in generalisation; and offer unifying principles underlying many entorhinal and hippocampal cell-types. We propose medial entorhinal cells form a basis describing structural knowledge, and hippocampal cells link this basis with sensory representations. Adopting these principles, we introduce the Tolman-Eichenbaum machine (TEM). After learning, TEM entorhinal cells include grid, band, border and object-vector cells. Hippocampal cells include place and landmark cells, remapping between environments. Crucially, TEM also predicts empirically recorded representations in complex non-spatial tasks. TEM predicts hippocampal remapping is not random as previously believed. Rather structural knowledge is preserved across environments. We confirm this in simultaneously recorded place and grid cells.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    B-SOiD: An Open Source Unsupervised Algorithm for Discovery of Spontaneous Behaviors

    The motivation, control, and selection of actions comprising naturalistic behaviors remains a tantalizing but difficult field of study. Detailed and unbiased quantification is critical. Interpreting the positions of animals and their limbs can be useful in studying behavior, and significant recent advances have made this step straightforward. However, body position alone does not provide a grasp of the dynamic range of naturalistic behaviors. Behavioral Segmentation of Open-field In DeepLabCut, or B-SOiD ("B-side"), is an unsupervised learning algorithm that serves to discover and classify behaviors that are not pre-defined by users. Our algorithm segregates statistically different, sub-second rodent behaviors with a single bottom-up perspective video camera. Upon DeepLabCut estimating the positions of 6 body parts (snout, the 4 paws, and the base of the tail), our software performs novel expectation maximization fitting of Gaussian mixture models on t-Distributed Stochastic Neighbor Embedding (t-SNE). The original features taken from dimensionally-reduced classes are then used build a multi-class support vector machine classifier that can decode millions of actions within seconds. We demonstrate that the highly reproducible, independently-classified behaviors can be used to extract kinematic parameters of individual actions as well as broader action sequences. This open-source platform enables the efficient study of the neural mechanisms of spontaneous behavior as well as the performance of disease-related behaviors that have been difficult to quantify, such as grooming and stride-length in Obsessive-Compulsive Disorder (OCD) and stroke research.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Succinylation Links Metabolic Reductions to Amyloid and Tau Pathology

    Abnormalities in glucose metabolism and misfolded protein deposits composed of the amyloid-Beta peptide (AB) and tau are the three most common neuropathological hallmarks of Alzheimer disease (AD), but their relationship(s) to the disease process or to each other largely remains unclear. In this report, the first human brain quantitative lysine succinylome together with a global proteome analysis from controls and patients reveals that lysine succinylation contributes to these three key AD-related pathologies. Succinylation, a newly discovered protein post-translational modification (PTM), of multiple proteins, particularly mitochondrial proteins, declines with the progression of AD. In contrast, amyloid precursor protein (APP) and tau consistently exhibit the largest AD-related increases in succinylation, occurring at specific sites in AD brains but never in controls. Transgenic mouse studies demonstrate that succinylated APP and succinylated tau are detectable in the hippocampus concurrent with AB assemblies in the oligomer and insoluble fiber assembly states. Multiple biochemical approaches revealed that succinylation of APP alters APP processing so as to promote AB accumulation, while succinylation of tau promotes its aggregation and impairs its microtubule binding ability. Succinylation, therefore, is the first single PTM that can be added in parallel to multiple substrates, thereby promoting amyloidosis, tauopathy, and glucose hypometabolism. These data raise the possibility that, in order to show meaningful clinical benefit, any therapeutic and/or preventative measures destined for success must have an activity to either prevent or reverse the molecular pathologies attributable to excess succinylation.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Dendritic GABAB receptors control nonlinear information transfer along the dendro-somatic axis in layer 5 pyramidal neurons

    Dendritic GABAB receptors (GABABRs) mediate a slow form of interhemispheric inhibition. Surprisingly, this inhibition has no detectable effect on the somatic membrane potential of layer 5 pyramidal neurons, whereas the action potential (AP) output is robustly decreased even when the input is proximal to the cell body. To elucidate the underlying mechanisms, we systematically mapped the AP frequency-current (F-I) relationship during dual patch-clamp recordings from soma and apical dendrite. The AP output function was governed by the synergistic interaction between dendritic and somatic compartments as the local input and transfer resistance from dendrite to soma (Kds) depended on the dendritic membrane potential. Thus, Kds doubled at an estimated rate of once per 28.7 mV depolarization due to HCN channel deactivation. In addition, dendritic L-type Ca2+ channels converted individual APs into dendritic Ca2+ spikes causing high-frequency bursts of APs (HFB) during large dendritic depolarization. Activation of dendritic GABABRs greatly reduced both nonlinear mechanisms. While direct block of Ltype Ca2+ channels reduced the number of HFBs, K+ channel activation decreased voltage-dependent input and transfer resistances and decreased the AP rate under all conditions. These results highlight the powerful modulation of the input integration in pyramidal neurons by metabotropic receptor-activated K+ channels.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Exploring the Links between Specific Depression Symptoms and Brain Structure: A Network Study

    The network approach to psychopathology has recently received considerable attention, and is as a novel way of conceptualizing mental disorders as causally interacting symptoms. In this study, we modeled a joint network of depression symptoms and depression-related brain structures, using 21 symptoms and five regional brain measures. We used a mixed sample of 268 individuals previously treated for one or more major depressive episodes and never depressed individuals. The network revealed associations between brain structure and unique depressive symptoms, which may clarify relationships regarding symptomatic and biological heterogeneity in depression.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Intention to learn modulates the impact of reward and punishment on sequence learning

    In real-world settings, learning is often characterised as intentional: learners are aware of the goal during the learning process. Recent evidence has shown that reward and punishment (collectively referred to as valenced feedback) are important factors that influence performance during learning. Presently, however, studies investigating the impact of valenced feedback on skill learning have only considered unintentional learning, and therefore the interaction between intentionality and valenced feedback has not been systematically examined. The present study investigated how reward and punishment impact behavioural performance when participants are instructed to learn in a goal-directed fashion rather than unintentionally. In Experiment 1, participants performed the serial response time task with reward, punishment, or control feedback and were instructed to ignore the presence of the sequence, i.e., learn unintentionally. Experiment 2 followed the same design, but participants were instructed to intentionally learn the sequence. We found that punishment was significantly beneficial to performance during learning only when participants learned unintentionally, and we observed no effect of punishment when participants learned intentionally. Thus, the impact of feedback on performance is influenced by goal of the learner.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases

    We conducted genome sequencing to search for rare variation contributing to early onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 493 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than 1 in 10,000 or private), computational prediction of deleteriousness (CADD 10 or 15 thresholds), and molecular function (protein loss-of-function only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions). Replication analysis was conducted on 16,871 independent cases and 15,941 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p=6.5x10-8, genome-wide corrected p=0.0037). Most of these variants were canonical loss-of-function or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of AD and FTD (replication only p=0.0071). The combined analysis odds ratio was 2.2 (95% CI 1.5-3.2) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 2.1 (95% CI 1.2-3.9). For loss-of-function variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.2 (95% CI 2.0-5.3). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Brain-wide genetic mapping identifies the indusium griseum as a prenatal and shared target of pharmacologically-unrelated psychostimulants

    Psychostimulant use is an ever-increasing socioeconomic burden, including a dramatic rise during pregnancy. Nevertheless, brain-wide effects of psychostimulant exposure are incompletely understood. Here, we performed Fos-CreERT2-based activity mapping, correlated for pregnant mouse dams and their fetuses with amphetamine, nicotine and caffeine applied acutely during mid-gestation. While light-sheet microscopy-assisted intact tissue imaging revealed drug- and age-specific neuronal activation, the indusium griseum (IG) appeared indiscriminately affected. By using GAD67gfp/+ mice we subdivided the IG into a dorsolateral domain populated by GABA interneurons and a ventromedial segment containing glutamatergic neurons, many showing drug-induced activation and sequentially expressing Pou3f3/Brn1 and secretagogin (Scgn) during differentiation. We then combined Patch-seq and circuit mapping to show that the ventromedial IG is a quasi-continuum of glutamatergic neurons (IG-Vglut1+) reminiscent to dentate granule cells in both rodents and humans, whose dendrites emanate perpendicularly towards, while their axons course parallel with the superior longitudinal fissure. IG-Vglut1+ neurons receive Vglut1+ and Vglut2+ excitatory afferents that topologically segregate along their somatodendritic axis. In turn, their efferents terminate in the olfactory bulb, thus being integral to a multi-synaptic circuit that could feed information antiparallel to the olfactory-cortical pathway. In IG-Vglut1+ neurons, prenatal psychostimulant exposure delayed the onset of Scgn expression. Genetic ablation of Scgn was then found to sensitize adult mice towards methamphetamine-induced epilepsy, suggesting a role for this Ca2+-binding protein in scaling IG-Vglut1+ neuronal excitability. Overall, our study identifies brain-wide targets of the most common psychostimulants, among which Scgn+/Vglut1+ neurons of the IG link limbic and olfactory circuits.

    in bioRxiv Subject Collection: Neuroscience on September 16, 2019 12:00 AM.

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    Issue Information

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Annals of Neurology: Volume 86, Number 4, October 2019

    A fluorescence photomicrograph (ultramicroscopy) demonstrating cerebral blood vessels (red) and Abeta amyloid (green) in the cerebral cortex of a transgenic mouse with the APPDutch mutation in the amyloid precursor protein. Vascular Abeta deposition started in large superficial arteries with few affected small penetrating vessels. Early treatment with beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) inhibitor prevented progression. See Schelle et al., pages 561–571, in this issue. ANN NEUROL 2019;86:1–1

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Why “Medicare for All” would be a disaster

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Amylin as a potential link between type 2 diabetes and alzheimer disease

    Objective

    Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and β‐amyloid (Aβ) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients.

    Methods

    We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined Aβ and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or Aβ interact with amylin in either the pancreas or brain of these subjects.

    Results

    Cytoplasmic tau and Aβ protein deposits were detected in pancreatic β cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with Aβ and tau in both the pancreas and hippocampus.

    Interpretation

    The presence of both tau and Aβ inclusions in pancreatic β cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019;86:539–551

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Probabilistic sweet spots predict motor outcome for deep brain stimulation in Parkinson disease

    Objective

    To investigate whether functional sweet spots of deep brain stimulation (DBS) in the subthalamic nucleus (STN) can predict motor improvement in Parkinson disease (PD) patients.

    Methods

    Stimulation effects of 449 DBS settings in 21 PD patients were clinically and quantitatively assessed through standardized monopolar reviews and mapped into standard space. A sweet spot for best motor outcome was determined using voxelwise and nonparametric permutation statistics. Two independent cohorts were used to investigate whether stimulation overlap with the sweet spot could predict acute motor outcome (10 patients, 163 settings) and long‐term overall Unified Parkinson's Disease Rating Scale Part III (UPDRS‐III) improvement (63 patients).

    Results

    Significant clusters for suppression of rigidity and akinesia, as well as for overall motor improvement, resided around the dorsolateral border of the STN. Overlap of the volume of tissue activated with the sweet spot for overall motor improvement explained R 2 = 37% of the variance in acute motor improvement, more than triple what was explained by overlap with the STN (R 2 = 9%) and its sensorimotor subpart (R 2 = 10%). In the second independent cohort, sweet spot overlap explained R 2 = 20% of the variance in long‐term UPDRS‐III improvement, which was equivalent to the variance explained by overlap with the STN (R 2 = 21%) and sensorimotor STN (R 2 = 19%).

    Interpretation

    This study is the first to predict clinical improvement of parkinsonian motor symptoms across cohorts based on local DBS effects only. The new approach revealed a distinct sweet spot for STN DBS in PD. Stimulation overlap with the sweet spot can predict short‐ and long‐term motor outcome and may be used to guide DBS programming. ANN NEUROL 2019;86:527–538

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Imaging gradual neurodegeneration in a basal ganglia model disease

    Objective

    X‐linked dystonia‐parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present.

    Methods

    We used multimodal structural magnetic resonance imaging (voxel‐based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age‐matched male controls.

    Results

    Voxel‐based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (−55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (−20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = −0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = −0.649, p = 0.004).

    Interpretation

    This multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome‐rich striatal areas in XDP. ANN NEUROL 2019;86:517–526

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Reduction of skin innervation is associated with a severe fibromyalgia phenotype

    Objective

    To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS).

    Methods

    One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C‐tactile afferents, and pain‐related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD‐P) and healthy women.

    Results

    Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63% of FMS patients (MD‐P: 10%, controls: 18%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity‐dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C‐tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain‐related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05).

    Interpretation

    The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS. ANN NEUROL 2019;86:504–516

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Associations between cerebrovascular risk factors and parkinson disease

    Objective

    To determine whether cerebrovascular risk factors are associated with subsequent diagnoses of Parkinson disease, and whether these associations are similar in magnitude to those with subsequent diagnoses of Alzheimer disease.

    Methods

    This was a retrospective cohort study using claims data from a 5% random sample of Medicare beneficiaries from 2008 to 2015. The exposures were stroke, atrial fibrillation, coronary disease, hyperlipidemia, hypertension, sleep apnea, diabetes mellitus, heart failure, peripheral vascular disease, chronic kidney disease, chronic obstructive pulmonary disease, valvular heart disease, tobacco use, and alcohol abuse. The primary outcome was a new diagnosis of idiopathic Parkinson disease. The secondary outcome was a new diagnosis of Alzheimer disease. Marginal structural Cox models adjusting for time‐dependent confounding were used to characterize the association between exposures and outcomes. We also evaluated the association between cerebrovascular risk factors and subsequent renal colic (negative control).

    Results

    Among 1,035,536 Medicare beneficiaries followed for a mean of 5.2 years, 15,531 (1.5%) participants were diagnosed with Parkinson disease and 81,974 (7.9%) were diagnosed with Alzheimer disease. Most evaluated cerebrovascular risk factors, including prior stroke (hazard ratio = 1.55; 95% confidence interval = 1.39–1.72), were associated with the subsequent diagnosis of Parkinson disease. The magnitudes of these associations were similar, but attenuated, to the associations between cerebrovascular risk factors and Alzheimer disease. Confirming the validity of our analytical model, most cerebrovascular risk factors were not associated with the subsequent diagnosis of renal colic.

    Interpretation

    Cerebrovascular risk factors are associated with Parkinson disease, an effect comparable to their association with Alzheimer disease. ANN NEUROL 2019;86:572–581

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Standards for Detecting, Interpreting, and Reporting Noncontrast Computed Tomographic Markers of Intracerebral Hemorrhage Expansion

    Significant hematoma expansion (HE) affects one‐fifth of people within 24 hours after acute intracerebral hemorrhage (ICH), and its prevention is an appealing treatment target. Although the computed tomography (CT)‐angiography spot sign predicts HE, only a minority of ICH patients receive contrast injection. Conversely, noncontrast CT (NCCT) is used to diagnose nearly all ICH, so NCCT markers represent a widely available alternative for prediction of HE. However, different NCCT signs describe similar features, with lack of consensus on the optimal image acquisition protocol, assessment, terminology, and diagnostic criteria. In this review, we propose practical guidelines for detecting, interpreting, and reporting NCCT predictors of HE. ANN NEUROL 2019;86:480–492

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Early Aβ reduction prevents progression of cerebral amyloid angiopathy

    Objective

    Clinical trials targeting β‐amyloid peptides (Aβ) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target. Targeting Aβ to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aβ for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aβ deposition.

    Methods

    APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA‐D). Mice were treated with a β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3‐dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aβ in cerebrospinal fluid (CSF) and brain.

    Results

    CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aβ increased with aging followed by a decrease of both Aβ40 and Aβ42 upon CAA onset, supporting the idea that combined reduction of CSF Aβ40 and Aβ42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aβ reduction in CSF and largely prevented CAA progression and associated pathologies.

    Interpretation

    This is the first study showing that Aβ reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aβ‐reducing treatments in patients at risk of CAA and in presymptomatic HCHWA‐D. ANN NEUROL 2019;86:561–571

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    A Trial of Sertraline or Cognitive Behavior Therapy for Depression in Epilepsy

    Objective

    Limited evidence is available to guide treatment of depression for persons with epilepsy. We evaluated the comparative effectiveness of sertraline and cognitive behavior therapy (CBT) for depression, quality of life, seizures, and adverse treatment effects.

    Methods

    We randomly assigned 140 adult outpatients with epilepsy and current major depressive disorder to sertraline or weekly CBT for 16 weeks. The primary outcome was remission from depression based on the Mini International Neuropsychiatric Interview (MINI). Secondary outcomes included the Quality of Life in Epilepsy Inventory‐89 (QOLIE‐89) seizure rates, the Adverse Events Profile (AEP), the Beck Depression Inventory, and MINI Suicide Risk Module.

    Results

    In the intention‐to‐treat analysis, 38 (52.8%; 95% confidence interval [CI] = ±12) of the 72 subjects assigned to sertraline and 41 (60.3%; 95% CI = ±11.6) of the 68 subjects in the CBT group achieved remission; the lower bound of efficacy for both groups was greater than our historical placebo control group upper bound of 33.7%. Difference in time to remission between groups was 2.8 days (95% CI = ±0.43; p = 0.79). The percent improvement of mean QOLIE‐89 scores was significant for both the CBT (25.7%; p < 0.001) and sertraline (28.3%; p < 0.001) groups. The difference in occurrence of generalized tonic–clonic seizures between groups was 0.3% (95% CI = ±8.6; p = 0.95). Suicide risk at final assessment was associated with persistent depression (p < 0.0001) but not seizures or sertraline.

    Interpretation

    Depression remitted in just over one‐half of subjects following sertraline or CBT. Despite the complex psychosocial disability associated with epilepsy, improving depression benefits quality of life. Serotonin reuptake inhibition does not appear to increase seizures or suicidality in persons with epilepsy. ANN NEUROL 2019;86:552–560

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Amyloid imaging of dutch‐type hereditary cerebral amyloid angiopathy carriers

    Objective

    To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular β‐amyloid (Aβ) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch‐type hereditary cerebral amyloid angiopathy (D‐CAA) mutation.

    Methods

    PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB‐PET in 19 D‐CAA mutation carriers (M+; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+, 8 M). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aβ concentrations in 17 M+ and 11 M participants who underwent lumbar puncture and compared the findings to PiB‐PET and CSF Aβ in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers.

    Results

    D‐CAA M+ showed greater age‐dependent FLR PiB retention (p < 0.001) than M, and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p = 0.004). Among M+, greater FLR PiB retention associated with reduced CSF concentrations of Aβ40 (r = −0.55, p = 0.021) but not Aβ42 (r = 0.01, p = 0.991). Despite comparably low CSF Aβ40 and Aβ42, PiB retention was substantially less in D‐CAA than ADAD (p < 0.001).

    Interpretation

    Increased PiB retention in D‐CAA and correlation with reduced CSF Aβ40 suggest this compound labels vascular amyloid, although to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. ANN NEUROL 2019;86:616–625

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Early results of nerve transfers for restoring function in severe cases of acute flaccid myelitis

    Objective

    To describe early functional outcomes of nerve transfer surgery in a relatively large cohort of patients with acute flaccid myelitis (AFM).

    Methods

    A retrospective case analysis was made of patients with AFM treated with nerve transfer surgery between 2007 and 2018. Surgical criteria were persistent motor deficits after 6 months from onset and available donor nerves. Thirty‐two patients with AFM were evaluated; 16 underwent nerve transfer surgeries. Motor function was evaluated by a licensed occupational therapist using the Active Movement Scale preoperatively and during follow‐up examinations. Patients with 6 or more months of follow‐up were included in the analysis. Patients with procedures other than nerve transfers were excluded.

    Results

    Sixteen patients with AFM had nerve transfers, with a male predominance (75%) and median age of 2.5 years (range = 4 months–12 years). Eleven patients had a minimum 6 months of follow‐up. Nerve transfers to restore elbow function had 87% excellent recovery for elbow flexion and 67% for elbow extension. Finger and thumb extension were full against gravity in 1 patient (100%). Shoulder external rotation was excellent in 50% of patients and shoulder abduction in only 20%. Nine of 10 patients (90%) had resolution of shoulder pseudosubluxation following nerve transfer to the suprascapular nerve.

    Interpretation

    Patients with AFM with persistent motor deficits 6 to 9 months after onset benefit from nerve transfer surgery. Restoration of elbow function was more reliable than restoration of shoulder function. We recommend early referral of patients with incomplete recovery to a center experienced in nerve transfers for timely evaluation and treatment. ANN NEUROL 2019;86:607–615

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Increased Immune Activation by Pathologic α‐Synuclein in Parkinson's Disease

    Objective

    Excessive inflammation in the central nervous system (CNS) and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although α‐synuclein pathology is the hallmark of Parkinson disease, it has not been investigated whether pathologic α‐synuclein is a specific trigger for excessive inflammatory responses in Parkinson disease.

    Methods

    We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of α‐synuclein by assessing cytokine release upon exposure.

    Results

    We show that pathologic α‐synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation‐ dependent, with increasing fibrillation and early onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular α‐synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of α‐synuclein. Blood extracellular vesicles from Parkinson disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson disease patients are dysregulated and hyperactive in response to stimulation with pathologic α‐synuclein. Furthermore, we demonstrate that α‐synuclein pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model.

    Interpretation

    Taken together, our data suggest that α‐synuclein pathology and dysregulation of monocytes in Parkinson disease can act together to induce excessive inflammatory responses to α‐synuclein. ANN NEUROL 2019;86:593–606

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Contribution of acute infarcts to cerebral small vessel disease progression

    Objective

    To determine the contribution of acute infarcts, evidenced by diffusion‐weighted imaging positive (DWI+) lesions, to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers.

    Methods

    We performed monthly 3T magnetic resonance imaging (MRI) for 10 consecutive months in 54 elderly individuals with SVD. MRI included high‐resolution multishell DWI, and 3‐dimensional fluid‐attenuated inversion recovery, T1, and susceptibility‐weighted imaging. We determined DWI+ lesion evolution, WMH progression rate (ml/mo), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions.

    Results

    We identified 39 DWI+ lesions on 21 of 472 DWI scans in 9 of 54 subjects. Of the 36 DWI+ lesions with follow‐up MRI, 2 evolved into WMH, 4 evolved into a lacune (3 with cavity <3mm), 3 evolved into a microbleed, and 27 were not detectable on follow‐up. WMH volume increased at a median rate of 0.027 ml/mo (interquartile range = 0.005–0.073), but was not significantly higher in subjects with DWI+ lesions compared to those without (p = 0.195). Of the 2 DWI+ lesions evolving into WMH on follow‐up, one explained 23% of the total WMH volume increase in one subject, whereas the WMH regressed in the other subject. DWI+ lesions preceded 4 of 5 incident lacunes and 3 of 10 incident microbleeds.

    Interpretation

    DWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost one‐third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. ANN NEUROL 2019;86:582–592

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Prognosis after intracerebral hemorrhage is uncertain, so why not do everything?

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Subicular pyramidal neurons gate drug resistance in temporal lobe epilepsy

    Objective

    Drug‐resistant epilepsy causes great clinical danger and still lacks effective treatments.

    Methods

    Here, we used multifaceted approaches combining electrophysiology, optogenetics, and chemogenetics in a classic phenytoin‐resistant epilepsy model to reveal the key target of subicular pyramidal neurons in phenytoin resistance.

    Results

    In vivo neural recording showed that the firing rate of pyramidal neurons in the subiculum, but not other hippocampal subregions, could not be inhibited by phenytoin in phenytoin‐resistant rats. Selective inhibition of subicular pyramidal neurons by optogenetics or chemogenetics reversed phenytoin resistance, whereas selective activation of subicular pyramidal neurons induced phenytoin resistance. Moreover, long‐term low‐frequency stimulation at the subiculum, which is clinically feasible, significantly inhibited the subicular pyramidal neurons and reversed phenytoin resistance. Furthermore, in vitro electrophysiology revealed that off‐target use of phenytoin on sodium channels of subicular pyramidal neurons was involved in the phenytoin resistance, and clinical neuroimaging data suggested the volume of the subiculum in drug‐resistant patients was related to the usage of sodium channel inhibitors.

    Interpretation

    These results highlight that the subicular pyramidal neurons may be a key switch control of drug‐resistant epilepsy and represent a new potential target for precise treatments. ANN NEUROL 2019;86:626–640

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Perspectives from the Laboratory at the National Institute of Neurological Disorders and Stroke Assessing JC Virus DNA in Clinical Samples as It Ends Its Operation

    in Wiley: Annals of Neurology: Table of Contents on September 14, 2019 10:28 AM.

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    Preferential activation of small cutaneous fibers through small pin electrode also depends on the shape of a long duration electrical current

    Electrical stimulation is widely used in experimental pain research but it lacks selectivity towards small nociceptive fibers. When using standard surface patch electrodes and rectangular pulses, large fibers ...

    in Most Recent Articles: BMC Neuroscience on September 14, 2019 12:00 AM.

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    Deep attention networks reveal the rules of collective motion in zebrafish

    by Francisco J. H. Heras, Francisco Romero-Ferrero, Robert C. Hinz, Gonzalo G. de Polavieja

    A variety of simple models has been proposed to understand the collective motion of animals. These models can be insightful but may lack important elements necessary to predict the motion of each individual in the collective. Adding more detail increases predictability but can make models too complex to be insightful. Here we report that deep attention networks can obtain a model of collective behavior that is simultaneously predictive and insightful thanks to an organization in modules. When using simulated trajectories, the model recovers the ground-truth interaction rule used to generate them, as well as the number of interacting neighbours. For experimental trajectories of large groups of 60-100 zebrafish, Danio rerio, the model obtains that interactions between pairs can approximately be described as repulsive, attractive or as alignment, but only when moving slowly. At high velocities, interactions correspond only to alignment or alignment mixed with repulsion at close distances. The model also shows that each zebrafish decides where to move by aggregating information from the group as a weighted average over neighbours. Weights are higher for neighbours that are close, in a collision path or moving faster in frontal and lateral locations. The network also extracts that the number of interacting individuals is dynamical and typically in the range 8–22, with 1–10 more important ones. Our results suggest that each animal decides by dynamically selecting information from the collective.

    in PLOS Computational Biology: New Articles on September 13, 2019 09:00 PM.

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    EMULSION: Transparent and flexible multiscale stochastic models in human, animal and plant epidemiology

    by Sébastien Picault, Yu-Lin Huang, Vianney Sicard, Sandie Arnoux, Gaël Beaunée, Pauline Ezanno

    Stochastic mechanistic epidemiological models largely contribute to better understand pathogen emergence and spread, and assess control strategies at various scales (from within-host to transnational scale). However, developing realistic models which involve multi-disciplinary knowledge integration faces three major challenges in predictive epidemiology: lack of readability once translated into simulation code, low reproducibility and reusability, and long development time compared to outbreak time scale. We introduce here EMULSION, an artificial intelligence-based software intended to address those issues and help modellers focus on model design rather than programming. EMULSION defines a domain-specific language to make all components of an epidemiological model (structure, processes, parameters…) explicit as a structured text file. This file is readable by scientists from other fields (epidemiologists, biologists, economists), who can contribute to validate or revise assumptions at any stage of model development. It is then automatically processed by EMULSION generic simulation engine, preventing any discrepancy between model description and implementation. The modelling language and simulation architecture both rely on the combination of advanced artificial intelligence methods (knowledge representation and multi-level agent-based simulation), allowing several modelling paradigms (from compartment- to individual-based models) at several scales (up to metapopulation). The flexibility of EMULSION and its capability to support iterative modelling are illustrated here through examples of progressive complexity, including late revisions of core model assumptions. EMULSION is also currently used to model the spread of several diseases in real pathosystems. EMULSION provides a command-line tool for checking models, producing model diagrams, running simulations, and plotting outputs. Written in Python 3, EMULSION runs on Linux, MacOS, and Windows. It is released under Apache-2.0 license. A comprehensive documentation with installation instructions, a tutorial and many examples are available from: https://sourcesup.renater.fr/www/emulsion-public.

    in PLOS Computational Biology: New Articles on September 13, 2019 09:00 PM.

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    Differential effects of dorsal and ventral medial prefrontal cortex inactivation during natural reward seeking, extinction, and cue-induced reinstatement

    ABSTRACT

    Rodent dorsal medial prefrontal cortex (mPFC), typically prelimbic cortex, is often described as promoting actions such as reward seeking, whereas ventral mPFC, typically infralimbic cortex, is thought to promote response inhibition. However, both dorsal and ventral mPFC are necessary for both expression and suppression of different behaviors, and each region may contribute to different functions depending on the specifics of the behavior tested. To better understand the roles of dorsal and ventral mPFC in motivated behavior we pharmacologically inactivated each area during operant fixed ratio 1 (FR1) seeking for a natural reward (sucrose), extinction, cue-induced reinstatement, and progressive ratio sucrose seeking in male Long-Evans rats. Bilateral inactivation of dorsal mPFC, but not ventral mPFC increased reward seeking during FR1. Inactivation of both dorsal and ventral mPFC decreased seeking during extinction. Bilateral inactivation of ventral mPFC, but not dorsal mPFC decreased reward seeking during cue-induced reinstatement. No effect of inactivation was found during progressive ratio. Our data contrast sharply with observations seen during drug seeking and fear conditioning, indicating that previously established roles of dorsal mPFC = going vs. ventral mPFC = stopping are not applicable to all motivated behaviors and/or outcomes. Our results indicate that dichotomous functions of dorsal vs. ventral mPFC, if they exist, may align better with other models, or may require the development of a new framework in which these multifaceted brain areas play different roles in action control depending on the behavioral context in which they are engaged.

    SIGNIFICANCE STATEMENT Dorsal and ventral medial prefrontal cortex have been proposed to control response execution and inhibition, respectively, in contexts such as drug seeking and fear learning. It is unclear, however, whether these roles are generalizable to all behaviors. We found that these opposing roles were not present during natural reward (sucrose) seeking, in contrast with previous drug seeking and fear conditioning literature. Dorsal and ventral mPFC inactivation did impact multiple aspects of seeking, but not in the bidirectional fashion predicted by a generalized go stop model. We conclude that, although these brain areas are clearly important in reward seeking, the dichotomous roles proposed previously are not broadly applicable, and mPFC contributions to these and related behaviors should be reconsidered.

    in RSS PAP on September 13, 2019 04:30 PM.

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    Emotion self-regulation training in major depressive disorder using simultaneous real-time fMRI and EEG neurofeedback. (arXiv:1909.05764v1 [q-bio.NC])

    Simultaneous real-time fMRI and EEG neurofeedback (rtfMRI-EEG-nf) is an emerging neuromodulation approach, that enables simultaneous volitional regulation of both hemodynamic (BOLD fMRI) and electrophysiological (EEG) regional brain activities. Here we report the first application of rtfMRI-EEG-nf for emotion self-regulation training in patients with major depressive disorder (MDD). In this proof-of-concept study, MDD patients in the experimental group (n=16) used rtfMRI-EEG-nf during a happy emotion induction task to simultaneously upregulate four brain activity measures relevant to MDD. The target measures included BOLD activities of the left amygdala (LA) and left rostral anterior cingulate cortex (rACC), and frontal EEG asymmetries in the alpha band (FAA, [7.5-12.5] Hz) and high-beta band (FBA, [21-30] Hz). MDD patients in the control group (n=8) were provided with sham feedback signals. The experimental group participants achieved significant increases in the LA BOLD activity, FAA, and FBA during the rtfMRI-EEG-nf task, as well as significant enhancement in fMRI connectivity between the LA and left rACC. Temporal correlations between the FAA and FBA time courses and the LA BOLD activity were significantly enhanced during the rtfMRI-EEG-nf task. The experimental group participants reported significant mood improvements after the training. Our results demonstrate potential of the rtfMRI-EEG-nf for treatment of MDD.

    in q-bio.NC updates on arXiv.org on September 13, 2019 01:30 AM.

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    Neural coding of fast frequency modulated sweeps. (arXiv:1909.05691v1 [q-bio.NC])

    Frequency modulation (FM) is a basic constituent of vocalisation. Formant transitions in speech are characterised by short rising and falling FM-sweeps in the kilohertz frequency range. These sounds elicit a pitch percept that deviates from their average frequency. This study uses this perceptual effect, termed here the sweep pitch shift, to inform a model characterising the neural encoding of FM. First, a reexamination of the classical effect, consisting of two perceptual experiments, provides a quantitative characterisation of the dependence of the sweep pitch shift with the properties of the sweeps. Next, simulations carried on the new experimental data show that classical temporal and spectral models of pitch processing cannot explain the pitch shift. Conversely, a modified spectral model considering a predictive interaction between frequency and FM encoding fully reproduces our and previous experimental data. The model introduces a feedback mechanism that modulates the neurons that are expected to respond to future portions of the sweeps, accelarating their onset response. Combined, the experimental and modelling results suggest that predictive feedback modulation plays an important role in the neural encoding of FM even at early stages of the processing hierarchy.

    in q-bio.NC updates on arXiv.org on September 13, 2019 01:30 AM.

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    Predicting intelligence based on cortical WM/GM contrast, cortical thickness and volumetry. (arXiv:1909.05660v1 [q-bio.NC])

    We propose a four-layer fully-connected neural network (FNN) for predicting fluid intelligence scores from T1-weighted MR images for the ABCD-challenge. In addition to the volumes of brain structures, the FNN uses cortical WM/GM contrast and cortical thickness at 78 cortical regions. These last two measurements were derived from the T1-weighted MR images using cortical surfaces produced by the CIVET pipeline. The age and gender of the subjects and the scanner manufacturer are also used as features for the learning algorithm. This yielded 283 features provided to the FNN with two hidden layers of 20 and 15 nodes. The method was applied to the data from the ABCD study. Trained with a training set of 3736 subjects, the proposed method achieved a MSE of 71.596 and a correlation of 0.151 in the validation set of 415 subjects. For the final submission, the model was trained with 3568 subjects and it achieved a MSE of 94.0270 in the test set comprised of 4383 subjects.

    in q-bio.NC updates on arXiv.org on September 13, 2019 01:30 AM.

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    Propagation of spiking moments in linear Hawkes networks. (arXiv:1810.09520v2 [q-bio.NC] UPDATED)

    The present paper provides exact mathematical expressions for the high-order moments of spiking activity in a recurrently-connected network of linear Hawkes processes. It extends previous studies that have explored the case of a (linear) Hawkes network driven by deterministic intensity functions to the case of a stimulation by external inputs (rate functions or spike trains) with arbitrary correlation structure. Our approach describes the spatio-temporal filtering induced by the afferent and recurrent connectivities (with arbitrary synaptic response kernels) using operators acting on the input moments. This algebraic viewpoint provides intuition about how the network ingredients shape the input-output mapping for moments, as well as cumulants. We also show using numerical simulation that our results hold for neurons with refractoriness implemented by self-inhibition, provided the corresponding negative feedback for each neuron only mildly alters its mean firing probability.

    in q-bio.NC updates on arXiv.org on September 13, 2019 01:30 AM.

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    Postural Changes During Exteroceptive Thin Plantar Stimulation: The Effect of Prolonged Use and Different Plantar Localizations

    Somatosensory information arising from the foot has an important role in posture as well as visual and vestibular cues. Our hypothesis is that the effects of prolonged stimulation are greater than those of short stimulation and that varying the plantar location can affect postural control. Forty healthy participants were recruited and randomly assigned to four different plantar location groups: Lateral Insert (LI), Medial Insert (MI), Disharmonious Insert (DI), and Central Insert (CI). An instrumental assessment was performed before the plantar stimulation (T0), immediately after the positioning of the inserts (T1), and after 7 days of daily stimulation (T7). A follow-up was performed 15 days after (T15). The following stabilometric parameters were considered for both open eyes (OE) and closed eyes (CE) conditions: length of the sway (L) of the Center of Pressure (CoP); CoP maximum movements in the medio-lateral (X), and antero-posterior directions (Y). Comparing the effects of different plantar insert locations, the MI and CI groups were significantly different in the follow-up measures at T15, specifically for closed eyes measures. When we compared measures across time within each location group, CI group increased measures of X and Y data at T7 compared to other assessment times (T0, T1, and T15). In both MI and LI groups, L was significantly reduced, and X significantly increased at the T7 assessment compared to the T0, T1, and T15 assessments. The prolonged use of exteroceptive plantar stimulation and the location of plantar inserts may have a role to reshape postural control.

    in Frontiers in Systems Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Gut Inflammation in Association With Pathogenesis of Parkinson’s Disease

    Parkinson’s disease (PD) is a neurodegenerative disease that is generally thought to be caused by multiple factors, including environmental and genetic factors. Emerging evidence suggests that intestinal disturbances, such as constipation, are common non-motor symptoms of PD. Gut inflammation may be closely associated with pathogenesis in PD. This review aims to discuss the cross-talk between gut inflammation and PD pathology initiation and progression. Firstly, we will highlight the studies demonstrating how gut inflammation is related to PD. Secondly, we will analyze how gut inflammation spreads from the gastro-intestine to the brain. Here, we will mainly discuss the neural pathway of pathologic α-syn and the systemic inflammatory routes. Thereafter, we will address how alterations in the brain subsequently lead to dopaminergic neuron degeneration, in which oxidative stress, glutamate excitotoxicity, T cell driven inflammation and cyclooxygenase-2 (COX-2) are involved. We conclude a model of PD triggered by gut inflammation, which provides a new angle to understand the mechanisms of the disease.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Novel Functions of Feedback in Electrosensory Processing

    Environmental signals act as input and are processed across successive stages in the brain to generate a meaningful behavioral output. However, a ubiquitous observation is that descending feedback projections from more central to more peripheral brain areas vastly outnumber ascending feedforward projections. Such projections generally act to modify how sensory neurons respond to afferent signals. Recent studies in the electrosensory system of weakly electric fish have revealed novel functions for feedback pathways in that their transformation of the afferent input generates neural firing rate responses to sensory signals mediating perception and behavior. In this review, we focus on summarizing these novel and recently uncovered functions and put them into context by describing the more “classical” functions of feedback in the electrosensory system. We further highlight the parallels between the electrosensory system and other systems as well as outline interesting future directions.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    VETA: An Open-Source Matlab-Based Toolbox for the Collection and Analysis of Electromyography Combined With Transcranial Magnetic Stimulation

    The combination of electromyography (EMG) and transcranial magnetic stimulation (TMS) offers a powerful non-invasive approach for investigating corticospinal excitability in both humans and animals. Acquiring and analyzing the data produced with this combination of tools requires overcoming multiple technical hurdles. Due in part to these technical hurdles, the field lacks standard routines for EMG data collection and analysis. This poses a problem for study replication and direct comparisons. Although software toolboxes already exist that perform either online EMG data visualization or offline analysis, there currently are no openly available toolboxes that flexibly perform both and also interface directly with peripheral EMG and TMS equipment. Here, we introduce Visualize EMG TMS Analyze (VETA), a MATLAB-based toolbox that supports simultaneous EMG data collection and visualization as well as automated offline processing and is specially tailored for use with motor TMS. The VETA toolbox enables the simultaneous recording of EMG, timed administration of TMS, and presentation of behavioral stimuli from a single computer. These tools also provide a streamlined analysis pipeline with interactive data visualization. Finally, VETA offers a standard EMG data format to facilitate data sharing and open science.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 13, 2019 12:00 AM.

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    Structural and Functional Connectivity of the Anterior Cingulate Cortex in Patients With Borderline Personality Disorder

    Background

    Emerging evidences supported the hypothesis that emotional dysregulation results from aberrant connectivity within the fronto-limbic neural networks in patients with borderline personality disorder (BPD). Considering its important role in emotional regulation, the anterior cingulate cortex (ACC) has not yet been fully explored in BPD patients. Therefore, using the seed-based resting state functional connectivity (rsFC) and probabilistic fiber tracking, we aimed to explore the alterations of functional and structural connectivity (SC) of the ACC in patients with BPD.

    Methods

    A cohort of 50 unmedicated, young BPD patients and 54 sex-, age-, and education-matched healthy controls (HCs) completed psychological tests and underwent rs-fMRI and diffuse tensor imaging (DTI) scanning. Rs-FC analysis and probabilistic fiber tracking were used to plot SC and FC of the ACC.

    Results

    With the left ACC selected as a seed, BPD patients exhibited increased rsFC and abnormal SC with the right middle frontal gyrus (MFG), and decreased rsFC with the left middle temporal gyrus (MTG), compared with HCs. Additionally, negative cognitive emotion regulation and depressive symptoms both correlated negatively with the rsFC of the left ACC in BPD patients.

    Conclusion

    Abnormal SC and FC of the ACC underlie the deficient emotional regulation circuitry in BPD patients. Such alterations may be important biomarkers of BPD and thus could point to potential BPD treatment targets.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 13, 2019 12:00 AM.

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    Dynamic Functional Connectivity Within the Fronto-Limbic Network Induced by Intermittent Theta-Burst Stimulation: A Pilot Study

    Purpose

    The utility of transcranial magnetic stimulation (TMS) has been growing rapidly in both neurocognitive studies and clinical applications in decades. However, it remains unclear how the responses of the stimulated site and the site-related functional network to the external TMS manipulation dynamically change over time.

    Methods

    A multi-session combining TMS-fMRI experiment was conducted to explore the spatiotemporal effects of TMS within the fronto-limbic network. Ten healthy volunteers were modulated by intermittent theta-burst stimulation (iTBS) at a precise site within the left dorsolateral prefrontal cortex (DLPFC, MNI coordinate [-44 36 20]), navigated by individual structural MRI image. Three-session resting-state fMRI images were acquired before iTBS (TP1), immediately after iTBS (TP2), and 15 min after iTBS (TP3) for each participant. Seventy-four regions of interests (ROIs) within the fronto-limbic network were chosen including the bilateral superior frontal gyrus (SFG), middle frontal gyrus (MidFG), inferior frontal gyrus (IFG), orbital gyrus (OrG), cingulate gyrus (CG), and subcortical nuclei (hippocampus and amygdala). Regional fractional amplitude of low-frequency fluctuation (fALFF) and ROI-to-ROI functional connectivity (FC) were compared among TP1, TP2, and TP3.

    Results

    The immediate iTBS effect was observed at the stimulated site. FC between the left dorsolateral SFG and left dorsal IFG and between the left rostral IFG and right MidFG increased at TP2 as compared to at TP1 (all FDR-p < 0.05), while FC within the left OrG decreased. The relatively long-term iTBS effect transmitted with decreased FC between the left IFG and right amygdala, increased FC between the left MidFG and left OrG, and decreased FC between bilateral IFG and OrG at TP3 than at TP1 (all FDR-p < 0.05). Meanwhile, mean fALFF values over the left SFG, MidFG, ventral CG, and IFG were significantly increased at TP3 as compared to those at TP2 (all p < 0.05 with Bonferroni correction).

    Conclusion

    By combining TMS and fMRI, it becomes possible to track the spatiotemporal dynamics of TMS after-effects within the fronto-limbic network. Our findings suggested that the iTBS effect dynamically changed over time from the local neural activation at the stimulated site to its connected remote regions within the fronto-limbic network.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 13, 2019 12:00 AM.

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    Altered Cingulate Cortex Functional Connectivity in Normal Aging and Mild Cognitive Impairment

    Purpose

    Resting-state functional Magnetic Resonance Imaging studies revealed that the brain is organized into specialized networks constituted by regions that show a coherent fluctuation of spontaneous activity. Among these networks, the cingulate cortex appears to play a crucial role, particularly in the default mode network, the dorsal attention network and the salience network. In the present study, we mapped the functional connectivity (FC) pattern of different regions of the cingulate cortex: the anterior cingulate cortex, midcingulate cortex and posterior cingulate cortex/retro splenial cortex, which have been in turn divided into a total of 9 subregions. We compared FC patterns of the cingulate subregions in a sample of mild cognitive impairment patients and healthy elderly subjects.

