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    Synaptic Integration of Thalamic and Limbic Inputs in Rodent Gustatory Cortex

    Abstract

    Neurons in the gustatory cortex (GC) process multiple aspects of a tasting experience, encoding not only the physiochemical identity of tastes, but also their anticipation and hedonic value. Information pertaining to these stimulus features is relayed to GC via the gustatory thalamus (VPMpc) and basolateral amygdala (BLA). It is not known whether these inputs drive separate groups of neurons, thus activating separate channels of information, or are integrated by neurons that receive both afferents. Here, we used anterograde labeling and in vivo intracellular recordings in anesthetized rats to assess the potential convergence of BLA and VPMpc inputs in GC, and to investigate the dynamics of integration of these inputs. We report substantial anatomic overlap of BLA and VPMpc axonal fields across GC, and identify a population of GC neurons receiving converging BLA and VPMpc inputs. Our data show that BLA modulates the gain of VPMpc-evoked responses in a time-dependent fashion and that this modulation is dependent on the recruitment of synaptic inhibition by both BLA and VPMpc. Our results suggest that BLA shapes cortical processing of thalamic inputs by dynamically gating the excitatory/inhibitory balance of the GC circuit.

    in eNeuro current issue on February 17, 2020 05:30 PM.

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    Cross-Modal Integration of Reward Value during Oculomotor Planning

    Abstract

    Reward value guides goal-directed behavior and modulates early sensory processing. Rewarding stimuli are often multisensory, but it is not known how reward value is combined across sensory modalities. Here we show that the integration of reward value critically depends on whether the distinct sensory inputs are perceived to emanate from the same multisensory object. We systematically manipulated the congruency in monetary reward values and the relative spatial positions of co-occurring auditory and visual stimuli that served as bimodal distractors during an oculomotor task performed by healthy human participants (male and female). The amount of interference induced by the distractors was used as an indicator of their perceptual salience. Our results across two experiments show that when reward value is linked to each modality separately, the value congruence between vision and audition determines the combined salience of the bimodal distractors. However, the reward value of vision wins over the value of audition if the two modalities are perceived to convey conflicting information regarding the spatial position of the bimodal distractors. These results show that in a task that highly relies on the processing of visual spatial information, the reward values from multiple sensory modalities are integrated with each other, each with their respective weights. This weighting depends on the strength of prior beliefs regarding a common source for incoming unisensory signals based on their congruency in reward value and perceived spatial alignment.

    in eNeuro current issue on February 17, 2020 05:30 PM.

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    The Epileptor model: a systematic mathematical analysis linked to the dynamics of seizures, refractory status epilepticus and depolarization block

    Abstract

    One characteristic of epilepsy is the variety of mechanisms leading to the epileptic state, which are still largely unknown. Refractory status epilepticus (RSE) and depolarization block (DB) are other pathological brain activities linked to epilepsy, whose patterns are different, and whose mechanisms remain poorly understood. In epileptogenic network modeling, the Epileptor is a generic phenomenological model that has been recently developed to describe the dynamics of seizures. Here, we performed a detailed qualitative analysis of the Epileptor model based on dynamical systems theory and bifurcation analysis, and investigate the dynamic evolution of" normal" activity toward seizures and to the pathological RSE and DB states. The mechanisms of the transition between states are called bifurcations. Our detailed analysis demonstrates that the generic model undergoes different bifurcation types at seizure offset, when varying some selected parameters. We show that the pathological and normal activities can co-exist within the same model under some conditions, and demonstrate that there are many pathways leading to and away from these activities. We here archive systematically all behaviors and dynamic regimes of the Epileptor model, to serve as a resource in the development of patient specific brain network models, and more generally in epilepsy research.

    Significance Statement Epilepsy is characterized by patient specific electrophysiological discharges. The range of mechanisms and pathways leading to the same type of seizure, however, is large. The Epileptor model has found many applications in epilepsy research and clinical applications, because it allows the classification and dynamic modeling of seizure types independent of the knowledge of its underlying biophysical mechanisms. It is based purely on the dynamic features of the seizure. We provide here a complete functional atlas of all possible behaviors of the Epileptor model, which serves as a useful ressource in modeling brain networks in epilepsy. More, we explore the contribution of the Epileptor model to better understand the dynamics of the RSE and DB phenomena which are linked to epilepsy.

    in RSS PAP on February 17, 2020 05:30 PM.

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    Binaural beats through the auditory pathway: from brainstem to connectivity patterns

    Abstract

    Binaural beating is a perceptual auditory illusion occurring when presenting two neighboring frequencies to each ear separately. Several controversial claims have been attributed to binaural beats regarding their ability to entrain human brain activity and mood, in both the scientific literature and the marketing realm. Here, we sought to address those questions in a robust fashion using a single-blind, active-controlled protocol. To do so, we compared the effects of binaural beats with a control beat stimulation (monaural beats, known to entrain brain activity but not mood) across four distinct levels in the human auditory pathway: subcortical and cortical entrainment, scalp-level Functional Connectivity and self-reports. Both stimuli elicited standard subcortical responses at the pure tone frequencies of the stimulus (i.e., Frequency Following Response), and entrained the cortex at the beat frequency (i.e., Auditory Steady State Response). Furthermore, Functional Connectivity patterns were modulated differentially by both kinds of stimuli, with binaural beats being the only one eliciting cross-frequency activity. Despite this, we did not find any mood modulation related to our experimental manipulation. Our results provide evidence that binaural beats elicit cross frequency connectivity patterns, but weakly entrain the cortex when compared to monaural beat stimuli. Whether binaural beats have an impact on cognitive performance or other mood measurements remains to be seen and can be further investigated within the proposed methodological framework.

    Significance Statement Binaural beats have been a source of speculation and debate in the scientific community. Our study addresses controversial claims and approaches them using proper experimental control and modern signal processing techniques. Here we show that binaural beats can both entrain the cortex and elicit specific connectivity patterns. Regardless of this, our monaural control condition was able to entrain the cortex more strongly, and both binaural beats and the control condition failed to regulate mood. All in all, though binaural beats entrain cortical activity and elicit complex patterns of connectivity, the functional significance (if any) of binaural beats, and whether they are more "special" than monaural beats remain open questions.

    in RSS PAP on February 17, 2020 05:30 PM.

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    Distributional robustness as a guiding principle for causality in cognitive neuroscience. (arXiv:2002.06060v1 [q-bio.NC])

    While probabilistic models describe the dependence structure between observed variables, causal models go one step further: they predict how cognitive functions are affected by external interventions that perturb neuronal activity. Inferring causal relationships from data is an ambitious task that is particularly challenging in cognitive neuroscience. Here, we discuss two difficulties in more detail: the scarcity of interventional data and the challenge of finding the right variables. We argue for distributional robustness as a guiding principle to tackle these problems. Modelling a target variable using the correct set of causal variables yields a model that generalises across environments or subjects (if these environments leave the causal mechanisms intact). Conversely, if a candidate model does not generalise, then either it includes non-causes of the target variable or the underlying variables are wrongly defined. In this sense, generalisability may serve as a guiding principle when defining relevant variables and can be used to partially compensate for the lack of interventional data.

    in q-bio.NC updates on arXiv.org on February 17, 2020 01:30 AM.