    Methods

    We enrolled 19 healthy elders (age range: 61–72 y.o.) and 16 Mild cognitive impairment patients (age range 64–87 y.o.). All participants had comparable levels of education (8–10 years) and were neurologically examined to exclude visual and motor impairments, major medical conditions, psychiatric or neurological disorders and consumption of psychotropic drugs. The diagnosis of mild cognitive impairment was performed according to Petersen criteria. Subjects were evaluated with Mini-Mental State Examination, Frontal Assessment Battery, and prose memory (Babcock story) tests. In addition, with functional Magnetic Resonance Imaging, we investigated resting-state network activities.

    Results

    Healthy elderly, compared to mild cognitive impairment, showed significant increased level of FC for the ventral part of the anterior cingulate cortex in correspondence to the bilateral caudate and ventromedial prefrontal cortex. Moreover, for the midcingulate cortex the healthy elderly group showed increased levels of FC in the somatomotor region, prefrontal cortex, and superior parietal lobule. Meanwhile, the mild cognitive impairment group showed an increased level of FC for the superior frontal gyrus, frontal eye field and orbitofrontal cortex compared to the healthy elderly group.

    Conclusion

    Our findings indicate that cognitive decline observed in mild cognitive impairment patients damages the global FC of the cingulate cortex, supporting the idea that abnormalities in resting-state activities of the cingulate cortex could be a useful additional tool in order to better understand the brain mechanisms of MCI.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 13, 2019 12:00 AM.

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    Human Memories Can Be Linked by Temporal Proximity

    Real-world memories involve the integration of multiple events across time, yet the mechanisms underlying this integration is unknown. Recent rodent studies show that distinct memories encoded within a few hours, but not several days, share a common neural ensemble, and a common fate whereby later fear conditioning can transfer from one memory to the other. Here, we tested if distinct memories could be linked by temporal proximity in humans. 74 young adults encoded two memories (A and B) close (3-h) or far apart (7-day) in time. One day after encoding the second memory (B), Memory A was updated by pairing it with electric shock (i.e., fear conditioning). We tested whether the memory and fear associated with Memory B would be stronger in the 3-h, compared with the 7-day condition. Results were generally consistent with rodent studies, where we found heightened Memory B fear expression when the two memories were encoded close, but not far apart, in time. Furthermore, there was less forgetting of Memory B in the 3-h compared to 7-day condition. Our results suggest that temporally proximal memories may be linked, such that updating one experience updates the other.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Why Isn’t the Head-Direction System Necessary for Direction? Lessons From the Lateral Mammillary Nuclei

    Complex spatial representations in the hippocampal formation and related cortical areas require input from the head direction system. However, a recurrent finding is that behavior apparently supported by these spatial representations does not appear to require input from generative head direction regions, i.e., lateral mammillary nuclei (LMN). Spatial tasks that tax direction discrimination should be particularly sensitive to the loss of head direction information, however, this has been repeatedly shown not to be the case. A further dissociation between electrophysiological properties of the head direction system and behavior comes in the form of geometric-based navigation which is impaired following lesions to the head direction system, yet head direction cells are not normally guided by geometric cues. We explore this apparent mismatch between behavioral and electrophysiological studies and highlight future experiments that are needed to generate models that encompass both neurophysiological and behavioral findings.

    in Frontiers in Neural Circuits | New and Recent Articles on September 13, 2019 12:00 AM.

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    Proliferation of Inhibitory Input to the Substantia Nigra in Experimental Parkinsonism

    The substantia nigra pars reticulata (SNr) is one of the output nuclei of the basal ganglia (BG) and plays a vital role in movement execution. Death of dopaminergic neurons in the neighboring nucleus, the substantia nigra pars compacta (SNc), leads to Parkinson's disease. The ensuing dopamine depletion affects all BG nuclei. However, the long-term effects of dopamine depletion on BG output are less characterized. In this in vitro study, we applied electrophysiological and immunohistochemical techniques to investigate the long-term effects of dopamine depletion on GABAergic transmission to the SNr. The findings showed a reduction in firing rate and regularity in SNr neurons after unilateral dopamine depletion with 6-OHDA, which we associate with homeostatic mechanisms. The strength of the GABAergic synapses between the globus pallidus (GP) and the SNr increased but not their short-term dynamics. Consistent with this observation, there was an increase in the frequency and amplitude of spontaneous inhibitory synaptic events to SNr neurons. Immunohistochemistry revealed an increase in the density of vGAT-labeled puncta in dopamine depleted animals. Overall, these results may suggest that synaptic proliferation can explain how dopamine depletion augments GABAergic transmission in the SNr.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Gentamicin Affects the Bioenergetics of Isolated Mitochondria and Collapses the Mitochondrial Membrane Potential in Cochlear Sensory Hair Cells

    Aminoglycoside antibiotics are widely prescribed to treat a variety of serious bacterial infections. They are extremely useful clinical tools, but have adverse side effects such as oto- and nephrotoxicity. Once inside a cell they are thought to cause mitochondrial dysfunction, subsequently leading to apoptotic cell death due to an increase in reactive oxygen species (ROS) production. Here we present evidence of a direct effect of gentamicin (the most commonly prescribed aminoglycoside) on the respiratory activities of isolated rat liver and kidney mitochondria. We show that gentamicin stimulates state 4 and inhibits state 3u respiratory rates, thereby reducing the respiratory control ratio (RCR) whilst simultaneously causing a collapse of the mitochondrial membrane potential (MtMP). We propose that gentamicin behaves as an uncoupler of the electron transport chain (ETC) – a hypothesis supported by our evidence that it reduces the production of mitochondrial ROS (MtROS). We also show that gentamicin collapses the MtMP in the sensory hair cells (HCs) of organotypic mouse cochlear cultures.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Fractalkine Modulates Microglia Metabolism in Brain Ischemia

    In the CNS, the chemokine CX3CL1 (fractalkine) is expressed on neurons while its specific receptor CX3CR1 is expressed on microglia and macrophages. Microglia play an important role in health and disease through CX3CL1/CX3CR1 signaling, and in many neurodegenerative disorders, microglia dysregulation has been associated with neuro-inflammation. We have previously shown that CX3CL1 has neuroprotective effects against cerebral ischemia injury. Here, we investigated the involvement of CX3CL1 in the modulation of microglia phenotype and the underlying neuroprotective effect on ischemia injury. The expression profiles of anti- and pro-inflammatory genes showed that CX3CL1 markedly inhibited microglial activation both in vitro and in vivo after permanent middle cerebral artery occlusion (pMCAO), accompanied by an increase in the expression of anti-inflammatory genes. Moreover, CX3CL1 induces a metabolic switch in microglial cells with an increase in the expression of genes related to the oxidative pathway and a reduction in those related to the glycolytic pathway, which is the metabolic state associated to the pro-inflammatory phenotype for energy production. The data reported in this paper suggest that CX3CL1 protects against cerebral ischemia modulating the activation state of microglia and its metabolism in order to restrain inflammation and organize a neuroprotective response against the ischemic insult.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Upregulated Expression of MicroRNA-204-5p Leads to the Death of Dopaminergic Cells by Targeting DYRK1A-Mediated Apoptotic Signaling Cascade

    MicroRNAs (miRs) downregulate or upregulate the mRNA level by binding to the 3′-untranslated region (3′UTR) of target gene. Dysregulated miR levels can be used as biomarkers of Parkinson’s disease (PD) and could participate in the etiology of PD. In the present study, 45 brain-enriched miRs were evaluated in serum samples from 50 normal subjects and 50 sporadic PD patients. The level of miR-204-5p was upregulated in serum samples from PD patients. An upregulated level of miR-204-5p was also observed in the serum and substantia nigra (SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Expression of miR-204-5p increased the level of α-synuclein (α-Syn), phosphorylated (phospho)-α-Syn, tau, or phospho-tau protein and resulted in the activation of endoplasmic reticulum (ER) stress in SH-SY5Y dopaminergic cells. Expression of miR-204-5p caused autophagy impairment and activation of c-Jun N-terminal kinase (JNK)-mediated apoptotic cascade in SH-SY5Y dopaminergic cells. Our study using the bioinformatic method and dual-luciferase reporter analysis suggests that miR-204-5p positively regulates mRNA expression of dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) by directly interacting with 3′UTR of DYRK1A. The mRNA and protein levels of DYRK1A were increased in SH-SY5Y dopaminergic cells expressing miR-204-5p and SN of MPTP-induced PD mouse model. Knockdown of DYRK1A expression or treatment of the DYRK1A inhibitor harmine attenuated miR-204-5p-induced increase in protein expression of phospho-α-Syn or phospho-tau, ER stress, autophagy impairment, and activation of JNK-mediated apoptotic pathway in SH-SY5Y dopaminergic cells or primary cultured dopaminergic neurons. Our results suggest that upregulated expression of miR-204-5p leads to the death of dopaminergic cells by targeting DYRK1A-mediated ER stress and apoptotic signaling cascade.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Post Stroke Seizures and Epilepsy: From Proteases to Maladaptive Plasticity

    Post stroke epilepsy (PSE) is the most common cause of seizures in the elderly, yet its underlying mechanism is poorly understood. The classification of PSE is confusing, and there is neither a clear agreement on its incidence and prognosis nor a consensus about specific treatments. The diagnosis of PSE requires the occurrence of late seizures: epileptic events occurring 1 week or more after an ischemic stroke. Late seizures differ from early seizures by the presence of permanent structural changes in the brain. Those structural changes cause a shift in the regulation of neuronal firing and lead to circuit dysfunctions, and thus to a long-term epileptic condition. The coagulation cascade and some of its major components, serine proteases such as thrombin, are known to participate in the acute phase of a stroke. Recent discoveries found that thrombin and its protease-activated receptor 1 (PAR1), are involved in the development of maladaptive plasticity. Therefore, we suggest that thrombin and PAR1 may have a role in the development of PSE by inducing permanent structural changes after the ischemic events toward the development of epileptic focuses. We are confident that future studies will lead to a better understanding of the pathophysiology of PSE, as well as development of more directed therapies for its treatment.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Galanin in an Agnathan: Precursor Identification and Localisation of Expression in the Brain of the Sea Lamprey Petromyzon marinus

    Galanin is a neuropeptide that is widely expressed in the mammalian brain, where it regulates many physiological processes, including feeding and nociception. Galanin has been characterized extensively in jawed vertebrates (gnathostomes), but little is known about the galanin system in the most ancient extant vertebrate class, the jawless vertebrates or agnathans. Here, we identified and cloned a cDNA encoding the sea lamprey (Petromyzon marinus) galanin precursor (PmGalP). Sequence analysis revealed that PmGalP gives rise to two neuropeptides that are similar to gnathostome galanins and galanin message-associated peptides. Using mRNA in situ hybridization, the distribution of PmGalP-expressing neurons was mapped in the brain of larval and adult sea lampreys. This revealed PmGalP-expressing neurons in the septum, preoptic region, striatum, hypothalamus, prethalamus, and displaced cells in lateral areas of the telencephalon and diencephalon. In adults, the laterally migrated PmGalP-expressing neurons are observed in an area that extends from the ventral pallium to the lateral hypothalamus and prethalamus. The striatal and laterally migrated PmGalP-expressing cells of the telencephalon were not observed in larvae. Comparison with studies on jawed vertebrates reveals that the presence of septal and hypothalamic galanin-expressing neuronal populations is highly conserved in vertebrates. However, compared to mammals, there is a more restricted pattern of expression of the galanin transcript in the brain of lampreys. This work provides important new information on the early evolution of the galanin system in vertebrates and provides a genetic and neuroanatomical basis for functional analyses of the galanin system in lampreys.

    in Frontiers in Neuroanatomy | New and Recent Articles on September 13, 2019 12:00 AM.

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    Role of Neurofilament Light Chain as a Potential Biomarker for Alzheimer's Disease: A Correlative Meta-Analysis

    Neurofilament light (NFL) is a putative biomarker of neurodegeneration. This study evaluates the correlative association of NFL with Alzheimer's disease (AD) indices. Relevant studies were identified after a literature search in electronic databases and study selection was based on pre-determined eligibility criteria. Correlation coefficients between NFL levels and important AD indices reported by individual studies were pooled as z-scores. Meta-regression analyses were performed to evaluate the relationships between important covariates. Data from 38 studies (age 68.3 years [95% confidence interval (CI): 65.7, 70.9]; 54 % [95% CI: 50, 57] females) were used. Meta-analyses of correlation coefficients reported by the included studies showed that NFL levels in blood and cerebrospinal fluid (CSF) correlated well (r = 0.59 [95% CI: 0.45, 0.71]; p < 0.0001). NFL levels correlated with MMSE score (r = −0.345 [95% CI: −0.43, −0.25]; p = 0.0001), and age (r = 0.485 [95% CI: 0.35, 0.61]; p = 0.00001). CSF NFL levels correlated with total tau (t-tau; r = 0.39 [95% CI: 0.27, 0.50]; p = 0.0001), phosphorylated tau (p-tau; r = 0.34 [95% CI: 0.19, 0.47]; p = 0.00001), and neurogranin (r = 0.25 [95% CI: 0.12, 0.37]; p = 0.001) but not with beta amyloid (Aβ) (r = 0.00 [95%CI: −0.13, 0.12]; p = 0.937). In meta-regression, MMSE scores were associated inversely with blood NFL (metaregression coefficient (MC) −0.236 [95% CI:−0.40, −0.072; p = 0.008), and age (MC) −0.235 [−0.36, −0.11]; p = 0.001) and positively with CSF Aβ-42 (MC 0.017 [0.010, 0.023]; p = 0.00001). NFL has good correlations with t-tau, and p-tau in CSF and CSF NFL levels correlates well with blood NFL levels. These results show that NFL can be a useful biomarker for improving diagnosis and predicting prognosis in AD patients especially if age weighted.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Overlap Between Apolipoprotein Eε4 Allele and Slowing Gait Results in Cognitive Impairment

    Background: Although apolipoprotein E polymorphism ε4 allele (ApoE4) and slow gait are well-known risk factors for cognitive impairment, examination of their combined effect on cognitive function is lacking. Our objective was to elucidate whether a combination of ApoE4 phenotyping and slow gait resulted in greater cognitive impairment.

    Methods: Overall, 1,085 community-dwelling older adults, either ApoE4 carriers (n = 167, 15.4%) or non-ApoE4 carriers, were included from the “Takashimadaira study.” Gait speed was assessed with an electronic walkway and slow gait was defined as <1 m/s. Cognitive performance was also assessed using the Mini-Mental State Exam (MMSE) and the Trail Making Test (TMT)-A and -B. A two-way analysis of covariance (ANCOVA; ApoE and gait velocity factors) adjusted for covariates was performed for each analysis.

    Results: Gait and cognitive performances were similar for ApoE4 and non-ApoE4 carriers. A two-way ANCOVA of the MMSE showed a significant interaction between the two factors. ApoE4 carriers with slow gait had lower MMSE scores than ApoE4 carriers without slow gait and non-ApoE4 carriers with slow gait. Also, a significant main effect of gait velocity on TMT-A was observed, indicating that slow gait is associated with lower scores irrespective of the presence of ApoE4. There was no main effect or interaction observed on the TMT-B.

    Conclusions: Our results suggest that the concurrent presence of at least one copy of ApoE4 and slow gait can define a subgroup with the lowest cognition. Elucidating the mechanisms underlying these associations may point out modifiable factors in populations at risk of dementia.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Structural and Functional Disruptions in Subcortical Vascular Mild Cognitive Impairment With and Without Depressive Symptoms

    Many previous studies have revealed structural and functional abnormalities in patients with the subcortical vascular mild cognitive impairment (svMCI). Although depression symptoms were suggested to serve as a potential marker of conversion to dementia in patients with svMCI, whether these disruptions or other new findings will be identified in the svMCI comorbid with depression symptoms has not been established. In the current study, we combined voxel-based morphometry (VBM) and the resting-state functional magnetic resonance imaging (fMRI) to investigate the structural and functional disruptions in the svMCI with and without depression symptoms using a cohort of 18 svMCI with depression symptoms (svMCI+D), 17 svMCI without depression symptoms (svMCI−D), and 23 normal controls (NC). As a result, we identified significantly decreased gray matter density in the left parahippocampus (ParaHIPP.L), the right hippocampus (HIPP.R), and the right middle cingulate cortex (MCC.R) in both svMCI+D and svMCI−D compared to NC. Most importantly, we also identified increased gray matter density in the MCC.R accompanied by increased resting-state functional connectivity (RSFC) with right parahippocampus (ParaHIPP.R) in the svMCI+D compared to svMCI−D. Moreover, the gray matter density of MCC.R and ParaHIPP.L was correlated with cognitive impairments and depression symptoms in the svMCI, respectively. In conclusion, these results extended previous studies and added weight to considerations of depression symptoms in the svMCI. Moreover, we suggested that a processing loop associated with HIPP, ParaHIPP, and MCC might underlie the mechanism of depression symptoms in the svMCI.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Can Acupuncture Treatment of Hypertension Improve Brain Health? A Mini Review

    With age, cerebrovascular and neurodegenerative diseases (e.g., dementia and Alzheimer’s) are some of the leading causes of death in the United States. Related to these outcomes is the increased prevalence of hypertension, which independently increases the development of cerebrovascular and neurodegenerative diseases. While a direct mechanistic link between hypertension and poor brain health is unknown, many hypothesize that the etiology stems from poor blood pressure (BP) and cerebrovascular regulation. This dysfunction fosters hypoperfusion of the brain, causing stress to the tissue through a nutrient mismatch, subtly damaging the brain over many years. Current Western medical treatment relies on pharmacological treatment (mainly beta-blockers, angiotensin-converting enzyme inhibitors, or a combination of the two). However, Western treatments have not been successful in mitigating brain health outcomes and are burdened with unwanted side effects and non-adherence issues. Alternatively, traditional East Asia medicine has used acupuncture as a treatment for hypertension and may offer a promising approach in response to the limitations of conventional therapy. While detailed clinical and mechanistic experimental evidence is lacking, acupuncture has been observed to reduce BP and improve endothelial function in hypertensive adults. Further, acupuncture has been shown to have specific cerebrovascular effects, increasing cerebrovascular reactivity in healthy adults, highlighting possible neuroprotective properties. Therefore, our review is aimed at evaluating acupuncture as a treatment for hypertension and the potential impact on brain health. We will interrogate the current literature as well as discuss the proposed neural and vascular mechanisms by which acupuncture acts.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    Age and Ketogenic Diet Have Dissociable Effects on Synapse-Related Gene Expression Between Hippocampal Subregions

    As the number of individuals living beyond the age of 65 is rapidly increasing, so is the need to develop strategies to combat the age-related cognitive decline that may threaten independent living. Although the link between altered neuronal signaling and age-related cognitive impairments is not completely understood, it is evident that declining cognitive abilities are at least partially due to synaptic dysfunction. Aging is accompanied by well-documented changes in both excitatory and inhibitory synaptic signaling across species. Age-related synaptic alterations are not uniform across the brain, however, with different regions showing unique patterns of vulnerability in advanced age. In the hippocampus, increased activity within the CA3 subregion has been observed across species, and this can be reversed with anti-epileptic medication. In contrast to CA3, the dentate gyrus shows reduced activity with age and declining metabolic activity. Ketogenic diets have been shown to decrease seizure incidence and severity in epilepsy, improve metabolic function in diabetes type II, and improve cognitive function in aged rats. This link between neuronal activity and metabolism suggests that metabolic interventions may be able to ameliorate synaptic signaling deficits accompanying advanced age. We therefore investigated the ability of a dietary regimen capable of inducing nutritional ketosis and improving cognition to alter synapse-related gene expression across the dentate gyrus, CA3 and CA1 subregions of the hippocampus. Following 12 weeks of a ketogenic or calorie-matched standard diet, RTq-PCR was used to quantify expression levels of excitatory and inhibitory synaptic signaling genes within CA1, CA3 and dentate gyrus. While there were no age or diet-related changes in CA1 gene expression, expression levels were significantly altered within CA3 by age and within the dentate gyrus by diet for several genes involved in presynaptic glutamate regulation and postsynaptic excitation and plasticity. These data demonstrate subregion-specific alterations in synaptic signaling with age and the potential for a ketogenic diet to alter these processes in dissociable ways across different brain structures that are uniquely vulnerable in older animals.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 13, 2019 12:00 AM.

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    How predictable is genome evolution?

    Similar patterns of genomic divergence have been observed in the evolution of plant species separated by oceans.

    in eLife: latest articles on September 13, 2019 12:00 AM.

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    Overcoming chromatin barriers

    Single-molecule experiments reveal the dynamics of transcription through a nucleosome with single-base-pair accuracy.

    in eLife: latest articles on September 13, 2019 12:00 AM.

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    The ER membrane protein complex is required to ensure correct topology and stable expression of flavivirus polyproteins

    Flaviviruses translate their genomes as multi-pass transmembrane proteins at the endoplasmic reticulum (ER) membrane. Here, we show that the ER membrane protein complex (EMC) is indispensable for the expression of viral polyproteins. We demonstrated that EMC was essential for accurate folding and post-translational stability rather than translation efficiency. Specifically, we revealed degradation of NS4A-NS4B, a region rich in transmembrane domains, in absence of EMC. Orthogonally, by serial passaging of virus on EMC-deficient cells, we identified two non-synonymous point mutations in NS4A and NS4B, which rescued viral replication. Finally, we showed a physical interaction between EMC and viral NS4B and that the NS4A-4B region adopts an aberrant topology in the absence of the EMC leading to degradation. Together, our data highlight how flaviviruses hijack the EMC for transmembrane protein biogenesis to achieve optimal expression of their polyproteins, which reinforces a role for the EMC in stabilizing challenging transmembrane proteins during synthesis.

    in eLife: latest articles on September 13, 2019 12:00 AM.

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    Correction: Minimal model of interictal and ictal discharges “Epileptor-2”

    by Anton V. Chizhov, Artyom V. Zefirov, Dmitry V. Amakhin, Elena Yu. Smirnova, Aleksey V. Zaitsev

    in PLOS Computational Biology: New Articles on September 12, 2019 09:00 PM.

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    Loop analysis of blood pressure/volume homeostasis

    by Bruno Burlando, Franco Blanchini, Giulia Giordano

    We performed a mathematical analysis of the dynamic control loops regulating the vasomotor tone of vascular smooth muscle, blood volume, and mean arterial pressure, which involve the arginine vasopressin (AVP) system, the atrial natriuretic peptide system (ANP), and the renin-angiotensin-aldosterone system (RAAS). Our loop analysis of the AVP-ANP-RAAS system revealed the concurrent presence of two different regulatory mechanisms, which perform the same qualitative function: one affects blood pressure by regulating vasoconstriction, the other by regulating blood volume. Both the systems are candidate oscillators consisting of the negative-feedback loop of a monotone system: they admit a single equilibrium that can either be stable or give rise to oscillatory instability. Also a subsystem, which includes ANP and AVP stimulation of vascular smooth muscle cells, turns out to be a candidate oscillator composed of a monotone system with multiple negative feedback loops, and we show that its oscillatory potential is higher when the delays along all feedback loops are comparable. Our results give insight into the physiological mechanisms ruling long-term homeostasis of blood hydraulic parameters, which operate based on dynamical loops of interactions.

    in PLOS Computational Biology: New Articles on September 12, 2019 09:00 PM.

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    Weak coupling between intracellular feedback loops explains dissociation of clock gene dynamics

    by Christoph Schmal, Daisuke Ono, Jihwan Myung, J. Patrick Pett, Sato Honma, Ken-Ichi Honma, Hanspeter Herzel, Isao T. Tokuda

    Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described in recent experimental studies that applied various perturbations such as slice preparations, light pulses, jet-lag, and culture medium exchange. In this paper, we provide evidence that this “presumably transient” dissociation of circadian gene expression oscillations may occur at the single-cell level. Conceptual and detailed mechanistic mathematical modeling suggests that such dissociation is due to a weak interaction between multiple feedback loops present within a single cell. The dissociable loops provide insights into underlying mechanisms and general design principles of the molecular circadian clock.

    in PLOS Computational Biology: New Articles on September 12, 2019 09:00 PM.

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    Long-term dynamics of measles in London: Titrating the impact of wars, the 1918 pandemic, and vaccination

    by Alexander D. Becker, Amy Wesolowski, Ottar N. Bjørnstad, Bryan T. Grenfell

    A key question in ecology is the relative impact of internal nonlinear dynamics and external perturbations on the long-term trajectories of natural systems. Measles has been analyzed extensively as a paradigm for consumer-resource dynamics due to the oscillatory nature of the host-pathogen life cycle, the abundance of rich data to test theory, and public health relevance. The dynamics of measles in London, in particular, has acted as a prototypical test bed for such analysis using incidence data from the pre-vaccination era (1944–1967). However, during this timeframe there were few external large-scale perturbations, limiting an assessment of the relative impact of internal and extra demographic perturbations to the host population. Here, we extended the previous London analyses to include nearly a century of data that also contains four major demographic changes: the First and Second World Wars, the 1918 influenza pandemic, and the start of a measles mass vaccination program. By combining mortality and incidence data using particle filtering methods, we show that a simple stochastic epidemic model, with minimal historical specifications, can capture the nearly 100 years of dynamics including changes caused by each of the major perturbations. We show that the majority of dynamic changes are explainable by the internal nonlinear dynamics of the system, tuned by demographic changes. In addition, the 1918 influenza pandemic and World War II acted as extra perturbations to this basic epidemic oscillator. Our analysis underlines that long-term ecological and epidemiological dynamics can follow very simple rules, even in a non-stationary population subject to significant perturbations and major secular changes.

    in PLOS Computational Biology: New Articles on September 12, 2019 09:00 PM.

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    Ten simple rules for helping newcomers become contributors to open projects

    by Dan Sholler, Igor Steinmacher, Denae Ford, Mara Averick, Mike Hoye, Greg Wilson

    in PLOS Computational Biology: New Articles on September 12, 2019 09:00 PM.

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    Perspective: Dimensions of the scientific method

    by Eberhard O. Voit

    The scientific method has been guiding biological research for a long time. It not only prescribes the order and types of activities that give a scientific study validity and a stamp of approval but also has substantially shaped how we collectively think about the endeavor of investigating nature. The advent of high-throughput data generation, data mining, and advanced computational modeling has thrown the formerly undisputed, monolithic status of the scientific method into turmoil. On the one hand, the new approaches are clearly successful and expect the same acceptance as the traditional methods, but on the other hand, they replace much of the hypothesis-driven reasoning with inductive argumentation, which philosophers of science consider problematic. Intrigued by the enormous wealth of data and the power of machine learning, some scientists have even argued that significant correlations within datasets could make the entire quest for causation obsolete. Many of these issues have been passionately debated during the past two decades, often with scant agreement. It is proffered here that hypothesis-driven, data-mining–inspired, and “allochthonous” knowledge acquisition, based on mathematical and computational models, are vectors spanning a 3D space of an expanded scientific method. The combination of methods within this space will most certainly shape our thinking about nature, with implications for experimental design, peer review and funding, sharing of result, education, medical diagnostics, and even questions of litigation.

    in PLOS Computational Biology: New Articles on September 12, 2019 09:00 PM.

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    Characterizing and dissociating multiple time-varying modulatory computations influencing neuronal activity

    by Kaiser Niknam, Amir Akbarian, Kelsey Clark, Yasin Zamani, Behrad Noudoost, Neda Nategh

    In many brain areas, sensory responses are heavily modulated by factors including attentional state, context, reward history, motor preparation, learned associations, and other cognitive variables. Modelling the effect of these modulatory factors on sensory responses has proven challenging, mostly due to the time-varying and nonlinear nature of the underlying computations. Here we present a computational model capable of capturing and dissociating multiple time-varying modulatory effects on neuronal responses on the order of milliseconds. The model’s performance is tested on extrastriate perisaccadic visual responses in nonhuman primates. Visual neurons respond to stimuli presented around the time of saccades differently than during fixation. These perisaccadic changes include sensitivity to the stimuli presented at locations outside the neuron’s receptive field, which suggests a contribution of multiple sources to perisaccadic response generation. Current computational approaches cannot quantitatively characterize the contribution of each modulatory source in response generation, mainly due to the very short timescale on which the saccade takes place. In this study, we use a high spatiotemporal resolution experimental paradigm along with a novel extension of the generalized linear model framework (GLM), termed the sparse-variable GLM, to allow for time-varying model parameters representing the temporal evolution of the system with a resolution on the order of milliseconds. We used this model framework to precisely map the temporal evolution of the spatiotemporal receptive field of visual neurons in the middle temporal area during the execution of a saccade. Moreover, an extended model based on a factorization of the sparse-variable GLM allowed us to disassociate and quantify the contribution of individual sources to the perisaccadic response. Our results show that our novel framework can precisely capture the changes in sensitivity of neurons around the time of saccades, and provide a general framework to quantitatively track the role of multiple modulatory sources over time.

    in PLOS Computational Biology: New Articles on September 12, 2019 09:00 PM.

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    Bioinformatics in Jordan: Status, challenges, and future directions

    by Qanita Bani Baker, Maryam S. Nuser

    Bioinformatics plays a key role in supporting the life sciences. In this work, we examine bioinformatics in Jordan, beginning with the current status of bioinformatics education and research, then exploring the challenges of advancing bioinformatics, and finally looking to the future for how Jordanian bioinformatics research may develop.

    in PLOS Computational Biology: New Articles on September 12, 2019 09:00 PM.

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    Temporal sequences of synapse disintegration triggered by afferent axon transection - time-lapse imaging study of pre- and post-synaptic molecules

    Abstract

    Traumatic brain injury (TBI) is one of the major causes of death and disability. Multiple animal models have been developed to explore therapeutic targets for TBI. However, heterogeneity of pathophysiology obstructs discovery of therapeutic targets. To facilitate understanding of TBI pathophysiology, each element of neuronal and glial responses should be studied separately. We focused on synapse remodeling which plays an important role in recovery from TBI and developed a new method, afferent elimination, for analyzing synapse remodeling after selective damage to presynaptic axons by mechanical transection in culture of mouse hippocampal neurons. Afferent elimination can induce various events related to synapse remodeling and we could determine their temporal orders and find relationships between them. Specifically, loss of presynaptic sites preceded loss of postsynaptic sites and spines. Some of the postsynaptic sites initially located inside spines showed translocation toward dendritic shafts. These translocation events started after the loss of contacting presynaptic sites. Also, these events could be blocked or delayed by NMDA receptor inhibition. Taken together, these findings suggest that postsynaptic changes occur in afferent elimination are NMDA dependent and imply that these NMDA-dependent events underlie synaptic remodeling of TBI.

    Significance Statement Traumatic brain injury (TBI) is one of the major causes of death and disability. However, heterogeneity of TBI pathophysiology obstructs discovery of therapeutic targets. To solve this, each element of neuronal and glial responses should be studied separately. We focused on synapse remodeling which plays an important role in recovery from TBI and developed a new method, afferent elimination. Afferent elimination can induce various events related to synapse remodeling and we could determine their temporal orders and find relationships between them. Also, these events could be blocked by NMDA receptor inhibition. Taken together, these findings suggest that postsynaptic changes after afferent elimination are NMDA receptor-dependent and imply that NMDA receptor-related signaling underlies synaptic remodeling in TBI.

    in RSS PAP on September 12, 2019 04:30 PM.

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    Neural Representation of Overlapping Path Segments and Reward Acquisitions in the Monkey Hippocampus

    Disambiguation of overlapping events is thought to be the hallmark of episodic memory. Recent rodent studies have reported that when navigating overlapping path segments in the different routes place cell activity in the same overlapping path segments were remapped according to different goal locations in different routes. However, it is unknown how hippocampal neurons disambiguate reward delivery in overlapping path segments in different routes. In the present study, we recorded monkey hippocampal neurons during performance of three virtual navigation (VN) tasks in which a monkey alternately navigated two different routes that included overlapping path segments (common central hallway) and acquired rewards in the same locations in overlapping path segments by manipulating a joystick. The results indicated that out of 106 hippocampal neurons, 57 displayed place-related activity (place-related neurons), and 18 neurons showed route-dependent activity in the overlapping path segments, consistent with a hippocampal role in the disambiguation of overlapping path segments. Moreover, 75 neurons showed neural correlates to reward delivery (reward-related neurons), whereas 56 of these 75 reward-related neurons showed route-dependent reward-related activity in the overlapping path segments. The ensemble activity of reward-related neurons represented reward delivery, locations, and routes in the overlapping path segments. In addition, ensemble activity patterns of hippocampal neurons more distinctly represented overlapping path segments than non-overlapping path segments. The present results provide neurophysiological evidence of disambiguation in the monkey hippocampus, consistent with a hippocampal role in episodic memory, and support a recent computational model of “neural differentiation,” in which overlapping items are better represented by repeated retrieval with competitive learning.

    in Frontiers in Systems Neuroscience | New and Recent Articles on September 12, 2019 12:00 AM.

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    The Ventriloquist Illusion as a Tool to Study Multisensory Processing: An Update

    Ventriloquism, the illusion that a voice appears to come from the moving mouth of a puppet rather than from the actual speaker, is one of the classic examples of multisensory processing. In the laboratory, this illusion can be reliably induced by presenting simple meaningless audiovisual stimuli with a spatial discrepancy between the auditory and visual components. Typically, the perceived location of the sound source is biased toward the location of the visual stimulus (the ventriloquism effect). The strength of the visual bias reflects the relative reliability of the visual and auditory inputs as well as prior expectations that the two stimuli originated from the same source. In addition to the ventriloquist illusion, exposure to spatially discrepant audiovisual stimuli results in a subsequent recalibration of unisensory auditory localization (the ventriloquism aftereffect). In the past years, the ventriloquism effect and aftereffect have seen a resurgence as an experimental tool to elucidate basic mechanisms of multisensory integration and learning. For example, recent studies have: (a) revealed top-down influences from the reward and motor systems on cross-modal binding; (b) dissociated recalibration processes operating at different time scales; and (c) identified brain networks involved in the neuronal computations underlying multisensory integration and learning. This mini review article provides a brief overview of established experimental paradigms to measure the ventriloquism effect and aftereffect before summarizing these pathbreaking new advancements. Finally, it is pointed out how the ventriloquism effect and aftereffect could be utilized to address some of the current open questions in the field of multisensory research.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on September 12, 2019 12:00 AM.

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    Lack of Temporal Impairment in Patients With Mild Cognitive Impairment

    In the present study, we investigate possible temporal impairment in patients with mild cognitive impairment (MCI) and the amount of temporal distortions caused by the presentation of emotional facial expressions (anger, shame, and neutral) in MCI patients and controls. Twelve older adults with MCI and 14 healthy older adults were enrolled in the present study. All participants underwent a complete neuropsychological evaluation. We used three timing tasks to tap temporal abilities, namely time bisection (standard intervals lasting 400 and 1600 ms), finger-tapping (free and 1 s), and simple reaction-time tasks. The stimuli used in the time bisection task were facial emotional stimuli expressing anger or shame to investigate a possible contribution of emotional information as previously observed in healthy adults. MCI patients showed temporal abilities comparable to controls. We observed an effect of facial emotional stimuli on time perception when data were analyzed in terms of proportion of long responses, and this result was mainly driven by the temporal overestimation when a facial expression of anger was presented in controls. Results seem to suggest that the severity of the cognitive dysfunction accounts more for subjective temporal impairment than a compromised internal clock.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on September 12, 2019 12:00 AM.

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    Brain Functional Connectivity Through Phase Coupling of Neuronal Oscillations: A Perspective From Magnetoencephalography

    Magnetoencephalography has gained an increasing importance in systems neuroscience thanks to the possibility it offers of unraveling brain networks at time-scales relevant to behavior, i.e., frequencies in the 1–100 Hz range, with sufficient spatial resolution. In the first part of this review, we describe, in a unified mathematical framework, a large set of metrics used to estimate MEG functional connectivity at the same or at different frequencies. The different metrics are presented according to their characteristics: same-frequency or cross-frequency, univariate or multivariate, directed or undirected. We focus on phase coupling metrics given that phase coupling of neuronal oscillations is a putative mechanism for inter-areal communication, and that MEG is an ideal tool to non-invasively detect such coupling. In the second part of this review, we present examples of the use of specific phase methods on real MEG data in the context of resting state, visuospatial attention and working memory. Overall, the results of the studies provide evidence for frequency specific and/or cross-frequency brain circuits which partially overlap with brain networks as identified by hemodynamic-based imaging techniques, such as functional Magnetic Resonance (fMRI). Additionally, the relation of these functional brain circuits to anatomy and to behavior highlights the usefulness of MEG phase coupling in systems neuroscience studies. In conclusion, we believe that the field of MEG functional connectivity has made substantial steps forward in the recent years and is now ready for bringing the study of brain networks to a more mechanistic understanding.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 12, 2019 12:00 AM.

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    The Influence of EEG References on the Analysis of Spatio-Temporal Interrelation Patterns

    The characterization of the functional network of the brain dynamics has become a prominent tool to illuminate novel aspects of brain functioning. Due to its excellent time resolution, such research is oftentimes based on electroencephalographic recordings (EEG). However, a particular EEG-reference might cause crucial distortions of the spatiotemporal interrelation pattern and may induce spurious correlations as well as diminish genuine interrelations originally present in the dataset. Here we investigate in which manner correlation patterns are affected by a chosen EEG reference. To this end we evaluate the influence of 7 popular reference schemes on artificial recordings derived from well controlled numerical test frameworks. In this respect we are not only interested in the deformation of spatial interrelations, but we test additionally in which way the time evolution of the functional network, estimated via some bi-variate interrelation measures, gets distorted. It turns out that the median reference as well as the global average show the best performance in most situations considered in the present study. However, if a collective brain dynamics is present, where most of the signals get correlated, these schemes may also cause crucial deformations of the functional network, such that the parallel use of different reference schemes seems advisable.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 12, 2019 12:00 AM.

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    Proceedings of the Sixth Deep Brain Stimulation Think Tank Modulation of Brain Networks and Application of Advanced Neuroimaging, Neurophysiology, and Optogenetics

    The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson’s disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year’s report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on September 12, 2019 12:00 AM.

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    Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment

    Major depressive disorder (MDD) is a common and disabling syndrome with multiple etiologies that is defined by clinically elicited signs and symptoms. In hopes of developing a list of candidate biological measures that reflect and relate closely to the severity of depressive symptoms, so-called “state-dependent” biomarkers of depression, this pilot study explored the biochemical underpinnings of treatment response to cognitive behavior therapy (CBT) in medication-free MDD outpatients. Plasma samples were collected at baseline and week 12 from a subset of MDD patients (N = 26) who completed a course of CBT treatment as part of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. Targeted metabolomic profiling using the AbsoluteIDQ® p180 Kit and LC-MS identified eight “co-expressed” metabolomic modules. Of these eight, three were significantly associated with change in depressive symptoms over the course of the 12-weeks. Metabolites found to be most strongly correlated with change in depressive symptoms were branched chain amino acids, acylcarnitines, methionine sulfoxide, and α-aminoadipic acid (negative correlations with symptom change) as well as several lipids, particularly the phosphatidlylcholines (positive correlation). These results implicate disturbed bioenergetics as an important state marker in the pathobiology of MDD. Exploratory analyses contrasting remitters to CBT versus those who failed the treatment further suggest these metabolites may serve as mediators of recovery during CBT treatment. Larger studies examining metabolomic change patterns in patients treated with pharmacotherapy or psychotherapy will be necessary to elucidate the biological underpinnings of MDD and the -specific biologies of treatment response.

    in Frontiers in Neuroscience | Systems Biology section | New and Recent Articles on September 12, 2019 12:00 AM.

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    Emotion in Chinese Words Could Not Be Extracted in Continuous Flash Suppression

    Previous studies have demonstrated the automatic vigilance effect for faces and pictures and have attributed it to the brain’s prioritized unconscious evaluation of early evolutionary stimuli that are critical to survival. Whether this effect exists for evolutionarily more recent stimuli, such as written words, has become the center of much debate. Apparently contradicting results have been reported in different languages, such as Hebrew, English, and Traditional Chinese (TC), with regard to the unconscious processing of emotional words in breaking continuous flash suppression (b-CFS). Our current study used two experiments (with two-character words or single-character words) to verify whether the emotional valence or the length of Simplified Chinese (SC) words would modulate conscious access in b-CFS. We failed to replicate the findings reported in Yang and Yeh (2011) using TC, but found that complex high-level emotional information could not be extracted from interocularly suppressed words regardless of their length. Our findings comply with the distinction between subliminal and preconscious states in Global Neuronal Workspace Theory and support the current notion that preconsciousness or partial awareness may be indispensable for high-level cognitive tasks such as reading comprehension.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 12, 2019 12:00 AM.

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    How In-Group Bias Influences Source Memory for Words Learned From In-Group and Out-Group Speakers

    Individuals rapidly extract information about others’ social identity, including whether or not they belong to their in-group. Group membership status has been shown to affect how attentively people encode information conveyed by those others. These findings are highly relevant for the field of psycholinguistics where there exists an open debate on how words are represented in the mental lexicon and how abstract or context-specific these representations are. Here, we used a novel word learning paradigm to test our proposal that the group membership status of speakers also affects how speaker-specific representations of novel words are. Participants learned new words from speakers who either attended their own university (in-group speakers) or did not (out-group speakers) and performed a task to measure their individual in-group bias. Then, their source memory of the new words was tested in a recognition test to probe the speaker-specific content of the novel lexical representations and assess how it related to individual in-group biases. We found that speaker group membership and participants’ in-group bias affected participants’ decision biases. The stronger the in-group bias, the more cautious participants were in their decisions. This was particularly applied to in-group related decisions. These findings indicate that social biases can influence recognition threshold. Taking a broader scope, defining how information is represented is a topic of great overlap between the fields of memory and psycholinguistics. Nevertheless, researchers from these fields tend to stay within the theoretical and methodological borders of their own field, missing the chance to deepen their understanding of phenomena that are of common interest. Here, we show how methodologies developed in the memory field can be implemented in language research to shed light on an important theoretical issue that relates to the composition of lexical representations.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 12, 2019 12:00 AM.

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    How Tool-Use Shapes Body Metric Representation: Evidence From Motor Training With and Without Robotic Assistance

    Previous evidence has shown that tool-use can reshape one’s own body schema, extending peripersonal space and modulating the representation of related body parts. Here, we investigated the role of tool action in shaping the body metric representation, by contrasting two different views. According to a first view, the shaping would rely on the mere execution of tool action, while the second view suggests that the shaping induced by tool action on body representation would primarily depend on the representation of the action goals to be accomplished. To this aim, we contrasted a condition in which participants voluntarily accomplish the movement by representing the program and goal of a tool action (i.e., active tool-use training) with a condition in which the tool-use training was produced without any prior goal representation (i.e., passive tool-use training by means of robotic assistance). If the body metric representation primarily depends on the coexistence between goal representation and bodily movements, we would expect an increase of the perceived forearm length in the post- with respect to the pre-training phase after the active training phase only. Healthy participants were asked to estimate the midpoint of their right forearm before and after 20 min of tool-use training. In the active condition, subjects performed “enfold-and-push” movements using a rake to prolong their arm. In the passive condition, subjects were asked to be completely relaxed while the movements were performed with robotic assistance. Results showed a significant increase in the perceived arm length in the post- with respect to the pre-training phase only in the active task. Interestingly, only in the post-training phase, a significant difference was found between active and passive conditions, with a higher perceived arm length in the former than in the latter. From a theoretical perspective, these findings suggest that tool-use may shape body metric representation only when action programs are motorically represented and not merely produced. From a clinical perspective, these results support the use of robots for the rehabilitation of brain-damaged hemiplegic patients, provided that robot assistance during the exercises is present only “as-needed” and that patients’ motor representation is actively involved.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 12, 2019 12:00 AM.

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    Deactivation of ATP-Binding Cassette Transporters ABCB1 and ABCC1 Does Not Influence Post-ischemic Neurological Deficits, Secondary Neurodegeneration and Neurogenesis, but Induces Subtle Microglial Morphological Changes

    ATP-binding cassette (ABC) transporters prevent the access of pharmacological compounds to the ischemic brain, thereby impeding the efficacy of stroke therapies. ABC transporters can be deactivated by selective inhibitors, which potently increase the brain accumulation of drugs. Concerns have been raised that long-term ABC transporter deactivation may promote neuronal degeneration and, under conditions of ischemic stroke, compromise neurological recovery. To elucidate this issue, we exposed male C57BL/6 mice to transient intraluminal middle cerebral artery occlusion (MCAO) and examined the effects of the selective ABCB1 inhibitor tariquidar (8 mg/kg/day) or ABCC1 inhibitor MK-571 (10 mg/kg/day), which were administered alone or in combination with each other over up to 28 days, on neurological recovery and brain injury. Mice were sacrificed after 14, 28, or 56 days. The Clark score, RotaRod, tight rope, and open field tests revealed reproducible motor-coordination deficits in mice exposed to intraluminal MCAO, which were not influenced by ABCB1, ABCC1, or combined ABCB1 and ABCC1 deactivation. Brain volume, striatum volume, and corpus callosum thickness were not altered by ABCB1, ABCC1 or ABCB1, and ABCC1 inhibitors. Similarly, neuronal survival and reactive astrogliosis, evaluated by NeuN and GFAP immunohistochemistry in the ischemic striatum, were unchanged. Iba1 immunohistochemistry revealed no changes of the overall density of activated microglia in the ischemic striatum of ABC transporter inhibitor treated mice, but subtle changes of microglial morphology, that is, reduced microglial cell volume by ABCB1 deactivation after 14 and 28 days and reduced microglial ramification by ABCB1, ABCC1 and combined ABCB1 and ABCC1 deactivation after 56 days. Endogenous neurogenesis, assessed by BrdU incorporation analysis, was not influenced by ABCB1, ABCC1 or combined ABCB1 and ABCC1 deactivation. Taken together, this study could not detect any exacerbation of neurological deficits or brain injury after long-term ABC transporter deactivation in this preclinical stroke model.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 12, 2019 12:00 AM.

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    A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+

    Accumulating evidence suggests that active maintenance of optimal levels of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+) is beneficial in conditions of either increased NAD+ turnover or inadequate synthesis, including Alzheimer’s disease and other neurodegenerative disorders and the aging process. While studies have documented the efficacy of some NAD+ precursors such as nicotinamide riboside (NR) in raising plasma NAD+, no data are currently available on the fate of directly infused NAD+ in a human cohort. This study, therefore, documented changes in plasma and urine levels of NAD+ and its metabolites during and after a 6 h 3 μmol/min NAD+ intravenous (IV) infusion. Surprisingly, no change in plasma (NAD+) or metabolites [nicotinamide, methylnicotinamide, adenosine phosphoribose ribose (ADPR) and nicotinamide mononucleotide (NMN)] were observed until after 2 h. Increased urinary excretion of methylnicotinamide and NAD+ were detected at 6 h, however, no significant rise in urinary nicotinamide was observed. This study revealed for the first time that: (i) at an infusion rate of 3 μmol/min NAD+ is rapidly and completely removed from the plasma for at least the first 2 h; (ii) the profile of metabolites is consistent with NAD+ glycohydrolase and NAD+ pyrophosphatase activity; and (iii) urinary excretion products arising from an NAD+ infusion include NAD+ itself and methyl nicotinamide (meNAM) but not NAM.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 12, 2019 12:00 AM.

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    In vivo Bioluminescence Imaging Used to Monitor Disease Activity and Therapeutic Response in a Mouse Model of Tauopathy

    Many studies of tauopathy use transgenic mice that overexpress the P301S mutant form of tau. Neuronal damage in these mice is associated with astrogliosis and induction of glial fibrillary acidic protein (GFAP) expression. GFAP-luc transgenic mice express firefly luciferase under the GFAP promoter, allowing bioluminescence to be measured non-invasively as a surrogate biomarker for astrogliosis. We bred double transgenic mice possessing both P301S and GFAP-luc cassettes and compared them to control mice bearing only the GFAP-luc transgene. We used serial bioluminescent images to define the onset and the time course of astrogliosis in these mice and this was correlated with the development of clinical deficit. Mice containing both GFAP-luc and P301S transgenes showed increased luminescence indicative of astroglial activation in the brain and spinal cord. Starting at 5 months old, the onset of clinical deterioration in these mice corresponded closely to the initial rise in the luminescent signal. Post mortem analysis showed the elevated luminescence was correlated with hyperphosphorylated tau deposition in the hippocampus of double transgenic mice. We used this method to determine the therapeutic effect of JM4 peptide [a small peptide immunomodulatory agent derived from human erythropoietin (EPO)] on double transgenic mice. JM4 treatment significantly decreased the intensity of luminescence, neurological deficit and hyperphosphorylated tau in mice with both the P301S and GFAP-luc transgenes. These findings indicate that bioluminescence imaging (BLI) is a powerful tool for quantifying GFAP expression in living P301S mice and can be used as a noninvasive biomarker of tau-induced neurodegeneration in preclinical therapeutic trials.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 12, 2019 12:00 AM.

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    Erratum: Caravagna, "Intricate Interplay between Innate Immune Cells and TRMP2 in a Mouse Model of Multiple Sclerosis"

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    An Epilepsy-Associated KCNT1 Mutation Enhances Excitability of Human iPSC-Derived Neurons by Increasing Slack KNa Currents

    Mutations in the KCNT1 (Slack, KNa1.1) sodium-activated potassium channel produce severe epileptic encephalopathies. Expression in heterologous systems has shown that the disease-causing mutations give rise to channels that have increased current amplitude. It is not known, however, whether such gain of function occurs in human neurons, nor whether such increased KNa current is expected to suppress or increase the excitability of cortical neurons. Using genetically engineered human induced pluripotent stem cell (iPSC)-derived neurons, we have now found that sodium-dependent potassium currents are increased several-fold in neurons bearing a homozygous P924L mutation. In current-clamp recordings, the increased KNa current in neurons with the P924L mutation acts to shorten the duration of action potentials and to increase the amplitude of the afterhyperpolarization that follows each action potential. Strikingly, the number of action potentials that were evoked by depolarizing currents as well as maximal firing rates were increased in neurons expressing the mutant channel. In networks of spontaneously active neurons, the mean firing rate, the occurrence of rapid bursts of action potentials, and the intensity of firing during the burst were all increased in neurons with the P924L Slack mutation. The feasibility of an increased KNa current to increase firing rates independent of any compensatory changes was validated by numerical simulations. Our findings indicate that gain-of-function in Slack KNa channels causes hyperexcitability in both isolated neurons and in neural networks and occurs by a cell-autonomous mechanism that does not require network interactions.

    SIGNIFICANCE STATEMENT KCNT1 mutations lead to severe epileptic encephalopathies for which there are no effective treatments. This study is the first demonstration that a KCNT1 mutation increases the Slack current in neurons. It also provides the first explanation for how this increased potassium current induces hyperexcitability, which could be the underlining factor causing seizures.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Reciprocal Predictive Relationships between Amyloid and Tau Biomarkers in Alzheimer's Disease Progression: An Empirical Model

    There is an urgent need to understand the relationships between amyloid-β (Aβ) and tau in the progression of Alzheimer's disease to identify treatment targets. Here we examine reciprocal predictions of brain Aβ burden quantified by positron emission tomography and CSF concentrations of Aβ42 and phosphorylated tau (p-tau). Each biomarker was examined over 48 months in two separate cross-lagged models; one in asymptomatic healthy elderly people (men and women), and one in patients with Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI). The models examine predictions of each biomarker on the progression of the others, considering each previous and concurrent measure. In healthy elderly, lower CSF Aβ42 predicted Aβ deposition and reciprocally, Aβ burden predicted a decrease in CSF Aβ42. Lower CSF Aβ42 predicted an increase in CSF p-tau, and CSF p-tau predicted Aβ deposition. In AD/MCI, lower CSF Aβ42 predicted Aβ deposition and Aβ burden reciprocally predicted CSF Aβ42 changes; however, in contrast to healthy elderly, CSF p-tau concentrations did not predict Aβ biomarkers, or vice versa. In post hoc models examining cognitive status, CSF Aβ42 predicted Mini Mental State Examination (MMSE) scores in healthy elderly, whereas Aβ burden and CSF p-tau predicted MMSE scores in AD/MCI. The findings describe reciprocal predictions between Aβ and tau biomarkers in healthy elderly and they implicate mechanisms underlying low CSF Aβ42 in Alzheimer's disease pathogenesis and progression. In symptomatic Alzheimer's disease, CSF Aβ42 and Aβ deposition predicted each other; however, Aβ and CSF p-tau progressed independently and they independently predicted cognitive decline.

    SIGNIFICANCE STATEMENT This study offers empirical evidence concerning the hypothesized "amyloid cascade", as it progressed over 4 years in healthy elderly people and in Alzheimer's disease patients. In healthy elderly, CSF amyloid changes predicted amyloid deposition, CSF phosphorylated tau concentrations, and a decline in cognitive status. Phosphorylated tau concentrations specifically predicted amyloid deposition. In Alzheimer's disease patients, although amyloid deposition and CSF amyloid changes continued to "cascade", there was no evidence to suggest that amyloid and tau biomarkers predicted each other, although both amyloid deposition and CSF tau progression predicted cognitive decline independently. Taking advantage of repeated amyloid PET and CSF measures, this dynamic view offers new insight into the progression of Alzheimer's disease biomarkers and their relationships with cognitive decline.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Differential Signaling Mediated by ApoE2, ApoE3, and ApoE4 in Human Neurons Parallels Alzheimer's Disease Risk

    In blood, apolipoprotein E (ApoE) is a component of circulating lipoproteins and mediates the clearance of these lipoproteins from blood by binding to ApoE receptors. Humans express three genetic ApoE variants, ApoE2, ApoE3, and ApoE4, which exhibit distinct ApoE receptor-binding properties and differentially affect Alzheimer's disease (AD), such that ApoE2 protects against, and ApoE4 predisposes to AD. In brain, ApoE-containing lipoproteins are secreted by activated astrocytes and microglia, but their functions and role in AD pathogenesis are largely unknown. Ample evidence suggests that ApoE4 induces microglial dysregulation and impedes Aβ clearance in AD, but the direct neuronal effects of ApoE variants are poorly studied. Extending previous studies, we here demonstrate that the three ApoE variants differentially activate multiple neuronal signaling pathways and regulate synaptogenesis. Specifically, using human neurons (male embryonic stem cell-derived) cultured in the absence of glia to exclude indirect glial mechanisms, we show that ApoE broadly stimulates signal transduction cascades. Among others, such stimulation enhances APP synthesis and synapse formation with an ApoE4>ApoE3>ApoE2 potency rank order, paralleling the relative risk for AD conferred by these ApoE variants. Unlike the previously described induction of APP transcription, however, ApoE-induced synaptogenesis involves CREB activation rather than cFos activation. We thus propose that in brain, ApoE acts as a glia-secreted signal that activates neuronal signaling pathways. The parallel potency rank order of ApoE4>ApoE3>ApoE2 in AD risk and neuronal signaling suggests that ApoE4 may in an apparent paradox promote AD pathogenesis by causing a chronic increase in signaling, possibly via enhancing APP expression.

    SIGNIFICANCE STATEMENT Humans express three genetic variants of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4. ApoE4 constitutes the most important genetic risk factor for Alzheimer's disease (AD), whereas ApoE2 protects against AD. Significant evidence suggests that ApoE4 impairs microglial function and impedes astrocytic Aβ clearance in brain, but the direct neuronal effects of ApoE are poorly understood, and the differences between ApoE variants in these effects are unclear. Here, we report that ApoE acts on neurons as a glia-secreted signaling molecule that, among others, enhances synapse formation. In activating neuronal signaling, the three ApoE variants exhibit a differential potency of ApoE4>ApoE3>ApoE2, which mirrors their relative effects on AD risk, suggesting that differential signaling by ApoE variants may contribute to AD pathogenesis.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Separate vmPFC Ensembles Control Cocaine Self-Administration Versus Extinction in Rats

    Recent studies suggest that the ventral medial prefrontal cortex (vmPFC) encodes both operant drug self-administration and extinction memories. Here, we examined whether these opposing memories are encoded by distinct neuronal ensembles within the vmPFC with different outputs to the nucleus accumbens (NAc) in male and female rats. Using cocaine self-administration (3 h/d for 14 d) and extinction procedures, we demonstrated that vmPFC was similarly activated (indexed by Fos) during cocaine-seeking tests after 0 (no-extinction) or 7 extinction sessions. Selective Daun02 lesioning of the self-administration ensemble (no-extinction) decreased cocaine seeking, whereas Daun02 lesioning of the extinction ensemble increased cocaine seeking. Retrograde tracing with fluorescent cholera toxin subunit B injected into NAc combined with Fos colabeling in vmPFC indicated that vmPFC self-administration ensembles project to NAc core while extinction ensembles project to NAc shell. Functional disconnection experiments (Daun02 lesioning of vmPFC and acute dopamine D1-receptor blockade with SCH39166 in NAc core or shell) confirm that vmPFC ensembles interact with NAc core versus shell to play dissociable roles in cocaine self-administration versus extinction, respectively. Our results demonstrate that neuronal ensembles mediating cocaine self-administration and extinction comingle in vmPFC but have distinct outputs to the NAc core and shell that promote or inhibit cocaine seeking.

    SIGNIFICANCE STATEMENT Neuronal ensembles within the vmPFC have recently been shown to play a role in self-administration and extinction of food seeking. Here, we used the Daun02 chemogenetic inactivation procedure, which allows selective inhibition of neuronal ensembles identified by the activity marker Fos, to demonstrate that different ensembles for cocaine self-administration and extinction memories coexist in the ventral mPFC and interact with distinct subregions of the nucleus accumbens.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Circular RNA TLK1 Aggravates Neuronal Injury and Neurological Deficits after Ischemic Stroke via miR-335-3p/TIPARP

    Circular RNAs (circRNAs) are expressed at high levels in the brain and are involved in various CNS diseases. However, the potential role of circRNAs in ischemic stroke-associated neuronal injury remains largely unknown. Here, we investigated the important functions of circRNA TLK1 (circTLK1) in this process. The levels of circTLK1 were significantly increased in brain tissues in a mouse model of focal cerebral ischemia and reperfusion. Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficits. Furthermore, circTLK1 functioned as an endogenous miR-335-3p sponge to inhibit miR-335-3p activity, resulting in the increase of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible poly (ADP-ribose) polymerase expression and a subsequent exacerbation of neuronal injury. Clinical studies confirmed increased levels of circTLK1 in the plasma of patients with acute ischemic stroke (59 males and 12 females). Our findings reveal a detrimental role of circTLK1 in ischemic brain injury.

    SIGNIFICANCE STATEMENT The extent of neuronal injury after brain ischemia is a primary factor determining stroke outcomes. However, the molecular switches that control the death of ischemic neurons are poorly understood. While our previous studies indicated the involvement of circRNAs in ischemic stroke, the potential role of circRNAs in neuronal injury remains largely unknown. The levels of circTLK1 were significantly increased in the brain tissue and plasma isolated from animal models of ischemic stroke and patients. Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved subsequent long-term neurological deficits. To our knowledge, these results provide the first definitive evidence that circTLK1 is detrimental in ischemic stroke.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    The Conditions under Which Consolidation of Serial-Order Conditioned Fear Requires De Novo Protein Synthesis in the Basolateral Amygdala Complex

    Consolidation of conditioned fear to a stimulus (S1) paired with shock requires de novo protein synthesis in the basolateral amygdala complex (BLA), whereas consolidation of conditioned fear to a stimulus (S2) paired with the fear-eliciting S1 requires DNA methylation but not de novo protein synthesis in the BLA. The present experiments merged these protocols by exposing rats to pairings of a serial S2-S1 compound and shock to examine if/when protein synthesis in the BLA is required to consolidate fear to S2. Rats received a BLA infusion of the protein synthesis inhibitor, cycloheximide, immediately after the S2-S1-shock session and were subsequently tested with S2. The infusion disrupted consolidation of fear to S2 when there had been no prior training of S1 (Experiment 1), the prior training had consisted of unpaired presentations of S1 and shock (Experiment 4), or in pairings of S1 and sucrose (Experiment 5). Consolidation of fear to S2 was unaffected by the infusion of cycloheximide but was disrupted by the DNA methyltransferase inhibitor, 5-AZA, when S1 had been previously fear-conditioned (Experiments 2a, 2b, and 3). These findings imply that what has already been learned about S1 determines the BLA processes that consolidate fear to S2. The already-fear-conditioned S1 blocks the S2-shock association that otherwise forms (and whose consolidation requires de novo protein synthesis in the BLA) while simultaneously acting as a learned source of danger for its S2 associate (whose consolidation requires DNA methylation but not de novo protein synthesis in the BLA).

    SIGNIFICANCE STATEMENT Protein synthesis is widely thought to be crucial for consolidating new learning into stable memories, including the consolidation of conditioned fear memories in the basolateral amygdala complex (BLA). However, our data provide clear evidence that the requirement for protein synthesis to consolidate conditioned fear in the BLA depends on an animal's previous training history, and the type of learning that is consolidated. Further, within the BLA, our data show that DNA methylation, and not protein synthesis, is necessary to consolidate higher-order conditioned fear, indicating that epigenetic mechanisms may provide a more fundamental mnemonic substrate.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Relating Divisive Normalization to Neuronal Response Variability

    Cortical responses to repeated presentations of a sensory stimulus are variable. This variability is sensitive to several stimulus dimensions, suggesting that it may carry useful information beyond the average firing rate. Many experimental manipulations that affect response variability are also known to engage divisive normalization, a widespread operation that describes neuronal activity as the ratio of a numerator (representing the excitatory stimulus drive) and denominator (the normalization signal). Although it has been suggested that normalization affects response variability, we lack a quantitative framework to determine the relation between the two. Here we extend the standard normalization model, by treating the numerator and the normalization signal as variable quantities. The resulting model predicts a general stabilizing effect of normalization on neuronal responses, and allows us to infer the single-trial normalization strength, a quantity that cannot be measured directly. We test the model on neuronal responses to stimuli of varying contrast, recorded in primary visual cortex of male macaques. We find that neurons that are more strongly normalized fire more reliably, and response variability and pairwise noise correlations are reduced during trials in which normalization is inferred to be strong. Our results thus suggest a novel functional role for normalization, namely, modulating response variability. Our framework could enable a direct quantification of the impact of single-trial normalization strength on the accuracy of perceptual judgments, and can be readily applied to other sensory and nonsensory factors.

    SIGNIFICANCE STATEMENT Divisive normalization is a widespread neural operation across sensory and nonsensory brain areas, which describes neuronal responses as the ratio between the excitatory drive to the neuron and a normalization signal. Normalization plays a key role in several important computations, including adjusting the neuron's dynamic range, reducing redundancy, and facilitating probabilistic inference. However, the relation between normalization and neuronal response variability (a fundamental aspect of neural coding) remains unclear. Here we develop a new model and test it on primary visual cortex responses. We show that normalization has a stabilizing effect on neuronal activity, beyond the known suppression of firing rate. This modulation of variability suggests a new functional role for normalization in neural coding and perception.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Functional Architecture and Encoding of Tactile Sensorimotor Behavior in Rat Posterior Parietal Cortex

    The posterior parietal cortex (PPC) in rodents is reciprocally connected to primary somatosensory and vibrissal motor cortices. The PPC neuronal circuitry could thus encode and potentially integrate incoming somatosensory information and whisker motor output. However, the information encoded across PPC layers during refined sensorimotor behavior remains largely unknown. To uncover the sensorimotor features represented in PPC during voluntary whisking and object touch, we performed loose-patch single-unit recordings and extracellular recordings of ensemble activity, covering all layers of PPC in anesthetized and awake, behaving male rats. First, using single-cell receptive field mapping, we revealed the presence of coarse somatotopy along the mediolateral axis in PPC. Second, we found that spiking activity was modulated during exploratory whisking in layers 2–4 and layer 6, but not in layer 5 of awake, behaving rats. Population spiking activity preceded actual movement, and whisker trajectory endpoints could be decoded by population spiking, suggesting that PPC is involved in movement planning. Finally, population spiking activity further increased in response to active whisker touch but only in PPC layers 2–4. Thus, we find layer-specific processing, which emphasizes the computational role of PPC during whisker sensorimotor behavior.

    SIGNIFICANCE STATEMENT The posterior parietal cortex (PPC) is thought to merge information on motor output and sensory input to orchestrate interaction with the environment, but the function of different PPC microcircuit components is poorly understood. We recorded neuronal activity in rat PPC during sensorimotor behavior involving motor and sensory pathways. We uncovered that PPC layers have dedicated function: motor and sensory information is merged in layers 2–4; layer 6 predominantly represents motor information. Collectively, PPC activity predicts future motor output, thus entailing a motor plan. Our results are important for understanding how PPC computationally processes motor output and sensory input. This understanding may facilitate decoding of brain activity when using brain–machine interfaces to overcome loss of function after, for instance, spinal cord injury.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Sensorimotor Cortical Oscillations during Movement Preparation in 16p11.2 Deletion Carriers

    Sensorimotor deficits are prevalent in many neurodevelopmental disorders like autism, including one of its common genetic etiologies, a 600 kb reciprocal deletion/duplication at 16p11.2. We have previously shown that copy number variations of 16p11.2 impact regional brain volume, white matter integrity, and early sensory responses in auditory cortex. Here, we test the hypothesis that abnormal cortical neurophysiology is present when genes in the 16p11.2 region are haploinsufficient, and in humans that this in turn may account for behavioral deficits specific to deletion carriers. We examine sensorimotor cortical network activity in males and females with 16p11.2 deletions compared with both typically developing individuals, and those with duplications of 16p11.2, using magnetoencephalographic imaging during preparation of overt speech or hand movements in tasks designed to be easy for all participants. In deletion carriers, modulation of beta oscillations (12–30 Hz) were increased during both movement types over effector-specific regions of motor cortices compared with typically developing individuals or duplication carriers, with no task-related performance differences between cohorts, even when corrected for their own cognitive and sensorimotor deficits. Reduced left hemispheric language specialization was observed in deletion carriers but not in duplication carriers. Neural activity over sensorimotor cortices in deletion carriers was linearly related to clinical measures of speech and motor impairment. These findings link insufficient copy number repeats at 16p11.2 to excessive neural activity (e.g., increased beta oscillations) in motor cortical networks for speech and hand motor control. These results have significant implications for understanding the neural basis of autism and related neurodevelopmental disorders.

    SIGNIFICANCE STATEMENT The recurrent ~600 kb deletion at 16p11.2 (BP4–BP5) is one of the most common genetic etiologies of ASD and, more generally, of neurodevelopmental disorders. Here, we use high-resolution magnetoencephalographic imaging (MEG-I) to define with millisecond precision the underlying neurophysiological signature of motor impairments for individuals with 16p11.2 deletions. We identify significant increases in beta (12–30 Hz) suppression in sensorimotor cortices related to performance during speech and hand movement tasks. These findings not only provide a neurophysiological phenotype for the clinical presentation of this genetic deletion, but also guide our understanding of how genetic variation encodes for neural oscillatory dynamics.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Dynamic Interaction between Cortico-Brainstem Pathways during Training-Induced Recovery in Stroke Model Rats

    Reorganization of residual descending motor circuits underlies poststroke recovery. We previously clarified a causal relationship between the cortico-rubral tract and intensive limb use-induced functional recovery after internal capsule hemorrhage (ICH). However, other descending tracts, such as the cortico-reticular tract, might also be involved in rehabilitation-induced compensation. To investigate whether rehabilitation-induced recovery after ICH involves a shift in the compensatory circuit from the cortico-rubral tract to the cortico-reticular tract, we established loss of function of the cortico-rubral tract or/and cortico-reticular tract using two sets of viral vectors comprising the Tet-on system and designer receptors exclusively activated by the designer drug system. We used an ICH model that destroyed almost 60% of the corticofugal fibers. Anterograde tracing in rehabilitated rats revealed abundant sprouting of axons from the motor cortex in the red nucleus but not in the medullary reticular formation during the early phase of recovery. This primary contribution of the cortico-rubral tract was demonstrated by its selective blockade, whereas selective cortico-reticular tract silencing had little effect. Interestingly, cortico-rubral tract blockade from the start of rehabilitation induced an obvious increase of axon sprouting in the reticular formation with substantial functional recovery. Additional cortico-reticular tract silencing under the cortico-rubral tract blockade significantly worsened the recovered forelimb function. Furthermore, the alternative recruitment of the cortico-reticular tract was gradually induced by intensive limb use under cortico-rubral tract blockade, in which cortico-reticular tract silencing caused an apparent motor deficit. These findings indicate that individual cortico-brainstem pathways have dynamic compensatory potency to support rehabilitative functional recovery after ICH.

    SIGNIFICANCE STATEMENT This study aimed to clarify the interaction between the cortico-rubral and the cortico-reticular tract during intensive rehabilitation and functional recovery after capsular stroke. Pathway-selective disturbance by two sets of viral vectors revealed that the cortico-rubral tract was involved in rehabilitation-induced recovery of forelimb function from an early phase after internal capsule hemorrhage, but that the cortico-reticular tract was not. The sequential disturbance of both tracts revealed that the cortico-reticular tract was recruited and involved in rehabilitation-induced recovery when the cortico-rubral tract failed to function. Our data demonstrate a dynamic compensatory action of individual cortico-brainstem pathways for recovery through poststroke rehabilitation.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Akt Phosphorylates NQO1 and Triggers its Degradation, Abolishing Its Antioxidative Activities in Parkinson's Disease

    The oxidative metabolism of dopamine and consequent oxidative stress are implicated in dopaminergic neuronal loss, mediating the pathogenesis of Parkinson's disease (PD). The inducible detoxifying antioxidative enzyme Quinone oxidoreductase (NQO1) (NAD(P)H: quinone oxidoreductase 1), neuroprotective to counteract reactive oxidative species, is most prominent in the active stage of the disease and virtually absent at the end stage of the disease. However, the molecular mechanism dictating NQO1 expression oscillation remains unclear. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase. Unphosphorylatable NQO1 mutant displays more robust neuroprotective activity than WT NQO1 in suppressing reactive oxidative species and against MPTP-induced dopaminergic cell death, rescuing the motor disorders in both α-synuclein transgenic transgenic male and female mice elicited by the neurotoxin. Thus, our findings demonstrate that blockade of Akt-mediated NQO1 degradation may ameliorate PD pathogenesis.

    SIGNIFICANCE STATEMENT Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with the imbalance of oxidative metabolism of dopamine. Quinone oxidoreductase (NQO1), a potent antioxidant system, its expression levels are prominently increased in the early and intermediate stages of PD and disappeared in the end-stage PD. The molecular modification behavior of NQO1 after it is upregulated by oxidative stress in the early stage of PD, however, remains unclear. This study shows that Akt binds and phosphorylates NQO1 at T128 residue and promotes its ubiquitination and degradation, and Parkin acts as an E3 ligase in this process, which affects the antioxidant capacity of NQO1. This finding provides a novel molecular mechanism for NQO1 oscillation in PD pathogenesis.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Distinct Properties of Layer 3 Pyramidal Neurons from Prefrontal and Parietal Areas of the Monkey Neocortex

    In primates, working memory function depends on activity in a distributed network of cortical areas that display different patterns of delay task-related activity. These differences are correlated with, and might depend on, distinctive properties of the neurons located in each area. For example, layer 3 pyramidal neurons (L3PNs) differ significantly between primary visual and dorsolateral prefrontal (DLPFC) cortices. However, to what extent L3PNs differ between DLPFC and other association cortical areas is less clear. Hence, we compared the properties of L3PNs in monkey DLPFC versus posterior parietal cortex (PPC), a key node in the cortical working memory network. Using patch-clamp recordings and biocytin cell filling in acute brain slices, we assessed the physiology and morphology of L3PNs from monkey DLPFC and PPC. The L3PN transcriptome was studied using laser microdissection combined with DNA microarray or quantitative PCR. We found that in both DLPFC and PPC, L3PNs were divided into regular spiking (RS-L3PNs) and bursting (B-L3PNs) physiological subtypes. Whereas regional differences in single-cell excitability were modest, B-L3PNs were rare in PPC (RS-L3PN:B-L3PN, 94:6), but were abundant in DLPFC (50:50), showing greater physiological diversity. Moreover, DLPFC L3PNs display larger and more complex basal dendrites with higher dendritic spine density. Additionally, we found differential expression of hundreds of genes, suggesting a transcriptional basis for the differences in L3PN phenotype between DLPFC and PPC. These data show that the previously observed differences between DLPFC and PPC neuron activity during working memory tasks are associated with diversity in the cellular/molecular properties of L3PNs.

    SIGNIFICANCE STATEMENT In the human and nonhuman primate neocortex, layer 3 pyramidal neurons (L3PNs) differ significantly between dorsolateral prefrontal (DLPFC) and sensory areas. Hence, L3PN properties reflect, and may contribute to, a greater complexity of computations performed in DLPFC. However, across association cortical areas, L3PN properties are largely unexplored. We studied the physiology, dendrite morphology and transcriptome of L3PNs from macaque monkey DLPFC and posterior parietal cortex (PPC), two key nodes in the cortical working memory network. L3PNs from DLPFC had greater diversity of physiological properties and larger basal dendrites with higher spine density. Moreover, transcriptome analysis suggested a molecular basis for the differences in the physiological and morphological phenotypes of L3PNs from DLPFC and PPC.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    How to Build a Fast and Highly Sensitive Sound Detector That Remains Robust to Temperature Shifts

    Frogs must have sharp hearing abilities during the warm summer months to successfully find mating partners. This study aims to understand how frog hair cell ribbon-type synapses preserve both sensitivity and temporal precision during temperature changes. Under room (~24°C) and high (~32°C) temperature, we performed in vitro patch-clamp recordings of hair cells and their afferent fibers in amphibian papillae of either male or female bullfrogs. Afferent fibers exhibited a wide heterogeneity in membrane input resistance (Rin) from 100 m to 1000 m, which may contribute to variations in spike threshold and firing frequency. At higher temperatures, most fibers increased their frequency of spike firing due to an increase in spontaneous EPSC frequencies. Hair cell resting membrane potential (Vrest) remained surprisingly stable during temperature increases, because Ca2+ influx and K+ outflux increased simultaneously. This increase in Ca2+ current likely enhanced spontaneous EPSC frequencies. These larger "leak currents" at Vrest also lowered Rin and produced higher electrical resonant frequencies. Lowering Rin will reduce the hair cells receptor potential and presumably moderate the systems sensitivity. Using membrane capacitance measurements, we suggest that hair cells can partially compensate for this reduced sensitivity by increasing exocytosis efficiency and the size of the readily releasable pool of synaptic vesicles. Furthermore, paired recordings of hair cells and their afferent fibers showed that synaptic delays shortened and multivesicular release becomes more synchronous at higher temperatures, which should improve temporal precision. Together, our results explain many previous in vivo observations on the temperature dependence of spikes in auditory nerves.

    SIGNIFICANCE STATEMENT The vertebrate inner ear detects and transmits auditory information over a broad dynamic range of sound frequency and intensity. It achieves remarkable sensitivity to soft sounds and precise frequency selectivity. How does the ear of cold-blooded vertebrates maintain its performance level as temperature changes? More specifically, how does the hair cell to afferent fiber synapse in bullfrog amphibian papilla adjust to a wide range of physiological temperatures without losing its sensitivity and temporal fidelity to sound signals? This study uses in vitro experiments to reveal the biophysical mechanisms that explain many observations made from in vivo auditory nerve fiber recordings. We find that higher temperature facilitates vesicle exocytosis and electrical tuning to higher sound frequencies, which benefits sensitivity and selectivity.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Early Life Inflammation Increases CA1 Pyramidal Neuron Excitability in a Sex and Age Dependent Manner through a Chloride Homeostasis Disruption

    Early life, systemic inflammation causes long-lasting changes in behavior. To unmask possible mechanisms associated with this phenomenon, we asked whether the intrinsic membrane properties in hippocampal neurons were altered as a consequence of early life inflammation. C57BL/6 mice were bred in-house and both male and female pups from multiple litters were injected with lipopolysaccharide (LPS; 100 μg/kg, i.p.) or vehicle at postnatal day (P)14, and kept until adolescence (P35–P45) or adulthood (P60–P70), when brain slices were prepared for whole-cell and perforated-patch recordings from CA1 hippocampal pyramidal neurons. In neurons of adult male mice pretreated with LPS, the number of action potentials elicited by depolarizing current pulses was significantly increased compared with control neurons, concomitant with increased input resistance, and a lower action potential threshold. Although these changes were not associated with changes in relevant sodium channel expression or differences in capacitance or dendritic architecture, they were linked to a mechanism involving intracellular chloride overload, revealed through a depolarized GABA reversal potential and increased expression of the chloride transporter, NKCC1. In contrast, no significant changes were observed in neurons of adult female mice pretreated with LPS, nor in adolescent mice of either sex. These data uncover a potential mechanism involving neonatal inflammation-induced plasticity in chloride homeostasis, which may contribute to early life inflammation-induced behavioral alterations.

    SIGNIFICANCE STATEMENT Early life inflammation results in long-lasting changes in many aspects of adult physiology. In this paper we reveal that a brief exposure to early life peripheral inflammation with LPS increases excitability in hippocampal neurons in a sex- and age-dependent manner through a chloride homeostasis disruption. As this hyperexcitability was only seen in adult males, and not in adult females or adolescent animals of either sex, it raises the possibility of a hormonal interaction with early life inflammation. Furthermore, as neonatal inflammation is a normal feature of early life in most animals, as well as humans, these findings may be very important for the development of animal models of disease that more appropriately resemble the human condition.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Gender in Science, Technology, Engineering, and Mathematics: Issues, Causes, Solutions

    The landscape of gender in education and the workforce has shifted over the past decades: women have made gains in representation, equitable pay, and recognition through awards, grants, and publications. Despite overall change, differences persist in the fields of science, technology, engineering, and mathematics (STEM). This Viewpoints article on gender disparities in STEM offers an overarching perspective by addressing what the issues are, why the issues may emerge, and how the issues may be solved. In Part 1, recent data on gaps in representation, compensation, and recognition (awards, grants, publications) are reviewed, highlighting differences across subfields (e.g., computer science vs biology) and across career trajectories (e.g., bachelor's degrees vs senior faculty). In Part 2, evidence on leading explanations for these gaps, including explanations centered on abilities, preferences, and explicit and implicit bias, is presented. Particular attention is paid to implicit bias: mental processes that exist largely outside of conscious awareness and control in both male and female perceivers and female targets themselves. Given its prevalence and persistence, implicit bias warrants a central focus for research and application. Finally, in Part 3, the current knowledge is presented on interventions to change individuals' beliefs and behaviors, as well as organizational culture and practices. The moral issues surrounding equal access aside, understanding and addressing the complex issues surrounding gender in STEM are important because of the possible benefits to STEM and society that will be realized only when full participation of all capable and qualified individuals is guaranteed.

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    This Week in The Journal

    in Journal of Neuroscience current issue on September 11, 2019 04:30 PM.

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    Chemogenetic silencing of prelimbic cortex to anterior dorsomedial striatum projection attenuates operant responding

    Abstract

    Operant (instrumental) conditioning is a laboratory analog for voluntary behavior and involves learning to make a response for a reinforcing outcome. The prelimbic cortex (PL), a region of the rodent medial prefrontal cortex, and the dorsomedial striatum (DMS), have been separately established as important in the acquisition of minimally-trained operant behavior. Despite dense anatomical connections between the two regions, experimenters have only recently linked projections from the PL to the posterior DMS in the acquisition of an operant response. Yet, it is still unknown if these projections mediate behavioral expression, and if more anterior regions of the DMS (aDMS), which receive dense projections from the PL, are also involved. Therefore, we utilized designer receptors exclusively activated by designer drugs (DREADDs) to test whether or not projections from the PL to the anterior DMS influence the expression of operant behavior. Rats underwent bilateral PL-targeted infusions of either a DREADD virus (AAV8-hSyn-hM4D(Gi)-mCherry) or a control virus (AAV8-hSyn-GFP). In addition, guide cannulae were implanted bilaterally in the aDMS. Rats were tested with both CNO (DREADD ligand) and vehicle infusions into the aDMS. Animals that had received the DREADD virus, but not the control virus, showed attenuated responding when they received CNO microinfusions into the aDMS, compared to vehicle infusions. Patch clamp electrophysiology verified the inhibitory effect of CNO on DREADDs-expressing PL neurons in acute brain slices. GFP-expressing control PL neurons were unaffected by CNO. The results add to the recent literature suggesting that connections between the PL and aDMS are important for the expression of minimally-trained operant responding.

    Significance statement Only very recently has it been shown that prelimbic cortex projections to the posterior dorsomedial striatum are important in the acquisition of operant responding. Here, we show that prelimbic cortex projections to the anterior dorsomedial striatum are important in the expression of operant responding.

    in RSS PAP on September 11, 2019 04:30 PM.

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    Lasting Effects of Low-Frequency Repetitive Transcranial Magnetic Stimulation in Writer’s Cramp: a Case Report

    The treatment of writer’s cramp (W’sC) is essentially based on the use of botulinum toxin. However, additional treatments are sometime required to prolong the effects of the toxin, compensate for its progressive loss of efficacy in some subjects, and re-educate handwriting (e.g., rehabilitation strategies). Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been employed to improve W’sC, but with short-lasting and controversial outcomes. We report on the effects of a long-lasting low-frequency rTMS paradigm on W’sC symptoms. A 25 year-old male with a diagnosis of simple W’sC was enrolled in the study. He underwent an objective assessment using the Writer's Cramp Rating Scale and the 1-minute writing test. Further, we recorded muscle activation of the upper limb during handwriting using an EMG wireless system. The patient was provided with 1200 biphasic magnetic pulses delivered at 1 Hz over the left premotor cortex (PMC), 15 times scheduled every two days, thus covering a period of 5 weeks, followed by 10 days of rest. This block of stimulations was practiced other four times, for a period of six months. The patient showed a gradual clinical improvement with the progression of the treatments. W’sC symptoms totally disappeared and all the clinical scores showed a significant improvement after rTMS completion. Such improvement lasted up to one year after the end of the treatment. Moreover, we detected a long-lasting improvement in sensorimotor plasticity as measured by a paired associative stimulation protocol. Our case suggests that the long-lasting application of 1Hz rTMS to PMC is a safe and potentially valuable tool to improve W’sC symptoms enduringly, probably by reverting maladaptive plasticity mechanisms within the sensory-motor areas of the hemisphere contralateral to the dystonic hand.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 11, 2019 05:42 AM.

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    Publisher Correction: Mechanisms of systems memory consolidation during sleep

    Nature Neuroscience, Published online: 11 September 2019; doi:10.1038/s41593-019-0507-z

    Publisher Correction: Mechanisms of systems memory consolidation during sleep

    in Nature Neuroscience - Issue - nature.com science feeds on September 11, 2019 12:00 AM.

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    Reprogramming astrocytes for repair

    Nature Reviews Neuroscience, Published online: 11 September 2019; doi:10.1038/s41583-019-0227-0

    Reprogramming astrocytes for repair

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on September 11, 2019 12:00 AM.

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    Accelerating reconstruction

    Nature Reviews Neuroscience, Published online: 11 September 2019; doi:10.1038/s41583-019-0226-1

    Accelerating reconstruction

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on September 11, 2019 12:00 AM.

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    A platform for coordinated signalling

    Nature Reviews Neuroscience, Published online: 11 September 2019; doi:10.1038/s41583-019-0225-2

    A platform for coordinated signalling

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on September 11, 2019 12:00 AM.

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    Aversive adaptations

    Nature Reviews Neuroscience, Published online: 11 September 2019; doi:10.1038/s41583-019-0224-3

    Aversive adaptations

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on September 11, 2019 12:00 AM.

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    Resilient networking

    Nature Reviews Neuroscience, Published online: 11 September 2019; doi:10.1038/s41583-019-0219-0

    In mice, CREB–Zfp189 interactions in the prefrontal cortex drive a transcriptional network that increases resilience to chronic social defeat stress.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on September 11, 2019 12:00 AM.