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    What is the function of inter-hemispheric inhibition?. (arXiv:2002.05774v1 [q-bio.NC])

    It is widely supposed that following unilateral brain injury, there arises an asymmetry in inter-hemispheric inhibition which has an adverse influence upon motor control. I argue that this 'inter-hemispheric imbalance' model arises from a fundamental misunderstanding of the roles played by inter-hemispheric (callosal) projections in mammalian brains. Drawing upon a large body of empirical data, derived largely from animal models, and associated theoretical modeling, it is demonstrated that inter-hemispheric projections perform contrast enhancing and integrative functions via mechanisms such as surround/lateral inhibition. The principal functional unit of callosal influence comprises a facilitatory centre and a depressing peripheral zone, that together shape the influence of converging inputs to pyramidal neurons. Inter-hemispheric inhibition is an instance of a more general feature of mammalian neural systems, whereby inhibitory interneurons act not simply to prevent over-excitation but to sculpt the output of specific circuits. The narrowing of the excitatory focus that occurs through crossed surround inhibition is a highly conserved motif of transcallosal interactions in mammalian sensory and motor cortices. A case is presented that the notion of 'inter-hemispheric imbalance' has been sustained, and clinical interventions derived from this model promoted, by erroneous assumptions concerning that revealed by investigative techniques such as transcranial magnetic stimulation (TMS). The alternative perspective promoted by the present analysis, also permits the basis of positive (e.g. post stroke) associations between the structural integrity of transcallosal projections and motor capability to be better understood.

    in q-bio.NC updates on arXiv.org on February 17, 2020 01:30 AM.

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    How spatial frequencies and color drive object search in real-world scenes: A new eye-movement corpus. (arXiv:1910.09904v2 [q-bio.NC] UPDATED)

    When studying how people search for objects in scenes, the inhomogeneity of the visual field is often ignored. Due to physiological limitations peripheral vision is blurred and mainly uses coarse-grained information (i.e., low spatial frequencies) for selecting saccade targets, whereas high-acuity central vision uses fine-grained information (i.e., high spatial frequencies) for analysis of details. Here we investigated how spatial frequencies and color affect object search in real-world scenes. Using gaze-contingent filters we attenuated high or low frequencies in central or peripheral vision while viewers searched color or grayscale scenes. Results showed that peripheral filters and central high-pass filters hardly affected search accuracy, whereas accuracy dropped drastically with central low-pass filters. Peripheral filtering increased the time to localize the target by decreasing saccade amplitudes and increasing number and duration of fixations. The use of coarse-grained information in the periphery was limited to color scenes. Central filtering increased the time to verify target identity instead, especially with low-pass filters. We conclude that peripheral vision is critical for object localization and central vision is critical for object identification. Visual guidance during peripheral object localization is dominated by low-frequency color information, whereas high-frequency information, relatively independent of color, is most important for object identification in central vision.

    in q-bio.NC updates on arXiv.org on February 17, 2020 01:30 AM.

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    Neurogenesis right under your nose

    Nature Neuroscience, Published online: 17 February 2020; doi:10.1038/s41593-020-0596-8

    Postmortem studies have previously suggested that adult olfactory neurogenesis occurs in humans. In new research, Durante and colleagues obtained fresh tissue from healthy adult humans via endoscopic nasal surgery and used single-cell RNA sequencing (RNA-seq) to identify the entire neurogenic trajectory in the olfactory epithelium, confirming the existence of human olfactory neurogenesis.

    in Nature Neuroscience - Issue - nature.com science feeds on February 17, 2020 12:00 AM.

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    Paraventricular nucleus CRH neurons encode stress controllability and regulate defensive behavior selection

    Nature Neuroscience, Published online: 17 February 2020; doi:10.1038/s41593-020-0591-0

    Prior stressful experience affects subsequent behavior even in different situations. Daviu et al. demonstrate that CRHPVN neurons encode stress controllability and contribute to shifts between active and passive innate defensive strategies.

    in Nature Neuroscience - Issue - nature.com science feeds on February 17, 2020 12:00 AM.

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    A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis

    Nature Neuroscience, Published online: 17 February 2020; doi:10.1038/s41593-020-0590-1

    Rodriguez et al. define a native role for RAN translation and CGG repeats in regulating mGluR-dependent fragile X protein (FMRP) synthesis. RAN-blocking antisense oligonucleotides increase FMRP and improve survival of neurons from patients with repeat expansions.

    in Nature Neuroscience - Issue - nature.com science feeds on February 17, 2020 12:00 AM.

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    Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice

    Nature Neuroscience, Published online: 17 February 2020; doi:10.1038/s41593-020-0589-7

    Alpha-synuclein fibrils can disrupt the enteric nervous system, which is mitigated by peripheral GBA1 gene transfer via systemic AAVs. Aging increases susceptibility to α-synuclein pathology progression from the gut to the brain.

    in Nature Neuroscience - Issue - nature.com science feeds on February 17, 2020 12:00 AM.

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    Single-cell analysis of olfactory neurogenesis and differentiation in adult humans

    Nature Neuroscience, Published online: 17 February 2020; doi:10.1038/s41593-020-0587-9

    Durante et al. report the presence of active neurogenic niches in adult humans using single-cell RNA sequencing of the human olfactory neuroepithelium. Data from the olfactory neuroepithelium niche provide evidence that neuron production may continue for decades in humans.

    in Nature Neuroscience - Issue - nature.com science feeds on February 17, 2020 12:00 AM.

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    Spatiotemporal single-cell analysis of gene expression in the mouse suprachiasmatic nucleus

    Nature Neuroscience, Published online: 17 February 2020; doi:10.1038/s41593-020-0586-x

    Wen et al. combined single-cell RNA-seq and spatiotemporal analysis techniques to characterize the basic cell types in the mouse SCN, identifying their spatial distributions and circadian and light-induced gene expression patterns.

    in Nature Neuroscience - Issue - nature.com science feeds on February 17, 2020 12:00 AM.

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    Ultrasonic signals associated with different types of social behavior of mice

    Nature Neuroscience, Published online: 17 February 2020; doi:10.1038/s41593-020-0584-z

    A sound source localization system reveals behavior-dependent vocal emission and thereby unmasks functions of social vocalization.

    in Nature Neuroscience - Issue - nature.com science feeds on February 17, 2020 12:00 AM.

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    Functionally distinct subgroups of oligodendrocyte precursor cells integrate neural activity and execute myelin formation

    Nature Neuroscience, Published online: 17 February 2020; doi:10.1038/s41593-019-0581-2

    Oligodendrocyte precursor cells divide or differentiate in response to external stimuli to control their numbers and to form new myelin. Using zebrafish, we show that these two functions are accomplished by distinct subgroups of cells.

    in Nature Neuroscience - Issue - nature.com science feeds on February 17, 2020 12:00 AM.

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    Translational initiation in E. coli occurs at the correct sites genome-wide in the absence of mRNA-rRNA base-pairing

    Shine-Dalgarno (SD) motifs are thought to play an important role in translational initiation in bacteria. Paradoxically, ribosome profiling studies in E. coli show no correlation between the strength of an mRNA's SD motif and how efficiently it is translated. Performing profiling on ribosomes with altered anti-Shine-Dalgarno sequences, we reveal a genome-wide correlation between SD strength and ribosome occupancy that was previously masked by other contributing factors. Using the antibiotic retapamulin to trap initiation complexes at start codons, we find that the mutant ribosomes select start sites correctly, arguing that start sites are hard-wired for initiation through the action of other mRNA features. We show that A-rich sequences upstream of start codons promote initiation. Taken together, our genome-wide study reveals that SD motifs are not necessary for ribosomes to determine where initiation occurs, though they do affect how efficiently initiation occurs.

    in eLife: latest articles on February 17, 2020 12:00 AM.

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    A single-parasite transcriptional atlas of Toxoplasma gondii reveals novel control of antigen expression

    Toxoplasma gondii, a protozoan parasite, undergoes a complex and poorly understood developmental process that is critical for establishing a chronic infection in its intermediate hosts. Here, we applied single-cell RNA-sequencing (scRNA-seq) on >5,400 Toxoplasma in both tachyzoite and bradyzoite stages using three widely studied strains to construct a comprehensive atlas of cell-cycle and asexual development, revealing hidden states and transcriptional factors associated with each developmental stage. Analysis of SAG1-related sequence (SRS) antigenic repertoire reveals a highly heterogeneous, sporadic expression pattern unexplained by measurement noise, cell cycle, or asexual development. Furthermore, we identified AP2IX-1 as a transcription factor that controls the switching from the ubiquitous SAG1 to rare surface antigens not previously observed in tachyzoites. In addition, comparative analysis between Toxoplasma and Plasmodium scRNA-seq results reveals concerted expression of gene sets, despite fundamental differences in cell division. Lastly, we built an interactive data-browser for visualization of our atlas resource.

    in eLife: latest articles on February 17, 2020 12:00 AM.