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    Climbing Fibers Provide Graded Error Signals in Cerebellar Learning

    The cerebellum plays a critical role in coordinating and learning complex movements. Although its importance has been well recognized, the mechanisms of learning remain hotly debated. According to the classical cerebellar learning theory, depression of parallel fiber synapses instructed by error signals from climbing fibers, drives cerebellar learning. The uniqueness of long-term depression (LTD) in cerebellar learning has been challenged by evidence showing multi-site synaptic plasticity. In Purkinje cells, long-term potentiation (LTP) of parallel fiber synapses is now well established and it can be achieved with or without climbing fiber signals, making the role of climbing fiber input more puzzling. The central question is how individual Purkinje cells extract global errors based on climbing fiber input. Previous data seemed to demonstrate that climbing fibers are inefficient instructors, because they were thought to carry “binary” error signals to individual Purkinje cells, which significantly constrains the efficiency of cerebellar learning in several regards. In recent years, new evidence has challenged the traditional view of “binary” climbing fiber responses, suggesting that climbing fibers can provide graded information to efficiently instruct individual Purkinje cells to learn. Here we review recent experimental and theoretical progress regarding modulated climbing fiber responses in Purkinje cells. Analog error signals are generated by the interaction of varying climbing fibers inputs with simultaneous other synaptic input and with firing states of targeted Purkinje cells. Accordingly, the calcium signals which trigger synaptic plasticity can be graded in both amplitude and spatial range to affect the learning rate and even learning direction. We briefly discuss how these new findings complement the learning theory and help to further our understanding of how the cerebellum works.

    in Frontiers in Systems Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    T Cells as an Emerging Target for Chronic Pain Therapy

    The immune system is critically involved in the development and maintenance of chronic pain. However, T cells, one of the main regulators of the immune response, have only recently become a focus of investigations on chronic pain pathophysiology. Emerging clinical data suggest that patients with chronic pain have a different phenotypic profile of circulating T cells compared to controls. At the preclinical level, findings on the function of T cells are mixed and differ between nerve injury, chemotherapy, and inflammatory models of persistent pain. Depending on the type of injury, the subset of T cells and the sex of the animal, T cells may contribute to the onset and/or the resolution of pain, underlining T cells as a major player in the transition from acute to chronic pain. Specific T cell subsets release mediators such as cytokines and endogenous opioid peptides that can promote, suppress, or even resolve pain. Inhibiting the pain-promoting functions of T cells and/or enhancing the beneficial effects of pro-resolution T cells may offer new disease-modifying strategies for the treatment of chronic pain, a critical need in view of the current opioid crisis.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    Generation and Characterization of Induced Pluripotent Stem Cells and Retinal Organoids From a Leber’s Congenital Amaurosis Patient With Novel RPE65 Mutations

    RPE65-associated Leber congenital amaurosis (LCA) is one of highly heterogeneous, early onset, severe retinal dystrophies with at least 130 gene mutation sites identified. Their pathogenicity has not been directly clarified due to lack of diseased cells. Here, we generated human-induced pluripotent stem cells (hiPSCs) from one putative LCA patient carrying two novel RPE65 mutations with c.200T>G (p.L67R) and c.430T>C (p.Y144H), named RPE65-hiPSCs, which were confirmed to contain the same mutations. The RPE65-hiPSCs presented typical morphological features with normal karyotype, expressed pluripotency markers, and developed teratoma in NOD-SCID mice. Moreover, the patient hiPSCs were able to differentiate toward retinal lineage fate and self-form retinal organoids with layered neural retina. All major retinal cell types including photoreceptor and retinal pigment epithelium (RPE) cells were also acquired overtime. Compared to healthy control, RPE cells from patient iPSCs had lower expression of RPE65, but similar phagocytic activity and VEGF secretion level. This study provided the valuable patient specific, disease targeted retinal organoids containing photoreceptor and RPE cells, which would facilitate the study of personalized pathogenic mechanisms of disease, drug screening, and cell replacement therapy.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    Semantic Incongruency Interferes With Endogenous Attention in Cross-Modal Integration of Semantically Congruent Objects

    Efficient multisensory integration is often influenced by other cognitive processes including, but not limited to, semantic congruency and focused endogenous attention. Semantic congruency can re-allocate processing resources to the location of a congruent stimulus, while attention can prioritize the integration of multi-sensory stimuli under focus. Here, we explore the robustness of this phenomenon in the context of three stimuli, two of which are in the focus of endogenous attention. Participants completed an endogenous attention task with a stimulus compound consisting of 3 different objects: (1) a visual object (V) in the foreground, (2) an auditory object (A), and (3) a visual background scene object (B). Three groups of participants focused their attention on either the visual object and auditory sound (Group VA, n = 30), the visual object and the background (VB, n = 27), or the auditory sound and the background (AB, n = 30), and judged the semantic congruency of the objects under focus. Congruency varied systematically across all 3 stimuli: All stimuli could be semantically incongruent (e.g., V, ambulance; A, church bell; and B, swimming-pool) or all could be congruent (e.g., V, lion; A, roar; and B, savannah), or two objects could be congruent with the remaining one incongruent to the other two (e.g., V, duck; A, quack; and B, phone booth). Participants exhibited a distinct pattern of errors: when participants attended two congruent objects (e.g., group VA: V, lion; A, roar), in the presence of an unattended, incongruent third object (e.g., B, bath room) they tended to make more errors than in any other stimulus combination. Drift diffusion modeling of the behavioral data revealed a significantly smaller drift rate in two-congruent-attended condition, indicating slower evidence accumulation, which was likely due to interference from the unattended, incongruent object. Interference with evidence accumulation occurred independently of which pair of objects was in the focus of attention, which suggests that the vulnerability of congruency judgments to incongruent unattended distractors is not affected by sensory modalities. A control analysis ruled out the simple explanation of a negative response bias. These findings implicate that our perceptual system is highly sensitive to semantic incongruencies even when they are not endogenously attended.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    Linear Registration of Brain MRI Using Knowledge-Based Multiple Intermediator Libraries

    Linear registration is often the crucial first step for various types of image analysis. Although this is mathematically simple, failure is not uncommon. When investigating the brain by magnetic resonance imaging (MRI), the brain is the target organ for registration but the existence of other tissues, in addition to a variety of fields of view, different brain locations, orientations and anatomical features, poses some serious fundamental challenges. Consequently, a number of different algorithms have been put forward to minimize potential errors. In the present study, we tested a knowledge-based approach that can be combined with any form of registration algorithm. This approach consisted of a library of intermediate images (mediators) with known transformation to the target image. Test images were first registered to all mediators and the best mediator was selected to ensure optimum registration to the target. In order to select the best mediator, we evaluated two similarity criteria: the sum of squared differences and mutual information. This approach was applied to 48 mediators and 96 test images. In order to reduce one of the main drawbacks of the approach, increased computation time, we reduced the size of the library by clustering. Our results indicated clear improvement in registration accuracy.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 11, 2019 12:00 AM.

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    Hub Patterns-Based Detection of Dynamic Functional Network Metastates in Resting State: A Test-Retest Analysis

    The spontaneous dynamic characteristics of resting-state functional networks contain much internal brain physiological or pathological information. The metastate analysis of brain functional networks is an effective technique to quantify the essence of brain functional connectome dynamics. However, the widely used functional connectivity-based metastate analysis ignored the topological structure, which could be locally reflected by node centrality. In this study, 23 healthy young volunteers (21–26 years) were recruited and scanned twice with a 1-week interval. Based on the time sequences of node centrality, we promoted a node centrality-based clustering method to find metastates of functional connectome and conducted a test-retest experiment to assess the stability of those identified metastates using the described method. The hub regions of metastates were further compared with the structural networks’ organization to depict its potential relationship with brain structure. Results of extracted metastates showed repeatable dynamic features between repeated scans and high overlapping rate of hub regions with brain intrinsic sub-networks. These identified hub patterns from metastates further highly overlapped with the structural hub regions. These findings indicated that the proposed node centrality-based metastates detection method could reveal reliable and meaningful metastates of spontaneous dynamics and indicate the underlying nature of brain dynamics as well as the potential relationship between these dynamics and the organization of the brain connectome.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 11, 2019 12:00 AM.

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    Is Bodily Experience an Epiphenomenon of Multisensory Integration and Cognition?

    in Frontiers in Human Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    Theories and Methods for Labeling Cognitive Workload: Classification and Transfer Learning

    There are a number of key data-centric questions that must be answered when developing classifiers for operator functional states. “Should a supervised or unsupervised learning approach be used? What degree of labeling and transformation must be performed on the data? What are the trade-offs between algorithm flexibility and model interpretability, as generally these features are at odds?” Here, we focus exclusively on the labeling of cognitive load data for supervised learning. We explored three methods of labeling cognitive states for three-state classification. The first method labels states derived from a tertiary split of trial difficulty during a spatial memory task. The second method was more adaptive; it employed a mixed-effects stress–strain curve and estimated an individual’s performance asymptotes with respect to the same spatial memory task. The final method was similar to the second approach; however, it employed a mixed-effects Rasch model to estimate individual capacity limits within the context of item response theory for the spatial memory task. To assess the strength of each of these labeling approaches, we compared the area under the curve (AUC) for receiver operating curves (ROCs) from elastic net and random forest classifiers. We chose these classifiers based on a combination of interpretability, flexibility, and past modeling success. We tested these techniques across two groups of individuals and two tasks to test the effects of different labeling techniques on cross-person and cross-task transfer. Overall, we observed that the Rasch model labeling paired with a random forest classifier led to the best model fits and showed evidence of both cross-person and cross-task transfer.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    Recurrence Resonance” in Three-Neuron Motifs

    Stochastic Resonance (SR) and Coherence Resonance (CR) are non-linear phenomena, in which an optimal amount of noise maximizes an objective function, such as the sensitivity for weak signals in SR, or the coherence of stochastic oscillations in CR. Here, we demonstrate a related phenomenon, which we call “Recurrence Resonance” (RR): noise can also improve the information flux in recurrent neural networks. In particular, we show for the case of three-neuron motifs with ternary connection strengths that the mutual information between successive network states can be maximized by adding a suitable amount of noise to the neuron inputs. This striking result suggests that noise in the brain may not be a problem that needs to be suppressed, but indeed a resource that is dynamically regulated in order to optimize information processing.

    in Frontiers in Computational Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    Developmental Aspects of Glucose and Calcium Availability on the Persistence of Memory Function Over the Lifespan

    An important aspect concerning the underlying nature of memory function is an understanding of how memories are acquired and lost. The stability, and ultimate demise, of memory over the lifespan of an organism remains a critical topic in determining the neurobiological mechanisms that mediate memory representations. This has important implications for the elucidation and treatment of neurodegenerative diseases such as Alzheimer’s disease (AD). One important question in the context of preserving functional plasticity over the lifespan is the determination of the neurobiological structural and functional changes that contribute to the formation of memory during the juvenile time frame that might provide protection against later memory dysfunction by promoting the establishment of redundant neural pathways. The main question being, if memory formation during the juvenile period does strengthen and preserve memory stability over the lifespan, what are the neurobiological structural or functional substrates that mediate this effect? One neural attribute whose function may be altered with early life experience and provide a mechanism to preserve memory through the lifespan is glucose transport-linked calcium (Ca2+) buffering. Because peak increases in glucose utilization overlap with a timeframe during which spatial training can enhance later memory processing, it might be the case that learning-associated changes in glucose utilization would provide an important neural functional change to preserve memory function throughout the lifespan. The glucose transporters are proteins that are reduced in AD pathology and there is evidence that glucose reductions can impair Ca2+ buffering. In the absence of an appropriate supply of ATP, provided via glucose transport and glycolysis, Ca2+ levels can rise leading to neural vulnerability with ensuing pathological outcomes. In this review, we explore the hypothesis that enhancing glucose utilization with spatial training during the preadolescent period will provide a functional enhancement that regulates glucose-dependent Ca2+ signaling during aging or neurodegeneration and provide essential neural resources to preserve functional plasticity and memory function.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    Longitudinal Assessment of Amyloid-β Deposition by [18F]-Flutemetamol PET Imaging Compared With [11C]-PIB Across the Spectrum of Alzheimer’s Disease

    This study evaluates the longitudinal changes in the amyloid-β (Aβ) deposition with [18F]-flutemetamol (FMM) PET imaging across the spectrum of Alzheimer’s disease (AD), compared with [11C]-Pittsburgh Compound-B (PIB) PET. Eleven AD, 17 mild cognitive impairment (MCI) and 13 cognitively normal (CN) subjects underwent neuropsychological assessment and amyloid PET imaging using [18F]-FMM and [11C]-PIB during a follow-up period. Regions of interest were defined on co-registered MRI, and the FMM and PIB standardized uptake value ratio (SUVR) was used in the same cortical regions. The annual rate of change in FMM and PIB SUVRs was calculated. Cortical FMM SUVR in amyloid-positive subjects increased over a follow-up of 3.1 ± 0.5 years. An individual FMM SUVR was significantly correlated with PIB SUVR at baseline and at follow-up in the same AD, MCI, and CN subjects. The annual rate of increase in FMM SUVR was significantly greater in typical amyloid-positive (0.033 ± 0.023, n = 7), focal positive MCI (0.076 ± 0.034, n = 4) and positive CN (0.039 ± 0.027, n = 4) while that in AD (0.020 ± 0.018, n = 11) was smaller. Among amyloid-positive patients, the baseline FMM SUVR was inversely related with the increased rate in FMM SUVR (r=−0.44, n = 26, p < 0.05). An individual annual rate in change of cortical FMM SUVR was significantly correlated with that in cortical PIB SUVR. Our results suggest that the [18F]-FMM PET imaging can clarify the longitudinal assessment of Aβ deposition across the AD spectrum, similarly to [11C]-PIB PET. The Increase in Aβ deposition is faster in the predementia stage but not at a constant rate across the clinical stages of the AD spectrum.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    PET Imaging of Astrogliosis and Tau Facilitates Diagnosis of Parkinsonian Syndromes

    Neurodegenerative parkinsonian syndromes comprise a number of disorders that are characterized by similar clinical features but are separated on the basis of different pathologies, i.e., aggregates of α-synuclein or tau protein. Due to the overlap of signs and symptoms a precise differentiation is often difficult, especially early in the disease course. Enormous efforts have been taken to develop tau-selective PET imaging agents, but strong off-target binding to monoamine oxidase B (MAO-B) has been observed across first generation ligands. Nonetheless, astrogliosis-related MAO-B elevation is a common histopathological known feature of all parkinsonian syndromes and might be itself an interesting imaging target. Therefore, this study aimed to investigate the performance of [18F]-THK5351, a combined MAO-B and tau tracer for differential diagnosis of parkinsonian syndromes. [18F]-THK5351 PET was performed in 34 patients: six with Parkinson’s disease (PD), nine with multiple system atrophy with predominant parkinsonism (MSA-P), six with MSA with predominant cerebellar ataxia (MSA-C), and 13 with progressive supranuclear palsy (PSP) Richardson’s syndrome. Volume-of-interest-based quantification of standardized-uptake-values was conducted in different parkinsonian syndrome-related target regions. PET results were subjected to multinomial logistic regression to create a prediction model discriminating among groups. Furthermore, we correlated tracer uptake with clinical findings. Elevated [18F]-THK5351 uptake in midbrain and diencephalon differentiated PSP patients from PD and MSA-C. MSA-C patients were distinguishable by high tracer uptake in the pons and cerebellar deep white matter when compared to PSP and PD patients, whereas MSA-P patients tended to show higher tracer uptake in the lentiform nucleus. A multinomial logistic regression classified 33/34 patients into the correct clinical diagnosis group. Tracer uptake in the pons, cerebellar deep white matter, and striatum was closely associated with the presence of cerebellar and parkinsonian symptoms of MSA patients. The current study demonstrates that combined MAO-B and tau binding of THK5351 facilitates differential diagnosis of parkinsonian syndromes. Furthermore, our data indicate a correlation of MSA phenotype with [18F]-THK5351 uptake in certain brain regions, illustrating their relevance for the emergence of clinical symptoms and underlining the potential of THK5351 PET as a biomarker that correlates with pathological changes as well as with disease stage.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 11, 2019 12:00 AM.

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    Ultrasonic Vocalizations Emitted during Defensive Behavior Alter the Influence of the Respiratory Rhythm on Brain Oscillatory Dynamics in the Fear Circuit of Rats

    Highlighted Research Paper: New Insights from 22-kHz Ultrasonic Vocalizations to Characterize Fear Responses: Relationship with Respiration and Brain Oscillatory Dynamics, by Maryne Dupin, Samuel Garcia, Julie Boulanger-Bertolus, Nathalie Buonviso, and Anne-Marie Mouly

    in eNeuro current issue on September 10, 2019 04:30 PM.

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    Brain-Dependent Processes Fuel Pain-Induced Hemorrhage After Spinal Cord Injury

    Pain (nociceptive) input caudal to a spinal contusion injury can undermine long-term recovery and increase tissue loss (secondary injury). Prior work suggests that nociceptive stimulation has this effect because it fosters the breakdown of the blood-spinal cord barrier (BSCB) at the site of injury, allowing blood to infiltrate the tissue. The present study examined whether these effects impact tissue rostral and caudal to the site of injury. In addition, the study evaluated whether cutting communication with the brain, by means of a rostral transection, affects the development of hemorrhage. Eighteen hours after rats received a lower thoracic (T11–12) contusion injury, half underwent a spinal transection at T2. Noxious electrical stimulation (shock) was applied 6 h later. Cellular assays showed that, in non-transected rats, nociceptive stimulation increased hemoglobin content, activated pro-inflammatory cytokines and engaged signals related to cell death at the site of injury. These effects were not observed in transected animals. In the next experiment, the spinal transection was performed at the time of contusion injury. Nociceptive stimulation was applied 24 h later and tissue was sectioned for microscopy. In non-transected rats, nociceptive stimulation increased the area of hemorrhage and this effect was blocked by spinal transection. These findings imply that the adverse effect of noxious stimulation depends upon spared ascending fibers and the activation of rostral (brain) systems. If true, stimulation should induce less hemorrhage after a severe contusion injury that blocks transmission to the brain. To test this, rats were given a mild, moderate, or severe, injury and electrical stimulation was applied 24 h later. Histological analyses of longitudinal sections showed that nociceptive stimulation triggered less hemorrhage after a severe contusion injury. The results suggest that brain-dependent processes drive pain-induced hemorrhage after spinal cord injury (SCI).

    in Frontiers in Systems Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    The Dialectics of Free Energy Minimization

    Karl Friston’s free energy minimization has been received with great enthusiasm. With good reason: it not only makes the bold claim to a unifying theory of the brain, but it is presented as an a priori principle applicable to living systems in general. In this article, we set out to show how the breadth of scope of Friston’s framework converges with the dialectics of Georg Hegel. Through an appeal to the work of Catherine Malabou, we aim to demonstrate how Friston not only reinvigorates Hegelian dialectics from the perspective of neuroscience, but that the implicit alignment with Hegel necessitates a reading of free energy minimization from the perspective of Hegel’s speculative philosophy. It is this reading that moves beyond the discussion between cognitivism and enactivism surrounding Friston’s framework; beyond the question whether the organism is a secluded entity separated from its surroundings, or whether it is a dynamical system characterized by perpetual openness and mutual exchange. From a Hegelian perspective, it is the tension between both positions itself that is operative at the level of the organism; as a contradiction the organism sustains over the course of its life. Not only does the organism’s secluded existence depend on a perpetual relation with its surroundings, but the condition for there to be such a relation is the existence of a secluded entity. We intend to show how this contradiction—tension internalized—is at the center of Friston’s anticipatory organism; how it is this contradiction that grounds the perpetual process of free energy minimization.

    in Frontiers in Systems Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    Long Non-coding RNA TUG1 Sponges Mir-145a-5p to Regulate Microglial Polarization After Oxygen-Glucose Deprivation

    Microglia plays a critical role in neuroinflammation after ischemic stroke by releasing diverse inflammatory cytokines. Long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) is widely expressed in adult brain and has been reported to participate in multiple biological processes associated with nervous system diseases. However, the role of TUG1 in microglial activation remains unidentified. BV-2 microglial cells were cultured in vitro and TUG1 siRNA was used to knock down its RNA level. Microglial cells were subjected to oxygen-glucose deprivation (OGD) for 4 h following TUG1 siRNA or scramble siRNA transient transfection. After 24 h reoxygenation, TUG1 level and microglial M1/M2 phenotype, as well as releasing inflammatory cytokines and their role to viability of SH-SY5Y neuroblastoma cells were determined by quantitative real-time PCR (qRT-PCR), ELISA, immunofluorescence and western blot. In addition, miR-145a-5p, a putative microRNA to bind with TUG1 by bioinformatics analysis, was simultaneously examined, then the interaction of TUG1 with miR-145a-5p and the potential involvement of NF-κB pathway were further evaluated by RNA-RNA pull-down assay and western blot. The cellular level of TUG1 was transiently up-regulated in microglial cells 24 h after OGD treatment, with an inverse correlation to downregulated miR-145a-5p. TUG1 knockdown drove microglial M1-like to M2-like phenotypic transformation with reduced production of pro-inflammatory cytokines (tumor necrosis factor-α, TNF-α; interleukin-6, IL-6) and incremental release of anti-inflammatory cytokine (interleukin-10, IL-10), as a result, promoted the survival of SH-SY5Y cells. Meanwhile, TUG1 knockdown prevented OGD-induced activation of NF-κB pathway as well, represented by decreased ratios of p-p65/p65 and p-IκBα/IκBα proteins. Furthermore, we found that TUG1 could physically bind to miR-145a-5p while miR-145a-5p inhibitor abolished the protective effects of TUG1 knockdown through activation of NF-κB pathway, suggesting a negative interaction between TUG1 and miR-145a-5p. Our study demonstrated that lncRNA TUG1, sponging miR-145a-5p with negative interaction, could regulate microglial polarization and production of inflammatory cytokines at a relatively early stage after OGD insult, where NF-κB pathway might be involved, possibly providing a promising therapeutic target against inflammatory injury.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    A Conserved Tyrosine Residue in Slitrk3 Carboxyl-Terminus Is Critical for GABAergic Synapse Development

    Single-passing transmembrane protein, Slitrk3 (Slit and Trk-like family member 3, ST3), is a synaptic cell adhesion molecule highly expressed at inhibitory synapses. Recent studies have shown that ST3, through its extracellular domain, selectively regulates inhibitory synapse development via the trans-synaptic interaction with presynaptic cell adhesion molecule, receptor protein tyrosine phosphatase δ (PTPδ) and the cis-interaction with postsynaptic cell adhesion molecule, Neuroligin 2 (NL2). However, little is known about the physiological function of ST3 intracellular, carboxyl (C)-terminal region. Here we report that in heterologous cells, ST3 C-terminus is not required for ST3 homo-dimerization and trafficking to the cell surface. In contrast, in hippocampal neurons, ST3 C-terminus, more specifically, the conserved tyrosine Y969 (in mice), is critical for GABAergic synapse development. Indeed, overexpression of ST3 Y969A mutant markedly reduced the gephyrin puncta density and GABAergic transmission in hippocampal neurons. In addition, single-cell genetic deletion of ST3 strongly impaired GABAergic transmission. Importantly, wild-type (WT) ST3, but not the ST3 Y969A mutant, could fully rescue GABAergic transmission deficits in neurons lacking endogenous ST3, confirming a critical role of Y969 in the regulation of inhibitory synapses. Taken together, our data identify a single critical residue in ST3 C-terminus that is important for GABAergic synapse development and function.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    Model-Based Evaluation of Closed-Loop Deep Brain Stimulation Controller to Adapt to Dynamic Changes in Reference Signal

    High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing the motor symptoms of Parkinson's disease (PD). Current clinically-deployed DBS technology operates in an open-loop fashion, i.e., fixed parameter high-frequency stimulation is delivered continuously, invariant to the needs or status of the patient. This poses two major challenges: (1) depletion of the stimulator battery due to the energy demands of continuous high-frequency stimulation, (2) high-frequency stimulation-induced side-effects. Closed-loop deep brain stimulation (CL DBS) may be effective in suppressing parkinsonian symptoms with stimulation parameters that require less energy and evoke fewer side effects than open loop DBS. However, the design of CL DBS comes with several challenges including the selection of an appropriate biomarker reflecting the symptoms of PD, setting a suitable reference signal, and implementing a controller to adapt to dynamic changes in the reference signal. Dynamic changes in beta oscillatory activity occur during the course of voluntary movement, and thus there may be a performance advantage to tracking such dynamic activity. We addressed these challenges by studying the performance of a closed-loop controller using a biophysically-based network model of the basal ganglia. The model-based evaluation consisted of two parts: (1) we implemented a Proportional-Integral (PI) controller to compute optimal DBS frequencies based on the magnitude of a dynamic reference signal, the oscillatory power in the beta band (13–35 Hz) recorded from model globus pallidus internus (GPi) neurons. (2) We coupled a linear auto-regressive model based mapping function with the Routh-Hurwitz stability analysis method to compute the parameters of the PI controller to track dynamic changes in the reference signal. The simulation results demonstrated successful tracking of both constant and dynamic beta oscillatory activity by the PI controller, and the PI controller followed dynamic changes in the reference signal, something that cannot be accomplished by constant open-loop DBS.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on September 10, 2019 12:00 AM.

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    Cognitive, Emotional and Psychological Manifestations in Amyotrophic Lateral Sclerosis at Baseline and Overtime: A Review

    It is now well recognized that, in addition to motor impairment, amyotrophic lateral sclerosis (ALS) may cause extra-motor clinical signs and symptoms. These can include the alteration of certain cognitive functions, impaired social cognition, and changes in the perception and processing of emotions. Where these extra-motor manifestations occur in ALS, they usually do so from disease onset. In about 10% of cases, the cognitive and behavioral changes meet the diagnostic criteria for frontotemporal dementia. The timecourse of behavioral and cognitive involvement in ALS is unclear. Whereas longitudinal studies have failed to show cognitive decline over time, some cross-sectional studies have demonstrated poorer cognitive performances in the advanced stages of the disease. Neuroimaging studies show that in ALS, extra-motor signs and symptoms are associated with specific brain lesions, but little is known about how they change over time. Finally, patients with ALS appear less depressed than might be expected, given the prognosis. Moreover, many patients achieve satisfactory psychosocial adjustment throughout the course of the disease, regardless of their degree of motor disability. There are scant longitudinal data on extra-motor impairment in ALS, and to our knowledge, no systematic review on this subject has yet been published. Even so, a better understanding of patients’ clinical trajectory is essential if they are to be provided with tailored care and given the best possible support. We therefore undertook to review the evidence for extra-motor changes and their time course in ALS, in both the cognitive, emotional and psychological domains, with a view to identifying mechanisms that may help these patients cope with their disease.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 10, 2019 12:00 AM.

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    Gene Editing Preserves Visual Functions in a Mouse Model of Retinal Degeneration

    Inherited retinal dystrophies (IRDs) are a large and heterogeneous group of degenerative diseases caused by mutations in various genes. Given the favorable anatomical and immunological characteristics of the eye, gene therapy holds great potential for their treatment. Our goal is to validate the preservation of visual functions by viral-free homology directed repair (HDR) in an autosomal recessive loss of function mutation. We used a tailored gene editing system based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) to prevent retinal photoreceptor death in the retinal degeneration 10 (Rd10) mouse model of retinitis pigmentosa. We tested the gene editing tool in vitro and then used in vivo subretinal electroporation to deliver it to one of the retinas of mouse pups at different stages of photoreceptor differentiation. Three months after gene editing, the treated eye exhibited a higher visual acuity compared to the untreated eye. Moreover, we observed preservation of light-evoked responses both in explanted retinas and in the visual cortex of treated animals. Our study validates a CRISPR/Cas9-based therapy as a valuable new approach for the treatment of retinitis pigmentosa caused by autosomal recessive loss-of-function point mutations.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 10, 2019 12:00 AM.

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    Ear-EEG Forward Models: Improved Head-Models for Ear-EEG

    Computational models for mapping electrical sources in the brain to potentials on the scalp have been widely explored. However, current models do not describe the external ear anatomy well, and is therefore not suitable for ear-EEG recordings. Here we present an extension to existing computational models, by incorporating an improved description of the external ear anatomy based on 3D scanned impressions of the ears. The result is a method to compute an ear-EEG forward model, which enables mapping of sources in the brain to potentials in the ear. To validate the method, individualized ear-EEG forward models were computed for four subjects, and ear-EEG and scalp EEG were recorded concurrently from the subjects in a study comprising both auditory and visual stimuli. The EEG recordings were analyzed with independent component analysis (ICA) and using the individualized ear-EEG forward models, single dipole fitting was performed for each independent component (IC). A subset of ICs were selected, based on how well they were modeled by a single dipole in the brain volume. The correlation between the topographic IC map and the topographic map predicted by the forward model, was computed for each IC. Generally, the correlation was high in the ear closest to the dipole location, showing that the ear-EEG forward models provided a good model to predict ear potentials. In addition, we demonstrated that the developed forward models can be used to explore the sensitivity to brain sources for different ear-EEG electrode configurations. We consider the proposed method to be an important step forward in the characterization and utilization of ear-EEG.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 10, 2019 12:00 AM.

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    Application of T1-/T2-Weighted Ratio Mapping to Elucidate Intracortical Demyelination Process in the Alzheimer’s Disease Continuum

    Background The biological diagnosis criteria of the Alzheimer’s disease (AD) suggests that previous work may misclassify the cognitive impairment caused by other factors into AD. Consequently, re-assessing the imaging profile of AD continuum is needed. Considering the high vulnerability of cortical association fibers, we aimed to elucidate the cortical demyelination process in the AD continuum biologically defined.

    Methods According to the biological diagnosis criteria, we determined the positive amyloid status (A+) as cerebrospinal fluid (CSF) amyloid142 < 192 pg/ml, Florbetapir Positron emission tomography (PET) composite standardized uptake value ratio (SUVR) >1.11. Also, the positive Tau status (T+) was determined as p-Tau181 > 23 pg/ml. Based on the cognitive characterization, we further categorized 252 subjects into 27 cognitively unimpaired with normal AD biomarkers (A−T−, controls), 49 preclinical AD (A+T+), 113 AD with mild cognitive impairment (MCI) (A+T+), and 63 AD dementia (A+T+). We estimated the intracortical myelin content used the T1- and T2-weighted (T1W/T2W) ratio mapping. To investigate the sensitivity of the ratio mapping, we also utilized well-validated AD imaging biomarkers as the reference, including gray matter volume and Fludeoxyglucose PET (FDG-PET). Based on the general linear model, we conducted the voxel-wise two-sample T-tests between the controls and each group in the AD continuum.

    Results Compared to the controls, the results showed that the preclinical AD patients exhibited decreased T1W/T2W ratio value in the right inferior parietal lobule (IPL); as the disease progresses, the prodromal AD patients demonstrated lower ratio value in bilateral IPL, with hippocampus (HP) atrophy. Lastly, the AD dementia patients exhibited decreased ratio value in bilateral IPL and hippocampus; also, we observed the bilateral temporal cortices atrophy and widespread decreased metabolism in the AD dementia patients. After corrected with gray volume, the results remained mostly unchanged.

    Conclusion Our study implied the decreased right IPL T1W/T2W ratio might represent early AD-related demyelination in disease continuum. Additionally, we demonstrated that the T1W/T2W ratio mapping is an easy-to-implement and sensitive metric to assess the intracortical myelin content in AD, particularly in the early stage.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 10, 2019 12:00 AM.

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    Bioenergetics and Autophagic Imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration

    Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide affecting 2–3% of the population over 65 years. This prevalence is expected to rise as life expectancy increases and diagnostic and therapeutic protocols improve. PD encompasses a multitude of clinical, genetic, and molecular forms of the disease. Even though the mechanistic of the events leading to neurodegeneration remain largely unknown, some molecular hallmarks have been repeatedly reported in most patients and models of the disease. Neuroinflammation, protein misfolding, disrupted endoplasmic reticulum-mitochondria crosstalk, mitochondrial dysfunction and consequent bioenergetic failure, oxidative stress and autophagy deregulation, are amongst the most commonly described. Supporting these findings, numerous familial forms of PD are caused by mutations in genes that are crucial for mitochondrial and autophagy proper functioning. For instance, late and early onset PD associated to mutations in Leucine-rich repeat kinase 2 (LRRK2) and Parkin (PRKN) genes, responsible for the most frequent dominant and recessive inherited forms of PD, respectively, have emerged as promising examples of disease due to their established role in commanding bioenergetic and autophagic balance. Concomitantly, the development of animal and cell models to investigate the etiology of the disease, potential biomarkers and therapeutic approaches are being explored. One of the emerging approaches in this context is the use of patient’s derived cells models, such as skin-derived fibroblasts that preserve the genetic background and some environmental cues of the patients. An increasing number of reports in these PD cell models postulate that deficient mitochondrial function and impaired autophagic flux may be determinant in PD accelerated nigral cell death in terms of limitation of cell energy supply and accumulation of obsolete and/or unfolded proteins or dysfunctional organelles. The reliance of neurons on mitochondrial oxidative metabolism and their post-mitotic nature, may explain their increased vulnerability to undergo degeneration upon mitochondrial challenges or autophagic insults. In this scenario, proper mitochondrial function and turnover through mitophagy, are gaining in strength as protective targets to prevent neurodegeneration, together with the use of patient-derived fibroblasts to further explore these events. These findings point out the presence of molecular damage beyond the central nervous system (CNS) and proffer patient-derived cell platforms to the clinical and scientific community, which enable the study of disease etiopathogenesis and therapeutic approaches focused on modifying the natural history of PD through, among others, the enhancement of mitochondrial function and autophagy.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 10, 2019 12:00 AM.

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    Culture-Related and Individual Differences in Regional Brain Volumes: A Cross-Cultural Voxel-Based Morphometry Study

    Converging behavioral and functional neuroimaging evidence indicates that East Asian and Western individuals have different orientations for processing information that may stem from contrasting cultural values. In this cross-cultural magnetic resonance imaging (MRI) study, we used voxel-based morphometry (VBM) approach to investigate culture-related and individual differences of independent-interdependent orientation in structural brain volume between 57 Taiwanese and 56 Western participants. Each participant’s degree of endorsement of independent and interdependent cultural value was assessed by their self-report on the Singelis Self-Construal Scale (SCS). Behaviorally, Taiwanese rated higher SCS scores than Westerners in interdependent value and Westerners rated higher SCS scores than Taiwanese in independent value. The VBM results demonstrated that Western participants showed greater gray matter (GM) volume in the fronto-parietal network, whereas Taiwanese participants showed greater regional volume in temporal and occipital regions. Our findings provide supportive evidence that socio-cultural experiences of learned independent-interdependent orientations may play a role in regional brain volumes. However, strategic differences in cognition, genetic variation, and/or modulations of other environmental factors should also be considered to interpret such culture-related effects and potential individual differences.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    Identifying the Speech Production Stages in Early and Late Adulthood by Using Electroencephalography

    Structural changes in the brain take place throughout one’s life. Changes related to cognitive decline may delay the stages of the speech production process in the aging brain. For example, semantic memory decline and poor inhibition may delay the retrieval of a concept from the mental lexicon. Electroencephalography (EEG) is a valuable method for identifying the timing of speech production stages. So far, studies using EEG mainly focused on a particular speech production stage in a particular group of subjects. Differences between subject groups and between methodologies have complicated identifying time windows of the speech production stages. For the current study, the speech production stages lemma retrieval, lexeme retrieval, phonological encoding, and phonetic encoding were tracked using a 64-channel EEG in 20 younger adults and 20 older adults. Picture-naming tasks were used to identify lemma retrieval, using semantic interference through previously named pictures from the same semantic category, and lexeme retrieval, using words with varying age of acquisition. Non-word reading was used to target phonological encoding (using non-words with a variable number of phonemes) and phonetic encoding (using non-words that differed in spoken syllable frequency). Stimulus-locked and response-locked cluster-based permutation analyses were used to identify the timing of these stages in the full time course of speech production from stimulus presentation until 100 ms before response onset in both subject groups. It was found that the timing of each speech production stage could be identified. Even though older adults showed longer response times for every task, only the timing of the lexeme retrieval stage was later for the older adults compared to the younger adults, while no such delay was found for the timing of the other stages. The results of a second cluster-based permutation analysis indicated that clusters that were observed in the timing of the stages for one group were absent in the other subject group, which was mainly the case in stimulus-locked time windows. A z-score mapping analysis was used to compare the scalp distributions related to the stages between the older and younger adults. No differences between both groups were observed with respect to scalp distributions, suggesting that the same groups of neurons are involved in the four stages, regardless of the adults’ age, even though the timing of the individual stages is different in both groups.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    Understanding the Consequences of Repetitive Subconcussive Head Impacts in Sport: Brain Changes and Dampened Motor Control Are Seen After Boxing Practice

    Objectives

    The potential effects of exposure to repetitive subconcussive head impacts through routine participation in sport are not understood. To investigate the effects of repetitive subconcussive head impacts we studied boxers following customary training (sparring) using transcranial magnetic stimulation (TMS), decomposition electromyographic (EMG) and tests of memory.

    Methods

    Twenty amateur boxers performed three 3-min sparring bouts. Parameters of brain function and motor control were assessed prior to sparring and again immediately, 1 h and 24 h post-sparring. Twenty control participants were assessed following mock-sparring.

    Results

    One hour after sparring boxers showed increased corticomotor inhibition, altered motor unit recruitment strategies, and decreased memory performance relative to controls, with values returning to baseline by the 24 h follow up.

    Conclusion

    Repetitive subconcussive head impacts associated with sparring resulted in acute and transient brain changes similar to those previously reported in soccer heading, providing convergent evidence that sport-related head impacts produce a GABAergic response. These acute changes in brain health are reminiscent of effects seen following brain injury, and suggest a potential mechanism underlying the damaging long-term effects of routine repetitive head impacts in sport.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    Discrimination of Prion Strain Targeting in the Central Nervous System via Reactive Astrocyte Heterogeneity in CD44 Expression

    Prion diseases or transmissible spongiform encephalopathies are fatal, progressive, neurodegenerative, protein-misfolding disorders. Prion diseases may arise spontaneously, be inherited genetically or be acquired by infection and affect a variety of mammalian species including humans. Prion infections in the central nervous system (CNS) cause extensive neuropathology, including abnormal accumulations of misfolded host prion protein, vacuolar change resulting in sponge-like (spongiform) appearance of CNS tissue, neurodegeneration and reactive glial responses. Many different prion agent strains exist and these can differ based on disease duration, clinical signs and the targeting and distribution of the neuropathology in distinct brain areas. Reactive astrocytes are a prominent feature in the prion disease affected CNS as revealed by distinct morphological changes and upregulation of glial fibrillary acidic protein (GFAP). The CD44 antigen is a transmembrane glycoprotein involved in cell-cell interactions, cell adhesion and migration. Here we show that CD44 is also highly expressed in a subset of reactive astrocytes in regions of the CNS targeted by prions. Astrocyte heterogeneity revealed by differential CD44 upregulation occurs coincident with the earliest neuropathological changes during the pre-clinical phase of disease, and is not affected by the route of infection. The expression and distribution of CD44 was compared in brains from a large collection of 15 distinct prion agent strains transmitted to mice of different prion protein (Prnp) genotype backgrounds. Our data show that the pattern of CD44 upregulation observed in the hippocampus in each prion agent strain and host Prnp genotype combination was unique. Many mouse-adapted prion strains and hosts have previously been characterized based on the pattern of the distribution of the spongiform pathology or the misfolded PrP deposition within the brain. Our data show that CD44 expression also provides a reliable discriminatory marker of prion infection with a greater dynamic range than misfolded prion protein deposition, aiding strain identification. Together, our data reveal CD44 as a novel marker to detect reactive astrocyte heterogeneity during CNS prion disease and for enhanced identification of distinct prion agent strains.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    Restoration of Olfactory Memory in Drosophila Overexpressing Human Alzheimer’s Disease Associated Tau by Manipulation of L-Type Ca2+ Channels

    The cellular underpinnings of memory deficits in Alzheimer’s disease (AD) are poorly understood. We utilized the tractable neural circuits sub-serving memory in Drosophila to investigate the role of impaired Ca2+ handling in memory deficits caused by expression of human 0N4R isoform of tau which is associated with AD. Expression of tau in mushroom body neuropils, or a subset of mushroom body output neurons, led to impaired memory. By using the Ca2+ reporter GCaMP6f, we observed changes in Ca2+ signaling when tau was expressed in these neurons, an effect that could be blocked by the L-type Ca2+ channel antagonist nimodipine or reversed by RNAi knock-down of the L-type channel gene. The L-type Ca2+ channel itself is required for memory formation, however, RNAi knock-down of the L-type Ca2+ channel in neurons overexpressing human tau resulted in flies whose memory is restored to levels equivalent to wild-type. Expression data suggest that Drosophila L-type Ca2+ channel mRNA levels are increased upon tau expression in neurons, thus contributing to the effects observed on memory and intracellular Ca2+ homeostasis. Together, our Ca2+ imaging and memory experiments suggest that expression of the 0N4R isoform of human tau increases the number of L-type Ca2+ channels in the membrane resulting in changes in neuronal excitability that can be ameliorated by RNAi knockdown or pharmacological blockade of L-type Ca2+ channels. This highlights a role for L-type Ca2+ channels in tauopathy and their potential as a therapeutic target for AD.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    Poly (ADP-Ribose) Polymerase-1 (PARP1) Deficiency and Pharmacological Inhibition by Pirenzepine Protects From Cisplatin-Induced Ototoxicity Without Affecting Antitumor Efficacy

    Cisplatin remains an indispensable drug for the systemic treatment of many solid tumors. However, a major dose-limiting side-effect is ototoxicity. In some scenarios, such as treatment of germ cell tumors or adjuvant therapy of non-small cell lung cancer, cisplatin cannot be replaced without undue loss of efficacy. Inhibition of polyadenosine diphosphate-ribose polymerase-1 (PARP1), is presently being evaluated as a novel anti-neoplastic principle. Of note, cisplatin-induced PARP1 activation has been related to inner ear cell death. Thus, PARP1 inhibition may exert a protective effect on the inner ear without compromising the antitumor activity of cisplatin. Here, we evaluated PARP1 deficiency and PARP1 pharmacological inhibition as a means to protect the auditory hair cells from cisplatin-mediated ototoxicity. We demonstrate that cisplatin-induced loss of sensory hair cells in the organ of Corti is attenuated in PARP1-deficient cochleae. The PARP inhibitor pirenzepine and its metabolite LS-75 mimicked the protective effect observed in PARP1-deficient cochleae. Moreover, the cytotoxic potential of cisplatin was unchanged by PARP inhibition in two different cancer cell lines. Taken together, the results from our study suggest that the negative side-effects of cisplatin anti-cancer treatment could be alleviated by a PARP inhibition adjunctive therapy.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    A Prospective Study on the Association Between Grip Strength and Cognitive Function Among Middle-Aged and Elderly Chinese Participants

    Objective

    To study the efficacy of grip strength (GS) as a predictor of cognitive function in a large, nationwide sample of Chinese participants aged 45 years and above.

    Methods

    We used data from three waves (W1, W2, and W3) fielded by the China Health and Retirement Longitudinal Study (CHARLS). Cognitive function was tested biennially and calculated using two categories: episodic memory and mental intactness. Demographics, health behaviors, and medical conditions were considered potential confounders. Using multivariate linear regression models (MLRMs), we examined the association between baseline GS (measure in W1) and cognitive function in W3. Using a generalized estimating equation (GEE), we examined baseline GS as a predictor of cognitive function change.

    Results

    Total 9,333 individuals (53.2% women), with a mean baseline episodic memory score of 6.5, mean baseline mental intactness score of 7.2, and aged over 45 years (mean age = 58.6), were selected. The mean follow-up time was 4.0 years (range: 3.3–5.0 years). Using MLRMs and comparing the lowest GS score with the highest baseline GS score, we observed a significant correlation with a higher global cognitive function in both women (β = 1.061, p < 0.001) and men (β = 1.233, p < 0.001). After adjusting baseline global cognition, the highest GS level was still statistically significant in both women (β = 0.543, p < 0.05) and men (β = 0.742, p < 0.001). GEE suggested that the participants in the highest GS quartile had better cognitive performance over time in both women (β = 0.116, p = 0.030) and men (β = 0.143, p = 0.008) than those in the lowest quartile.

    Conclusion

    Higher baseline level of GS was significantly related to better cognitive function and slowed the rate of its decline. Thus, it is an independent predictor of better cognitive status in middle-aged and elderly Chinese.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 10, 2019 12:00 AM.

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    An Open Source Syringe Pump Controller for Fluid Delivery of Multiple Volumes

    Abstract

    Syringe pumps are a necessary piece of laboratory equipment that are used for fluid delivery in behavioral neuroscience laboratories. Many experiments provide rodents and primates with fluid rewards such as juice, water, or liquid sucrose. Current commercialized syringe pumps are not customizable and do not have the ability to deliver multiple volumes of fluid based on different inputs to the pump. Additionally, many syringe pumps are expensive and cannot be used in experiments with paired neurophysiological recordings due to electrical noise. We developed an open source syringe pump controller using commonly available parts. The controller adjusts the acceleration and speed of the motor to deliver three different volumes of fluid reward within one common time epoch. This syringe pump controller is cost effective and has been successfully implemented in rodent behavioral experiments with paired neurophysiological recordings in the rat frontal cortex while rats lick for different volumes of liquid sucrose rewards. Our syringe pump controller will enable new experiments to address the potential confound of temporal information in studies of reward signaling by fluid magnitude.

    in eNeuro current issue on September 09, 2019 04:30 PM.

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    Large-Scale Networks for Auditory Sensory Gating in the Awake Mouse

    Abstract

    The amplitude of the brain response to a repeated auditory stimulus is diminished as compared to the response to the first tone (T1) for interstimulus intervals (ISI) lasting up to hundreds of milliseconds. This adaptation process, called auditory sensory gating (ASG), is altered in various psychiatric diseases including schizophrenia and is classically studied by focusing on early evoked cortical responses to the second tone (T2) using 500-ms ISI. However, mechanisms underlying ASG are still not well-understood. We investigated ASG in awake mice from the brainstem to cortex at variable ISIs (125–2000 ms) using high-density EEG and intracerebral recordings. While ASG decreases at longer ISIs, it is still present at durations (500–2000 ms) far beyond the time during which brain responses to T1 could still be detected. T1 induces a sequence of specific stable scalp EEG topographies that correspond to the successive activation of distinct neural networks lasting about 350 ms. These brain states remain unaltered if T2 is presented during this period, although T2 is processed by the brain, suggesting that ongoing networks of brain activity are active for longer than early evoked-potentials and are not overwritten by an upcoming new stimulus. Intracerebral recordings demonstrate that ASG is already present at the level of ventral cochlear nucleus (vCN) and inferior colliculus and is amplified across the hierarchy in bottom-up direction. This study uncovers the extended stability of sensory-evoked brain states and long duration of ASG, and sheds light on generators of ASG and possible interactions between bottom-up and top-down mechanisms.

    in eNeuro current issue on September 09, 2019 04:30 PM.

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    Machine Learning of Time Series Using Time-Delay Embedding and Precision Annealing

    Neural Computation, Volume 31, Issue 10, Page 2004-2024, October 2019.

    in MIT Press: Neural Computation: Table of Contents on September 09, 2019 06:38 AM.

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    A Real-Time Health 4.0 Framework with Novel Feature Extraction and Classification for Brain-Controlled IoT-Enabled Environments

    Neural Computation, Volume 31, Issue 10, Page 1915-1944, October 2019.

    in MIT Press: Neural Computation: Table of Contents on September 09, 2019 06:38 AM.

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    One Step Back, Two Steps Forward: Interference and Learning in Recurrent Neural Networks

    Neural Computation, Volume 31, Issue 10, Page 1985-2003, October 2019.

    in MIT Press: Neural Computation: Table of Contents on September 09, 2019 06:38 AM.

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    A Mechanism for Synaptic Copy Between Neural Circuits

    Neural Computation, Volume 31, Issue 10, Page 1964-1984, October 2019.

    in MIT Press: Neural Computation: Table of Contents on September 09, 2019 06:38 AM.

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    A Minimum Free Energy Model of Motor Learning

    Neural Computation, Volume 31, Issue 10, Page 1945-1963, October 2019.

    in MIT Press: Neural Computation: Table of Contents on September 09, 2019 06:38 AM.

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    A neuronal circuit for activating descending modulation of neuropathic pain

    Nature Neuroscience, Published online: 09 September 2019; doi:10.1038/s41593-019-0481-5

    Huang and colleagues functionally map a brain circuit connecting the amygdala and the spinal cord that is altered after nerve injury and contributes to chronic pain.

    in Nature Neuroscience - Issue - nature.com science feeds on September 09, 2019 12:00 AM.

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    Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity

    Nature Neuroscience, Published online: 09 September 2019; doi:10.1038/s41593-019-0479-z

    Fecher et al. devise an approach to isolate cell-type-specific mitochondria from the mouse CNS. They demonstrate proteomic diversity of cerebellar mitochondria covering bioenergetics, calcium handling and organelle contact sites.

    in Nature Neuroscience - Issue - nature.com science feeds on September 09, 2019 12:00 AM.

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    Immediate and deferred epigenomic signatures of in vivo neuronal activation in mouse hippocampus

    Nature Neuroscience, Published online: 09 September 2019; doi:10.1038/s41593-019-0476-2

    Multi-omic analyses of transcriptional, chromatin occupancy and chromatin interaction dynamics in hippocampal excitatory neurons of adult mice upon activation by status epilepticus or novel context exploration reveals short- and long-lasting changes.

    in Nature Neuroscience - Issue - nature.com science feeds on September 09, 2019 12:00 AM.

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    Corrigendum: HDAC1 Silence Promotes Neuroprotective Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Mouse Model of Traumatic Brain Injury via PI3K/AKT Pathway

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 09, 2019 12:00 AM.

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    Introducing a Novel Approach for Evaluation and Monitoring of Brain Health Across Life Span Using Direct Non-invasive Brain Network Electrophysiology

    Objective

    Evaluation and monitoring of brain health throughout aging by direct electrophysiological imaging (DELPHI) which analyzes TMS (transcranial magnetic stimulation) evoked potentials.

    Methods

    Transcranial magnetic stimulation evoked potentials formation, coherence and history dependency, measured using electroencephalogram (EEG), was extracted from 80 healthy subjects in different age groups, 25–85 years old, and 20 subjects diagnosed with mild dementia (MD), over 70 years old. Subjects brain health was evaluated using MRI scans, neurocognitive evaluation, and computerized testing and compared to DELPHI analysis of brain network functionality.

    Results

    A significant decrease in signal coherence is observed with age in connectivity maps, mostly in inter-hemispheric temporal, and parietal areas. MD patients display a pronounced decrease in global and inter-hemispheric frontal connectivity compared to healthy controls. Early and late signal slope ratio also display a significant, age dependent, change with pronounced early slope, phase shift, between normal healthy aging, and MD. History dependent analysis demonstrates a binary step function classification of healthy brain vs. abnormal aging subjects mostly for late slope. DELPHI measures demonstrate high reproducibility with reliability coefficients of around 0.9.

    Conclusion

    These results indicate that features of evoked response, as charge transfer, slopes of response, and plasticity are altered during abnormal aging and that these fundamental properties of network functionality can be directly evaluated and monitored using DELPHI.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 09, 2019 12:00 AM.

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    Adaptations during Maturation in an Identified Honeybee Interneuron Responsive to Waggle Dance Vibration Signals

    Abstract

    Honeybees are social insects, and individual bees take on different social roles as they mature, performing a multitude of tasks that involve multi-modal sensory integration. Several activities vital for foraging, like flight and waggle dance communication, involve sensing air vibrations through their antennae. We investigated changes in the identified vibration-sensitive interneuron DL-Int-1 in the honeybee Apis mellifera during maturation by comparing properties of neurons from newly emerged adult and forager honeybees. Although comparison of morphological reconstructions of the neurons revealed no significant changes in gross dendritic features, consistent and region-dependent changes were found in dendritic density. Comparison of electrophysiological properties showed an increase in the firing rate differences between stimulus and nonstimulus periods in foragers compared with newly emerged adult bees. The observed differences in neurons of foragers compared with newly emerged adult honeybees suggest refined connectivity, improved signal propagation, and enhancement of response features possibly important for the network processing of air vibration signals relevant for the waggle dance communication of honeybees.

    in eNeuro current issue on September 06, 2019 04:30 PM.

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    The brain’s default network: updated anatomy, physiology and evolving insights

    Nature Reviews Neuroscience, Published online: 06 September 2019; doi:10.1038/s41583-019-0212-7

    The brain’s default network is thought to comprise a set of regions in the association cortex. Randy Buckner and Lauren DiNicola review findings from humans, monkeys and rodents indicating that multiple subnetworks make up the default network and explore the implications of these observations.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on September 06, 2019 12:00 AM.

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    Dimethylethanolamine Decreases Epileptiform Activity in Acute Human Hippocampal Slices in vitro

    Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy with about 30% of patients developing pharmacoresistance. These patients continue to suffer from seizures despite polytherapy with antiepileptic drugs (AEDs) and have an increased risk for premature death, thus requiring further efforts for the development of new antiepileptic therapies. The molecule dimethylethanolamine (DMEA) has been tested as a potential treatment in various neurological diseases, albeit the functional mechanism of action was never fully understood. In this study, we investigated the effects of DMEA on neuronal activity in single-cell recordings of primary neuronal cultures. DMEA decreased the frequency of spontaneous synaptic events in a concentration-dependent manner with no apparent effect on resting membrane potential (RMP) or action potential (AP) threshold. We further tested whether DMEA can exert antiepileptic effects in human brain tissue ex vivo. We analyzed the effect of DMEA on epileptiform activity in the CA1 region of the resected hippocampus of TLE patients in vitro by recording extracellular field potentials in the pyramidal cell layer. Epileptiform burst activity in resected hippocampal tissue from TLE patients remained stable over several hours and was pharmacologically suppressed by lacosamide, demonstrating the applicability of our platform to test antiepileptic efficacy. Similar to lacosamide, DMEA also suppressed epileptiform activity in the majority of samples, albeit with variable interindividual effects. In conclusion, DMEA might present a new approach for treatment in pharmacoresistant TLE and further studies will be required to identify its exact mechanism of action and the involved molecular targets.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Sensory Over-Responsivity as an Added Dimension in ADHD

    Years of research have added to our understanding of Attention Deficit Hyperactivity Disorder (ADHD). None-the-less there is still much that is poorly understood. There is a need for, and ongoing interest in, developing a deeper understanding of this disorder to optimally identify risk and better inform treatment. Here, we present a compilation of findings examining ADHD both behaviorally and using neurophysiologic markers. Drawing on early work of McIntosh and co-investigators, we examined response to sensory challenge in children with ADHD, measuring HPA activity and electrodermal response (EDR) secondary to sensory stressors. In addition, we have examined the relationship between these physiologic measures, and reports of behavioral sensory over-responsivity and anxiety. Findings suggest that sensory responsivity differentiates among children with ADHD and warrants consideration. We link these findings with research conducted both prior to and after our own work and emphasize that there a growing knowledge supporting a relationship between ADHD and sensory over-responsivity, but more research is needed. Given the call from the National Institute of Health to move toward a more dimensional diagnostic process for mental health concerns, and away from the more routine categorical diagnostic process, we suggest sensory over-responsivity as a dimension in the diagnostic process for children with ADHD.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Modulation of Neural Activity for Myelination in the Central Nervous System

    Electrical stimulation has been playing a significant role in revealing various functions and mechanisms of the nervous system. It is no different for myelination, a process in which oligodendrocytes in the central nervous system (CNS) or Schwann Cells in the peripheral nerve system (PNS) wrap around axons to provide an insulating layer in vitro and in vivo. It has been widely recognized that the myelin sheath accelerates axon signal conduction and provides neuroprotection. Recent studies have begun to reveal its role in plasticity. The major mechanism that enables this process is activity-dependent myelination – the phenomenon where neuronal activity supports oligodendrocyte maturation and myelin sheath formation. In light of recent discoveries, a better understanding of this phenomenon has a potential to provide therapeutic targets for not only demyelinating diseases, but also psychiatric disorders. There is a growing need for experimental platforms capable of dissecting the effect of neural activity on myelination in health and disease. The effect of neural activity is commonly studied by comparing the myelination levels in cultures with neurons of low and high activity. Electrical stimulation is particularly well suited as a method of inducing neural activity in these systems. In this review, we describe in vitro platforms for studying activity-dependent myelination, which utilize neuron stimulation via electrical field. We also discuss stimulation profiles, as well as the alternatives to electrical stimulation in the context of regular, compartmentalized, and organotypic co-cultures.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on September 06, 2019 12:00 AM.

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    Novel Optogenetic Approaches in Epilepsy Research

    Epilepsy is a major neurological disorder characterized by repeated seizures afflicting 1% of the global population. The emergence of seizures is associated with several comorbidities and severely decreases the quality of life of patients. Unfortunately, around 30% of patients do not respond to first-line treatment using anti-seizure drugs (ASDs). Furthermore, it is still unclear how seizures arise in the healthy brain. Therefore, it is critical to have well developed models where a causal understanding of epilepsy can be investigated. While the development of seizures has been studied in several animal models, using chemical or electrical induction, deciphering the results of such studies has been difficult due to the uncertainty of the cell population being targeted as well as potential confounds such as brain damage from the procedure itself. Here we describe novel approaches using combinations of optical and genetic methods for studying epileptogenesis. These approaches can circumvent some shortcomings associated with the classical animal models and may thus increase the likelihood of developing new treatment options.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on September 06, 2019 12:00 AM.

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    Neurons Induced From Fibroblasts of c9ALS/FTD Patients Reproduce the Pathology Seen in the Central Nervous System

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative conditions. A non-coding hexanucleotide (GGGGCC) repeat expansion in the c9orf72 gene is the most common genetic cause of ALS/FTD. We present a cellular model of c9ALS/FTD where induced neurons (iNeurons) are generated within 2 weeks by direct conversion of patients‘ dermal fibroblasts through down-regulation of polypyrimidine-tract-binding protein 1 (PTB1). While sense (S) and anti-sense (AS) intranuclear RNA foci were observed in both fibroblasts and iNeurons, the accumulation of (S) and (AS) repeat-associated non-ATG translation (RANT) products were detected only in iNeurons. Importantly, anti-sense oligonucleotides (ASOs) against the (S) repeat transcript lead to decreased (S) RNA foci staining and a reduction of the corresponding RANT products without affecting its (AS) counterparts. ASOs treatment also rescued the cell viability upon stressful stimulus. The results indicate that iNeurons is an advantageous model that not only recapitulates c9ALS/FTD hallmark features but can also help uncover promising therapeutics.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 06, 2019 12:00 AM.

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    Flexible and Lightweight Devices for Wireless Multi-Color Optogenetic Experiments Controllable via Commercial Cell Phones

    Optogenetics provide a potential alternative approach to the treatment of chronic pain, in which complex pathology often hampers efficacy of standard pharmacological approaches. Technological advancements in the development of thin, wireless, and mechanically flexible optoelectronic implants offer new routes to control the activity of subsets of neurons and nerve fibers in vivo. This study reports a novel and advanced design of battery-free, flexible, and lightweight devices equipped with one or two miniaturized LEDs, which can be individually controlled in real time. Two proof-of-concept experiments in mice demonstrate the feasibility of these devices. First, we show that blue-light devices implanted on top of the lumbar spinal cord can excite channelrhodopsin expressing nociceptors to induce place aversion. Second, we show that nocifensive withdrawal responses can be suppressed by green-light optogenetic (Archaerhodopsin-mediated) inhibition of action potential propagation along the sciatic nerve. One salient feature of these devices is that they can be operated via modern tablets and smartphones without bulky and complex lab instrumentation. In addition to the optical stimulation, the design enables the simultaneously wireless recording of the temperature in proximity of the stimulation area. As such, these devices are primed for translation to human patients with implications in the treatment of neurological and psychiatric conditions far beyond chronic pain syndromes.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on September 06, 2019 12:00 AM.

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    Evaluation of Neural Degeneration Biomarkers in the Prefrontal Cortex for Early Identification of Patients With Mild Cognitive Impairment: An fNIRS Study

    Mild cognitive impairment (MCI), a condition characterizing poor cognition, is associated with aging and depicts early symptoms of severe cognitive impairment, known as Alzheimer’s disease (AD). Meanwhile, early detection of MCI can prevent progression to AD. A great deal of research has been performed in the past decade on MCI detection. However, availability of biomarkers for MCI detection requires greater attention. In our study, we evaluated putative and reliable biomarkers for diagnosing MCI by performing different mental tasks (i.e., N-back task, Stroop task, and verbal fluency task) using functional near-infrared spectroscopy (fNIRS) signals on a group of 15 MCI patients and 9 healthy control (HC). The 15 digital biomarkers (i.e., five means, seven slopes, peak, skewness, and kurtosis) and two image biomarkers (t-map, correlation map) in the prefrontal cortex (PFC) (i.e., left PFC, middle PFC, and right PFC) between the MCI and HC groups were investigated by the statistical analysis, linear discriminant analysis (LDA), and convolutional neural network (CNN) individually. The results reveal that the statistical analysis using digital biomarkers (with a p-value < 0.05) could not distinguish the MCI patients from the HC over 60% accuracy. Therefore, the current statistical analysis needs to be improved to be used for diagnosing the MCI patients. The best accuracy with LDA was 76.67% with the N-back and Stroop tasks. However, the CNN classification results trained by image biomarkers showed a high accuracy. In particular, the CNN results trained via t-maps revealed the best accuracy (90.62%) with the N-back task, whereas the CNN result trained by the correlation maps was 85.58% with the N-back task. Also, the results illustrated that investigating the sub-regions (i.e., right, middle, left) of the PFC for detecting MCI would be better than examining the whole PFC. The t-map (or/and the correlation map) is conclusively recommended as an image biomarker for early detection of AD. The combination of CNN and image biomarkers can provide a reliable clinical tool for diagnosing MCI patients.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Adaptation to Laterally Asymmetrical Visuomotor Delay Has an Effect on Action But Not on Perception

    When interacting with the environment, the sensorimotor system faces temporal and spatial discrepancies between sensory inputs, such as delay in sensory information transmission, and asymmetrical visual inputs across space. These discrepancies can affect motor control and the representation of space. We recently showed that adaptation to a laterally asymmetric delay in the visual feedback induces neglect-like effects in blind drawing movements, expressed by asymmetrical elongation of circles that are drawn in different workspaces and directions; this establishes a possible connection between delayed feedback and asymmetrical spatial processing in the control of action. In the current study, we investigate whether such adaptation also influences visual perception. In addition, we examined transfer to another motor task – a line bisection task that is commonly used to detect spatial disorders, and extend these results to examine the mapping of these neglect-like effects. We performed two sets of experiments in which participants executed lateral reaching movements, and were exposed to visual feedback delay only in the left workspace. We examined transfer of adaptation to a perceptual line bisection task – answers about the perceived midline of lines that were presented in different directions and workspaces, and to a blind motor line bisection task – reaching movements toward the centers of similar lines. We found that the adaptation to the asymmetrical delay transferred to the control of lateral movements, but did not affect the perceived location of the midlines. Our results clarify the effect of asymmetrical delayed visual feedback on perception and action, and provide potential insights on the link between visuomotor delay and neurological disorders such as the hemispatial neglect syndrome.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    How Neurophysiological Measures Can be Used to Enhance the Evaluation of Remote Tower Solutions

    New solutions in operational environments are often, among objective measurements, evaluated by using subjective assessment and judgment from experts. Anyhow, it has been demonstrated that subjective measures suffer from poor resolution due to a high intra and inter-operator variability. Also, performance measures, if available, could provide just partial information, since an operator could achieve the same performance but experiencing a different workload. In this study, we aimed to demonstrate: (i) the higher resolution of neurophysiological measures in comparison to subjective ones; and (ii) how the simultaneous employment of neurophysiological measures and behavioral ones could allow a holistic assessment of operational tools. In this regard, we tested the effectiveness of an electroencephalography (EEG)-based neurophysiological index (WEEG index) in comparing two different solutions (i.e., Normal and Augmented) in terms of experienced workload. In this regard, 16 professional air traffic controllers (ATCOs) have been asked to perform two operational scenarios. Galvanic Skin Response (GSR) has also been recorded to evaluate the level of arousal (i.e., operator involvement) during the two scenarios execution. NASA-TLX questionnaire has been used to evaluate the perceived workload, and an expert was asked to assess performance achieved by the ATCOs. Finally, reaction times on specific operational events relevant for the assessment of the two solutions, have also been collected. Results highlighted that the Augmented solution induced a local increase in subjects performance (Reaction times). At the same time, this solution induced an increase in the workload experienced by the participants (WEEG). Anyhow, this increase is still acceptable, since it did not negatively impact the performance and has to be intended only as a consequence of the higher engagement of the ATCOs. This behavioral effect is totally in line with physiological results obtained in terms of arousal (GSR), that increased during the scenario with augmentation. Subjective measures (NASA-TLX) did not highlight any significant variation in perceived workload. These results suggest that neurophysiological measure provide additional information than behavioral and subjective ones, even at a level of few seconds, and its employment during the pre-operational activities (e.g., design process) could allow a more holistic and accurate evaluation of new solutions.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Simultaneous EEG-NIRS Measurement of the Inferior Parietal Lobule During a Reaching Task With Delayed Visual Feedback

    We investigated whether the inferior parietal lobule (IPL) responds in real-time to multisensory inconsistency during movement. The IPL is thought to be involved in both the detection of inconsistencies in multisensory information obtained during movement and that obtained during self-other discrimination. However, because of the limited temporal resolution of conventional neuroimaging techniques, it is difficult to distinguish IPL activity during movement from that during self-other discrimination. We simultaneously conducted electroencephalography (EEG) and near-infrared spectroscopy (NIRS) with the goal of examining IPL activity with a high spatiotemporal resolution during single reaching movements. Under a visual feedback-delay condition, gamma event-related synchronization (γ-ERS), i.e., an increase in gamma (31–47 Hz) EEG power occurred during reaching movements. This γ-ERS is considered to reflect processing of information about prediction errors. To integrate this temporal information with spatial information from the NIRS signals, we developed a new analysis technique that enabled estimation of the regions that show a hemodynamic response characterized by EEG fluctuation present in the visual feedback-delay condition. As a result, IPL activity was explained by γ-ERS specific to visual feedback delay during movements. Thus, we succeeded in demonstrating real-time activation of the IPL in response to multisensory inconsistency. However, we did not find any correlation between either IPL activity or γ-ERS with the sense of agency. Therefore, our results suggest that while the IPL is influenced by prediction error signals, it does not engage in direct processing underlying the conscious experience of making a movement, which is the foundation of self-other discrimination.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Transcranial Direct Current Stimulation Over Dorsolateral Prefrontal Cortex Modulates Risk-Attitude in Motor Decision-Making

    Humans often face situations requiring a decision about where to throw an object or when to respond to a stimulus under risk. Several behavioral studies have shown that such motor decisions can be suboptimal, which results from a cognitive bias toward risk-seeking behavior. However, brain regions involved in risk-attitude of motor decision-making remain unclear. Here, we investigated the role of the dorsolateral prefrontal cortex (DLPFC) in risky motor decisions using transcranial direct current stimulation (tDCS). The experiment comprised a selective timing task requiring participants to make a continuous decision about the timing of their response under the risk of no rewards. The participants performed this task twice in a day: before and while receiving either anodal stimulation over the right DLPFC with cathodal stimulation over the left DLPFC (20 min, 2 mA), cathodal stimulation over the right DLPFC with anodal stimulation over the left DLPFC, or sham stimulation. In line with previous studies, their strategies before the stimulation were biased toward risk-seeking. During anodal stimulation over right DLPFC with cathodal stimulation over left DLPFC, participants showed a more conservative strategy to avoid the risk of no rewards. The additional experiment confirmed that tDCS did not affect the ability of timing control regarding the time intervals at which they aimed to respond. These results suggest a potential role for the DLPFC in modulating action selection in motor decision-making under risk.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Brain–Computer Interface-Based Adaptive Automation to Prevent Out-Of-The-Loop Phenomenon in Air Traffic Controllers Dealing With Highly Automated Systems

    Increasing the level of automation in air traffic management is seen as a measure to increase the performance of the service to satisfy the predicted future demand. This is expected to result in new roles for the human operator: he will mainly monitor highly automated systems and seldom intervene. Therefore, air traffic controllers (ATCos) would often work in a supervisory or control mode rather than in a direct operating mode. However, it has been demonstrated how human operators in such a role are affected by human performance issues, known as Out-Of-The-Loop (OOTL) phenomenon, consisting in lack of attention, loss of situational awareness and de-skilling. A countermeasure to this phenomenon has been identified in the adaptive automation (AA), i.e., a system able to allocate the operative tasks to the machine or to the operator depending on their needs. In this context, psychophysiological measures have been highlighted as powerful tool to provide a reliable, unobtrusive and real-time assessment of the ATCo’s mental state to be used as control logic for AA-based systems. In this paper, it is presented the so-called “Vigilance and Attention Controller”, a system based on electroencephalography (EEG) and eye-tracking (ET) techniques, aimed to assess in real time the vigilance level of an ATCo dealing with a highly automated human–machine interface and to use this measure to adapt the level of automation of the interface itself. The system has been tested on 14 professional ATCos performing two highly realistic scenarios, one with the system disabled and one with the system enabled. The results confirmed that (i) long high automated tasks induce vigilance decreasing and OOTL-related phenomena; (ii) EEG measures are sensitive to these kinds of mental impairments; and (iii) AA was able to counteract this negative effect by keeping the ATCo more involved within the operative task. The results were confirmed by EEG and ET measures as well as by performance and subjective ones, providing a clear example of potential applications and related benefits of AA.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Safety and Feasibility of Transcranial Direct Current Stimulation for Cognitive Rehabilitation in Patients With Mild or Major Neurocognitive Disorders: A Randomized Sham-Controlled Pilot Study

    Introduction

    Transcranial direct current stimulation (tDCS) is a potentially novel strategy for cognitive enhancement in patients with mild or major neurocognitive disorders. This study aims to assess the safety and efficacy of tDCS during cognitive training on cognitive functioning in patients with mild or major neurocognitive disorders.

    Methods

    This study was primarily a single arm for safety, secondary a two-arm, parallel, randomized, and sham-controlled trial for potential efficacy. Patients with mild or major neurocognitive disorders were recruited. The participants and raters were blinded to the group assignment. The participants in the active arm received tDCS (anodal; F3, cathodal, Fp2, 2A, 20 min) twice daily for five consecutive days, whereas those in the sham arm received the same amount of sham-tDCS. Calculation and reading tasks were conducted in both arms as a form of cognitive intervention for 20 min during tDCS. The primary outcome was the attrition rate during the trial in the active arm, which is expected to be less than 10%. The secondary outcomes were the between-group differences of adjusted means for several cognitive scales from baseline to post-intervention and follow-up.

    Results

    Twenty patients [nine women (45%)], with a mean (standard deviation) age of 76.1 years participated; nine patients (45%) with minor neurocognitive disorders and 11 (55%) with major neurocognitive disorders were randomized, and 19 of them completed the trial. The attrition rate in the active arm was 0%, with no serious adverse events. Further, in the Intention-to-Treat analysis, patients in the active arm showed no statistically significant improvement compared with those who received the sham in the mean change scores of the mini-mental state examination [0.41; 95% CI (−1.85; 2.67) at day five, 1.08; 95% CI (−1.31; 3.46) at follow-up] and Alzheimer’s disease assessment scale – cognition subscale [1.61; 95% CI (−4.2; 0.98) at day 5, 0.36; 95%CI (−3.19; 2.47) at follow-up].

    Conclusion

    These findings suggest that tDCS is safe and tolerable but causes no statistically significant cognitive effects in patients with mild or major neurocognitive disorders. Additional large-scale, well-designed clinical trials are warranted to evaluate the cognitive effects of tDCS as an augmentation to cognitive training.

    Clinical Trial Registration

    www.ClinicalTrials.gov, identifier NCT03050385.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Metastable Resting State Brain Dynamics

    Metastability refers to the fact that the state of a dynamical system spends a large amount of time in a restricted region of its available phase space before a transition takes place, bringing the system into another state from where it might recur into the previous one. beim Graben and Hutt (2013) suggested to use the recurrence plot (RP) technique introduced by Eckmann et al. (1987) for the segmentation of system's trajectories into metastable states using recurrence grammars. Here, we apply this recurrence structure analysis (RSA) for the first time to resting-state brain dynamics obtained from functional magnetic resonance imaging (fMRI). Brain regions are defined according to the brain hierarchical atlas (BHA) developed by Diez et al. (2015), and as a consequence, regions present high-connectivity in both structure (obtained from diffusion tensor imaging) and function (from the blood-level dependent-oxygenation—BOLD—signal). Remarkably, regions observed by Diez et al. were completely time-invariant. Here, in order to compare this static picture with the metastable systems dynamics obtained from the RSA segmentation, we determine the number of metastable states as a measure of complexity for all subjects and for region numbers varying from 3 to 100. We find RSA convergence toward an optimal segmentation of 40 metastable states for normalized BOLD signals, averaged over BHA modules. Next, we build a bistable dynamics at population level by pooling 30 subjects after Hausdorff clustering. In link with this finding, we reflect on the different modeling frameworks that can allow for such scenarios: heteroclinic dynamics, dynamics with riddled basins of attraction, multiple-timescale dynamics. Finally, we characterize the metastable states both functionally and structurally, using templates for resting state networks (RSNs) and the automated anatomical labeling (AAL) atlas, respectively.

    in Frontiers in Computational Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse

    Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer’s disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered and its contribution to AD onset is currently unknown. Here, we observe decreased expression of SNX8 in human AD and AD mouse brain. SNX8 predominantly localized to early and late endosomes, where SNX8 overexpression enhanced total APP levels, cell surface APP distribution and consequent soluble APPα cleavage. SNX8 depletion resulted in elevated β-amyloid (Aβ) levels, while SNX8 overexpression reduced Aβ levels in cells and in an APP/PS1 AD mouse model. Importantly, SNX8 overexpression rescued cognitive impairment in APP/PS1 mice. Together, these results implicate a neuroprotective role for SNX8 in enhancing non-amyloidogenic APP trafficking and processing pathways. Given that endosomal dysfunction is an early event in AD, restoration of dysfunctional endosomal components such as SNX8 may be beneficial in future therapeutic strategies.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Excitability Tuning of Axons by Afterdepolarization

    The axon provides a sole output of the neuron which propagates action potentials reliably to the axon terminal and transmits neuronal information to the postsynaptic neuron across the synapse. A classical view of neuronal signaling is based on these two processes, namely binary (all or none) signaling along the axon and graded (tunable) signaling at the synapse. Recent studies, however, have revealed that the excitability of the axon is subject to dynamic tuning for a short period after axonal action potentials. This was first described as post-spike hyperexcitability, as measured by the changes in stimulus threshold for a short period after an action potential. Later on, direct recordings from central nervous system (CNS) axons or axon terminals using subcellular patch-clamp recording showed that axonal spikes are often followed by afterdepolarization (ADP) lasting for several tens of milliseconds and has been suggested to mediate post-spike hyperexcitability. In this review article, I focused on the mechanisms as well as the functional significance of ADP in fine-scale modulation of axonal spike signaling in the CNS, with special reference to hippocampal mossy fibers, one of the best-studied CNS axons. As a common basic mechanism underlying axonal ADP, passive propagation by the capacitive discharge of the axonal membrane as well as voltage-dependent K+ conductance underlies the generation of ADP. Small but prolonged axonal ADP lasting for several tens of milliseconds may influence the subsequent action potential and transmitter release from the axon terminals. Both duration and amplitude of axonal spike are subject to such modulation by preceding action potential-ADP sequence, deviating from the conventional assumption of digital nature of axonal spike signaling. Impact on the transmitter release is also discussed in the context of axonal spike plasticity. Axonal spike is subject to dynamic control on a fine-scale and thereby contributes to the short-term plasticity at the synapse.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Large-Scale Mapping of Axonal Arbors Using High-Density Microelectrode Arrays

    Understanding the role of axons in neuronal information processing is a fundamental task in neuroscience. Over the last years, sophisticated patch-clamp investigations have provided unexpected and exciting data on axonal phenomena and functioning, but there is still a need for methods to investigate full axonal arbors at sufficient throughput. Here, we present a new method for the simultaneous mapping of the axonal arbors of a large number of individual neurons, which relies on their extracellular signals that have been recorded with high-density microelectrode arrays (HD-MEAs). The segmentation of axons was performed based on the local correlation of extracellular signals. Comparison of the results with both, ground truth and receiver operator characteristics, shows that the new segmentation method outperforms previously used methods. Using a standard HD-MEA, we mapped the axonal arbors of 68 neurons in <6 h. The fully automated method can be extended to new generations of HD-MEAs with larger data output and is estimated to provide data of axonal arbors of thousands of neurons within recording sessions of a few hours.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Unique Features of Network Bursts Emerge From the Complex Interplay of Excitatory and Inhibitory Receptors in Rat Neocortical Networks

    Spontaneous network activity plays a fundamental role in the formation of functional networks during early development. The landmark of this activity is the recurrent emergence of intensive time-limited network bursts (NBs) rapidly spreading across the entire dissociated culture in vitro. The main excitatory mediators of NBs are glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-Methyl-D-aspartic-acid receptors (NMDARs) that express fast and slow ion channel kinetics, respectively. The fast inhibition of the activity is mediated through gamma-aminobutyric acid type A receptors (GABAARs). Although the AMPAR, NMDAR and GABAAR kinetics have been biophysically characterized in detail at the monosynaptic level in a variety of brain areas, the unique features of NBs emerging from the kinetics and the complex interplay of these receptors are not well understood. The goal of this study is to analyze the contribution of fast GABAARs on AMPAR- and NMDAR- mediated spontaneous NB activity in dissociated neonatal rat cortical cultures at 3 weeks in vitro. The networks were probed by both acute and gradual application of each excitatory receptor antagonist and combinations of acute excitatory and inhibitory receptor antagonists. At the same time, the extracellular network-wide activity was recorded with microelectrode arrays (MEAs). We analyzed the characteristic NB measures extracted from NB rate profiles and the distributions of interspike intervals, interburst intervals, and electrode recruitment time as well as the similarity of spatio-temporal patterns of network activity under different receptor antagonists. We show that NBs were rapidly initiated and recruited as well as diversely propagated by AMPARs and temporally and spatially maintained by NMDARs. GABAARs reduced the spiking frequency in AMPAR-mediated networks and dampened the termination of NBs in NMDAR-mediated networks as well as slowed down the recruitment of activity in all networks. Finally, we show characteristic super bursts composed of slow NBs with highly repetitive spatio-temporal patterns in gradually AMPAR blocked networks. To the best of our knowledge, this study is the first to unravel in detail how the three main mediators of synaptic transmission uniquely shape the NB characteristics, such as the initiation, maintenance, recruitment and termination of NBs in cortical cell cultures in vitro.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Accelerated Ovarian Failure as a Unique Model to Study Peri-Menopause Influence on Alzheimer’s Disease

    Despite decades of extensive research efforts, efficacious therapies for Alzheimer’s disease (AD) are lacking. The multi-factorial nature of AD neuropathology and symptomatology has taught us that a single therapeutic approach will most likely not fit all. Women constitute ~70% of the affected AD population, and pathology and rate of symptoms progression are 2–3 times higher in women than men. Epidemiological data suggest that menopausal estrogen loss may be causative of the more severe symptoms observed in AD women, however, results from clinical trials employing estrogen replacement therapy are inconsistent. AD pathological hallmarks—amyloid β (Aβ), neurofibrillary tangles (NFTs), and chronic gliosis—are laid down during a 20-year prodromal period before clinical symptoms appear, which coincides with the menopause transition (peri-menopause) in women (~45–54-years-old). Peri-menopause is marked by widely fluctuating estrogen levels resulting in periods of irregular hormone-receptor interactions. Recent studies showed that peri-menopausal women have increased indicators of AD phenotype (brain Aβ deposition and hypometabolism), and peri-menopausal women who used hormone replacement therapy (HRT) had a reduced AD risk. This suggests that neuroendocrine changes during peri-menopause may be a trigger that increases risk of AD in women. Studies on sex differences have been performed in several AD rodent models over the years. However, it has been challenging to study the menopause influence on AD due to lack of optimal models that mimic the human process. Recently, the rodent model of accelerated ovarian failure (AOF) was developed, which uniquely recapitulates human menopause, including a transitional peri-AOF period with irregular estrogen fluctuations and a post-AOF stage with low estrogen levels. This model has proven useful in hypertension and cognition studies with wild type animals. This review article will highlight the molecular mechanisms by which peri-menopause may influence the female brain vulnerability to AD and AD risk factors, such as hypertension and apolipoprotein E (APOE) genotype. Studies on these biological mechanisms together with the use of the AOF model have the potential to shed light on key molecular pathways underlying AD pathogenesis for the development of precision medicine approaches that take sex and hormonal status into account.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia

    Nowadays, Alzheimer’s disease (AD) is a severe sociological and clinical problem. Since it was first described, there has been a constant increase in its incidence and, for now, there are no effective treatments since current approved medications have only shown short-term symptomatic benefits. Therefore, it is imperative to increase efforts in the search for molecules and non-pharmacological strategies that are capable of slowing or stopping the progress of the disease and, ideally, to reverse it. The amyloid cascade hypothesis based on the fundamental role of amyloid has been the central hypothesis in the last 30 years. However, since amyloid-directed treatments have shown no relevant beneficial results other theories have been postulated to explain the origin of the pathology. The brain is a highly metabolically active energy-consuming tissue in the human body. It has an almost complete dependence on the metabolism of glucose and uses most of its energy for synaptic transmission. Thus, alterations on the utilization or availability of glucose may be cause for the appearance of neurodegenerative pathologies like AD. In this review article, the hypothesis known as Type 3 Diabetes (T3D) will be evaluated by summarizing some of the data that has been reported in recent years. According to published research, the adherence over time to low saturated fatty acids diets in the context of the Mediterranean diet would reduce the inflammatory levels in brain, with a decrease in the pro-inflammatory glial activation and mitochondrial oxidative stress. In this situation, the insulin receptor pathway would be able to fine tune the mitochondrial biogenesis in neuronal cells, regulation the adenosine triphosphate/adenosine diphosphate intracellular balance, and becoming a key factor involved in the preservation of the synaptic connexions and neuronal plasticity. In addition, new targets and strategies for the treatment of AD will be considered in this review for their potential as new pharmacological or non-pharmacological approaches.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Plasma Markers of Inflammation Linked to Clinical Progression and Decline During Preclinical AD

    Objective

    To examine the prospective association between blood biomarkers of immune functioning (i.e., innate immune activation, adaptive immunity, and inflammation) and subsequent cognitive decline and clinical progression to mild cognitive impairment (MCI) in cognitively normal individuals.

    Methods

    The BIOCARD study is an observational cohort study of N = 191 initially cognitively healthy participants (mean age 65.2 years). Blood plasma samples were assayed for markers of chronic inflammation (TNFR1, IL-6), adaptive immunity (CD25), and innate immune activation (CD14 and CD163). Participants were followed annually for ongoing clinical assessment and cognitive testing for up to 7.3 years. Primary study outcomes were progression to MCI and cognitive change over time, as measured by a global factor score encompassing multiple cognitive domains.

    Results

    Higher levels of plasma TNFR1 were associated with greater risk of progression from normal cognition to MCI (HR: 3.27; 95% confidence interval, CI: 1.27, 8.40). Elevated levels of TNFR1 were also associated with steeper rate of cognitive decline on follow-up but not with baseline cognitive performance. Baseline IL-6 levels and markers of innate and adaptive immune activation showed no relationship with MCI risk or cognitive decline.

    Conclusion

    Inflammation, mediated by TNF signaling, may play a selective role in the early phase of AD. Accordingly, plasma TNFR1 may facilitate improved prediction of disease progression for individuals in the preclinical stage of AD.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 06, 2019 12:00 AM.

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    Long-Lasting Input-Specific Experience-Dependent Changes of Hippocampus Synaptic Function Measured in the Anesthetized Rat

    Abstract

    How experience causes long-lasting changes in the brain is a central question in neuroscience. The common view is that synaptic function is altered by experience to change brain circuit functions that underlie conditioned behavior. We examined hippocampus synaptic circuit function in vivo, in three groups of animals, to assess the impact of experience on hippocampus function in rats. The "conditioned" group acquired a shock-conditioned place response during a cognitively-challenging, hippocampus synaptic plasticity-dependent task. The no-shock group had similar exposure to the environmental conditions but no conditioning. The home-cage group was experimentally naive. After the one-week retention test, under anesthesia, we stimulated the perforant path inputs to CA1, which terminate in stratum lacunosum moleculare (slm), and to the dentate gyrus (DG), which terminate in the molecular layer. We find synaptic compartment specific changes that differ amongst the groups. The evoked field EPSP (fEPSP) and pre-spike field response are enhanced only at the DG input layer and only in conditioned animals. The DG responses, measured by the population spiking activity and post-spike responses, are enhanced in both the conditioned and no-shock groups compared to home-cage animals. These changes are pathway specific because no differences are observed in slm of CA1. These findings demonstrate long-term, experience-dependent, pathway-specific alterations to synaptic circuit function of the hippocampus.

    in eNeuro current issue on September 05, 2019 04:30 PM.

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    Open Source Tools and Methods: A New Category of Short Papers to Share Knowledge, Accelerate Research, and Acknowledge Those Who Develop Such Tools and Methods

    in eNeuro current issue on September 05, 2019 04:30 PM.

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    Bursts with High and Low Load of Epileptiform Spikes Show Context-Dependent Correlations in Epileptic Mice

    Hypersynchronous network activity is the defining hallmark of epilepsy and manifests in a wide spectrum of phenomena, of which electrographic activity during seizures is only one extreme. The aim of this study was to differentiate between different types of epileptiform activity (EA) patterns and investigate their temporal succession and interactions. We analyzed local field potentials (LFPs) from freely behaving male mice that had received an intrahippocampal kainate injection to model mesial temporal lobe epilepsy (MTLE). Epileptiform spikes occurred in distinct bursts. Using machine learning, we derived a scale reflecting the spike load of bursts and three main burst categories that we labeled high-load, medium-load, and low-load bursts. We found that bursts of these categories were non-randomly distributed in time. High-load bursts formed clusters and were typically surrounded by transition phases with increased rates of medium-load and low-load bursts. In apparent contradiction to this, increased rates of low-load bursts were also associated with longer background phases, i.e., periods lacking high-load bursting. Furthermore, the rate of low-load bursts was more strongly correlated with the duration of background phases than the overall rate of epileptiform spikes. Our findings are consistent with the hypothesis that low-level EA could promote network stability but could also participate in transitions towards major epileptiform events, depending on the current state of the network.

    in eNeuro current issue on September 05, 2019 04:30 PM.

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    Stimulus-Locked Responses on Human Upper Limb Muscles and Corrective Reaches are Preferentially Evoked by Low Spatial Frequencies

    Abstract

    In situations requiring immediate action, humans can generate visually-guided responses at remarkably short latencies. Here, to better understand the visual attributes that best evoke such rapid responses, we recorded upper limb muscle activity while participants performed visually-guided reaches towards Gabor patches composed of differing spatial frequencies. We studied reaches initiated from a stable posture (experiment 1, a static condition), or during on-line reach corrections to an abruptly displaced target (experiment 2, a dynamic condition). In both experiments, we detail the latency and prevalence of stimulus-locked responses (SLRs), which are brief bursts of EMG activity that are time-locked to target presentation rather than movement onset. SLRs represent the first wave of EMG recruitment influenced by target presentation, and enable quantification of rapid visuomotor transformations. In both experiments, reach targets composed of low spatial frequencies elicited the shortest latency and most prevalent SLRs, with SLR latency increasing and SLR prevalence decreasing for reach targets composed of progressively higher spatial frequencies. SLRs could be evoked in either the static or dynamic condition, and when present in experiment 2, were associated with shorter latency and larger magnitude corrections. The results in experiment 2 are consistent with a linkage between the forces produced by SLRs and the earliest portion of on-line reach corrections. Overall, our results demonstrate that stimuli composed of low spatial frequencies preferentially evoke the most rapid visuomotor responses that, in the context of rapidly correcting an on-going reaching movement, are associated with earlier and larger on-line reach corrections.

    Significance Statement Humans have a remarkable capacity to respond quickly to changes in our visual environment. Although our visual world is composed of a range of spatial frequencies, surprisingly little is known about which frequencies preferentially evoke rapid reaching responses. Here, we systematically varied the spatial frequency of peripheral reach targets while measuring EMG activity on an upper limb muscle. We found that visual stimuli composed of low-spatial frequencies elicit the most rapid and robust EMG responses, and also elicit corrective reaches at shorter latencies. Thus, when time is of the essence, low spatial frequencies preferentially drive fast visuomotor responses.

    in RSS PAP on September 05, 2019 04:30 PM.

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    Automated Behavioral Experiments in Mice Reveal Periodic Cycles of Task Engagement within Circadian Rhythms

    Abstract

    High-throughput automated experiments accelerate discovery in neuroscience research and reduce bias. To enable high-throughput behavioral experiments, we developed a user-friendly and scalable automated system that can simultaneously train hundreds of mice on behavioral tasks, with time-stamped behavioral information recorded continuously for weeks. We trained 12 cages of C57Bl6/J mice (24 mice, 2 mice per cage) to perform auditory behavioral tasks. We found that circadian rhythms modulated overall behavioral activity as expected for nocturnal animals. However, auditory detection and discrimination accuracy remained consistently high in both light and dark cycles. We also found a periodic modulation of behavioral response rates only during the discrimination task, suggesting that the mice periodically reduce task-engagement (i.e., take ‘breaks’) when task difficulty increases due to the more complex stimulus-response paradigm for discrimination vs detection. Our results highlight how automated systems for continuous high-throughput behavioral experiments enable both efficient data collection and new observations on animal behavior.