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    EDEM2 stably disulfide-bonded to TXNDC11 catalyzes the first mannose trimming step in mammalian glycoprotein ERAD

    Sequential mannose trimming of N-glycan (Man9GlcNAc2 -> Man8GlcNAc2 -> Man7GlcNAc2) facilitates endoplasmic reticulum-associated degradation of misfolded glycoproteins (gpERAD). Our gene knockout experiments in human HCT116 cells have revealed that EDEM2 is required for the first step. However, it was previously shown that purified EDEM2 exhibited no a1,2-mannosidase activity toward Man9GlcNAc2 in vitro. Here, we found that EDEM2 was stably disulfide-bonded to TXNDC11, an endoplasmic reticulum protein containing five thioredoxin (Trx)-like domains. C558 present outside of the mannosidase homology domain of EDEM2 was linked to C692 in Trx5, which solely contains the CXXC motif in TXNDC11. This covalent bonding was essential for mannose trimming and subsequent gpERAD in HCT116 cells. Furthermore, EDEM2-TXNDC11 complex purified from transfected HCT116 cells converted Man9GlcNAc2 to Man8GlcNAc2(isomerB) in vitro. Our results establish the role of EDEM2 as an initiator of gpERAD, and represent the first clear demonstration of in vitro mannosidase activity of EDEM family proteins.

    in eLife: latest articles on February 17, 2020 12:00 AM.

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    ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL

    Eukaryotic genomes are folded into loops. It is thought that these are formed by cohesin complexes via extrusion, either until loop expansion is arrested by CTCF or until cohesin is removed from DNA by WAPL. Although WAPL limits cohesin's chromatin residence time to minutes, it has been reported that some loops exist for hours. How these loops can persist is unknown. We show that during G1-phase, mammalian cells contain acetylated cohesinSTAG1 which binds chromatin for hours, whereas cohesinSTAG2 binds chromatin for minutes. Our results indicate that CTCF and the acetyltransferase ESCO1 protect a subset of cohesinSTAG1 complexes from WAPL, thereby enable formation of long and presumably long-lived loops, and that ESCO1, like CTCF, contributes to boundary formation in chromatin looping. Our data are consistent with a model of nested loop extrusion, in which acetylated cohesinSTAG1 forms stable loops between CTCF sites, demarcating the boundaries of more transient cohesinSTAG2 extrusion activity.

    in eLife: latest articles on February 17, 2020 12:00 AM.

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    Repression of viral gene expression and replication by the unfolded protein response effector XBP1u

    The unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 (Xbp1) mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic β-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced Xbp1 mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation.

    in eLife: latest articles on February 17, 2020 12:00 AM.

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    Neonatal-derived IL-17 producing dermal γδ T cells are required to prevent spontaneous atopic dermatitis

    Atopic Dermatitis (AD) is a T cell-mediated chronic skin disease and is associated with altered skin barrier integrity. Infants with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most do not develop or sustain the diseases, suggesting that there exist regulatory immune mechanisms to prevent aberrant inflammation. The absence of one single murine dermal cell type, the innate neonatal-derived IL-17 producing γδ T (Tγδ17) cells, from birth resulted in spontaneous, highly penetrant AD with many of the major hallmarks of human AD. In Tγδ17 cell-deficient mice, basal keratinocyte transcriptome was altered months in advance of AD induction. Tγδ17 cells respond to skin commensal bacteria and the fulminant disease in their absence was driven by skin commensal bacteria dysbiosis. AD in this model was characterized by highly expanded dermal αβ T clonotypes that produce the type three cytokines, IL-17 and IL-22. These results demonstrate that neonatal Tγδ17 cells are innate skin regulatory T cells that are critical for skin homeostasis, and that IL-17 has dual homeostatic and inflammatory function in the skin.

    in eLife: latest articles on February 17, 2020 12:00 AM.

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    Distinct natural syllable-selective neuronal ensembles in the primary auditory cortex of awake marmosets

    Vocal communication is crucial for animals' survival, but the underlying neural mechanism remains largely unclear. Using calcium imaging of large neuronal populations in the primary auditory cortex (A1) of head-fixed awake marmosets, we found specific ensembles of A1 neurons that responded selectively to distinct monosyllables or disyllables in natural marmoset calls. These selective responses were stable over one-week recording time, and disyllable-selective cells completely lost selective responses after anesthesia. No selective response was found for novel disyllables constructed by reversing the sequence of constituent monosyllables or by extending the interval between them beyond ~1 second. These findings indicate that neuronal selectivity to natural calls exists in A1 and pave the way for studying circuit mechanisms underlying vocal communication in awake non-human primates.

    in bioRxiv Subject Collection: Neuroscience on February 16, 2020 12:00 AM.

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    Prior short-term habituation to auditory feedback delays does not mitigate their disruptive effect on speech auditory-motor adaptation

    Perceiving the sensory consequences of our own actions with a delay alters the interpretation of these afferent signals and impacts motor learning. For reaching movements, delayed visual feedback of hand position reduces the rate and extent of visuo-motor adaptation, but substantial adaptation still occurs. Moreover, the detrimental effect of visual feedback delay on reach motor learning -- in particular its explicit component -- can be mitigated by prior habituation to the delay. Auditory-motor learning for speech has been reported to be more sensitive to feedback delay, and it remains unknown whether prior habituation to auditory delay reduces its negative impact on learning. We investigated whether 30 minutes of exposure to auditory feedback delay during speaking (a) affects the subjective perception of this delay, and (b) mitigates its disruptive effect on speech auditory-motor learning. During a speech adaptation task with real-time perturbation of vowel spectral properties, participants heard this frequency-shifted auditory feedback with either no delay, 75 ms delay, or 115 ms delay. In the delay groups, half of the participants had been exposed to the delay throughout a preceding 30-minute block of speaking whereas the remaining participants completed this initial block without delay. Even though habituation reduced the subjective perception of delay, no improvement in adaptation to the spectral perturbation was observed as compared with non-habituated participants. Thus, short-term habituation to auditory feedback delays is not effective in reducing the negative impact of delay on speech auditory-motor adaptation, suggesting the involvement of predominantly implicit learning mechanisms in this form of sensorimotor learning.

    in bioRxiv Subject Collection: Neuroscience on February 16, 2020 12:00 AM.

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    Signal propagation via cortical hierarchies

    The wiring of the brain is organized around a putative unimodal-transmodal hierarchy. Here we investigate how this intrinsic hierarchical organization of the brain shapes the transmission of information among regions. The hierarchical positioning of individual regions was quantified by applying diffusion map embedding to resting state functional MRI networks. Structural networks were reconstructed from diffusion spectrum imaging and topological shortest paths among all brain regions were computed. Sequences of nodes encountered along a path were labelled by their hierarchical position, tracing out path motifs. We find that the cortical hierarchy guides communication in the network. Specifically, nodes are more likely to forward signals to nodes closer in the hierarchy and cover a range of unimodal and transmodal regions, potentially enriching or diversifying signals en route. We also find evidence of systematic detours, particularly in attention networks, where communication is re-routed. Altogether, the present work highlights how the cortical hierarchy shapes signal exchange and imparts behaviourally-relevant communication patterns in brain networks.

    in bioRxiv Subject Collection: Neuroscience on February 16, 2020 12:00 AM.

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    Issue Information

    in Wiley: Annals of Neurology: Table of Contents on February 15, 2020 07:00 PM.