    Significance Statement Automated high-throughput behavioral experiments in mice promise researchers the ability to quickly and reliably asses the behavior of large animal populations, while also minimizing experimenter-induced bias. However, the technical complexities of automation have limited widespread adoption of high-throughput behavioral methods. Here, we present a new tool for behavioral research, the ToneBox, which allows both novice and expert behaviorists to automatically test hundreds of mice simultaneously on different behavioral tasks. We provide manufacturing specifications and detailed documentation of system operation. Using C57Bl6/J mice we show that the ToneBox tracks circadian cycles via behavioral response rates, and that task difficultly modulates duty-cycles of task-engagement.

    in RSS PAP on September 05, 2019 04:30 PM.

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    Hypoxia Inducible Factor 1 alpha (HIF-1{alpha}) counteracts the acute death of cells transplanted into the injured spinal cord

    ABSTRACT

    Cellular transplantation is in clinical testing for a number of central nervous system disorders, including spinal cord injury (SCI). One challenge is acute transplanted cell death. To prevent this death, there is a need to both establish when the death occurs and develop approaches to mitigate its effects. Here, using luciferase (luc) and green fluorescent protein (GFP) expressing Schwann cell (SC) transplants in the contused thoracic rat spinal cord 7 days post-injury, we establish via in vivo bioluminescent (IVIS) imaging and stereology that cell death occurs prior to 2-3 days post-implantation. We then test an alternative approach to the current paradigm of enhancing transplant survival by including multiple factors along with the cells. To stimulate multiple cellular adaptive pathways concurrently, we activate the hypoxia inducible factor 1 alpha (HIF-1α) transcriptional pathway. Retroviral expression of VP16-HIF-1α in SCs increased HIF-α by 5.9-fold and its target genes implicated in oxygen transport and delivery (VEGF, 2.2-fold) and cellular metabolism (enolase, 1.7-fold). In cell death assays in vitro, HIF-1α protected cells from H2O2-induced oxidative damage. It also provided some protection against camptothecin-induced DNA damage, but not thapsigargin-induced endoplasmic reticulum stress or tunicamycin-induced unfolded protein response. Following transplantation, VP16-HIF-1α increased SC survival by 34.3%. The increase in cell survival was detectable by stereology, but not by in vivo luciferase or ex vivo GFP IVIS imaging. The results support the hypothesis that activating adaptive cellular pathways enhances transplant survival and identifies an alternative pro-survival approach that, with optimization, could be amenable to clinical translation.

    SIGNIFICANCE STATEMENT To maximize the benefits of cellular transplants for human therapeutic use, there is a critical need to develop strategies that effectively promote transplant survival and permit rapid assessment of transplant survival. The current study: 1) identifies the narrow time window in which transplanted cells die within the injured rat spinal cord, thus establishing the time window in which cytoprotection should be targeted to counteract transplanted cell death; 2) tests the effects of elevating HIF-1α on spinal cord transplant survival, thus demonstrating that activating adaptive transcriptional pathways is protective in SCI, and; 3) demonstrates, by comparing three approaches to quantifying transplant survival, that until faster and more sensitive methods can be developed, stereology remains the most reliable method.

    in RSS PAP on September 05, 2019 04:30 PM.

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    Neuroinflammation and Functional Connectivity in Alzheimer's Disease: Interactive Influences on Cognitive Performance

    Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease (AD). We tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [11C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 patients (12 females/16 males) with clinical diagnosis of probable AD or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy controls (8 females/6 males). Source-based "inflammetry" was used to extract principal components of [11C]PK11195 PET signal variance across all participants. rs-fMRI data were preprocessed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal covariance between neuroinflammation and brain connectivity profiles, in relation to the diagnostic group (patients, controls) and cognitive status.

    Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, frontal, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.

    Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer's disease. Neuroinflammation, and its association with functionally-relevant reorganization of brain networks, is proposed as a target for emerging immunotherapeutic strategies aimed at preventing or slowing the emergence of dementia.

    SIGNIFICANCE STATEMENT Neuroinflammation is an important aspect of Alzheimer's disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit. Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between neuro inflammation and functional network connectivity is relevant to cognitive impairment. We suggest that future studies should address how neuroinflammation relates to network function as AD progresses, and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.

    in Journal of Neuroscience current issue on September 04, 2019 04:30 PM.

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    Indirect Medium Spiny Neurons in the Dorsomedial Striatum Regulate Ethanol-Containing Conditioned Reward Seeking

    Adenosine 2A receptor (A2AR)-containing indirect medium spiny neurons (iMSNs) in the dorsomedial striatum (DMS) contribute to reward-seeking behaviors. However, those roles for ethanol-seeking behaviors remain unknown. To investigate ethanol-seeking behaviors, we used an ethanol-containing reward (10% ethanol and 10% sucrose solution; 10E10S). Upon conditioning with 10E10S, mice that initially only preferred 10% sucrose, not 10E10S, showed a stronger preference for 10E10S. Then, we investigated whether the manipulation of the DMS–external globus pallidus (GPe) iMSNs circuit alters the ethanol-containing reward (10E10S) seeking behaviors using the combination of pharmacologic and optogenetic approaches. DMS A2AR activation dampened operant conditioning-induced ethanol-containing reward, whereas A2AR antagonist abolished the effects of the A2AR agonist and restored ethanol-containing reward-seeking. Moreover, pre-ethanol exposure potentiated the A2AR-dependent reward-seeking. Interestingly, mice exhibiting ethanol-containing reward-seeking showed the reduction of the DMS iMSNs activity, suggesting that disinhibiting iMSNs decreases reward-seeking behaviors. In addition, we found that A2AR activation reversed iMSNs neural activity in the DMS. Similarly, optogenetic stimulation of the DMS-GPe iMSNs reduced ethanol-containing reward-seeking, whereas optogenetic inhibition of the DMS-GPe iMSNs reversed this change. Together, our study demonstrates that DMS A2AR and iMSNs regulate ethanol-containing reward-seeking behaviors.

    SIGNIFICANCE STATEMENT Our findings highlight the mechanisms of how operant conditioning develops the preference of ethanol-containing conditioned reward. Mice exhibiting ethanol-containing reward-seeking showed a reduction of the indirect medium spiny neuronal activity in the dorsomedial striatum. Pharmacological activation of adenosine A2A receptor (A2AR) or optogenetic activation of indirect medium spiny neurons dampened operant conditioned ethanol-containing reward-seeking, whereas inhibiting this neuronal activity restored ethanol-containing reward-seeking. Furthermore, repeated intermittent ethanol exposure potentiated A2AR-dependent reward-seeking. Therefore, our finding suggests that A2AR-containing indirect medium spiny neuronal activation reduces ethanol-containing reward-seeking, which may provide a potential therapeutic target for alcohol use disorder.

    in Journal of Neuroscience current issue on September 04, 2019 04:30 PM.

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    Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

    Clinical and experimental data indicate striatal cholinergic dysfunction in dystonia, a movement disorder typically resulting in twisted postures via abnormal muscle contraction. Three forms of isolated human dystonia result from mutations in the TOR1A (DYT1), THAP1 (DYT6), and GNAL (DYT25) genes. Experimental models carrying these mutations facilitate identification of possible shared cellular mechanisms. Recently, we reported elevated extracellular striatal acetylcholine by in vivo microdialysis and paradoxical excitation of cholinergic interneurons (ChIs) by dopamine D2 receptor (D2R) agonism using ex vivo slice electrophysiology in Dyt1GAG/+ mice. The paradoxical excitation was caused by overactive muscarinic receptors (mAChRs), leading to a switch in D2R coupling from canonical Gi/o to noncanonical β-arrestin signaling. We sought to determine whether these mechanisms in Dyt1GAG/+ mice are shared with Thap1C54Y/+ knock-in and Gnal+/– knock-out dystonia models and to determine the impact of sex. We found Thap1C54Y/+ mice of both sexes have elevated extracellular striatal acetylcholine and D2R-induced paradoxical ChI excitation, which was reversed by mAChR inhibition. Elevated extracellular acetylcholine was absent in male and female Gnal+/– mice, but the paradoxical D2R-mediated ChI excitation was retained and only reversed by inhibition of adenosine A2ARs. The Gi/o-preferring D2R agonist failed to increase ChI excitability, suggesting a possible switch in coupling of D2Rs to β-arrestin, as seen previously in a DYT1 model. These data show that, whereas elevated extracellular acetylcholine levels are not always detected across these genetic models of human dystonia, the D2R-mediated paradoxical excitation of ChIs is shared and is caused by altered function of distinct G-protein-coupled receptors.

    SIGNIFICANCE STATEMENT Dystonia is a common and often disabling movement disorder. The usual medical treatment of dystonia is pharmacotherapy with nonselective antagonists of muscarinic acetylcholine receptors, which have many undesirable side effects. Development of new therapeutics is a top priority for dystonia research. The current findings, considered in context with our previous investigations, establish a role for cholinergic dysfunction across three mouse models of human genetic dystonia: DYT1, DYT6, and DYT25. The commonality of cholinergic dysfunction in these models arising from diverse molecular etiologies points the way to new approaches for cholinergic modulation that may be broadly applicable in dystonia.

    in Journal of Neuroscience current issue on September 04, 2019 04:30 PM.

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    Perirhinal circuits for memory processing

    Nature Reviews Neuroscience, Published online: 04 September 2019; doi:10.1038/s41583-019-0213-6

    The perirhinal cortex forms part of the medial temporal lobe and has an established role in episodic memory formation. Yasushi Miyashita reviews the neural circuitry and the function of the perirhinal cortex and proposes that it acts as a hub linking episodic and semantic memory.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on September 04, 2019 12:00 AM.

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    Neuronal Avalanches in Input and Associative Layers of Auditory Cortex

    The primary auditory cortex processes acoustic sequences for the perception of behaviorally meaningful sounds such as speech. Sound information arrives at its input layer four from where activity propagates to associative layer 2/3. It is currently not known whether there is a characteristic organization of neuronal population activity across layers and sound levels during sound processing. Here, we identify neuronal avalanches, which in theory and experiments have been shown to maximize dynamic range and optimize information transfer within and across networks, in primary auditory cortex. We used in vivo 2-photon imaging of pyramidal neurons in cortical layers L4 and L2/3 of mouse A1 to characterize the populations of neurons that were active spontaneously, i.e., in the absence of a sound stimulus, and those recruited by single-frequency tonal stimuli at different sound levels. Single-frequency sounds recruited neurons of widely ranging frequency selectivity in both layers. We defined neuronal ensembles as neurons being active within or during successive temporal windows at the temporal resolution of our imaging. For both layers, neuronal ensembles were highly variable in size during spontaneous activity as well as during sound presentation. Ensemble sizes distributed according to power laws, the hallmark of neuronal avalanches, and were similar across sound levels. Avalanches activated by sound were composed of neurons with diverse tuning preference, yet with selectivity independent of avalanche size. Our results suggest that optimization principles identified for avalanches guide population activity in L4 and L2/3 of auditory cortex during and in-between stimulus processing.

    in Frontiers in Systems Neuroscience | New and Recent Articles on September 04, 2019 12:00 AM.

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    Genome-Wide Alteration of 5-Hydroxymethylcytosine in Hypoxic-Ischemic Neonatal Rat Model of Cerebral Palsy

    Cerebral palsy (CP) is a neurodevelopmental disorder usually occurring early in life and persisting through the whole life. Several risk factors, including perinatal hypoxia-ischemia (HI), may contribute to occurrence of CP in preterm infants. DNA hydroxymethylation has been shown to play an important role in neurodevelopment and neurodegenerative disorders. However, the effect of DNA hydroxymethylation in CP remains unknown. The aim of this study is to explore whether and how DNA hydroxymethylation is involved in CP pathogenesis. We observed that overall 5-hydroxymethylcytosine (5hmC) abundance in the cortex of the temporal lobe of rat pups was decreased significantly after hypoxic-ischemic injury, and the reduced expression of Tet1 and Tet2 enzymes might be responsible for this change. Identified differential hydroxymethylation regions (DhMRs) were richly involved in multiple signaling pathways related to neuronal development and function. Furthermore, we found that reduced 5hmC modification on the DhMRs-related genes were accompanied by decrease of their mRNA expression levels. These results suggest that 5hmC modifications are involved in the CP pathogenesis and may potentially serve as a new therapeutic target.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on September 04, 2019 12:00 AM.

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    Dynamic Orchestration of Brains and Instruments During Free Guitar Improvisation

    Playing music in ensemble requires enhanced sensorimotor coordination and the non-verbal communication of musicians that need to coordinate their actions precisely with those of others. As shown in our previous studies on guitar duets, and also on a guitar quartet, intra- and inter-brain synchronization plays an essential role during such interaction. At the same time, sensorimotor coordination as an essential part of this interaction requires being in sync with the auditory signals coming from the played instruments. In this study, using acoustic recordings of guitar playing and electroencephalographic (EEG) recordings of brain activity from guitarists playing in duet, we aimed to explore whether the musicians' brain activity synchronized with instrument sounds produced during guitar playing. To do so, we established an analytical method based on phase synchronization between time-frequency transformed guitar signals and raw EEG signals. Given phase synchronization, or coupling between guitar and brain signals, we constructed so-called extended hyper-brain networks comprising all possible interactions between two guitars and two brains. Applying a graph-theoretical approach to these networks assessed across time, we present dynamic changes of coupling strengths or dynamic orchestration of brains and instruments during free guitar improvisation for the first time. We also show that these dynamic network topology changes are oscillatory in nature and are characterized by specific spectral peaks, indicating the temporal structure in the synchronization patterns between guitars and brains. Moreover, extended hyper-brain networks exhibit specific modular organization varying in time, and binding each time, different parts of the network into the modules, which were mostly heterogeneous (i.e., comprising signals from different instruments and brains or parts of them). This suggests that the method capturing synchronization between instruments and brains when playing music provides crucial information about the underlying mechanisms. We conclude that this method may be an indispensable tool in the investigation of social interaction, music therapy, and rehabilitation dynamics.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on September 04, 2019 12:00 AM.

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    Evaluating Mental Load During Realistic Driving Simulations by Means of Round the Ear Electrodes

    Film based round the ear electrodes (cEEGrids) provide both, the accessibility of unobtrusive mobile EEG as well as a rapid EEG application in stationary settings when extended measurements are not possible. In a large-scale evaluation of driving abilities of older adults (N > 350) in a realistic driving simulation, we evaluated to what extent mental demands can be measured using cEEGrids in a completely unrestricted environment. For a first frequency-based analysis, the driving scenario was subdivided into different street segments with respect to their task loads (low, medium, high) that was a priori rated by an expert. Theta activity increased with task load but no change in Alpha power was found. Effects gained clarity after removing pink noise effects, that were potentially high in this data set due to motion artifacts. Theta fraction increased with task load and Alpha fraction decreased. We mapped this effect to specific street segments by applying a track-frequency analysis. Whilst participants drove with constant speed and without high steering wheel activity, Alpha was high and theta low. The reverse was the case in sections that required either high activity or increased attentional allocation to the driving context. When calculating mental demands for different street segments based on EEG, this measure is highly significant correlated with the experts’ rating of task load. Deviances can be explained by specific features within the segments. Thus, modulations in spectral power of the EEG were validly reflected in the cEEGrids data. All findings were in line with the prominent literature in the field. The results clearly demonstrate the usability of this low-density EEG method for application in real-world settings where an increase in ecological validity might outweigh the loss of certain aspects of internal validity.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 04, 2019 12:00 AM.

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    Impairment of Mitochondrial Redox Status in Peripheral Lymphocytes of Multiple Sclerosis Patients

    Literature suggests that oxidative stress (OS) may be involved in the pathogenesis of multiple sclerosis (MS), in which the immune system is known to play a key role. However, to date, the OS in peripheral lymphocytes and its contribution to the disease remain unknown. The aim of the present study was to explore the influence of OS in peripheral lymphocytes of MS patients. To that end, a cross-sectional, observational pilot study was conducted [n = 58: 34 MS and 24 healthy subjects (control group)]. We have measured superoxide production and protein mitochondrial complex levels in peripheral blood mononuclear cells (PBMCs) isolated from MS patients and control. Lactate levels and the antioxidant capacity were determined in plasma. We adjusted the comparisons between study groups by age, sex and cell count according to case. Results demonstrated that PBMCs, specifically T cells, from MS patients exhibited significantly increased superoxide anion production compared to control group (p = 0.027 and p = 0.041, respectively). Increased superoxide production in PBMCs was maintained after the adjustment (p = 0.044). Regarding mitochondrial proteins, we observe a significant decrease in the representative protein content of the mitochondrial respiratory chain complexes I-V in PBMCs of MS patients (p = 0.002, p = 0.037, p = 0.03, p = 0.044, and p = 0.051, respectively), which was maintained for complexes I, III, and V after the adjustment (p = 0.026; p = 0.033; p = 0.033, respectively). In MS patients, a trend toward increased plasma lactate concentration was detected [8.04 mg lactate/dL (5.25, 9.49) in the control group, 11.36 mg lactate/dL (5.41, 14.81) in MS patients] that was statistically significant after the adjustment (p = 0.013). This might be indicative of compromised mitochondrial function. Finally, antioxidant capacity was also decreased in plasma from MS patients, both before (p = 0.027) and after adjusting for sex and age (p = 0.006). Our findings demonstrate that PBMCs of MS patients show impaired mitochondrial redox status and deficient antioxidant capacity. These results demonstrate for the first time the existence of mitochondrial alterations in the cells immune cells of MS patients already at the peripheral level.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 04, 2019 12:00 AM.

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    Profiles of 14-3-3 and Total Tau in CSF Samples of Chinese Patients of Different Genetic Prion Diseases

    Background

    The abnormal alterations of proteins 14-3-3 and tau in cerebrospinal fluid (CSF) are widely used for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), while the situations of CSF biomarkers in genetic prion diseases (gPrDs), particularly in Chinese gPrDs patients, have not been well documented.

    Methods

    Here, with the help of commercial 14-3-3 and total tau ELISA kits, we evaluated the levels of proteins 14-3-3 and tau in the CSF samples of 140 Chinese patients of 14 different types of gPrDs.

    Results

    We found that CSF 14-3-3 ELISA values in the patients with P102L GSS and D178N FFI were remarkably low, while those in the patients with T188K, E196A, and E200K gCJD were relatively high. Linear correlation assays identified a positive correlation between positive rate in Western blot (WB) and ELISA values of CSF 14-3-3. ELISA assays for total tau in CSF samples identified relatively high levels in the cases of T188K, E196A, and E200K gCJD (median: 133840.81, 159992.80, and 153342.92 AU/ml), but relatively low levels in those of P102L GSS and D178N FFI (median: 64397.77 and 43856.79 AU/ml).

    Conclusion

    These data illustrate heterogeneous profiles of CSF 14-3-3 and tau in various types of gPrDs, depending on the differences in the mutations in PRNP.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 04, 2019 12:00 AM.

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    Increased Serum Levels of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Subjects With Parkinson’s Disease

    Background

    Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) promote the survival of midbrain dopamine neurons in animal models of Parkinson’s disease (PD). However, little is known about endogenous concentrations of MANF and CDNF in human PD patients, and their relation to PD pathogenesis. Our main objective was to study whether circulating concentrations of MANF and CDNF differ between PD patients and controls, and if they correlate with clinical parameters. Levels of circulating CDNF were studied for the first time.

    Methods

    MANF and CDNF levels were measured from serum samples of 34 PD patients and 35 controls using validated in-lab-designed enzyme-linked immunosorbent assay (ELISAs). MANF and CDNF mRNA levels in whole blood samples of 60 PD patients and 30 controls were measured by quantitative real time polymerase chain reaction (qRT-PCR). MANF concentrations in different blood cell types were measured by ELISA.

    Results

    Circulating MANF concentrations were significantly higher in PD patients compared to controls (P < 0.001) and were positively correlated with Beck Depression Inventory (BDI) depression rating. MANF protein was present in blood cells, however, MANF mRNA levels in the blood did not differ between PD patients and controls (P = 0.44). The mean concentration of serum CDNF was 33 pg/ml in the controls. CDNF levels were not altered in PD patients (P = 0.25).

    Conclusion

    MANF but not CDNF level was increased in the blood of PD patients. It would be interesting to examine the blood level of MANF from early stage PD patients in future studies to test whether MANF can be used as a clinical marker of PD.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 04, 2019 12:00 AM.

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    Vagus Nerve Stimulation in Rodent Models: An Overview of Technical Considerations

    Over the last several decades, vagus nerve stimulation (VNS) has evolved from a treatment for select neuropsychiatric disorders to one that holds promise in treating numerous inflammatory conditions. Growing interest has focused on the use of VNS for other indications, such as heart failure, rheumatoid arthritis, inflammatory bowel disease, ischemic stroke, and traumatic brain injury. As pre-clinical research often guides expansion into new clinical avenues, animal models of VNS have also increased in recent years. To advance this promising treatment, however, there are a number of experimental parameters that must be considered when planning a study, such as physiology of the vagus nerve, electrical stimulation parameters, electrode design, stimulation equipment, and microsurgical technique. In this review, we discuss these important considerations and how a combination of clinically relevant stimulation parameters can be used to achieve beneficial therapeutic results in pre-clinical studies of sub-acute to chronic VNS, and provide a practical guide for performing this work in rodent models. Finally, by integrating clinical and pre-clinical research, we present indeterminate issues as opportunities for future research.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on September 04, 2019 12:00 AM.

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    Intrinsic Frequencies of the Resting-State fMRI Signal: The Frequency Dependence of Functional Connectivity and the Effect of Mode Mixing

    The frequency characteristics of the resting-state BOLD fMRI (rs-fMRI) signal are of increasing scientific interest, as we discover more frequency-specific biological interpretations. In this work, we use variational mode decomposition (VMD) to precisely decompose the rs-fMRI time series into its intrinsic mode functions (IMFs) in a data-driven manner. The accuracy of the VMD decomposition of constituent IMFs is verified through simulations, with higher reconstruction accuracy and much-reduced mode mixing relative to previous methods. Furthermore, we examine the relative contribution of the VMD-derived modes (frequencies) to the rs-fMRI signal as well as functional connectivity measurements. Our primary findings are: (1) The rs-fMRI signal within the 0.01–0.25 Hz range can be consistently characterized by four intrinsic frequency clusters, centered at 0.028 Hz (IMF4), 0.080 Hz (IMF3), 0.15 Hz (IMF2) and 0.22 Hz (IMF1); (2) these frequency clusters were highly reproducible, and independent of rs-fMRI data sampling rate; (3) not all frequencies were associated with equivalent network topology, in contrast to previous findings. In fact, while IMF4 is most likely associated with physiological fluctuations due to respiration and pulse, IMF3 is most likely associated with metabolic processes, and IMF2 with vasomotor activity. Both IMF3 and IMF4 could produce the brain-network topology typically observed in fMRI, whereas IMF1 and IMF2 could not. These findings provide initial evidence of feasibility in decomposing the rs-fMRI signal into its intrinsic oscillatory frequencies in a reproducible manner.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on September 04, 2019 12:00 AM.

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    Valproic Acid Enhances Reprogramming Efficiency and Neuronal Differentiation on Small Molecules Staged-Induction Neural Stem Cells: Suggested Role of mTOR Signaling

    Inducing somatic cells into neural stem cells (iNSCs) in specific ways provides a new cell therapy in a variety of neurological diseases. In the past, iNSCs were generated by transcription factors which increased the risk of mutagenesis, tumor formations, and immune reactions by viral transduction vectors. Therefore, in this study, different small molecules were used to induce mouse embryonic fibroblasts (MEFs) into iNSCs in different reprogramming stages, which showed high reprogramming efficiency without altering the genome. We demonstrated that the small molecules staged-induction neural stem cells (SMSINS) have the characteristics of neural stem cells (NSCs) in morphology, gene expression, self-renewal and differentiation potential. Furthermore, valproic acid (VPA), one of small molecules, was showed to enhance neural induction with highest efficiency compared with six other small molecules, which were also investigated in the present study. Moreover, our results suggested that activating the mammalian target of rapamycin (mTOR) signaling enhanced the induction efficiency and neuronal differentiation. Collectively, our findings indicated that using this induction program allowed us to obtain safe and efficient iNSCs which were free of genetic manipulation. The VPA-mediated mTOR signaling pathway may enhance reprogramming efficiency and neuronal differentiation. So we suggested that this program could be a new method of obtaining iNSCs for the treatment of neurological diseases by cell replacement therapy in the future.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on September 04, 2019 12:00 AM.

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    Recommendations for Processing Head CT Data

    Many research applications of neuroimaging use magnetic resonance imaging (MRI). As such, recommendations for image analysis and standardized imaging pipelines exist. Clinical imaging, however, relies heavily on X-ray computed tomography (CT) scans for diagnosis and prognosis. Currently, there is only one image processing pipeline for head CT, which focuses mainly on head CT data with lesions. We present tools and a complete pipeline for processing CT data, focusing on open-source solutions, that focus on head CT but are applicable to most CT analyses. We describe going from raw DICOM data to a spatially normalized brain within CT presenting a full example with code. Overall, we recommend anonymizing data with Clinical Trials Processor, converting DICOM data to NIfTI using dcm2niix, using BET for brain extraction, and registration using a publicly-available CT template for analysis.

    in Frontiers in Neuroinformatics | New and Recent Articles on September 04, 2019 12:00 AM.

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    Increases in Theta Oscillatory Activity During Episodic Memory Retrieval Following Mindfulness Meditation Training

    Mindfulness meditation has been shown to improve episodic memory and increase theta oscillations which are known to play a role in episodic memory retrieval. The present study examined the effect of mindfulness meditation on episodic memory retrieval and theta oscillations. Using a longitudinal design, subjects in the mindfulness meditation experimental group who underwent 4 weeks of mindfulness meditation training and practice were compared to a waitlist control group. During the pre-training and post-training experimental sessions, subjects completed the Five Facet Mindfulness Questionnaire (FFMQ) and studied adjectives and either imagined a scene (Place Task) or judged its pleasantness (Pleasant Task). During the recognition test, subjects decided which task was performed with each word (“Old Place Task” or “Old Pleasant Task”) or “New.” FFMQ scores and source discrimination were greater post-training than pre-training in the mindfulness meditation experimental group. Electroencephalography (EEG) results revealed that for the mindfulness meditation experimental group theta power was greater post-training than pre-training in right frontal and left parietal channels and changes in FFMQ scores correlated with changes in theta oscillations in right frontal channels (n = 20). The present results suggest that mindfulness meditation increases source memory retrieval and theta oscillations in a fronto-parietal network.

    in Frontiers in Human Neuroscience | New and Recent Articles on September 04, 2019 12:00 AM.

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    Controlling Synchronization of Spiking Neuronal Networks by Harnessing Synaptic Plasticity

    Disrupting the pathological synchronous firing patterns of neurons with high frequency stimulation is a common treatment for Parkinsonian symptoms and epileptic seizures when pharmaceutical drugs fail. In this paper, our goal is to design a desynchronization strategy for large networks of spiking neurons such that the neuronal activity of the network remains in the desynchronized regime for a long period of time after the removal of the stimulation. We develop a novel “Forced Temporal-Spike Time Stimulation (FTSTS)” strategy that harnesses the spike-timing dependent plasticity to control the synchronization of neural activity in the network by forcing the neurons in the network to artificially fire in a specific temporal pattern. Our strategy modulates the synaptic strengths of selective synapses to achieve a desired synchrony of neural activity in the network. Our simulation results show that the FTSTS strategy can effectively synchronize or desynchronize neural activity in large spiking neuron networks and keep them in the desired state for a long period of time after the removal of the external stimulation. Using simulations, we demonstrate the robustness of our strategy in desynchronizing neural activity of networks against uncertainties in the designed stimulation pulses and network parameters. Additionally, we show in simulation, how our strategy could be incorporated within the existing desynchronization strategies to improve their overall efficacy in desynchronizing large networks. Our proposed strategy provides complete control over the synchronization of neurons in large networks and can be used to either synchronize or desynchronize neural activity based on specific applications. Moreover, it can be incorporated within other desynchronization strategies to improve the efficacy of existing therapies for numerous neurological and psychiatric disorders associated with pathological synchronization.

    in Frontiers in Computational Neuroscience | New and Recent Articles on September 04, 2019 12:00 AM.

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    Normal and Pathological Tau Uptake Mediated by M1/M3 Muscarinic Receptors Promotes Opposite Neuronal Changes

    The microtubule associated protein tau is mainly found in the cell’s cytosol but recently it was also shown in the extracellular space. In neurodegenerative diseases, like Alzheimer’s disease (AD), pathological tau spreads from neuron to neuron enhancing neurodegeneration. Here, we show that HEK293 cells and neurons in culture uptake extracellular normal and pathological Tau. Muscarinic receptor antagonists atropine and pirenzepine block 80% this uptake. CHO cells do not express these receptors therefore cannot uptake tau, unless transfected with M1 and/or M3 receptor. These results strongly suggest that muscarinic receptors mediate this process. Uptake of normal tau in neurons enhances neuronal process formation but a pseudophosphorylated form of tau (pathological human tau, PH-Tau) disrupts them and accumulates in the somatodendritic compartment. AD hyperphosphorylated tau (AD P-Tau) has similar effects as PH-Tau on cultured neurons. Addition of either PH-Tau or AD P-tau to neuronal cultures induced microglial activation. In conclusion, uptake of extracellular tau is mediated by muscarinic receptors with opposite effects: normal tau stabilizes neurites; whereas pathological tau disrupts this process leading to neurodegeneration.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on September 04, 2019 12:00 AM.

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    Memory Decline and Behavioral Inflexibility in Aged Mice Are Correlated With Dysregulation of Protein Synthesis Capacity

    Understanding the molecular mechanisms underlying age-associated cognitive impairments will not only contribute to our general knowledge about “aging” biology, but also provide insights for more effective strategies to prevent and improve the quality of life for both normal aging and pathological aging such as Alzheimer’s disease (AD). Here we first assessed and compared the performance of cognition and synaptic plasticity in young (3–5-month old) and aged c57BL/6J mice (19–21 months old). Findings from behavioral tests demonstrated that old mice, compared to young mice, displayed impairments in spatial learning/memory, working memory, and behavioral flexibility. Further, synaptic electrophysiology experiments on hippocampal slices revealed that the early form of long-term potentiation (LTP, a synaptic model for memory formation) was inhibited in old mice. At the molecular level, biochemical assays on the hippocampus showed dysregulation of signaling pathways controlling protein synthesis capacity including: up-regulation of AKT-mTORC1-p70S6K signaling, which is associated with translation of terminal oligopyrimidine (TOP) class of mRNAs that encode translational machinery; hyper-phosphorylation of mRNA translational elongation factor 2 (eEF2) and its upstream regulator AMP-activated protein kinase (AMPK), indicating repression of general protein synthesis. Moreover, young and old mice exhibited similar brain levels of translational initiation factor 2α (eIF2α) phosphorylation, which is known to be increased in AD and linked to the disease pathophysiology. Thus, our data provide evidence at the molecular level to highlight the similarity and difference between normal and pathological aging, which may contribute to future studies on diagnostic/prognostic biomarkers for aging-related dementia syndromes.

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 04, 2019 12:00 AM.

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    Differential Associations Between Volumes of Atrophic Cortical Brain Regions and Memory Performances in Early and Late Mild Cognitive Impairment

    Background

    Early and late mild cognitive impairment (MCI) patients have been reported to have a distinctive prognosis of converting to Alzheimer’s disease.

    Objective

    To evaluate the difference in gray matter volume and assess the association between cognitive function evaluated by comprehensive cognitive function test, and cortical thickness across healthy controls (HCs) (n = 37), early (n = 30), and late MCI patients (n = 35).

    Methods

    Differences in gray matter volume were evaluated by whole brain voxel-based morphometry across the groups. Multiple regression analysis was used to analyze group by memory performance interactions for the normalized gray matter volume.

    Results

    The early MCI group showed reduced gray matter volume in the right middle temporal gyrus in comparison to the HC group. The late MCI group displayed atrophy in the left parahippocampal gyrus in comparison to the HC group. Late MCI patients exhibited a decreased gray matter volume in the left fusiform gyrus in comparison to patients in the early MCI group (Monte Carlo simulation corrected p < 0.01, Tukey post hoc tests). Furthermore, there was a significant group (HC vs. early MCI) by memory performance interaction for the normalized cortical volume of the right middle temporal gyrus. Additionally, a significant group (early MCI vs. late MCI) by memory performance interaction was found for the normalized gray matter volume of the left fusiform gyrus (p < 0.001).

    Conclusion

    Early and late MCI patients showed distinctive associations of gray matter volumes in compensatory brain regions with memory performances. The findings can contribute to a better understanding of the structural changes in compensatory brain regions to elucidate memory decline in the trajectory of the subdivided prodromal stages of the Alzheimer’s disease (AD).

    in Frontiers in Aging Neuroscience | New and Recent Articles on September 04, 2019 12:00 AM.

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    Device Removal Following Brain Implant Research

    The development of implanted neural devices to manage neurological and psychiatric disorders or to restore loss of physiological function is a rapidly advancing area of neuroscience research. Sierra-Mercado, Zuk, et al. consider whether investigators of brain implant studies have an obligation to facilitate device explantation for participants who request it at study conclusion.

    in Neuron on September 04, 2019 12:00 AM.

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    A Circuit Perspective on State-Dependent Effects of Dopamine Stimulants

    Drugs often target multiple neuronal types. Thus, their behavioral effects may vary according to brain-state-dependent inter-neuronal interactions. In this issue of Neuron, Alhadeff et al. (2019) document hunger and dopamine-dependent alcohol effects, revealing specific circuit-level determinants of variable drug outcomes.

    in Neuron on September 04, 2019 12:00 AM.

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    Memo1 Tiles the Radial Glial Cell Grid

    What are the mechanisms regulating the orderly buildup of the laminated cerebral cortex during development? In this issue of Neuron, Nakagawa et al. (2019) discovered that Memo1 plays a crucial role by mediating the tiling of the radial glial cell grid.

    in Neuron on September 04, 2019 12:00 AM.

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    NO Hemodynamic Speed Limit for Hippocampal Neurogenesis

    In this issue of Neuron, Shen et al. (2019) address the coupling between vascular flow and neurogenic output, showing that pre-existing hippocampal circuits modulate hemodynamics in a NO-dependent manner to promote IGF-1-dependent survival of newly generated neuroblasts.

    in Neuron on September 04, 2019 12:00 AM.

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    Bringing Order out of Chaos: Establishing an Epistatic Relationship between CD33 and TREM2

    TREM2 and CD33 are microglial receptors associated with Alzheimer’s disease (AD) risk. In this issue of Neuron, Griciuc et al. (2019) demonstrate opposing effects of CD33 and TREM2 on AD phenotypes, where CD33 deletion promotes neuroprotection in a manner dependent on TREM2.

    in Neuron on September 04, 2019 12:00 AM.

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    The Value of Persistent Value

    In this issue of Neuron, Bari et al. (2019) show that neurons in medial frontal cortex, but not a nearby premotor area, encode the relative value of available options with long-lasting persistent activity states during naturalistic foraging. These long-lasting activity states serve to preferentially guide choices to more likely rewarded options.

    in Neuron on September 04, 2019 12:00 AM.

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    Mechanisms of Pathogen Invasion into the Central Nervous System

    Cain et al. provide a comprehensive overview of our current knowledge of the mechanisms by which neurotropic pathogens gain access into the CNS, including those that may be exploited for drug delivery.

    in Neuron on September 04, 2019 12:00 AM.

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    Thalamocortical Circuit Motifs: A General Framework

    Halassa and Sherman highlight the role of the thalamus in cortical function and the lack of knowledge surrounding thalamocortical connectivity at single-cell resolution. They propose thalamocortical motifs as units of organization with potential to inform cognitively relevant functional models.

    in Neuron on September 04, 2019 12:00 AM.

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    Distinct mechanisms of imagery differentially influence speech perception

    Abstract

    Neural representation can be induced without external stimulation, such as in mental imagery. Our previous study found that imagined speaking and imagined hearing modulated perceptual neural responses in opposite directions, suggesting motor-to-sensory transformation and memory retrieval as two separate routes that induce auditory representation (Tian & Poeppel, J Cogn Neurosci. 2013 25:1020-36). We hypothesized that the precision of representation induced from different types of speech imagery led to different modulation effects. Specifically, we predicted that the one-to-one mapping between motor and sensory domains established during speech production would evoke a more precise auditory representation in imagined speaking than retrieving the same sounds from memory in imagined hearing. To test this hypothesis, we built the function of representational precision as the modulation of connection strength in a neural network model. The model fitted the MEG imagery repetition effects, and the best-fitting parameters showed sharper tuning after imagined speaking than imagined hearing, consistent with the representational precision hypothesis. Moreover, this model predicted that different types of speech imagery would affect perception differently. In an imagery-adaptation experiment, the categorization of/ba/-/da/continuum from male and female human participants showed more positive shifts towards the preceding imagined syllable after imagined speaking than imagined hearing. These consistent simulation and behavioral results support our hypothesis that distinct mechanisms of speech imagery construct auditory representation with varying degrees of precision and differentially influence auditory perception. This study provides a mechanistic connection between neural-level activity and psychophysics that reveals the neural computation of mental imagery.

    Significance Statement Our brain processes sensory information that we receive from the environment and mediates mental activity such as imagination. How do mental and perceptual processes interact to shape our cognition? We constructed a computational model that simulated how two types of imagery – imagined speaking and imagined hearing –differentially modulated perception via two distinct neural pathways. This model further predicted a choice shift in perceptual responses to ambiguous auditory stimuli, which was confirmed in a follow-up imagery-adaptation experiment. These results suggest that parallel neural pathways for mental imagery provide distinct functions to influence perception. These findings may implicate multiple strategies for constructing the brain-computer interface.

    in RSS PAP on September 03, 2019 04:30 PM.

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    Off-target effects in transgenic mice: Characterization of Dopamine transporter (DAT)-Cre transgenic mouse lines exposes multiple non-dopaminergic neuronal clusters available for selective targeting within limbic neurocircuitry

    Abstract

    Transgenic mouse lines are instrumental in our attempt to understand brain function. Promoters driving transgenic expression of the gene encoding Cre recombinase are crucial to ensure selectivity in Cre-mediated targeting of floxed alleles using the Cre-Lox system. For the study of dopamine neurons, promoter sequences driving expression of the Dopamine transporter (Dat) gene are often implemented and several DAT-Cre transgenic mouse lines have been found to faithfully direct Cre activity to dopamine neurons.

    Significance statement DAT-Cre transgenic mouse lines have been particularly useful in resolving the diverse functions of the brain{acute}s dopamine systems. Here we report DAT-Cre-driven reporter gene expression in cell bodies of non-dopaminergic limbic brain areas, including the lateral septum, the amygdala and the lateral habenula. Co-labeling analysis identified that these DAT-Cre neurons were glutamatergic or GABAergic. Injection of viral-genetic constructs verified the activity of the DAT-Cre transgene in the adult brain, and also enabled identification of projection patterns. This study proposes a new angle by which available DAT-Cre transgenic mice can be implemented as tools for driving targeting to a restricted number of non-dopaminergic neurons of limbic neurocircuitry.

    in RSS PAP on September 03, 2019 04:30 PM.

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    Movement and VIP interneuron activation differentially modulate encoding in mouse auditory cortex

    Abstract

    Information processing in sensory cortex is highly sensitive to non-sensory variables such as anesthetic state, arousal, and task engagement. Recent work in mouse visual cortex (VCtx) suggests that evoked firing rates, stimulus-response mutual information, and encoding efficiency increase when animals are engaged in movement. A disinhibitory circuit appears central this change: inhibitory neurons expressing vasoactive intestinal peptide (VIP) are activated during movement, and disinhibit pyramidal cells by suppressing other inhibitory interneurons. Paradoxically, although movement activates a similar disinhibitory circuit in auditory cortex (ACtx), most ACtx studies report reduced spiking during movement. It is unclear whether the resulting changes in spike rates result in corresponding changes in stimulus-response mutual information. We examined ACtx responses evoked by tone cloud stimuli, in awake mice of both sexes, during spontaneous movement and still conditions. VIP+ cells were optogenetically activated on half of trials, permitting independent analysis of the consequences of movement and VIP activation, as well as their intersection. Movement decreased stimulus-related spike rates as well as mutual information and encoding efficiency. VIP interneuron activation tended to increase stimulus-evoked spike rates but not stimulus-response mutual information, thus reducing encoding efficiency. The intersection of movement and VIP activation was largely consistent with a linear combination of these main effects: VIP activation recovered movement-induced reduction in spike rates, but not information transfer.

    Significance Statement The ability of the brain to represent information about the sensory environment is heavily influenced by the behavioral state of the animal. In visual cortex, it is well known that locomotor activity enhances visual stimulus processing. By contrast, the present study found that sound processing in auditory cortex is degraded during locomotor activity. Whereas enhanced stimulus processing in visual cortex is thought to depend on VIP+ interneuron activation, optogenetic activation of VIP+ interneurons in auditory cortex failed to improve stimulus processing. These findings imply that circuitry activated during movement has opposite influences on stimulus processing in visual and auditory cortices. Such differences could reflect a resource allocation shift during movement favoring spatial perception in service of the animal’s navigational needs.

    in RSS PAP on September 03, 2019 04:30 PM.

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    Syntaphilin-mediated docking of mitochondria at the growth cone is dispensable for axon elongation in vivo

    Abstract

    Mitochondria are abundantly detected at the growth cone, the dynamic distal tip of developing axons that directs growth and guidance. It is however poorly understood how mitochondrial dynamics relate to growth cone behavior in vivo, and which mechanisms are responsible for anchoring mitochondria at the growth cone during axon pathfinding. Here, we show that in retinal axons elongating along the optic tract in zebrafish, mitochondria accumulate in the central area of the growth cone and are occasionally observed in filopodia extending from the growth cone periphery. Mitochondrial behavior at the growth cone in vivo is dynamic, with mitochondrial positioning and anterograde transport strongly correlating with growth cone behavior and axon outgrowth. Using novel zebrafish mutant lines that lack the mitochondrial anchoring proteins Syntaphilin a and b, we further show that Syntaphilins contribute to mitochondrial immobilization at the growth cone. Syntaphilins are however not required for proper growth cone morphology and axon growth in vivo, indicating that Syntaphilin-mediated anchoring of mitochondria at the growth cone only plays a minor role in elongating axons.

    Significance statement Proper axon elongation and pathfinding are essential for nervous system wiring. The growth cone, a dynamic structure at the distal end of axons, mediates axonal growth and guidance. Here, we describe for the first time in vivo the behavior of mitochondria at the growth cone of elongating axons. We show that mitochondria accumulate in the growth cone central area and are also present in its periphery. We further provide evidence that Syntaphilin, which immobilizes mitochondria along mature axons, also docks mitochondria at the growth cone. However, loss of Syntaphilin did not cause a complete depletion of mitochondria from the growth cone and did not affect axon elongation, indicating that other mitochondria-docking factors regulate axon growth during development.

    in RSS PAP on September 03, 2019 04:30 PM.

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    LSO:Ce Inorganic Scintillators Are Biocompatible With Neuronal and Circuit Function

    Optogenetics is widely used in neuroscience to control neural circuits. However, non-invasive methods for light delivery in brain are needed to avoid physical damage caused by current methods. One potential strategy could employ x-ray activation of radioluminescent particles (RPLs), enabling localized light generation within the brain. RPLs composed of inorganic scintillators can emit light at various wavelengths depending upon composition. Cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light in response to x-ray or ultraviolet (UV) stimulation, could potentially be used to control neural circuits through activation of channelrhodopsin-2 (ChR2), a light-gated cation channel. Whether inorganic scintillators themselves negatively impact neuronal processes and synaptic function is unknown, and was investigated here using cellular, molecular, and electrophysiological approaches. As proof of principle, we applied UV stimulation to 4 μm LSO:Ce particles during whole-cell recording of CA1 pyramidal cells in acute hippocampal slices from mice that expressed ChR2 in glutamatergic neurons. We observed an increase in frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), indicating activation of ChR2 and excitation of neurons. Importantly, LSO:Ce particles did not affect survival of primary mouse cortical neurons, even after 24 h of exposure. In extracellular dendritic field potential recordings, no change in the strength of basal glutamatergic transmission was observed during exposure to LSO:Ce microparticles. However, the amplitude of the fiber volley was slightly reduced with high stimulation. Additionally, there was a slight decrease in the frequency of sEPSCs in whole-cell voltage-clamp recordings from CA1 pyramidal cells, with no change in current amplitudes. The amplitude and frequency of spontaneous inhibitory postsynaptic currents were unchanged. Finally, long term potentiation (LTP), a synaptic modification believed to underlie learning and memory and a robust measure of synaptic integrity, was successfully induced, although the magnitude was slightly reduced. Together, these results show LSO:Ce particles are biocompatible even though there are modest effects on baseline synaptic function and long-term synaptic plasticity. Importantly, we show that light emitted from LSO:Ce particles is able to activate ChR2 and modify synaptic function. Therefore, LSO:Ce inorganic scintillators are potentially viable for use as a new light delivery system for optogenetics.

    in Frontiers in Synaptic Neuroscience | New and Recent Articles on September 03, 2019 12:00 AM.

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    Peripheral Amyloid Precursor Protein Derivative Expression in Fragile X Syndrome

    Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is associated with increased risk for autism spectrum disorder (ASD), anxiety, ADHD, and epilepsy. While our understanding of FXS pathophysiology has improved, a lack of validated blood-based biomarkers of disease continues to impede bench-to-bedside efforts. To meet this demand, there is a growing effort to discover a reliable biomarker to inform treatment discovery and evaluate treatment target engagement. Such a marker, amyloid-beta precursor protein (APP), has shown potential dysregulation in the absence of fragile X mental retardation protein (FMRP) and may therefore be associated with FXS pathophysiology. While APP is best understood in the context of Alzheimer disease, there is a growing body of evidence suggesting the molecule and its derivatives play a broader role in regulating neuronal hyperexcitability, a well-characterized phenotype in FXS. To evaluate the viability of APP as a peripheral biological marker in FXS, we conducted an exploratory ELISA-based evaluation of plasma APP-related species involving 27 persons with FXS (mean age: 22.0 ± 11.5) and 25 age- and sex-matched persons with neurotypical development (mean age: 21.1 ± 10.7). Peripheral levels of both Aβ(1–40) and Aβ(1–42) were increased, while sAPPα was significantly decreased in persons with FXS as compared to control participants. These results suggest that dysregulated APP processing, with potential preferential β-secretase processing, may be a readily accessible marker of FXS pathophysiology.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on September 03, 2019 12:00 AM.

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    IFNγ-Stimulated Dendritic Cell Exosomes for Treatment of Migraine Modeled Using Spreading Depression

    Migraine is a common headache disorder characterized by unilateral, intense headaches. In migraine with aura, the painful headache is preceded by focal neurological symptoms that can be visual, sensory, or motor in nature. Spreading depression (the most likely cause of migraine with aura and perhaps related headache pain) results in increased neuronal excitability and related increases in inflammation and production of reactive oxygen species. This in turn can promote the transformation of low-frequency, episodic migraine into higher-frequency and eventually chronic migraine. Though migraine affects 11% of adults worldwide, with 3% experiencing chronic headache, existing therapies offer only modest benefits. Here, we focus on the mechanisms by which environmental enrichment (i.e., volitionally increased intellectual, social, and physical activity) mitigates spreading depression. In prior work, we have shown that exposure to environmental enrichment reduces susceptibility to spreading depression in rats. This protective effect is at least in part due to environmental enrichment-mediated changes in the character of serum exosomes produced by circulating immune cells. We went on to show that environmental enrichment-mimetic exosomes can be produced by stimulating dendritic cells with low levels of interferon gamma (a cytokine that is phasically increased during environmental enrichment). Interferon gamma-stimulated dendritic cell exosomes (IFNγ-DC-Exos) significantly improve myelination and reduce oxidative stress when applied to hippocampal slice cultures. Here, we propose that they may also be effective against spreading depression. We found that administration of IFNγ-DC-Exos reduced susceptibility to spreading depression in vivo and in vitro, suggesting that IFNγ-DC-Exos may be a potential therapeutic for migraine.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 03, 2019 12:00 AM.

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    Role of the Immune System in the Development of the Central Nervous System

    The central nervous system (CNS) and the immune system are both intricate and highly organized systems that regulate the entire body, with both sharing certain common features in developmental mechanisms and operational modes. It is known that innate immunity-related molecules, such as cytokines, toll-like receptors, the complement family, and acquired immunity-related molecules, such as the major histocompatibility complex and antibody receptors, are also expressed in the brain and play important roles in brain development. Moreover, although the brain has previously been regarded as an immune-privileged site, it is known to contain lymphatic vessels. Not only microglia but also lymphocytes regulate cognition and play a vital role in the formation of neuronal circuits. This review provides an overview of the function of immune cells and immune molecules in the CNS, with particular emphasis on their effect on neural developmental processes.

    in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on September 03, 2019 12:00 AM.

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    Laminin and Environmental Cues Act in the Inhibition of the Neuronal Differentiation of Enteric Glia in vitro

    The enteric glia, a neural crest-derived cell type that composes the Enteric Nervous System, is involved in controlling gut functions, including motility, gut permeability, and neuronal communication. Moreover this glial cell could to give rise to new neurons. It is believed that enteric neurons are generated up to 21 days postnatally; however, adult gut cells with glial characteristics can give rise to new enteric neurons under certain conditions. The factors that activate this capability of enteric glia to differentiate into neurons remain unknown. Here, we followed the progress of this neuronal differentiation and investigated this ability by challenging enteric glial cells with different culture conditions. We found that, in vitro, enteric glial cells from the gut of adult and neonate mice have a high capability to acquire neuronal markers and undergoing morphological changes. In a co-culture system with 3T3 fibroblasts, the number of glial cells expressing βIIItubulin decreased after 7 days. The effect of 3T3-conditioned medium on adult cells was not significant, and fewer enteric glial cells from neonate mice began the neurogenic process in this medium. Laminin, an extracellular matrix protein that is highly expressed by the niche of the enteric ganglia, seemed to have a large role in inhibiting the differentiation of enteric glia, at least in cells from the adult gut. Our results suggest that, in an in vitro approach that provides conditions more similar to those of enteric glial cells in vivo, these cells could, to some extent, retain their morphology and marker expression, with their neurogenic potential inhibited. Importantly, laminin seemed to inhibit differentiation of adult enteric glial cells. It is possible that the differentiation of enteric glia into neurons is related to severe changes in the microenvironment, leading to disruption of the basement membrane. In summary, our data indicated that the interaction between the enteric glial cells and their microenvironment molecules significantly affects the control of their behavior and functions.

    in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on September 03, 2019 12:00 AM.

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    On the Validation of a Multiple-Network Poroelastic Model Using Arterial Spin Labeling MRI Data

    The Multiple-Network Poroelastic Theory (MPET) is a numerical model to characterize the transport of multiple fluid networks in the brain, which overcomes the problem of conducting separate analyses on individual fluid compartments and losing the interactions between tissue and fluids, in addition to the interaction between the different fluids themselves. In this paper, the blood perfusion results from MPET modeling are partially validated using cerebral blood flow (CBF) data obtained from arterial spin labeling (ASL) magnetic resonance imaging (MRI), which uses arterial blood water as an endogenous tracer to measure CBF. Two subjects—one healthy control and one patient with unilateral middle cerebral artery (MCA) stenosis are included in the validation test. The comparison shows several similarities between CBF data from ASL and blood perfusion results from MPET modeling, such as higher blood perfusion in the gray matter than in the white matter, higher perfusion in the periventricular region for both the healthy control and the patient, and asymmetric distribution of blood perfusion for the patient. Although the partial validation is mainly conducted in a qualitative way, it is one important step toward the full validation of the MPET model, which has the potential to be used as a testing bed for hypotheses and new theories in neuroscience research.

    in Frontiers in Computational Neuroscience | New and Recent Articles on September 03, 2019 12:00 AM.

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    Spatio-temporal characterization of S- and M/L-cone degeneration in the Rd1 mouse model of retinitis pigmentosa

    The Pde6brd1 (Rd1) mouse is widely used as a murine model for human retinitis pigmentosa. Understanding the spatio-temporal patterns of cone degeneration is important for evaluating potential treatments. In th...

    in Most Recent Articles: BMC Neuroscience on September 03, 2019 12:00 AM.

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    Altered excitability of small cutaneous nerve fibers during cooling assessed with the perception threshold tracking technique

    There is a need for new approaches to increase the knowledge of the membrane excitability of small nerve fibers both in healthy subjects, as well as during pathological conditions. Our research group has previ...

    in Most Recent Articles: BMC Neuroscience on September 03, 2019 12:00 AM.

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    Functions of adult-born neurons in hippocampal memory interference and indexing

    Nature Neuroscience, Published online: 02 September 2019; doi:10.1038/s41593-019-0484-2

    In this Review, Miller and Sahay discuss how adult-born neurons recruit inhibitory microcircuits to support hippocampal memory indexing and pattern separation.

    in Nature Neuroscience - Issue - nature.com science feeds on September 02, 2019 12:00 AM.

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    The next generation of approaches to investigate the link between synaptic plasticity and learning

    Nature Neuroscience, Published online: 02 September 2019; doi:10.1038/s41593-019-0480-6

    The authors review the most recent measurement and manipulation approaches that enable links between synaptic plasticity and learning to be examined, and they propose potential future approaches to tackle this endeavor.

    in Nature Neuroscience - Issue - nature.com science feeds on September 02, 2019 12:00 AM.

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    Simultaneous multi-area recordings suggest that attention improves performance by reshaping stimulus representations

    Nature Neuroscience, Published online: 02 September 2019; doi:10.1038/s41593-019-0477-1

    Ruff and Cohen find that the prominent hypotheses about how attention improves perception do not account for behavioral improvements. Instead, their results suggest that attention reshapes sensory representations so the relevant information guides behavior.

    in Nature Neuroscience - Issue - nature.com science feeds on September 02, 2019 12:00 AM.

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    Immune Mediated Degeneration and Possible Protection in Glaucoma

    The underlying pathomechanisms for glaucoma, one of the most common causes of blindness worldwide, are still not identified. In addition to increased intraocular pressure (IOP), oxidative stress, excitotoxicity, and immunological processes seem to play a role. Several pharmacological or molecular/genetic methods are currently investigated as treatment options for this disease. Altered autoantibody levels were detected in serum, aqueous humor, and tissue sections of glaucoma patients. To further analyze the role of the immune system, an IOP-independent, experimental autoimmune glaucoma (EAG) animal model was developed. In this model, immunization with ocular antigens leads to antibody depositions, misdirected T-cells, retinal ganglion cell death and degeneration of the optic nerve, similar to glaucomatous degeneration in patients. Moreover, an activation of the complement system and microglia alterations were identified in the EAG as well as in ocular hypertension models. The inhibition of these factors can alleviate degeneration in glaucoma models with and without high IOP. Currently, several neuroprotective approaches are tested in distinct models. It is necessary to have systems that cover underlying pathomechanisms, but also allow for the screening of new drugs. In vitro models are commonly used, including single cell lines, mixed-cultures, and even organoids. In ex vivo organ cultures, pathomechanisms as well as therapeutics can be investigated in the whole retina. Furthermore, animal models reveal insights in the in vivo situation. With all these models, several possible new drugs and therapy strategies were tested in the last years. For example, hypothermia treatment, neurotrophic factors or the blockage of excitotoxity. However, further studies are required to reveal the pressure independent pathomechanisms behind glaucoma. There is still an open issue whether immune mechanisms directly or indirectly trigger cell death pathways. Hence, it might be an imbalance between protective and destructive immune mechanisms. Moreover, identified therapy options have to be evaluated in more detail, since deeper insights could lead to better treatment options for glaucoma patients.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on September 02, 2019 12:00 AM.

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    Subscription and Copyright Information

    in Trends in Neurosciences on September 01, 2019 12:00 AM.

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    Editorial Board and Contents

    in Trends in Neurosciences on September 01, 2019 12:00 AM.

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    Practical Considerations for Navigating Registered Reports

    Recent open science efforts to improve rigor and reliability have sparked great enthusiasm. Among these, the Registered Report publication format integrates best practices in hypothesis-driven research with peer review that occurs before the research is conducted. Here, we detail practical recommendations to help researchers negotiate the mechanics of this developing format.

    in Trends in Neurosciences on September 01, 2019 12:00 AM.

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    An argument for hyperbolic geometry in neural circuits

    Publication date: October 2019

    Source: Current Opinion in Neurobiology, Volume 58

    Author(s): Tatyana O Sharpee

    This review connects several lines of research to argue that hyperbolic geometry should be broadly applicable to neural circuits as well as other biological circuits. The reason for this is that networks that conform to hyperbolic geometry are maximally responsive to external and internal perturbations. These networks also allow for efficient communication under conditions where nodes are added or removed. We will argue that one of the signatures of hyperbolic geometry is the celebrated Zipf’s law (also sometimes known as the Pareto distribution) that states that the probability to observe a given pattern is inversely related to its rank. Zipf’s law is observed in a variety of biological systems — from protein sequences, neural networks to economics. These observations provide further evidence for the ubiquity of networks with an underlying hyperbolic metric structure. Recent studies in neuroscience specifically point to the relevance of a three-dimensional hyperbolic space for neural signaling. The three-dimensional hyperbolic space may confer additional robustness compared to other dimensions. We illustrate how the use of hyperbolic coordinates revealed a novel topographic organization within the olfactory system. The use of such coordinates may facilitate representation of relevant signals elsewhere in the brain.

    in ScienceDirect Publication: Current Opinion in Neurobiology on August 31, 2019 11:00 AM.

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    Coupling the State and Contents of Consciousness

    One fundamental feature of consciousness is that the contents of consciousness depend on the state of consciousness. Here, we propose an answer to why this is so: both the state and the contents of consciousness depend on the activity of cortical layer 5 pyramidal (L5p) neurons. These neurons affect both cortical and thalamic processing, hence coupling the cortico-cortical and thalamo-cortical loops with each other. Functionally this coupling corresponds to the coupling between the state and the contents of consciousness. Together the cortico-cortical and thalamo-cortical loops form a thalamo-cortical broadcasting system, where the L5p cells are the central elements. This perspective makes one quite specific prediction: cortical processing that does not include L5p neurons will be unconscious. More generally, the present perspective suggests that L5p neurons have a central role in the mechanisms underlying consciousness.

    in Frontiers in Systems Neuroscience | New and Recent Articles on August 30, 2019 12:00 AM.

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    Effects of Acupuncture on Neurological Disease in Clinical- and Animal-Based Research

    Neurological disease, including Alzheimer’s disease (AD), Parkinson’s disease (PD), which were caused by abnormalities in the nervous system involves the accumulation of false proteins, neurotransmitter abnormalities, neuronal apoptosis, etc. As an alternative supplementary medicine (ASM), acupuncture plays an important role in the treatment of neurological diseases. In this review article, we summarized the current evidence for the treatment efficacy of acupuncture in AD and PD from the perspective of clinical trials and animal model. Acupuncture can inhibit the accumulation of toxic proteins in neurological diseases, modulate energy supply based on glucose metabolism, depress neuronal apoptosis, etc., and exert a wide range of neuroprotective effects.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on August 30, 2019 12:00 AM.

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    TNF-α antagonist attenuates systemic lipopolysaccharide-induced brain white matter injury in neonatal rats

    Systemic inflammation is an important risk factor for neurodevelopmental impairments in preterm infants. Premyelinating oligodendrocytes are main building blocks of white matter in preterm infants and vulnerab...

    in Most Recent Articles: BMC Neuroscience on August 30, 2019 12:00 AM.

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    A Computational Model of Oxytocin Modulation of Olfactory Recognition Memory

    Abstract

    Social recognition in mammals depends on complex interactions between sensory and other brain areas as well as modulatory inputs by specific neuropeptides such as oxytocin (OXT). Social recognition memory specifically has been shown to depend among others on olfactory processing, and can be probed using methods similar to those used when probing non-social odor memory. We here use a computational model of two interconnected olfactory networks in the mouse, the olfactory bulb (OB) and anterior olfactory nucleus, to propose a mechanism for olfactory short-term recognition memory and its modulation in social situations. Based on previous experiments, we propose one early locus for memory to be the OB. During social encounters in mice, pyramidal cells in the anterior olfactory nucleus, themselves driven by olfactory input, are rendered more excitable by OXT release, resulting in stronger feedback to OB local interneurons. This additional input to the OB creates stronger dynamics and improves signal-to-noise ratio of odor responses in the OB proper. As a consequence, mouse social olfactory memories are more strongly encoded and their duration is modulated.

    in eNeuro current issue on August 29, 2019 04:30 PM.

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    Screen time: studying gene function in iPSCs

    Nature Reviews Neuroscience, Published online: 29 August 2019; doi:10.1038/s41583-019-0217-2

    Two studies demonstrate the power of combining induced pluripotent stem cell technology with CRISPR-mediated gene editing to investigate neurobiological mechanisms.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on August 29, 2019 12:00 AM.

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    Cortical mechanisms of spatial hearing

    Nature Reviews Neuroscience, Published online: 29 August 2019; doi:10.1038/s41583-019-0206-5

    Humans and other animals use spatial hearing to rapidly localize events in the environment. Here, van der Heijden and colleagues discuss the latest insights from neurophysiological, neuroimaging and computational modelling studies into the cortical encoding of sound location.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on August 29, 2019 12:00 AM.

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    Depalmitoylation by Palmitoyl-Protein Thioesterase 1 in Neuronal Health and Degeneration

    Protein palmitoylation is the post-translational, reversible addition of a 16-carbon fatty acid, palmitate, to proteins. Protein palmitoylation has recently garnered much attention, as it robustly modifies the localization and function of canonical signaling molecules and receptors. Protein depalmitoylation, on the other hand, is the process by which palmitic acid is removed from modified proteins and contributes, therefore, comparably to palmitoylated-protein dynamics. Palmitoylated proteins also require depalmitoylation prior to lysosomal degradation, demonstrating the significance of this process in protein sorting and turnover. Palmitoylation and depalmitoylation serve as particularly crucial regulators of protein function in neurons, where a specialized molecular architecture and cholesterol-rich membrane microdomains contribute to synaptic transmission. Three classes of depalmitoylating enzymes are currently recognized, the acyl protein thioesterases, α/β hydrolase domain-containing 17 proteins (ABHD17s), and the palmitoyl-protein thioesterases (PPTs). However, a clear picture of depalmitoylation has not yet emerged, in part because the enzyme-substrate relationships and specific functions of depalmitoylation are only beginning to be uncovered. Further, despite the finding that loss-of-function mutations affecting palmitoyl-protein thioesterase 1 (PPT1) function cause a severe pediatric neurodegenerative disease, the role of PPT1 as a depalmitoylase has attracted relatively little attention. Understanding the role of depalmitoylation by PPT1 in neuronal function is a fertile area for ongoing basic science and translational research that may have broader therapeutic implications for neurodegeneration. Here, we will briefly introduce the rapidly growing field surrounding protein palmitoylation and depalmitoylation, then will focus on the role of PPT1 in development, health, and neurological disease.

    in Frontiers in Synaptic Neuroscience | New and Recent Articles on August 29, 2019 12:00 AM.

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    Glucocorticoid-Driven NLRP3 Inflammasome Activation in Hippocampal Microglia Mediates Chronic Stress-Induced Depressive-Like Behaviors

    Chronic stress is a key risk factor for depression, and microglia have been implicated in the pathogenesis of the disease. Recent studies show that the Nod-like receptor protein 3 (NLRP3) inflammasome is expressed in microglia and may play a crucial role in depression. However, the mechanism of NLRP3 inflammasome activation in hippocampal microglia and its role in depressive-like behaviors remain poorly understood. In this study, rats were subjected to 6 h of restraint stress per day for 21 days to produce a model of stress-induced depression. Behavioral tests and serum corticosterone were used to assess the success of the model. Furthermore, HAPI cells were pretreated with dexamethasone (5 × 10–7 M) to assess stress-induced changes in microglial cells in culture. The microglial marker Iba-1, reactive oxygen species (ROS), nuclear factor kappa B (NF-κB) and key components of the NLRP3 inflammasome and its downstream inflammatory effectors (IL-1β and IL-18) were measured. Chronic stress induced depressive-like behavior, increased serum corticosterone levels and produced hippocampal structural changes. Chronic stress and dexamethasone both increased Iba-1 expression and ROS formation and also elevated levels of NF-κB, NLRP3, cleaved caspase-1, IL-1β and IL-18. After use of the NF-κB inhibitor BAY 117082 and knocked out NLRP3 in vitro decreased ROS formation and the expression of Iba-1, NF-κB and NLRP3 as well as levels of cleaved caspase-1, IL-1β and IL-18. These findings suggest that activation of the glucocorticoid receptor-NF-κB-NLRP3 pathway in hippocampal microglia mediates chronic stress-induced hippocampal neuroinflammation and depression-like behavior.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 29, 2019 12:00 AM.

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    EK7 Regulates NLRP3 Inflammasome Activation and Neuroinflammation Post-traumatic Brain Injury

    As one of the most common causes of mortality and disability, traumatic brain injury (TBI) is a huge psychological and economic burden to patients, families, and societies worldwide. Neuroinflammation reduction may be a favorable option to alleviate secondary brain injuries and ameliorate the outcome of TBI. The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome, has been shown to be involved in TBI. NIMA-related kinase 7 (NEK7) has been verified as an essential mediator of NLRP3 inflammasome activation that is recruited upstream of the formation of inflammasomes in response to NLRP3 activators. However, the underlying mechanism by which NEK7 operates post-TBI remains undefined. In this study, we performed both in vivo and in vitro experiments. Using an in vivo mouse TBI model, mice were administered an intracerebroventricular injection of NEK7-shRNA virus. For the in vitro analysis, primary cortical neurons with NEK7-shRNA were stimulated with lipopolysaccharide (LPS)/ATP or potassium (K+). We evaluated the effects of NEK7 knock-down on neurological deficits, NLRP3 inflammasomes, caspase-1 activation, and neuronal injury. During the 0–168 h post-TBI period in vivo, NEK7 and NLRP3 inflammasome activation increased in what appeared to be a time-dependent manner. As well as pyroptosis-related markers, caspase-1 activation (p20) and interleukin-1β (IL-1β) activation (p17) were up-regulated. NEK7 down-regulation attenuated neurological deficits, NLRP3 inflammasomes, caspase-1 activation, and neuronal injury. The same phenomena were observed during the in vitro experiments. Furthermore, NEK7 knock-down suppressed NLRP3 inflammasome activation and pyroptosis, which were triggered by K+ efflux, and the LPS + ATP-triggered NEK7–NLRP3 complex was reversed in primary cortical neurons placed in 50 mM K+ medium. Collectively, the data demonstrated that NEK7, as a modulator, regulates NLRP3 inflammasomes and downstream neuroinflammation in response to K+ efflux, through NEK7–NLRP3 assembly, pro-caspase-1 recruitment, caspase-1 activation, and pyroptosis in nerve injuries, post-TBI. NEK7 may be a potential therapeutic target for attenuating neuroinflammation and nerve injury post-TBI.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 29, 2019 12:00 AM.

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    Perspective: Of Mice and Men – How Widespread Is Adult Neurogenesis?

    These are exciting times for research on adult hippocampal neurogenesis (AHN). Debate and controversy regarding the existence of generation of new neurons in the adult, and even diseased human brain flourishes as articles against and in favor accumulate. Adult neurogenesis in the human brain is a phenomenon that does not share the qualities of quantum mechanics. The scientific community should agree that human AHN exists or does not, but not both at the same time. In this commentary, we discuss the latest research articles about hAHN and what their findings imply for the neurogenesis field.

    in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on August 29, 2019 12:00 AM.

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    Pinpointing Morphology and Projection of Excitatory Neurons in Mouse Visual Cortex

    The excitatory neurons in the visual cortex are of great significance for us in understanding brain functions. However, the diverse neuron types and their morphological properties have not been fully deciphered. In this paper, we applied the brain-wide positioning system (BPS) to image the entire brain of two Thy1-eYFP H-line male mice at 0.2 μm × 0.2 μm × 1 μm voxel resolution. A total of 103 neurons were reconstructed in layers 5 and 6 of the visual cortex with single-axon-level resolution. Based on the complete topology of neurons and the inherent positioning function of the imaging method, we classified the observed neurons into six types according to their apical dendrites and somata location: star pyramidal cells in layer 5 (L5-sp), slender-tufted pyramidal cells in layer 5 (L5-st), tufted pyramidal cells in layer 5 (L5-tt), spiny stellate-like cells in layer 6 (L6-ss), star pyramidal cells in layer 6 (L6-sp), and slender-tufted pyramidal cells in layer 6 (L6-st). By examining the axonal projection patterns of individual neurons, they can be categorized into three modes: ipsilateral circuit connection neurons, callosal projection neurons and corticofugal projection neurons. Correlating the two types of classifications, we have found that there are at least two projection modes comprised in the former defined neuron types except for L5-tt. On the other hand, each projection mode may consist of four dendritic types defined in this study. The axon projection mode only partially correlates with the apical dendrite feature. This work has demonstrated a paradigm for resolving the visual cortex through single-neuron-level quantification and has shown potential to be extended to reveal the connectome of other defined sensory and motor systems.

    in Frontiers in Neuroscience | Systems Biology section | New and Recent Articles on August 29, 2019 12:00 AM.

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    Corrigendum: Effects of Different Re-referencing Methods on Spontaneously Generated Ear-EEG

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on August 29, 2019 12:00 AM.

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    The Adult Ts65Dn Mouse Model of Down Syndrome Shows Altered Swallow Function

    There are increased risks for deglutition disorders in people with Down syndrome (DS). Although mouse models have been used to study the biological underpinnings of DS in other areas, relatively little is known about swallowing phenotypes in these models. We hypothesized that swallowing performance would be affected in adult mouse models of DS, relative to typical control mice. Videofluoroscopic swallow studies (VFSS) were conducted on adults of two mouse models of DS: Ts65Dn and Dp(16)1Yey, and evaluated in comparison with age-matched controls. Relative to other groups, adult Ts65Dn showed significantly slower swallow rates, longer inter-swallow intervals (ISI), and greater numbers of jaw excursion cycles preceding each swallow. In contrast, adult Dp(16)1Yey mice showed swallowing performance similar to control mice. Exploratory quantitative analyses of the intrinsic tongue (transverse muscle), and extrinsic tongue muscles [genioglossus (GG), styloglossus (SG), and hyoglossus (HG)] showed no significant differences between genotype groups in myosin heavy chain isoform profiles. Collectively, these findings suggest that while swallowing is typical in adult Dp(16)1Yey, swallowing in adult Ts65Dn is atypical due to unknown causes. The finding that adult Ts65Dn may have utility as a model of dysphagia provides new opportunities to elucidate biological underpinnings of dysphagia associated with DS.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on August 29, 2019 12:00 AM.

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    Leucine-Rich Repeat Kinase 2 Is Associated With Activation of the Paraventricular Nucleus of the Hypothalamus and Stress-Related Gastrointestinal Dysmotility

    Leucine-rich repeat kinase 2 (LRRK2) is a molecule associated with familial and sporadic Parkinson’s disease. It regulates many central neuronal functions, such as cell proliferation, apoptosis, autophagy, and axonal extension. Recently, it has been revealed that LRRK2 is related to anxiety/depression-like behavior, implying an association between LRRK2 and stress. In the present study, we investigated for the first time the stress pathway and its relationship to gastrointestinal motility in LRRK2-knockout (KO) mice. The mice were subjected to acute restraint stress, and analyzed for activation of the paraventricular nucleus of the hypothalamus (PVN) using an immunohistochemical approach. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) was assessed by Western blotting. The KO mice showed a lower number of c-Fos-positive cells and disruption of the ERK signaling pathway in the PVN in the presence of restraint stress. Stress responses in terms of both upper and lower gastrointestinal motility were alleviated in the mice, accompanied by lower c-Fos immunoreactivity in enteric excitatory neurons. Our present findings suggest that LRRK2 is a newly recognized molecule regulating the stress pathway in the PVN, playing a role in stress-related gastrointestinal dysmotility.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on August 29, 2019 12:00 AM.

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    Intracranial Atherosclerotic Disease-Related Acute Middle Cerebral Artery Occlusion Can Be Predicted by Diffusion-Weighted Imaging

    Background: The differentiation of large vessel occlusion caused by intracranial atherosclerotic stenosis (ICAS) or intracranial embolism significantly impacts the course of treatment (i.e., intravenous thrombolysis versus mechanical thrombectomy) for acute cerebral infarction. Currently, there is no objective evidence to indicate ICAS-related middle cerebral artery M1 segment occlusion before treatment. In cases of ICAS, it is often observed that the infarct core caused by ICAS-related M1 segment middle cerebral artery occlusion (MCAO) is located in deeper parts of the brain (basal ganglia or semiovoid region).

    Objective: To evaluate whether the location of the infarct core, identified using diffusion-weighted imaging (DWI), can be used to differentiate ICAS from intracranial embolism.

    Methods: Thirty-one consecutive patients diagnosed with acute cerebral infarction caused by middle cerebral artery M1 segment occlusion were retrospectively included based on angiographic findings to distinguish ICAS from embolic occlusion. Patients were divided into two groups based on the location of the infarct core on DWI: in the deep part of the brain (basal ganglia or semiovoid region) or more superficially (i.e., cortex).

    Results: In 16 patients, the infarct core was mainly in the deep part of the brain on DWI [14 of 16 patients in the ICAS group and only 2 in the non-ICAS group (93.3 vs. 6.7%, respectively; P < 0.001)]. The diagnostic sensitivity of DWI for ICAS was 93.3%, with a specificity of 87.5%, a Positive predictive value (PPV) of 87.5%, and an Negative predictive value (NPV) of 93.3%, the accuracy was 88.5%.

    Conclusion: Intracranial atherosclerotic disease-related acute MCAO can be predicted using DWI.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on August 29, 2019 12:00 AM.

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    Distinct Mechanism of Audiovisual Integration With Informative and Uninformative Sound in a Visual Detection Task: A DCM Study

    Previous studies have shown that task-irrelevant auditory information can provide temporal clues for the detection of visual targets and improve visual perception; such sounds are called informative sounds. The neural mechanism of the integration of informative sound and visual stimulus has been investigated extensively, using behavioral measurement or neuroimaging methods such as functional magnetic resonance imaging (fMRI) and event-related potential (ERP), but the dynamic processes of audiovisual integration cannot be characterized formally in terms of directed neuronal coupling. The present study adopts dynamic causal modeling (DCM) of fMRI data to identify changes in effective connectivity in the hierarchical brain networks that underwrite audiovisual integration and memory. This allows us to characterize context-sensitive changes in neuronal coupling and show how visual processing is contextualized by the processing of informative and uninformative sounds. Our results show that audiovisual integration with informative and uninformative sounds conforms to different optimal models in the two conditions, indicating distinct neural mechanisms of audiovisual integration. The findings also reveal that a sound is uninformative owing to low-level automatic audiovisual integration and informative owing to integration in high-level cognitive processes.

    in Frontiers in Computational Neuroscience | New and Recent Articles on August 29, 2019 12:00 AM.

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    The Brain Anatomy of the Brown Bear (Carnivora, Ursus arctos L., 1758) Compared to That of Other Carnivorans: A Cross-Sectional Study Using MRI

    In this study, we aimed to provide a neuroanatomy atlas derived from cross-sectional and magnetic resonance imaging (MRI) of the encephalon of the brown bear (Ursus arctos). A postmortem brain analysis using magnetic resonance imaging (MRI – 1,5T; a high-resolution submillimeter three-dimensional T1-3D FFE) and cross-sectional macroscopic anatomy methods revealed major embryological and anatomical subdivisions of the encephalon, including the ventricular system. Most of the internal structures were comparably identifiable in both methods. The tractus olfactorius medialis, corpus subthalamicum, brachium colliculi rostralis, fasciculus longitudinalis medialis, nuclei vestibulares, velum medullare rostrale, nucleus fastigii, fasciculi cuneatus et gracilis were identified entirely by cross-sectional macroscopic analysis. However, the glandula pinealis, lemniscus lateralis and nuclei rhaphe were visualized only with MRI. Gross neuroanatomic analysis provided information about sulci and gyri of the cerebral hemispheres, components of the vermis and cerebellar hemispheres, and relative size and morphology of constituents of the rhinencephalon and cerebellum constituents. Similarities and discrepancies in identification of structures provided by both methods, as well as hallmarks of the structures facilitating identification using these methods are discussed. Finally, we compare the brown bear encephalon with other carnivores and discuss most of the identified structures compared to those of the domestic dog, the domestic cat, Ursidae and Mustelidae families and Pinnipedia clade.

    in Frontiers in Neuroanatomy | New and Recent Articles on August 29, 2019 12:00 AM.

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    Constraining computational models using electron microscopy wiring diagrams

    Publication date: October 2019

    Source: Current Opinion in Neurobiology, Volume 58

    Author(s): Ashok Litwin-Kumar, Srinivas C Turaga

    Numerous efforts to generate “connectomes,” or synaptic wiring diagrams, of large neural circuits or entire nervous systems are currently underway. These efforts promise an abundance of data to guide theoretical models of neural computation and test their predictions. However, there is not yet a standard set of tools for incorporating the connectivity constraints that these datasets provide into the models typically studied in theoretical neuroscience. This article surveys recent approaches to building models with constrained wiring diagrams and the insights they have provided. It also describes challenges and the need for new techniques to scale these approaches to ever more complex datasets.

    in ScienceDirect Publication: Current Opinion in Neurobiology on August 28, 2019 11:00 PM.

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    Using a Multiplex Nucleic Acid in situ Hybridization Technique to Determine HCN4 mRNA Expression in the Adult Rodent Brain

    Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels carry a non-selective cationic conductance, Ih, which is important for modulating neuron excitability. Four genes (HCN1-4) encode HCN channels, with each gene having distinct expression and biophysical profiles. Here we use multiplex nucleic acid in situ hybridization to determine HCN4 mRNA expression within the adult mouse brain. We take advantage of this approach to detect HCN4 mRNA simultaneously with either HCN1 or HCN2 mRNA and markers of excitatory (VGlut-positive) and inhibitory (VGat-positive) neurons, which was not previously reported. We have developed a Fiji-based analysis code that enables quantification of mRNA expression within identified cell bodies. The highest HCN4 mRNA expression was found in the habenula (medial and lateral) and the thalamus. HCN4 mRNA was particularly high in the medial habenula with essentially no co-expression of HCN1 or HCN2 mRNA. An absence of Ih-mediated “sag” in neurons recorded from the medial habenula of knockout mice confirmed that HCN4 channels are the predominant subtype in this region. Analysis in the thalamus revealed HCN4 mRNA in VGlut2-positive excitatory neurons that was always co-expressed with HCN2 mRNA. In contrast, HCN4 mRNA was undetectable in the nucleus reticularis. HCN4 mRNA expression was high in a subset of VGat-positive cells in the globus pallidus external. The majority of these neurons co-expressed HCN2 mRNA while a smaller subset also co-expressed HCN1 mRNA. In the striatum, a small subset of large cells which are likely to be giant cholinergic interneurons co-expressed high levels of HCN4 and HCN2 mRNA. The amygdala, cortex and hippocampus expressed low levels of HCN4 mRNA. This study highlights the heterogeneity of HCN4 mRNA expression in the brain and provides a morphological framework on which to better investigate the functional roles of HCN4 channels.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 28, 2019 12:00 AM.

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    Localization of Retinal Ca2+/Calmodulin-Dependent Kinase II-β (CaMKII-β) at Bipolar Cell Gap Junctions and Cross-Reactivity of a Monoclonal Anti-CaMKII-β Antibody With Connexin36

    Neuronal gap junctions formed by connexin36 (Cx36) and chemical synapses share striking similarities in terms of plasticity. Ca2+/calmodulin-dependent protein kinase II (CaMKII), an enzyme known to induce memory formation at chemical synapses, has recently been described to potentiate electrical coupling in the retina and several other brain areas via phosphorylation of Cx36. The contribution of individual CaMKII isoforms to this process, however, remains unknown. We recently identified CaMKII-β at electrical synapses in the mouse retina. Now, we set out to identify cell types containing Cx36 gap junctions that also express CaMKII-β. To ensure precise description, we first tested the specificity of two commercially available antibodies on CaMKII-β-deficient retinas. We found that a polyclonal antibody was highly specific for CaMKII-β. However, a monoclonal antibody (CB-β-1) recognized CaMKII-β but also cross-reacted with the C-terminal tail of Cx36, making localization analyses with this antibody inaccurate. Using the polyclonal antibody, we identified strong CaMKII-β expression in bipolar cell terminals that were secretagogin- and HCN1-positive and thus represent terminals of type 5 bipolar cells. In these terminals, a small fraction of CaMKII-β also colocalized with Cx36. A similar pattern was observed in putative type 6 bipolar cells although there, CaMKII expression seemed less pronounced. Next, we tested whether CaMKII-β influenced the Cx36 expression in bipolar cell terminals by quantifying the number and size of Cx36-immunoreactive puncta in CaMKII-β-deficient retinas. However, we found no significant differences between the genotypes, indicating that CaMKII-β is not necessary for the formation and maintenance of Cx36-containing gap junctions in the retina. In addition, in wild-type retinas, we observed frequent association of Cx36 and CaMKII-β with synaptic ribbons, i.e., chemical synapses, in bipolar cell terminals. This arrangement resembled the composition of mixed synapses found for example in Mauthner cells, in which electrical coupling is regulated by glutamatergic activity. Taken together, our data imply that CaMKII-β may fulfill several functions in bipolar cell terminals, regulating both Cx36-containing gap junctions and ribbon synapses and potentially also mediating cross-talk between these two types of bipolar cell outputs.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 28, 2019 12:00 AM.

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    Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of Hypoxia

    Recently, extracellular vesicles (EVs), such as exosomes, have been proposed to play an influential role in the cell-to-cell spread of neurodegenerative diseases, including the intercellular transmission of α-synuclein (α-syn). However, the regulation of EV biogenesis and its relation to Parkinson’s disease (PD) is only partially understood. The generation of EVs through the ESCRT-independent pathway depends on the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2) to produce ceramide, which causes the membrane of endosomal multivesicular bodies to bud inward. nSMase2 is sensitive to oxidative stress, a common process in PD brains; however, little is known about the role of sphingomyelin metabolism in the pathogenesis of PD. This is the first study to show that inhibiting nSMase2 decreases the transfer of oligomeric aggregates of α-syn between neuron-like cells. Furthermore, it reduced the accumulation and aggregation of high-molecular-weight α-syn. Hypoxia, as a model of oxidative stress, reduced the levels of nSMase2, but not its enzymatic activity, and significantly altered the lipid composition of cells without affecting EV abundance or the transfer of α-syn. These data show that altering sphingolipids can mitigate the spread of α-syn, even under hypoxic conditions, potentially suppressing PD progression.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 28, 2019 12:00 AM.

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    Modeling Interval Timing by Recurrent Neural Nets

    The purpose of this study was to take a new approach in showing how the central nervous system might encode time at the supra-second level using recurrent neural nets (RNNs). This approach utilizes units with a delayed feedback, whose feedback weight determines the temporal properties of specific neurons in the network architecture. When these feedback neurons are coupled, they form a multilayered dynamical system that can be used to model temporal responses to steps of input in multidimensional systems. The timing network was implemented using separate recurrent “Go” and “No-Go” neural processing units to process an individual stimulus indicating the time of reward availability. Outputs from these distinct units on each time step are converted to a pulse reflecting a weighted sum of the separate Go and No-Go signals. This output pulse then drives an integrator unit, whose feedback weight and input weights shape the pulse distribution. This system was used to model empirical data from rodents performing in an instrumental “peak interval timing” task for two stimuli, Tone and Flash. For each of these stimuli, reward availability was signaled after different times from stimulus onset during training. Rodent performance was assessed on non-rewarded trials, following training, with each stimulus tested individually and simultaneously in a stimulus compound. The associated weights in the Go/No-Go network were trained using experimental data showing the mean distribution of bar press rates across an 80 s period in which a tone stimulus signaled reward after 5 s and a flash stimulus after 30 s from stimulus onset. Different Go/No-Go systems were used for each stimulus, but the weighted output of each fed into a final recurrent integrator unit, whose weights were unmodifiable. The recurrent neural net (RNN) model was implemented using Matlab and Matlab’s machine learning tools were utilized to train the network using the data from non-rewarded trials. The neural net output accurately fit the temporal distribution of tone and flash-initiated bar press data. Furthermore, a “Temporal Averaging” effect was also obtained when the flash and tone stimuli were combined. These results indicated that the system combining tone and flash responses were not superposed as in a linear system, but that there was a non-linearity, which interacted between tone and flash. In order to achieve an accurate fit to the empirical averaging data it was necessary to implement non-linear “saliency functions” that limited the output signal of each stimulus to the final integrator when the other was co-present. The model suggests that the central nervous system encodes timing generation as a dynamical system whose timing properties are embedded in the connection weights of the system. In this way, event timing is coded similar to the way other sensory-motor systems, such as the vestibulo-ocular and optokinetic systems, which combine sensory inputs from the vestibular and visual systems to generate the temporal aspects of compensatory eye movements.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on August 28, 2019 12:00 AM.

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    Editorial: The Involvement of NGF in the Alzheimer's Pathology

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on August 28, 2019 12:00 AM.

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    Type-2-Diabetes Alters CSF but Not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

    Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer’s disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the majority of pathophysiological changes, including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau, occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and amyloid pathology including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, pre-diabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabaeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to PreD and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ40 and CSF Aβ42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with previous studies in mice, CSF Aβ40 and CSF Aβ42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ40 and CSF Aβ42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on August 28, 2019 12:00 AM.

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    The LONI QC System: A Semi-Automated, Web-Based and Freely-Available Environment for the Comprehensive Quality Control of Neuroimaging Data

    Quantifying, controlling, and monitoring image quality is an essential prerequisite for ensuring the validity and reproducibility of many types of neuroimaging data analyses. Implementation of quality control (QC) procedures is the key to ensuring that neuroimaging data are of high-quality and their validity in the subsequent analyses. We introduce the QC system of the Laboratory of Neuro Imaging (LONI): a web-based system featuring a workflow for the assessment of various modality and contrast brain imaging data. The design allows users to anonymously upload imaging data to the LONI-QC system. It then computes an exhaustive set of QC metrics which aids users to perform a standardized QC by generating a range of scalar and vector statistics. These procedures are performed in parallel using a large compute cluster. Finally, the system offers an automated QC procedure for structural MRI, which can flag each QC metric as being ‘good’ or ‘bad.’ Validation using various sets of data acquired from a single scanner and from multiple sites demonstrated the reproducibility of our QC metrics, and the sensitivity and specificity of the proposed Auto QC to ‘bad’ quality images in comparison to visual inspection. To the best of our knowledge, LONI-QC is the first online QC system that uniquely supports the variety of functionality where we compute numerous QC metrics and perform visual/automated image QC of multi-contrast and multi-modal brain imaging data. The LONI-QC system has been used to assess the quality of large neuroimaging datasets acquired as part of various multi-site studies such as the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). LONI-QC’s functionality is freely available to users worldwide and its adoption by imaging researchers is likely to contribute substantially to upholding high standards of brain image data quality and to implementing these standards across the neuroimaging community.

    in Frontiers in Neuroinformatics | New and Recent Articles on August 28, 2019 12:00 AM.