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    Annals of Neurology: Volume 87, Number 3, March 2020

    A confocal fluorescence micrograph of a Meissner corpuscle in the fingertip skin of a control subject. Green immunohistochemical staining for PGP identifies the nerves and red staining for Collagen type IV outlines the corpuscle and the basement membrane; the background is stained blue for keratinocytes. The density of innervation of the Meissner corpuscles can be followed during compressive median neuropathy and during reinnervation after surgery. See Provitera et al., pp. 456–465. Ann Neurol 2020;87:1–1

    in Wiley: Annals of Neurology: Table of Contents on February 15, 2020 07:00 PM.

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    The genotypic and phenotypic spectrum of BICD2 variants in spinal muscular atrophy

    ABSTRACT

    The bicaudal D cargo adaptor 2 (BICD2) gene encodes a conserved cargo adapter protein required for dynein‐mediated transport. Inherited and de novo variants in BICD2 cause spinal muscular atrophy, lower extremity dominant 2 (SMALED2), and a subset have recently been reported to cause severe, often lethal disease. However, a true genotype‐phenotype correlation for BICD2 has not been performed, and cases described to date are scattered among at least 14 publications. In this review, we identify the characteristics of disease‐causing variants in BICD2 that distinguish them from benign variation, and perform genotype‐phenotype correlations for 99 BICD2 variant carriers from 35 families.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 15, 2020 08:00 AM.

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    Sleep deprivation affects tau phosphorylation in human cerebrospinal fluid

    Abstract

    Tau hyperphosphorylation is an early step in tau‐mediated neurodegeneration and is associated with intracellular aggregation of tau as neurofibrillary tangles, neuronal and synaptic loss, and eventual cognitive dysfunction in Alzheimer's disease. Sleep loss increases the cerebrospinal fluid concentration of amyloid‐β and tau. Using mass spectrometry, we measured tau and phosphorylated tau concentrations in serial samples of cerebrospinal fluid collected from participants who were sleep‐deprived, treated with sodium oxybate, or allowed to sleep normally. We found that sleep loss affected phosphorylated tau differently depending on the modified site. These findings suggest a mechanism for sleep loss to increase risk of Alzheimer's disease.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 15, 2020 08:00 AM.

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    Cancer Risk for Fingolimod, Natalizumab, and Rituximab in MS Patients

    Abstract

    Objective

    Novel, highly effective disease‐modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking.

    Methods

    In this nationwide register‐based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national healthcare and census registers. We included 4187 first‐ever initiations of rituximab, 1620 of fingolimod, and 1670 of natalizumab, in 6136 MS patients, age‐sex‐and‐location matched to 37801 non‐MS general population subjects. Primary outcome was time to first invasive cancer.

    Results

    We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate, IR, per 10,000 person years 34.4 [95% confidence interval 23.7–48.3]), fingolimod 28 (44.0 [29.2–63.5]), and natalizumab 17 (26.0 [15.1–41.6]). The general population IR was 31.0 [27.8–34.4]. Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population, but a possibly higher risk with fingolimod compared to the general population (1.53 [0.98–2.38]) and rituximab (hazard ratio 1.68 [1.00–2.84]).

    Interpretation

    In this first, large, comparative study of three highly effective MS disease‐modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline‐significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer and further studies are warranted to validate these findings.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 15, 2020 08:00 AM.

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    Validation of rapid magnetic resonance myelin imaging in multiple sclerosis

    Abstract

    Objective

    MRI is essential for multiple sclerosis diagnostics but is not specific to demyelination. Myelin imaging is often hampered by long scanning times, complex post‐processing or lack of clinical approval. This study aimed to assess the specificity, robustness and clinical value of Rapid Estimation of Myelin for Diagnostic Imaging, a new myelin imaging technique based on time‐efficient simultaneous T1/T2‐relaxometry and proton density mapping, in multiple sclerosis.

    Methods

    Rapid myelin imaging was applied using 3 Tesla MRI; ex vivo in three multiple sclerosis brain samples and in vivo in a prospective cohort of 71 multiple sclerosis patients and 21 age/sex‐matched healthy controls, with scan‐rescan repeatability in a subcohort. Disability in patients was assessed by the Expanded Disability Status Scale and the Symbol Digit Modalities Test at baseline and 2‐year follow‐up.

    Results

    Rapid myelin imaging correlated with myelin‐related stains (proteolipid protein‐immunostaining and Luxol fast blue) and demonstrated good precision. Multiple sclerosis patients had, relative to controls, lower normalized whole‐brain and normal‐appearing white matter myelin fractions, which correlated with baseline cognitive and physical disability. Longitudinally, these myelin fractions correlated with follow‐up physical disability, even with correction for baseline disability.

    Interpretation

    Rapid Estimation of Myelin for Diagnostic Imaging provides robust myelin quantification that detects diffuse demyelination in normal‐appearing tissue in multiple sclerosis, which is associated with both cognitive and clinical disability. Since the technique is fast with automatic post‐processing and FDA/CE clinical approval, it can be a clinically feasible biomarker that may be suitable to monitor myelin dynamics and evaluate treatments aiming at remyelination.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 15, 2020 08:00 AM.

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    Path integration changes as a cognitive marker for vascular cognitive impairment? - a pilot study

    Path integration spatial navigation processes are emerging as promising cognitive markers for prodromal and clinical Alzheimer's disease (AD). However, such path integration changes have been little explored in Vascular Cognitive Impairment (VCI), despite neurovascular change being a major contributing factor to dementia and potentially AD. In particular, the sensitivity and specificity of path integration impairments in VCI compared to AD is unclear. In the current pilot study, we explore path integration performance in AD and VCI patient groups and hypothesise that i) medial parietal mediated egocentric processes will be more affected in VCI and ii) medial temporal mediated allocentric processes will be more affected in AD. This retrospective cross-sectional study included early stage VCI patients (n=9), AD patients (n=10) and healthy age-matched controls (n=20). All participants underwent extensive neuropsychological testing, as well as spatial navigation testing. The spatial navigation tests included the virtual reality 'Supermarket' task assessing egocentric (body-based) and allocentric (map-based) navigation as well as the 'Clock Orientation' test assessing egocentric and path integration processes. Results showed that egocentric path integration processes are only impaired in VCI, potentially distinguishing it from AD. However, in contrast to our prediction, allocentric path integration was similarly impaired for VCI and AD. These preliminary findings suggest limited specificity of allocentric path integration deficits between VCI and AD. By contrast, egocentric path integration deficits emerge as more specific to VCI, potentially allowing for more specific diagnostic and treatment outcome measures for vascular impairment in dementia.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Faster than thought: Detecting sub-second activation sequences with sequential fMRI pattern analysis

    Neural computations are often anatomically localized and executed on sub-second time scales. Understanding the brain therefore requires methods that offer sufficient spatial and temporal resolution. This poses a particular challenge for the study of the human brain because non-invasive methods have either high temporal or spatial resolution, but not both. Here, we introduce a novel multivariate analysis method for conventional blood-oxygen-level dependent functional magnetic resonance imaging (BOLD fMRI) that allows to study sequentially activated neural patterns separated by less than 100 ms with anatomical precision. Human participants underwent fMRI and were presented with sequences of visual stimuli separated by 32 to 2048 ms. Probabilistic pattern classifiers were trained on fMRI data to detect the presence of image-specific activation patterns in early visual and ventral temporal cortex. The classifiers were then applied to data recorded during sequences of the same images presented at increasing speeds. Our results show that probabilistic classifier time courses allowed to detect neural representations and their order, even when images were separated by only 32 ms. Moreover, the frequency spectrum of the statistical sequentiality metric distinguished between sequence speeds on sub-second versus supra-second time scales. These results survived when data with high levels of noise and rare sequence events at unknown times were analyzed. Our method promises to lay the groundwork for novel investigations of fast neural computations in the human brain, such as hippocampal replay.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    MCT2 Overexpression Rescues Metabolic Vulnerability and Protects Retinal Ganglion Cells in Two Models of Glaucoma