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    Microglia Regulate Pruning of Specialized Synapses in the Auditory Brainstem

    The assembly of uniquely organized sound localization circuits in the brainstem requires precise developmental mechanisms. Glial cells have been shown to shape synaptic connections in the retinogeniculate system during development, but their contributions to specialized auditory synapses have not been identified. Here we investigated the role of microglia in auditory brainstem circuit assembly, focusing on the formation and pruning of the calyx of Held in the medial nucleus of the trapezoid body (MNTB). Microglia were pharmacologically depleted in mice early in development using subcutaneous injections of an inhibitor of colony stimulating factor 1 receptor, which is essential for microglia survival. Brainstems were examined prior to and just after hearing onset, at postnatal days (P) 8 and P13, respectively. We found that at P13 there were significantly more polyinnervated MNTB neurons when microglia were depleted, consistent with a defect in pruning. Expression of glial fibrillary acidic protein (GFAP), a mature astrocyte marker that normally appears in the MNTB late in development, was significantly decreased in microglia-depleted mice at P13, suggesting a delay in astrocyte maturation. Our results demonstrate that monoinnervation of MNTB neurons by the calyx of Held is significantly disrupted or delayed in the absence of microglia. This finding may reflect a direct role for microglia in synaptic pruning. A secondary role for microglia may be in the maturation of astrocytes in MNTB. These findings highlight the significant function of glia in pruning during calyx of Held development.

    in Frontiers in Neural Circuits | New and Recent Articles on August 28, 2019 12:00 AM.

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    A common ground for pain and depression

    Nature Neuroscience, Published online: 27 August 2019; doi:10.1038/s41593-019-0499-8

    Chronic pain is associated with anxio-depressive comorbidities, but the neuroanatomical substrates remain unknown. A specific serotonergic pathway from the dorsal raphe nucleus to the lateral habenula via the central amygdala is now uncovered as a key neural circuit governing comorbid depressive symptoms in chronic pain.

    in Nature Neuroscience - Issue - nature.com science feeds on August 27, 2019 12:00 AM.

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    Birds of a different feather sing together

    Nature Neuroscience, Published online: 27 August 2019; doi:10.1038/s41593-019-0485-1

    A new study sheds light on how sensitivity to communication sounds is established in the brain. Juvenile finches raised with tutors of either the same or different species always learned the tutors’ songs. Cortical neurons developed selectivity for the learned song by tuning for its secondary acoustic features.

    in Nature Neuroscience - Issue - nature.com science feeds on August 27, 2019 12:00 AM.

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    Aversive state processing in the posterior insular cortex

    Nature Neuroscience, Published online: 27 August 2019; doi:10.1038/s41593-019-0469-1

    Gehrlach et al. show how the posterior insular cortex processes and modulates diverse internally and externally generated aversive states, and they dissect the functional contribution of segregated projections mediating inhibition of ongoing behaviors.

    in Nature Neuroscience - Issue - nature.com science feeds on August 27, 2019 12:00 AM.

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    Global landscape and genetic regulation of RNA editing in cortical samples from individuals with schizophrenia

    Nature Neuroscience, Published online: 27 August 2019; doi:10.1038/s41593-019-0463-7

    Breen et al. map RNA editing profiles in cortical samples from individuals with schizophrenia and controls, and find links between altered RNA editing in glutamatergic and postsynaptic density genes and schizophrenia genetic risk architecture.

    in Nature Neuroscience - Issue - nature.com science feeds on August 27, 2019 12:00 AM.

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    Damaged wires

    Nature Reviews Neuroscience, Published online: 27 August 2019; doi:10.1038/s41583-019-0216-3

    The 15q11.2 copy number deletion, which is associated with an increased risk of psychiatric disorders, is found in rodents to result in reduced myelin thickness, lower functional connectivity and motor deficits.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on August 27, 2019 12:00 AM.

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    Different Approaches to Modulation of Microglia Phenotypes After Spinal Cord Injury

    Microglial cells, which are highly plastic, immediately respond to any change in the microenvironment by becoming activated and shifting the phenotype toward neurotoxicity or neuroprotection. The polarization of microglia/macrophages after spinal cord injury (SCI) seems to be a dynamic process and can change depending on the microenvironment, stage, course, and severity of the posttraumatic process. Effective methods to modulate microglia toward a neuroprotective phenotype in order to stimulate neuroregeneration are actively sought for. In this context, available approaches that can selectively impact the polarization of microglia/macrophages regulate synthesis of trophic factors and cytokines/chemokines in them, and their phagocytic function and effects on the course and outcome of SCI are discussed in this review.

    in Frontiers in Systems Neuroscience | New and Recent Articles on August 27, 2019 12:00 AM.

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    TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Corpus Callosum

    The neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in a cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after 1-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 27, 2019 12:00 AM.

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    New Insights Into Cholinergic Neuron Diversity

    Cholinergic neurons comprise a small population of cells in the striatum but have fundamental roles in fine tuning brain function, and in the etiology of neurological and psychiatric disorders such as Parkinson’s disease (PD) or schizophrenia. The process of developmental cell specification underlying neuronal identity and function is an area of great current interest. There has been significant progress in identifying the developmental origins, commonalities in molecular markers, and physiological properties of the cholinergic neurons. Currently, we are aware of a number of key factors that promote cholinergic fate during development. However, the extent of cholinergic cell diversity is still largely underestimated. New insights into the biological basis of their specification indicate that cholinergic neurons may be far more diverse than previously thought. This review article, highlights the physiological features and the synaptic properties that segregate cholinergic cell subtypes. It provides an accurate picture of cholinergic cell diversity underlying their organization and function in neuronal networks. This review article, also discusses current challenges in deciphering the logic of the cholinergic cell heterogeneity that plays a fundamental role in the control of neural processes in health and disease.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 27, 2019 12:00 AM.

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    Transcript Analysis of Zebrafish GLUT3 Genes, slc2a3a and slc2a3b, Define Overlapping as Well as Distinct Expression Domains in the Zebrafish (Danio rerio) Central Nervous System

    The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 27, 2019 12:00 AM.

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    Mucosal Administration of E-selectin Limits Disability in Models of Multiple Sclerosis

    E-selectin plays an important role in mediating the rolling of leukocytes along and thus, the subsequent extravasation across activated endothelial cells comprising the microvasculature of the blood brain barrier (BBB). In multiple sclerosis (MS) and other inflammatory disorders of the central nervous system (CNS), the microvasculature is altered and immune cells infiltrate the brain and spinal cord contributing to damage, demyelination and ultimately disability. While mucosal administration is typically used to affect lymphocyte hyporesponsiveness or tolerance to suspect autoantigens, intranasal administration to E-selectin has previously been shown to protect against CNS inflammatory insults. We characterized the potential for mucosal administration of E-selectin to modulate CNS autoimmunity in the experimental autoimmune encephalomyelitis (EAE) model of MS. Intranasally administered E-selectin reduced swelling by as much as 50% in delayed-type hypersensitivity reactions compared to ovalbumin-tolerized controls. Intranasal E-selectin delivery prior to disease induction with myelin oligodendrocyte glycoprotein (MOG)35–55 reduced disease severity and total disease burden by more than 50% compared to PBS-tolerized animals; this protection was not associated with differences in the magnitude of the autoimmune response. Examination after the onset of disease showed that protection was associated with significant reductions in inflammatory infiltrates throughout the spinal cord. Tolerization to E-selectin did not influence encephalitogenic characteristics of autoreactive T cells such as IFN-gamma or IL-17 production. Clinical disease was also significantly reduced when E-selectin was first delivered after the onset of clinical symptoms. Splenic and lymph node (LN) populations from E-selectin-tolerized animals showed E-selectin-specific T cell responses and production of the immunomodulatory cytokine IL-10. Transfer of enriched CD4+ T cells from E-selectin tolerized mice limited disability in the passive SJL model of relapsing remitting MS. These results suggest a role for influencing E-selectin specific responses to limit neuroinflammation that warrants further exploration and characterization to better understand its potential to mitigate neurodegeneration in disorders such as MS.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 27, 2019 12:00 AM.

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    Comparing the Effects of Rhythm-Based Music Training and Pitch-Based Music Training on Executive Functions in Preschoolers

    Previous research has indicated the beneficial effects of music training on executive functions (EFs) in children. However, researchers have not clearly determined which component of music training produces these beneficial effects or whether different components exert different effects on EFs. In the present study, we examined the impact of rhythm-based music training compared to pitch-based music training and sports training as a control on EFs in preschoolers. Children aged between 5 and 6 years (N = 76) were randomly assigned to one of the three training groups and received training in small groups three times a week for 20 min in German kindergartens. Before and after training, children completed tests designed to assess inhibition, set-shifting, and visuospatial working memory. Parental education, family income, personality, and IQ served as control variables. We observed a significant training group × time interaction for the measure of inhibition. Children from the rhythm group exhibited significant improvements in inhibition from pre- to post-tests (dRM = 0.56), whereas children from the other groups did not. Furthermore, children from the rhythm group significantly differed from the sports control group at post-test (dcorr = 0.82). Concerning the measures of set-shifting and visuospatial working memory, the descriptive data revealed similar results; however, we did not observe significant training group × time interactions. Based on our findings, rhythm-based music training specifically enhances inhibition in preschoolers and might affect other EFs, such as set-shifting and visuospatial working memory.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on August 27, 2019 12:00 AM.

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    A Systematic Review of Paired Associative Stimulation (PAS) to Modulate Lower Limb Corticomotor Excitability: Implications for Stimulation Parameter Selection and Experimental Design

    Non-invasive neuromodulatory interventions have the potential to influence neural plasticity and augment motor rehabilitation in people with stroke. Paired associative stimulation (PAS) involves the repeated pairing of single pulses of electrical stimulation to a peripheral nerve and single pulses of transcranial magnetic stimulation over the contralateral primary motor cortex. Efficacy of PAS in the lower limb of healthy and stroke populations has not been systematically appraised. Optimal protocols including stimulation parameter settings have yet to be determined. This systematic review (a) examines the efficacy of PAS on lower limb corticomotor excitability in healthy and stroke populations and (b) evaluates the stimulation parameters employed. Five databases were searched for randomized, non-randomized, and pre-post experimental studies evaluating lower limb PAS in healthy and stroke populations. Two independent reviewers identified eligible studies and assessed methodological quality using a modified Downs and Blacks Tool and the TMS Checklist. Intervention stimulation parameters and TMS measurement details were also extracted and compared. Twelve articles, comprising 24 experiments, met the inclusion criteria. Four articles evaluated PAS in people with stroke. Following a single session of PAS, 21 experiments reported modulation of corticomotor excitability, lasting up to 60 min; however, the research lacked methodological rigor. Intervention stimulation parameters were highly variable across experiments, and whilst these appeared to influence efficacy, variations in the intervention and outcome assessment methods hindered the ability to draw conclusions about optimal parameters. Lower limb PAS research requires further investigation before considering its translation into clinical practice. Eight key recommendations serve as guide for enhancing future research in the field.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on August 27, 2019 12:00 AM.

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    From the Lab to the Field: Potential Applications of Dry EEG Systems to Understand the Brain-Behavior Relationship in Sports

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on August 27, 2019 12:00 AM.

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    In the Long Run: Physical Activity in Early Life and Cognitive Aging

    A certain degree of age-related cognitive decline is normal; however, some people retain more cognitive function than others. Cognitive impairment is associated with an increased risk of dementia. Thus, understanding the factors that contribute to cognitive reserve is crucial, so effective strategies for the prevention of dementia can be developed. Engaging in physical activity can delay cognitive decline and reduce the risk of dementia and a number of early life conditions have been shown to have long-lasting effects on cognition. This mini-review combines these two observations to evaluate the evidence from both animal models and epidemiological studies for physical activity in early life (≤30 years) delaying cognitive decline in later life (cognition tested ≥60 years). Three epidemiological studies were found; two showed a positive association and one found none. The latter was deemed to have an unreliable method. A review of animal studies found none that analyzed the effect of physical activity in early life on cognition in later life. However, in rodent models that analyzed mid-life cognition, runners showed improved cognition and enhanced adult hippocampal neurogenesis, changes which were preserved across the life span. Currently, there is insufficient evidence to conclude whether physical activity in early life may delay cognitive decline in later life, but these results indicate that further studies are warranted. Future human research should be in the form of longitudinal studies that begin below ≤15 years and assess sex differences. Crucially, the physical activity data must define type, quantity and intensity of exercise.

    in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on August 27, 2019 12:00 AM.

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    An Effective Method for Acute Vagus Nerve Stimulation in Experimental Inflammation

    Neural reflexes regulate inflammation and electrical activation of the vagus nerve reduces inflammation in models of inflammatory disease. These discoveries have generated an increasing interest in targeted neurostimulation as treatment for chronic inflammatory diseases. Data from the first clinical trials that use vagus nerve stimulation (VNS) in treatment of rheumatoid arthritis and Crohn’s disease suggest that there is a therapeutic potential of electrical VNS in diseases characterized by excessive inflammation. Accordingly, there is an interest to further explore the molecular mechanisms and therapeutic potential of electrical VNS in a range of experimental settings and available genetic mouse models of disease. Here, we describe a method for electrical VNS in experimental inflammation in mice.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on August 27, 2019 12:00 AM.

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    The Impact of Self-Reported Hearing Difficulties on Memory Collaboration in Older Adults

    Cognitive scientists and philosophers recently have highlighted the value of thinking about people at risk of or living with dementia as intertwined parts of broader cognitive systems that involve their spouse, family, friends, or carers. By this view, we rely on people and things around us to “scaffold” mental processes such as memory. In the current study, we identified 39 long-married, older adult couples who are part of the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Ageing; all were cognitively healthy but half were subjective memory complainers. During two visits to their homes 1 week apart, we assessed husbands’ and wives’ cognitive performance across a range of everyday memory tasks working alone (Week 1) versus together (Week 2), including a Friends Task where they provided first and last names of their friends and acquaintances. As reported elsewhere, elderly couples recalled many more friends’ names working together compared to alone. Couples who remembered successfully together used well-developed, rich, sensitive, and dynamic communication strategies to boost each other’s recall. However, if one or both spouses self-reported mild-to-moderate or severe hearing difficulties (56% of husbands, 31% of wives), couples received less benefit from collaboration. Our findings imply that hearing loss may disrupt collaborative support structures that couples (and other intimate communicative partners) hone over decades together. We discuss the possibility that, cut off from the social world that scaffolds them, hearing loss may place older adults at greater risk of cognitive decline and dementia.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on August 27, 2019 12:00 AM.

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    A Multi-parametric MRI-Based Radiomics Signature and a Practical ML Model for Stratifying Glioblastoma Patients Based on Survival Toward Precision Oncology

    Purpose: Predicting patients' survival outcomes is recognized of key importance to clinicians in oncology toward determining an ideal course of treatment and patient management. This study applies radiomics analysis on pre-operative multi-parametric MRI of patients with glioblastoma from multiple institutions to identify a signature and a practical machine learning model for stratifying patients into groups based on overall survival.

    Methods: This study included 163 patients' data with glioblastoma, collected by BRATS 2018 Challenge from multiple institutions. In this proposed method, a set of 147 radiomics image features were extracted locally from three tumor sub-regions on standardized pre-operative multi-parametric MR images. LASSO regression was applied for identifying an informative subset of chosen features whereas a Cox model used to obtain the coefficients of those selected features. Then, a radiomics signature model of 9 features was constructed on the discovery set and it performance was evaluated for patients stratification into short- (<10 months), medium- (10–15 months), and long-survivors (>15 months) groups. Eight ML classification models, trained and then cross-validated, were tested to assess a range of survival prediction performance as a function of the choice of features.

    Results: The proposed mpMRI radiomics signature model had a statistically significant association with survival (P < 0.001) in the training set, but was not confirmed (P = 0.110) in the validation cohort. Its performance in the validation set had a sensitivity of 0.476 (short-), 0.231 (medium-), and 0.600 (long-survivors), and specificity of 0.667 (short-), 0.732 (medium-), and 0.794 (long-survivors). Among the tested ML classifiers, the ensemble learning model's results showed superior performance in predicting the survival classes, with an overall accuracy of 57.8% and AUC of 0.81 for short-, 0.47 for medium-, and 0.72 for long-survivors using the LASSO selected features combined with clinical factors.

    Conclusion: A derived GLCM feature, representing intra-tumoral inhomogeneity, was found to have a high association with survival. Clinical factors, when added to the radiomics image features, boosted the performance of the ML classification model in predicting individual glioblastoma patient's survival prognosis, which can improve prognostic quality a further step toward precision oncology.

    in Frontiers in Computational Neuroscience | New and Recent Articles on August 27, 2019 12:00 AM.

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    Cellular and Network Mechanisms for Temporal Signal Propagation in a Cortical Network Model

    The mechanisms underlying an effective propagation of high intensity information over a background of irregular firing and response latency in cognitive processes remain unclear. Here we propose a SSCCPI circuit to address this issue. We hypothesize that when a high-intensity thalamic input triggers synchronous spike events (SSEs), dense spikes are scattered to many receiving neurons within a cortical column in layer IV, many sparse spike trains are propagated in parallel along minicolumns at a substantially high speed and finally integrated into an output spike train toward or in layer Va. We derive the sufficient conditions for an effective (fast, reliable, and precise) SSCCPI circuit: (i) SSEs are asynchronous (near synchronous); (ii) cortical columns prevent both repeatedly triggering SSEs and incorrectly synaptic connections between adjacent columns; and (iii) the propagator in interneurons is temporally complete fidelity and reliable. We encode the membrane potential responses to stimuli using the non-linear autoregressive integrated process derived by applying Newton's second law to stochastic resilience systems. We introduce a multithreshold decoder to correct encoding errors. Evidence supporting an effective SSCCPI circuit includes that for the condition, (i) time delay enhances SSEs, suggesting that response latency induces SSEs in high-intensity stimuli; irregular firing causes asynchronous SSEs; asynchronous SSEs relate to healthy neurons; and rigorous SSEs relate to brain disorders. For the condition (ii) neurons within a given minicolumn are stereotypically interconnected in the vertical dimension, which prevents repeated triggering SSEs and ensures signal parallel propagation; columnar segregation avoids incorrect synaptic connections between adjacent columns; and signal propagation across layers overwhelmingly prefers columnar direction. For the condition (iii), accumulating experimental evidence supports temporal transfer precision with millisecond fidelity and reliability in interneurons; homeostasis supports a stable fixed-point encoder by regulating changes to synaptic size, synaptic strength, and ion channel function in the membrane; together all-or-none modulation, active backpropagation, additive effects of graded potentials, and response variability functionally support the multithreshold decoder; our simulations demonstrate that the encoder-decoder is temporally complete fidelity and reliable in special intervals contained within the stable fixed-point range. Hence, the SSCCPI circuit provides a possible mechanism of effective signal propagation in cortical networks.

    in Frontiers in Computational Neuroscience | New and Recent Articles on August 27, 2019 12:00 AM.

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    The Concept of Transmission Coefficient Among Different Cerebellar Layers: A Computational Tool for Analyzing Motor Learning

    High-fidelity regulation of information transmission among cerebellar layers is mainly provided by synaptic plasticity. Therefore, determining the regulatory foundations of synaptic plasticity in the cerebellum and translating them to behavioral output are of great importance. To date, many experimental studies have been carried out in order to clarify the effect of synaptic defects, while targeting a specific signaling pathway in the cerebellar function. However, the contradictory results of these studies at the behavioral level further add to the ambiguity of the problem. Information transmission through firing rate changes in populations of interconnected neurons is one of the most widely accepted principles of neural coding. In this study, while considering the efficacy of synaptic interactions among the cerebellar layers, we propose a firing rate model to realize the concept of transmission coefficient. Thereafter, using a computational approach, we test the effect of different values of transmission coefficient on the gain adaptation of a cerebellar-dependent motor learning task. In conformity with the behavioral data, the proposed model can accurately predict that disruption in different forms of synaptic plasticity does not have the same effect on motor learning. Specifically, impairment in training mechanisms, like in the train-induced LTD in parallel fiber-Purkinje cell synapses, has a significant negative impact on all aspects of learning, including memory formation, transfer, and consolidation, although it does not disrupt basic motor performance. In this regard, the overinduction of parallel fiber-molecular layer interneuron LTP could not prevent motor learning impairment, despite its vital role in preserving the robustness of basic motor performance. In contrast, impairment in plasticity induced by interneurons and background activity of climbing fibers is partly compensable through overinduction of train-induced parallel fiber-Purkinje cell LTD. Additionally, blockade of climbing fiber signaling to the cerebellar cortex, referred to as olivary system lesion, shows the most destructive effect on both motor learning and basic motor performance. Overall, the obtained results from the proposed computational framework are used to provide a map from procedural motor memory formation in the cerebellum. Certainly, the generalization of this concept to other multi-layered networks of the brain requires more physiological and computational researches.

    in Frontiers in Neural Circuits | New and Recent Articles on August 27, 2019 12:00 AM.

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    A neural circuit for comorbid depressive symptoms in chronic pain

    Nature Neuroscience, Published online: 26 August 2019; doi:10.1038/s41593-019-0468-2

    Zhou et al. report a novel 5-HT circuit from the dorsal raphe nucleus to somatostatin-expressing neurons in the central nucleus of the amygdala that partially mediates depressive-like behavior in a mouse model of chronic pain.

    in Nature Neuroscience - Issue - nature.com science feeds on August 26, 2019 12:00 AM.

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    Mechanisms of systems memory consolidation during sleep

    Nature Neuroscience, Published online: 26 August 2019; doi:10.1038/s41593-019-0467-3

    While we sleep, the brain replays memories of our experiences during the day. In this review, Klinzing et al. provide a concise overview of how the sleeping brain transforms and builds persisting memories through this process.

    in Nature Neuroscience - Issue - nature.com science feeds on August 26, 2019 12:00 AM.

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    Landscape of ribosome-engaged transcript isoforms reveals extensive neuronal-cell-class-specific alternative splicing programs

    Nature Neuroscience, Published online: 26 August 2019; doi:10.1038/s41593-019-0465-5

    Furlanis, Traunmüller et al. uncover hundreds of alternative splicing events that distinguish neuronal cell classes. Splice isoforms primarily encode synaptic and intrinsic neuronal properties. Data are available online in the SpliceCode database.

    in Nature Neuroscience - Issue - nature.com science feeds on August 26, 2019 12:00 AM.

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    Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage

    Nature Neuroscience, Published online: 26 August 2019; doi:10.1038/s41593-019-0461-9

    The authors leverage extensive RNA sequencing data from postmortem brains of controls and individuals with autism spectrum disorder (ASD) to identify altered patterns of allele specific gene expression.

    in Nature Neuroscience - Issue - nature.com science feeds on August 26, 2019 12:00 AM.

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    Interrogating Synaptic Architecture: Approaches for Labeling Organelles and Cytoskeleton Components

    Synaptic transmission has been studied for decades, as a fundamental step in brain function. The structure of the synapse, and its changes during activity, turned out to be key aspects not only in the transfer of information between neurons, but also in cognitive processes such as learning and memory. The overall synaptic morphology has traditionally been studied by electron microscopy, which enables the visualization of synaptic structure in great detail. The changes in the organization of easily identified structures, such as the presynaptic active zone, or the postsynaptic density, are optimally studied via electron microscopy. However, few reliable methods are available for labeling individual organelles or protein complexes in electron microscopy. For such targets one typically relies either on combination of electron and fluorescence microscopy, or on super-resolution fluorescence microscopy. This review focuses on approaches and techniques used to specifically reveal synaptic organelles and protein complexes, such as cytoskeletal assemblies. We place the strongest emphasis on methods detecting the targets of interest by affinity binding, and we discuss the advantages and limitations of each method.

    in Frontiers in Synaptic Neuroscience | New and Recent Articles on August 23, 2019 12:00 AM.

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    Phosphoinositides: Regulators of Nervous System Function in Health and Disease

    Phosphoinositides, the seven phosphorylated derivatives of phosphatidylinositol have emerged as regulators of key sub-cellular processes such as membrane transport, cytoskeletal function and plasma membrane signaling in eukaryotic cells. All of these processes are also present in the cells that constitute the nervous system of animals and in this setting too, these are likely to tune key aspects of cell biology in relation to the unique structure and function of neurons. Phosphoinositides metabolism and function are mediated by enzymes and proteins that are conserved in evolution, and analysis of knockouts of these in animal models implicate this signaling system in neural function. Most recently, with the advent of human genome analysis, mutations in genes encoding components of the phosphoinositide signaling pathway have been implicated in human diseases although the cell biological basis of disease phenotypes in many cases remains unclear. In this review we evaluate existing evidence for the involvement of phosphoinositide signaling in human nervous system diseases and discuss ways of enhancing our understanding of the role of this pathway in the human nervous system’s function in health and disease.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 23, 2019 12:00 AM.

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    Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders

    Effective treatments for pain management remain elusive due to the dangerous side-effects of current gold-standard opioid analgesics, including the respiratory depression that has led to skyrocketing death rates from opioid overdoses over the past decade. In an attempt to address the horrific opioid crisis worldwide, the National Institute on Drug Abuse has recently proposed boosting research on specific pharmacological mechanisms mediated by a number of G protein-coupled receptors (GPCRs). This research is expected to expedite the discovery of medications for opioid overdose and opioid use disorders, leading toward a safer and more effective treatment of pain. Here, we review mechanistic insights from recent all-atom molecular dynamics simulations of a specific subset of GPCRs for which high-resolution experimental structures are available, including opioid, cannabinoid, orexin, metabotropic glutamate, and dopamine receptor subtypes.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on August 23, 2019 12:00 AM.

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    Early Pain Exposure Influences Functional Brain Connectivity in Very Preterm Neonates

    Background

    Early exposure to nociceptive events may cause brain structural alterations in preterm neonates, with long-lasting consequences on neurodevelopmental outcome. Little is known on the extent to which early pain may affect brain connectivity. We aim to evaluate brain functional connectivity changes in preterm neonate that underwent multiple invasive procedures during the postnatal period, and to correlate them with the neurodevelopmental outcome at 24 months.

    Methods

    In this prospective case-control study, we collected information about exposure to painful events during the early postnatal period and resting-state BOLD-fMRI data at term equivalent age from two groups of preterm neonate: 33 subjected to painful procedures during the neonatal intensive care (mean gestational age 27.9 ± 1.8 weeks) and 13 who did not require invasive procedures (average gestational age 31.2 ± 2.1 weeks). A data-driven principal-component-based multivariate pattern analysis (MVPA) was used to investigate the effect of early pain exposure on brain functional connectivity, and the relationship between connectivity changes and neurodevelopmental outcome at 24 months, assessed with Griffiths, Developmental Scale-Revised: 0–2.

    Results

    Early pain was associated with decreased functional connectivity between thalami and bilateral somatosensory cortex, and between the right insular cortex and ipsilateral amygdala and hippocampal regions, with a more evident effect in preterm neonate undergoing more invasive procedures. Functional connectivity of the right thalamocortical pathway was related to neuromotor outcome at 24 months (P = 0.003).

    Conclusion

    Early exposure to pain is associated with abnormal functional connectivity of developing networks involved in the modulation of noxious stimuli in preterm neonate, contributing to the neurodevelopmental consequence of preterm birth.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on August 23, 2019 12:00 AM.

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    Inferior Longitudinal Fasciculus’ Role in Visual Processing and Language Comprehension: A Combined MEG-DTI Study

    The inferior longitudinal fasciculus (ILF) is a white matter tract that connects the occipital and the temporal lobes. ILF abnormalities have been associated with deficits in visual processing and language comprehension in dementia patients, thus suggesting that its integrity is important for semantic processing. However, it remains elusive whether ILF microstructural organization per se impacts the visual semantic processing efficiency in the healthy brain. The present study aims to investigate whether there is an association between ILF’s microstructural organization and visual semantic processing at the individual level. We hypothesized that the efficiency of visual semantic processing positively correlates with the degree of anisotropy of the ILF. We studied 10 healthy right-handed subjects. We determined fractional anisotropy (FA) of the ILF using diffusion tensor imaging (DTI). We extracted N400m latency and amplitude from magnetoencephalography (MEG) signals during a visual semantic decision task. N400m and mean FA of the ILF were left lateralized with the higher FA value in the left hemisphere. Inter-individual analysis showed that FA of the ILF negatively correlated with the N400m latency and amplitude, which suggests that high ILF anisotropy is associated with more efficient semantic processing. In summary, our findings provide supporting evidence for a role of the ILF in language comprehension.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on August 23, 2019 12:00 AM.

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    A Fully Automatic Framework for Parkinson’s Disease Diagnosis by Multi-Modality Images

    Background

    Parkinson’s disease (PD) is a prevalent long-term neurodegenerative disease. Though the criteria of PD diagnosis are relatively well defined, current diagnostic procedures using medical images are labor-intensive and expertise-demanding. Hence, highly integrated automatic diagnostic algorithms are desirable.

    Methods

    In this work, we propose an end-to-end multi-modality diagnostic framework, including segmentation, registration, feature extraction and machine learning, to analyze the features of striatum for PD diagnosis. Multi-modality images, including T1-weighted MRI and 11C-CFT PET, are integrated into the proposed framework. The reliability of this method is validated on a dataset with the paired images from 49 PD subjects and 18 Normal (NL) subjects.

    Results

    We obtained a promising diagnostic accuracy in the PD/NL classification task. Meanwhile, several comparative experiments were conducted to validate the performance of the proposed framework.

    Conclusion

    We demonstrated that (1) the automatic segmentation provides accurate results for the diagnostic framework, (2) the method combining multi-modality images generates a better prediction accuracy than the method with single-modality PET images, and (3) the volume of the striatum is proved to be irrelevant to PD diagnosis.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on August 23, 2019 12:00 AM.

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    Dynamics of Segregation and Integration in Directional Brain Networks: Illustration in Soldiers With PTSD and Neurotrauma

    Brain functioning relies on various segregated/specialized neural regions functioning as an integrated-interconnected network (i.e., metastability). Various psychiatric and neurologic disorders are associated with aberrant functioning of these brain networks. In this study, we present a novel framework integrating the strength and temporal variability of metastability in brain networks. We demonstrate that this approach provides novel mechanistic insights which enables better imaging-based predictions. Using whole-brain resting-state fMRI and a graph-theoretic framework, we integrated strength and temporal-variability of complex-network properties derived from effective connectivity networks, obtained from 87 U.S. Army soldiers consisting of healthy combat controls (n = 28), posttraumatic stress disorder (PTSD; n = 17), and PTSD with comorbid mild-traumatic brain injury (mTBI; n = 42). We identified prefrontal dysregulation of key subcortical and visual regions in PTSD/mTBI, with all network properties exhibiting lower variability over time, indicative of poorer flexibility. Larger impairment in the prefrontal-subcortical pathway but not prefrontal-visual pathway differentiated comorbid PTSD/mTBI from the PTSD group. Network properties of the prefrontal-subcortical pathway also had significant association (R2 = 0.56) with symptom severity and neurocognitive performance; and were also found to possess high predictive ability (81.4% accuracy in classifying the disorders, explaining 66–72% variance in symptoms), identified through machine learning. Our framework explained 13% more variance in behaviors compared to the conventional framework. These novel insights and better predictions were made possible by our novel framework using static and time-varying network properties in our three-group scenario, advancing the mechanistic understanding of PTSD and comorbid mTBI. Our contribution has wide-ranging applications for network-level characterization of healthy brains as well as mental disorders.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on August 23, 2019 12:00 AM.

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    Somatostatin-Expressing Interneurons Form Axonal Projections to the Contralateral Hippocampus

    Conscious memories are critically dependent upon bilateral hippocampal formation, and interhemispheric commissural projections made by mossy cells and CA3 pyramidal cells. GABAergic interneurons also make long-range axonal projections, but little is known regarding their commissural, inter-hippocampal connections. We used retrograde and adeno-associated viral tracing, immunofluorescence and electron microscopy, and in vitro optogenetics to assess contralateral projections of neurochemically defined interneuron classes. We found that contralateral-projecting interneurons were 24-fold less common compared to hilar mossy cells, and mostly consisted of somatostatin- and parvalbumin-expressing types. Somatostatin-expressing cells made denser contralateral axonal projections than parvalbumin-expressing cells, although this was typically 10-fold less than the ipsilateral projection density. Somatostatin-expressing cells displayed a topographic-like innervation according to the location of their somata, whereas parvalbumin-expressing cells mostly innervated CA1. In the dentate gyrus molecular layer, commissural interneuron post-synaptic targets were predominantly putative granule cell apical dendrites. In the hilus, varicosities in close vicinity to various interneuron subtypes, as well as mossy cells, were observed, but most contralateral axon varicosities had no adjacent immunolabeled structure. Due to the relative sparsity of the connection and the likely distal dendritic location of their synapses, commissural projections made by interneurons were found to be weak. We postulate that these projections may become functionally active upon intense network activity during tasks requiring increased memory processing.

    in Frontiers in Neural Circuits | New and Recent Articles on August 23, 2019 12:00 AM.

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    Structural Insights Into the Dynamic Evolution of Neuronal Networks as Synaptic Density Decreases

    The human brain is thought to be an extremely complex but efficient computing engine, processing vast amounts of information from a changing world. The decline in the synaptic density of neuronal networks is one of the most important characteristics of brain development, which is closely related to synaptic pruning, synaptic growth, synaptic plasticity, and energy metabolism. However, because of technical limitations in observing large-scale neuronal networks dynamically connected through synapses, how neuronal networks are organized and evolve as their synaptic density declines remains unclear. Here, by establishing a biologically reasonable neuronal network model, we show that despite a decline in the synaptic density, the connectivity, and efficiency of neuronal networks can be improved. Importantly, by analyzing the degree distribution, we also find that both the scale-free characteristic of neuronal networks and the emergence of hub neurons rely on the spatial distance between neurons. These findings may promote our understanding of neuronal networks in the brain and have guiding significance for the design of neuronal network models.

    in Frontiers in Neuroscience | Systems Biology section | New and Recent Articles on August 22, 2019 12:00 AM.

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    Phospho-S129 Alpha-Synuclein Is Present in Human Plasma but Not in Cerebrospinal Fluid as Determined by an Ultrasensitive Immunoassay

    Accumulation and aggregation of misfolded alpha-synuclein is believed to be a cause of Parkinson’s disease (PD). Phosphorylation of alpha-synuclein at S129 is known to be associated with the pathological misfolding process, but efforts to investigate the relevance of this post-translational modification for pathology have been frustrated by difficulties in detecting and quantifying it in relevant samples. We report novel, ultrasensitive immunoassays based on single-molecule counting technology, useful for detecting alpha-synuclein and its S129 phosphorylated form in clinical samples in the low pg/ml range. Using human CSF and plasma samples, we find levels of alpha-synuclein comparable to those previously reported. However, while alpha-synuclein phosphorylated on S129 could easily be detected in human plasma, where its detection is extremely sensitive to protein phosphatases, its levels in CSF were undetectable, with a possible influence of a matrix effect. In plasma samples from a small test cohort comprising 5 PD individuals and five age-matched control individuals we find that pS129 alpha-synuclein levels are increased in PD plasma samples, in line with previous reports. We conclude that pS129 alpha-synuclein is not detectable in CSF and recommend the addition of phosphatase inhibitors to plasma samples at the time of collection. Moreover, the findings obtained on the small cohort of clinical plasma samples point to plasma pS129 alpha-synuclein levels as a candidate diagnostic biomarker in PD.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on August 22, 2019 12:00 AM.

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    Decreased Cross-Domain Mutual Information in Schizophrenia From Dynamic Connectivity States

    The study of dynamic functional network connectivity (dFNC) has been important to understand the healthy and diseased brain. Recent developments model groups of functionally related brain structures (defined as functional domains) as entities that can send and receive information. A domain analysis starts by detecting a finite set of connectivity patterns known as domain states within each functional domain. Dynamic functional domain connectivity (DFDC) is a novel information theoretic framework for studying the temporal sequence of the domain states and the amount of information shared among domains. In this setting, the information flow among functional domains can be compared to the flow of bits among entities in a digital network. Schizophrenia is a chronic psychiatric disorder which is associated with how the brain processes information. Here, we employed the DFDC framework to analyze a dataset containing resting-state fMRI scans from 163 healthy controls (HCs) and 151 schizophrenia patients (SZs). As in other information theory methods, this study measured domain state probabilities, entropy within each DFDC and the cross-domain mutual information (CDMI) between pairs of DFDC. Results indicate that SZs show significantly higher (transformed) entropy than HCs in subcortical (SC)-SC; default mode network (DMN)-visual (VIS) and frontoparietal (FRN)-VIS DFDCs. SZs also show lower (transformed) CDMI between SC-VIS vs. SC-sensorimotor (SM), attention (ATTN)-VIS vs. ATTN-SM and ATTN-SM vs. ATTN-ATTN DFDC pairs after correcting for multiple comparisons. These results imply that different DFDC pairs function in a more independent manner in SZs compared to HCs. Our findings present evidence of higher uncertainty and randomness in SZ brain function.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on August 22, 2019 12:00 AM.

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    Behavior, protein, and dendritic changes after model traumatic brain injury and treatment with nanocoffee particles

    Traumatic brain injury (TBI) is a widespread public health problem and a signature injury of our military in modern conflicts. Despite the long-term effects of even mild brain injuries, an effective treatment ...

    in Most Recent Articles: BMC Neuroscience on August 22, 2019 12:00 AM.

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    Exploring the Phase-Locking Mechanisms Yielding Delayed and Anticipated Synchronization in Neuronal Circuits

    Synchronization is one of the brain mechanisms allowing the coordination of neuronal activity required in many cognitive tasks. Anticipated Synchronization (AS) is a specific type of out-of-phase synchronization that occurs when two systems are unidirectionally coupled and, consequently, the information is transmitted from the sender to the receiver, but the receiver leads the sender in time. It has been shown that the primate cortex could operate in a regime of AS as part of normal neurocognitive function. However it is still unclear what is the mechanism that gives rise to anticipated synchronization in neuronal motifs. Here, we investigate the synchronization properties of cortical motifs on multiple scales and show that the internal dynamics of the receiver, which is related to its free running frequency in the uncoupled situation, is the main ingredient for AS to occur. For biologically plausible parameters, including excitation/inhibition balance, we found that the phase difference between the sender and the receiver decreases when the free running frequency of the receiver increases. As a consequence, the system switches from the usual delayed synchronization (DS) regime to an AS regime. We show that at three different scales, neuronal microcircuits, spiking neuronal populations and neural mass models, both the inhibitory loop and the external current acting on the receiver mediate the DS-AS transition for the sender-receiver configuration by changing the free running frequency of the receiver. Therefore, we propose that a faster internal dynamics of the receiver system is the main mechanism underlying anticipated synchronization in brain circuits.

    in Frontiers in Systems Neuroscience | New and Recent Articles on August 21, 2019 12:00 AM.

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    Whisker-Mediated Touch System in Rodents: From Neuron to Behavior

    A key question in systems neuroscience is to identify how sensory stimuli are represented in neuronal activity, and how the activity of sensory neurons in turn is “read out” by downstream neurons and give rise to behavior. The choice of a proper model system to address these questions, is therefore a crucial step. Over the past decade, the increasingly powerful array of experimental approaches that has become available in non-primate models (e.g., optogenetics and two-photon imaging) has spurred a renewed interest for the use of rodent models in systems neuroscience research. Here, I introduce the rodent whisker-mediated touch system as a structurally well-established and well-organized model system which, despite its simplicity, gives rise to complex behaviors. This system serves as a behaviorally efficient model system; known as nocturnal animals, along with their olfaction, rodents rely on their whisker-mediated touch system to collect information about their surrounding environment. Moreover, this system represents a well-studied circuitry with a somatotopic organization. At every stage of processing, one can identify anatomical and functional topographic maps of whiskers; “barrelettes” in the brainstem nuclei, “barreloids” in the sensory thalamus, and “barrels” in the cortex. This article provides a brief review on the basic anatomy and function of the whisker system in rodents.

    in Frontiers in Systems Neuroscience | New and Recent Articles on August 21, 2019 12:00 AM.

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    Corticofugal Augmentation of the Auditory Brainstem Response With Respect to Cortical Preference

    Physiological studies documented highly specific corticofugal modulations making subcortical centers focus processing on sounds that the auditory cortex (AC) has experienced to be important. Here, we show the effects of focal conditioning (FC) of the primary auditory cortex (FCAI) on auditory brainstem response (ABR) amplitudes and latencies in house mice. FCAI significantly increased ABR peak amplitudes (peaks I–V), decreased thresholds, and shortened peak latencies in responses to the frequency tuned by conditioned cortical neurons. The amounts of peak amplitude increases and latency decreases were specific for each processing level up to the auditory midbrain. The data provide new insights into possible corticofugal modulation of inner hair cell synapses and new corticofugal effects as neuronal enhancement of processing in the superior olivary complex (SOC) and lateral lemniscus (LL). Thus, our comprehensive ABR approach confirms the role of the AC as instructor of lower auditory levels and extends this role specifically to the cochlea, SOC, and LL. The whole pathway from the cochlea to the inferior colliculus appears, in a common mode, instructed in a very similar way.

    in Frontiers in Systems Neuroscience | New and Recent Articles on August 21, 2019 12:00 AM.

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    Organization of Posterior Parietal–Frontal Connections in the Rat

    Recent investigations of the rat posterior parietal cortex (PPC) suggest that this region plays a central role in action control together with the frontal cortical areas. Posterior parietal-frontal cortical connections have been described in rats, but little is known about whether these connections are topographically organized as in the primate. Here, we injected retrograde and anterograde tracers into subdivisions of PPC as well as the frontal midline and orbital cortical areas to explore possible topographies within their connections. We found that PPC projects to several frontal cortical areas, largely reciprocating the densest input received from the same areas. All PPC subdivisions are strongly connected with the secondary motor cortex (M2) in a topographically organized manner. The medial subdivision (medial posterior parietal cortex, mPPC) has a dense reciprocal connection with the most caudal portion of M2 (cM2), whereas the lateral subdivision (lateral posterior parietal cortex, lPPC) and the caudolateral subdivision (PtP) are reciprocally connected with the intermediate rostrocaudal portion of M2 (iM2). Sparser reciprocal connections were seen with anterior cingulate area 24b. mPPC connects with rostral, and lPPC and PtP connect with caudal parts of 24b, respectively. There are virtually no connections with area 24a, nor with prelimbic or infralimbic cortex. PPC and orbitofrontal cortices are also connected, showing a gradient such that mPPC entertains reciprocal connections mainly with the ventral orbitofrontal cortex (OFC), whereas lPPC and PtP are preferentially connected with medial and central portions of ventrolateral OFC, respectively. Our results thus indicate that the connections of PPC with frontal cortices are organized in a topographical fashion, supporting functional heterogeneity within PPC and frontal cortices.

    in Frontiers in Systems Neuroscience | New and Recent Articles on August 21, 2019 12:00 AM.

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    Conceptual, Regulatory and Strategic Imperatives in the Early Days of EEG-Based Biomarker Validation for Neurodevelopmental Disabilities

    Biological treatment development for syndromal neuropsychiatric conditions such as autism has seen slow progress for decades. Speeding drug discovery may result from the judicious development and application of biomarker measures of brain function to select patients for clinical trials, to confirm target engagement and to optimize drug dose. For neurodevelopmental disorders, electrophysiology (EEG) offers considerable promise because of its ability to monitor brain activity with high temporal resolution and its more ready application for pediatric populations relative to MRI. Here, we discuss conceptual/definitional issues related to biomarker development, discuss practical implementation issues, and suggest preliminary guidelines for validating EEG approaches as biomarkers with a context of use in neurodevelopmental disorder drug development.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on August 21, 2019 12:00 AM.

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