    Improving cellular access to energy substrates is one strategy to overcome observed declines in energy production and utilization in the aged and pathologic central nervous system. Monocarboxylate transporters (MCTs), the movers of lactate, pyruvate, and ketone bodies into or out of a cell, are significantly decreased in the DBA/2J mouse model of glaucoma. In order to confirm MCT decreases are disease-associated, we decreased MCT2 in the retinas of MCT2fl/+ mice using an injection of AAV2-cre, observing significant decline in ATP production and visual evoked potential. Restoring MCT2 levels in retinal ganglion cells (RGCs) via intraocular injection of AAV2-GFP-MCT2 in two models of glaucoma, the DBA/2J (D2), and a magnetic bead model of ocular hypertension (OHT), preserved RGCs and their function. Viral-mediated overexpression of MCT2 increased RGC density and axon number, reduced energy imbalance, and increased mitochondrial function as measured by cytochrome c oxidase and succinate dehydrogenase activity in both models of glaucoma. Ocular hypertensive mice injected with AAV2:MCT2 had significantly greater P1 amplitude as measured by pattern electroretinogram than mice with OHT alone. These findings indicate overexpression of MCT2 improves energy homeostasis in the glaucomatous visual system, suggesting that expanding energy input options for cells is a viable option to combat neurodegeneration.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

    Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes are unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Parvalbumin+ and Npas1+ Pallidal Neurons Have Distinct Circuit Topology and Function

    The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. Phasic changes in the activity of GPe neurons during movement and their alterations in Parkinsons disease (PD) argue that the GPe is important in motor control. PV+ neurons and Npas1+ neurons are the two principal neuron classes in the GPe. The distinct electrophysiological properties and axonal projection patterns argue that these two neuron classes serve different roles in regulating motor output. However, the causal relationship between GPe neuron classes and movement remains to be established. Here, by using optogenetic approaches, we showed that PV+ neurons and Npas1+ neurons promoted and suppressed locomotion, respectively. Moreover, PV+ neurons and Npas1+ neurons are under different synaptic influences from the subthalamic nucleus (STN). The selective weakening of STN inputs to PV+ neurons in the chronic 6-OHDA lesion model of PD reinforces the idea that the reciprocally connected GPe-STN network plays a key role in disease symptomatology and thus provides the basis for future circuit-based therapies.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Enteric glia as a source of neural progenitors in adult zebrafish

    The presence and identity of neural progenitors in the enteric nervous system (ENS) of vertebrates is a matter of intense debate. Here we demonstrate that the non-neuronal ENS cell compartment of teleosts shares molecular and morphological characteristics with mammalian enteric glia but cannot be identified by the expression of canonical glia markers. However, unlike their mammalian counterparts, which are generally quiescent and do not undergo neuronal differentiation during homeostasis, we show that a relatively high proportion of zebrafish enteric glia proliferate under physiological conditions giving rise to progeny that differentiate into enteric neurons. We also provide evidence that, similar to brain neural stem cells, the activation and neuronal differentiation of enteric glia are regulated by Notch signalling. Our experiments reveal remarkable similarities between enteric glia and brain neural stem cells in teleosts and open new possibilities for use of mammalian enteric glia as a potential source of neurons to restore the activity of intestinal neural circuits compromised by injury or disease.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Genetic variation and sex differences are missed opportunities for addiction biology.

    Though risk for cocaine use disorder is subject to substantial inter-individual variation, the sources of that variation -- including, genetics and sex -- are too often ignored in studies of this phenomenon. In genetically diverse laboratory mice, these individual differences explain the majority of variance in important cocaine-related behavioral, physiological, and striatum transcriptional responses traits. This individual variation represents a missed opportunity for discovery and translation of addiction mechanisms.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Long-term implicit memory for sequential auditory patterns in humans

    To understand auditory scenes, listeners track and retain the statistics of sensory inputs as they unfold over time. We combined behavioural manipulation and modelling to investigate how sequence statistics are encoded into long-term memory and used to interpret incoming sensory signals. In a series of experiments, participants detected the emergence of regularly repeating patterns in novel rapid sound sequences. Unbeknownst to them, a few regular patterns reoccurred sparsely (every ~3 minutes). Reoccurring sequences showed a rapidly growing detection time advantage over novel sequences. This effect was implicit, robust to interference, and persisted up to 7 weeks. Human performance was reproduced by a memory-constrained probabilistic model, where sequences are stored as n-grams and are subject to memory decay. Results suggest that similar psychological mechanisms may underlie integration processes over different-time scales in memory formation and flexible retrieval.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Central vestibular tuning arises from patterned convergence of otolith afferents

    As sensory information moves through the brain, higher-order areas exhibit more complex tuning than lower areas. Though models predict this complexity is due to convergent inputs from neurons with diverse response properties, in most vertebrate systems convergence has only been inferred rather than tested directly. Here we measure sensory computations in zebrafish vestibular neurons across multiple axes in vivo. We establish that whole-cell physiological recordings reveal tuning of individual vestibular afferent inputs and their postsynaptic targets. An independent approach, serial section electron microscopy, supports the inferred connectivity. We find that afferents with similar or differing preferred directions converge on central vestibular neurons, conferring more simple or complex tuning, respectively. Our data also resolve a long-standing contradiction between anatomical and physiological analyses by revealing that sensory responses are produced by sparse but powerful inputs from vestibular afferents. Together these results provide a direct, quantifiable demonstration of feedforward input convergence in vivo.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Disulfide bridge formation prevents CaMKII/Calmodulin interaction in Parkinson's disease

    There is increasing evidence for disordered Ca2+ signaling in dopamine neurons in Parkinson's disease (PD), and this likely involves altered Ca2+/calmodulin-dependent protein kinase II (CaMKII) function. Previous work suggests that oxidative stress - a major feature in PD pathogenesis - affects regulatory methionine residues that sustain CaMKII activity in a Ca2+/CaM-independent manner. Here, applying computational modeling, we predicted formation of a defined disulfide bridge close to the CaMKII docking site for Ca2+/CaM binding. In vitro and in vivo investigations using PD models revealed formation of a disulfide bridge and loss of the CaMKII-calmodulin interaction. Mutagenesis of the relevant cysteine residues abrogated disulfide bridge formation and recovered the CaMKII-calmodulin interaction. Importantly, dopamine neurons from post-mortem PD brain specimens also lost this regulatory protein-protein interaction, providing relevance in the human disease. This study provides novel insights into oxidative CaMKII-CaM dysfunction, which may contribute to the pathophysiology of PD.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    The binding of palonosetron and other antiemetic drugs to the serotonin 5-HT3 receptor

    Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting (CINV). These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryo-EM structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in the clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Temporal discounting in adolescents and adults with Tourette syndrome

    Background: Tourette syndrome is a neurodevelopmental disorder with the clinical hallmarks of motor and phonic tics which are associated with hyperactivity in dopaminergic networks. Dopaminergic hyperactivity in the basal ganglia has previously been linked to increased sensitivity to positive reinforcement and increases in choice impulsivity. Objective: We address whether this extends to changes in temporal discounting, where impulsivity is operationalized as an increased preference to choose smaller-but-sooner over larger-but-later rewards. Results are discussed with respect to neural models of temporal discounting, dopaminergic alterations in Tourette syndrome and the developmental trajectory of temporal discounting. Methods: In the first study we included nineteen adolescent patients with Tourette syndrome and nineteen age- and education matched controls. In the second study, we compared twenty-five adult patients with Tourette syndrome and twenty-five age- and education-matched controls. Results: In the light of the dopaminergic hyperactivity model, we predicted differences in temporal discounting in patients with Tourette syndrome. However, computational modeling of choice behavior using hierarchical Bayesian parameter estimation revealed reduced impulsive choice in adolescent patients, and no group differences in adults. Conclusion: We speculate that adolescents might show reduced discounting due to improved inhibitory functions that also affect choice impulsivity and/or the developmental trajectory of executive control functions. The absence of an effect in adults might be due to differences in the clinical population (e.g. patients who acquired successful tic inhibition during adolescence might have gone into remission). Future studies would benefit from adopting longitudinal approaches to further elucidate the developmental trajectory of these effects.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Biomarkers of Depression Symptoms Defined by Direct Intracranial Neurophysiology

    Quantitative biomarkers of depression are critical for development of rational therapeutics, but limitations of current low-resolution, indirect brain assays may impede their discovery. We applied graph theory and machine learning to a large unique dataset of intracranial electrophysiological recordings to generate a four-dimensional whole-brain model of neural activity. Using this model, we found patterns of network activity that correctly classified depression in over 80% of individuals. These complex patterns were especially evident in alpha and beta spectral power across frontal and occipital brain regions, respectively. Our findings reveal a widespread network of abnormal activity that may inform advanced personalized treatment.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Angiopathy with impaired glucose logistics observed in schizophrenia-like model mice

    Dietary sugar in humans has increased dramatically in the modern era. However, it is unclear whether and how high sugar diets affect the pathogenesis of psychiatric disorders. Here we demonstrate that a high sugar diet induces expression of schizophrenia-associated positive, negative, and cognitive symptoms in mice deficient for glyoxalase-1, an enzyme associated with schizophrenia involved in the detoxification of carbonyl compounds. We found that a high sugar diet increased nondiabetic vascular damage in glyoxalase-1 mutant mice, and reduced glucose uptake into the brain parenchyma. Chronic aspirin treatment reduced vascular damage, increased glucose uptake into the brain, and prevented development of several schizophrenia-associated phenotypes. Postmortem analysis of brains from patients with schizophrenia revealed similar vascular damage to what we observe in our mutant mice. Our results indicate that schizophrenia is associated with vascular damage likely caused by metabolic dysfunction.

    in bioRxiv Subject Collection: Neuroscience on February 15, 2020 12:00 AM.

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    Enhancing reproducibility of gene expression analysis with known protein functional relationships: The concept of well-associated protein

    by Joël R. Pradines, Victor Farutin, Nicholas A. Cilfone, Abouzar Ghavami, Elma Kurtagic, Jamey Guess, Anthony M. Manning, Ishan Capila

    Identification of differentially expressed genes (DEGs) is well recognized to be variable across independent replications of genome-wide transcriptional studies. These are often employed to characterize disease state early in the process of discovery and prioritize novel targets aimed at addressing unmet medical need. Increasing reproducibility of biological findings from these studies could potentially positively impact the success rate of new clinical interventions. This work demonstrates that statistically sound combination of gene expression data with prior knowledge about biology in the form of large protein interaction networks can yield quantitatively more reproducible observations from studies characterizing human disease. The novel concept of Well-Associated Proteins (WAPs) introduced herein—gene products significantly associated on protein interaction networks with the differences in transcript levels between control and disease—does not require choosing a differential expression threshold and can be computed efficiently enough to enable false discovery rate estimation via permutation. Reproducibility of WAPs is shown to be on average superior to that of DEGs under easily-quantifiable conditions suggesting that they can yield a significantly more robust description of disease. Enhanced reproducibility of WAPs versus DEGs is first demonstrated with four independent data sets focused on systemic sclerosis. This finding is then validated over thousands of pairs of data sets obtained by random partitions of large studies in several other diseases. Conditions that individual data sets must satisfy to yield robust WAP scores are examined. Reproducible identification of WAPs can potentially benefit drug target selection and precision medicine studies.

    in PLOS Computational Biology: New Articles on February 14, 2020 10:00 PM.

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    RAINBOW: Haplotype-based genome-wide association study using a novel SNP-set method

    by Kosuke Hamazaki, Hiroyoshi Iwata

    Difficulty in detecting rare variants is one of the problems in conventional genome-wide association studies (GWAS). The problem is closely related to the complex gene compositions comprising multiple alleles, such as haplotypes. Several single nucleotide polymorphism (SNP) set approaches have been proposed to solve this problem. These methods, however, have been rarely discussed in connection with haplotypes. In this study, we developed a novel SNP-set method named “RAINBOW” and applied the method to haplotype-based GWAS by regarding a haplotype block as a SNP-set. Combining haplotype block estimation and SNP-set GWAS, haplotype-based GWAS can be conducted without prior information of haplotypes. We prepared 100 datasets of simulated phenotypic data and real marker genotype data of Oryza sativa subsp. indica, and performed GWAS of the datasets. We compared the power of our method, the conventional single-SNP GWAS, the conventional haplotype-based GWAS, and the conventional SNP-set GWAS. Our proposed method was shown to be superior to these in three aspects: (1) controlling false positives; (2) in detecting causal variants without relying on the linkage disequilibrium if causal variants were genotyped in the dataset; and (3) it showed greater power than the other methods, i.e., it was able to detect causal variants that were not detected by the others, primarily when the causal variants were located very close to each other, and the directions of their effects were opposite. By using the SNP-set approach as in this study, we expect that detecting not only rare variants but also genes with complex mechanisms, such as genes with multiple causal variants, can be realized. RAINBOW was implemented as an R package named “RAINBOWR” and is available from CRAN (https://cran.r-project.org/web/packages/RAINBOWR/index.html) and GitHub (https://github.com/KosukeHamazaki/RAINBOWR).

    in PLOS Computational Biology: New Articles on February 14, 2020 10:00 PM.

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    From whole-organ imaging to in-silico blood flow modeling: A new multi-scale network analysis for revisiting tissue functional anatomy

    by Pol Kennel, Jules Dichamp, Corinne Barreau, Christophe Guissard, Lise Teyssedre, Jacques Rouquette, Julien Colombelli, Anne Lorsignol, Louis Casteilla, Franck Plouraboué

    We present a multi-disciplinary image-based blood flow perfusion modeling of a whole organ vascular network for analyzing both its structural and functional properties. We show how the use of Light-Sheet Fluorescence Microscopy (LSFM) permits whole-organ micro-vascular imaging, analysis and modelling. By using adapted image post-treatment workflow, we could segment, vectorize and reconstruct the entire micro-vascular network composed of 1.7 million vessels, from the tissue-scale, inside a ∼ 25 × 5 × 1 = 125mm3 volume of the mouse fat pad, hundreds of times larger than previous studies, down to the cellular scale at micron resolution, with the entire blood perfusion modeled. Adapted network analysis revealed the structural and functional organization of meso-scale tissue as strongly connected communities of vessels. These communities share a distinct heterogeneous core region and a more homogeneous peripheral region, consistently with known biological functions of fat tissue. Graph clustering analysis also revealed two distinct robust meso-scale typical sizes (from 10 to several hundred times the cellular size), revealing, for the first time, strongly connected functional vascular communities. These community networks support heterogeneous micro-environments. This work provides the proof of concept that in-silico all-tissue perfusion modeling can reveal new structural and functional exchanges between micro-regions in tissues, found from community clusters in the vascular graph.

    in PLOS Computational Biology: New Articles on February 14, 2020 10:00 PM.

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    Bayesian inference and comparison of stochastic transcription elongation models

    by Jordan Douglas, Richard Kingston, Alexei J. Drummond

    Transcription elongation can be modelled as a three step process, involving polymerase translocation, NTP binding, and nucleotide incorporation into the nascent mRNA. This cycle of events can be simulated at the single-molecule level as a continuous-time Markov process using parameters derived from single-molecule experiments. Previously developed models differ in the way they are parameterised, and in their incorporation of partial equilibrium approximations. We have formulated a hierarchical network comprised of 12 sequence-dependent transcription elongation models. The simplest model has two parameters and assumes that both translocation and NTP binding can be modelled as equilibrium processes. The most complex model has six parameters makes no partial equilibrium assumptions. We systematically compared the ability of these models to explain published force-velocity data, using approximate Bayesian computation. This analysis was performed using data for the RNA polymerase complexes of E. coli, S. cerevisiae and Bacteriophage T7. Our analysis indicates that the polymerases differ significantly in their translocation rates, with the rates in T7 pol being fast compared to E. coli RNAP and S. cerevisiae pol II. Different models are applicable in different cases. We also show that all three RNA polymerases have an energetic preference for the posttranslocated state over the pretranslocated state. A Bayesian inference and model selection framework, like the one presented in this publication, should be routinely applicable to the interrogation of single-molecule datasets.

    in PLOS Computational Biology: New Articles on February 14, 2020 10:00 PM.

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    Plasticity in olfactory bulb circuits

    Publication date: October 2020

    Source: Current Opinion in Neurobiology, Volume 64

    Author(s): An Wu, Bin Yu, Takaki Komiyama

    Olfaction is crucial for animal survival and human well-being. The olfactory bulb is the obligatory input station for olfactory information. In contrast to the traditional view as a static relay station, recent evidence indicates that the olfactory bulb dynamically processes olfactory information in an experience-dependent and context-dependent manner. Here, we review recent studies on experience-dependent plasticity of the main circuit components within the olfactory bulb of rodents. We argue that the olfactory bulb plasticity allows optimal representations of behaviorally-relevant odors in the continuously changing olfactory environment.

    in ScienceDirect Publication: Current Opinion in Neurobiology on February 14, 2020 07:00 PM.

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    Does Birth Trigger Cell Death in the Developing Brain?

    Developmental cell death eliminates half of the neurons initially generated in the mammalian brain, and occurs perinatally in many species. It is possible that the timing of neuronal cell death is developmentally programmed, and only coincidentally associated with birth. Alternatively, birth may play a role in shaping cell death. To test these competing hypotheses, we experimentally advanced or delayed birth by 1 d in mice (within the normal range of gestation for the species) and examined effects on the temporal pattern and magnitude (amount) of neuronal cell death, using immunohistochemical detection of activated caspase-3 as a cell death marker. In order to detect effects of subtle changes in birth timing, we focused on brain areas that exhibit sharp postnatal peaks in cell death. We find that advancing birth advances peak cell death, supporting the hypothesis that birth triggers cell death. However, a delay of birth does not delay cell death. Thus, birth can advance cell death, but if postponed, a developmental program governs. Advancing or delaying birth also caused region-specific changes in the overall magnitude of cell death. Our findings shed light on the long-standing question of what controls the timing and magnitude of developmental neuronal cell death, and position birth as an orchestrator of brain development. Because humans across the world now routinely alter birth timing, these findings may have implications for current obstetric practices.

    in eNeuro current issue on February 14, 2020 05:30 PM.

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    Response to the Commentary from Bevelacqua et al.

    in eNeuro current issue on February 14, 2020 05:30 PM.

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    Comments on "New Concerns for Neurocognitive Function during Deep Space Exposures to Chronic, Low Dose Rate, Neutron Radiation"

    Abstract

    Evaluations of the biological effects of space radiation must carefully consider the biological system response and the specific nature of the source term. Acharya et al. (2019) review neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation, but do not use a source term that reflects the actual space environment in terms of radiation types and their respective energies. In addition, important biological effects, including the adaptive response to the space radiation environment, are not addressed.

    in eNeuro current issue on February 14, 2020 05:30 PM.

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    A How-to-Model Guide for Neuroscience

    Abstract

    Within neuroscience, models have many roles, including driving hypotheses, making assumptions explicit, synthesizing knowledge, making experimental predictions, and facilitating applications to medicine. While specific modeling techniques are often taught, the process of constructing models for a given phenomenon or question is generally left opaque. Here, informed by guiding many students through modeling exercises at our summer school in CoSMo (Computational Sensory-Motor Neuroscience), we provide a practical 10-step breakdown of the modeling process. This approach makes choices and criteria more explicit and replicable. Experiment design has long been taught in neuroscience; the modeling process should receive the same attention.

    in eNeuro current issue on February 14, 2020 05:30 PM.

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    The Neural Dynamics of Individual Differences in Episodic Autobiographical Memory

    Abstract

    The ability to mentally travel to specific events from one’s past, dubbed episodic autobiographical memory (E-AM), contributes to adaptive functioning. Nonetheless, the mechanisms underlying its typical interindividual variation remain poorly understood. To address this issue, we capitalize on existing evidence that successful performance on E-AM tasks draws on the ability to visualize past episodes and reinstate their unique spatiotemporal context. Hence, here, we test whether features of the brain’s functional architecture relevant to perceptual versus conceptual processes shape individual differences in both self-rated E-AM and laboratory-based episodic memory for random visual scene sequences (visual EM). We propose that superior subjective E-AM and visual EM are associated with greater similarity in static neural organization patterns, potentially indicating greater efficiency in switching, between rest and mental states relevant to encoding perceptual information. Complementarily, we postulate that impoverished subjective E-AM and visual EM are linked to dynamic brain organization patterns implying a predisposition towards semanticizing novel perceptual information. Analyses were conducted on resting state and task-based fMRI data from 329 participants (160 women) in the Human Connectome Project who completed visual and verbal EM assessments, and an independent gender diverse sample (N = 59) who self-rated their E-AM. Interindividual differences in subjective E-AM were linked to the same neural mechanisms underlying visual, but not verbal, EM, in general agreement with the hypothesized static and dynamic brain organization patterns. Our results suggest that higher E-AM entails more efficient processing of temporally extended information sequences, whereas lower E-AM entails more efficient semantic or gist-based processing.

    Significance Statement The ability to revisit specific events from one’s past is key to identity formation and optimal interpersonal functioning. Nonetheless, the mechanisms underlying its typical interindividual variation are yet to be fully characterized. Here, we provide novel evidence that, among younger adults, dispositional variations in subjective mental time travel draw on the same dynamic and static features of the brain’s architecture that are uniquely implicated in memory for spatiotemporal contexts. Specifically, the subjective sense of being able to revisit one’s past relates to neural mechanisms supporting serial mental operations, whereas difficulties in accessing past experiences may be traced back to a predisposition towards gist-based processing of incoming information

    in RSS PAP on February 14, 2020 05:29 PM.

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    Mapping of sensory nerve subsets within the vagal ganglia and the brainstem using reporter mice for Pirt, TRPV1, 5HT3 and Tac1 expression

    Abstract

    Vagal afferent sensory nerves, originating in jugular and nodose ganglia, are comprised of functionally distinct subsets whose activation evokes distinct thoracic and abdominal reflex responses. We used Cre-expressing mouse strains to identify specific vagal afferent populations and map their central projections within the brainstem. We show that Pirt is expressed in virtually all vagal afferents; whereas 5HT3 is expressed only in nodose neurons, with little expression in jugular neurons. TRPV1, the capsaicin receptor, is expressed in a subset of small nodose and jugular neurons. Tac1, the gene for tachykinins, is expressed predominantly in jugular neurons, some of which also express TRPV1. Vagal fibers project centrally to the nucleus tractus solitarius (nTS), paratrigeminal complex, area postrema and to a limited extent the dorsal motor nucleus of the vagus. nTS subnuclei preferentially receive projections by specific afferent subsets, with TRPV1+ fibers terminating in medial and dorsal regions predominantly caudal of obex, whereas TRPV1-negative fibers terminate in ventral and lateral regions throughout the rostral-caudal aspect of the medulla. Many vagal Tac1+ afferents (mostly derived from the jugular ganglion) terminate in the nTS. The paratrigeminal complex was the target of multiple vagal afferent subsets. Importantly, lung-specific TRPV1+ and Tac1+ afferent terminations were restricted to the caudal medial nTS, with no innervation of other medulla regions. In summary, this study identifies the specific medulla regions innervated by vagal afferent subsets. The distinct terminations provide a neuroanatomic substrate for the diverse range of reflexes initiated by vagal afferent activation.

    Significance statement Vagal afferents transmit sensory information from visceral organs to the brainstem, where their activity alters sensation and visceral reflexes. Vagal afferents are comprised of distinct subsets which serve distinct functions. Little is known of the neuroanatomy of central projections of distinct vagal subsets, thus there remains an incomplete understanding of how visceral events evoke appropriate behavioral and reflex responses. This precludes rationally-developed pharmacological or electroceutical interventions to modify aberrant sensations/reflexes. Here, we used cell-specific reporter expression to identify the brainstem pathways of distinct vagal afferent subsets. We show that TRPV1+ vagal afferents innervate ipsilateral and contralateral dorsal/medial nTS subnuclei and the ipsilateral paratrigeminal complex, whereas TRPV1-negative vagal afferents innervate the ipsilateral rostral/ventral/lateral nTS subnuclei and the ipsilateral paratrigeminal complex.

    in RSS PAP on February 14, 2020 05:29 PM.

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    Likelihood Based Learning Rule for Temporal Coding In Recurrent Spiking Neural Networks. (arXiv:2002.05619v1 [q-bio.NC])

    Recurrent spiking neural networks (RSNN) in the brain learn to perform a wide range of perceptual, cognitive and motor tasks very efficiently in terms of time and energy consumption. This is due to the optimality of coding and learning schemes, which have yet to be unveiled. The formulation of biologically inspired networks capable to perform complex computations can mediate a synergetic interaction between Machine Learning and Neuroscience bringing to mutual benefits and helping to improve our understanding of biological and artificial intelligence. Even though several models have been proposed, it remains a challenging task to design RSNNs which use biologically plausible mechanisms. We propose a general probabilistic framework which relies on the principle of maximizing the likelihood for the network to solve the task. This principle permits to analytically work out an explicit and completely local plasticity rule supporting the efficient solution of several tasks. We show that the learning algorithm can be achieved in a very few iterations, and that the online approximation of the likelihood maximization is extremely beneficial to fast learning. Our model is very general and it can be applied to a wide variety of network architectures and types of biological neurons. The derived plasticity learning rule is specific to each neuron model producing a theoretical prediction which can be verified experimentally.

    in q-bio.NC updates on arXiv.org on February 14, 2020 01:30 AM.

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    End-to-end semantic segmentation of personalized deep brain structures for non-invasive brain stimulation. (arXiv:2002.05487v1 [eess.IV])

    Electro-stimulation or modulation of deep brain regions is commonly used in clinical procedures for the treatment of several nervous system disorders. In particular, transcranial direct current stimulation (tDCS) is widely used as an affordable clinical application that is applied through electrodes attached to the scalp. However, it is difficult to determine the amount and distribution of the electric field (EF) in the different brain regions due to anatomical complexity and high inter-subject variability. Personalized tDCS is an emerging clinical procedure that is used to tolerate electrode montage for accurate targeting. This procedure is guided by computational head models generated from anatomical images such as MRI. Distribution of the EF in segmented head models can be calculated through simulation studies. Therefore, fast, accurate, and feasible segmentation of different brain structures would lead to a better adjustment for customized tDCS studies. In this study, a single-encoder multi-decoders convolutional neural network is proposed for deep brain segmentation. The proposed architecture is trained to segment seven deep brain structures using T1-weighted MRI. Network generated models are compared with a reference model constructed using a semi-automatic method, and it presents a high matching especially in Thalamus (Dice Coefficient (DC) = 94.70%), Caudate (DC = 91.98%) and Putamen (DC = 90.31%) structures. Electric field distribution during tDCS in generated and reference models matched well each other, suggesting its potential usefulness in clinical practice.

    in q-bio.NC updates on arXiv.org on February 14, 2020 01:30 AM.

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    Monosynaptic Tracing Success Depends Critically on Helper Virus Concentrations

    Monosynaptically-restricted transsynaptic tracing using deletion-mutant rabies virus (RV) has become a widely used technique in neuroscience, allowing identification, imaging, and manipulation of neurons directly presynaptic to a starting neuronal population. Its most common implementation is to use Cre mouse lines in combination with Cre-dependent “helper” adeno-associated viral vectors (AAVs) to supply the required genes to the targeted population before subsequent injection of a first-generation (ΔG) rabies viral vector. Here we show that the efficiency of transsynaptic spread and the degree of nonspecific labeling in wild-type control animals depend strongly on the concentrations of these helper AAVs. Our results suggest practical guidelines for achieving good results.

    in Frontiers in Synaptic Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Peripheral Delta Opioid Receptors Mediate Formoterol Anti-allodynic Effect in a Mouse Model of Neuropathic Pain

    Neuropathic pain is a challenging condition for which current therapies often remain unsatisfactory. Chronic administration of β2 adrenergic agonists, including formoterol currently used to treat asthma and chronic obstructive pulmonary disease, alleviates mechanical allodynia in the sciatic nerve cuff model of neuropathic pain. The limited clinical data currently available also suggest that formoterol would be a suitable candidate for drug repurposing. The antiallodynic action of β2 adrenergic agonists is known to require activation of the delta-opioid (DOP) receptor but better knowledge of the molecular mechanisms involved is necessary. Using a mouse line in which DOP receptors were selectively ablated in neurons expressing Nav1.8 sodium channels (DOP cKO), we showed that these DOP peripheral receptors were necessary for the antiallodynic action of the β2 adrenergic agonist formoterol in the cuff model. Using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP), we established in a previous study, that mechanical allodynia is associated with a smaller percentage of DOPeGFP positive small peptidergic sensory neurons in dorsal root ganglia (DRG), with a reduced density of DOPeGFP positive free nerve endings in the skin and with increased DOPeGFP expression at the cell surface. Here, we showed that the density of DOPeGFP positive free nerve endings in the skin is partially restored and no increase in DOPeGFP translocation to the plasma membrane is observed in mice in which mechanical pain is alleviated upon chronic oral administration of formoterol. This study, therefore, extends our previous results by confirming that changes in the mechanical threshold are associated with changes in peripheral DOP profile. It also highlights the common impact on DOP receptors between serotonin noradrenaline reuptake inhibitors such as duloxetine and the β2 mimetic formoterol.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Predicting Empathy From Resting State Brain Connectivity: A Multivariate Approach

    Recent task fMRI studies suggest that individual differences in trait empathy and empathic concern are mediated by patterns of connectivity between self-other resonance and top-down control networks that are stable across task demands. An untested implication of this hypothesis is that these stable patterns of connectivity should be visible even in the absence of empathy tasks. Using machine learning, we demonstrate that patterns of resting state fMRI connectivity (i.e. the degree of synchronous BOLD activity across multiple cortical areas in the absence of explicit task demands) of resonance and control networks predict trait empathic concern (n = 58). Empathic concern was also predicted by connectivity patterns within the somatomotor network. These findings further support the role of resonance-control network interactions and of somatomotor function in our vicariously driven concern for others. Furthermore, a practical implication of these results is that it is possible to assess empathic predispositions in individuals without needing to perform conventional empathy assessments.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Using Mobile EEG to Investigate Alpha and Beta Asymmetries During Hand and Foot Use

    The Edinburgh Handedness Inventory (EHI) and the Waterloo Footedness Questionnaire (WFQ) are two of the most widely used questionnaires to assess lateralized everyday behavior in human participants. However, it is unclear to what extent the specific behavior assessed in these questionnaires elicit lateralized neural activity when performed in real-life situations. To illuminate this unresolved issue, we assessed EEG alpha and beta asymmetries during real-life performance of the behaviors assessed in the EHI and WFQ using a mobile EEG system. This methodology provides high ecological validity for studying neural correlates of motor behavior under more naturalistic conditions. Our results indicate that behavioral performance of items of both the EHI and WFQ differentiate between left- and right-handers and left- and right-footers on the neural level, especially in the alpha frequency band. These results were unaffected by movement parameters. Furthermore, we could demonstrate that neural activity elicited specifically during left-sided task performance provides predictive power for the EHI or WFQ score of the participants. Overall, our results show that these prominent questionnaires not only distinguish between different motor preferences on the behavioral level, but also on the neurophysiological level. Furthermore, we could show that mobile EEG systems are a powerful tool to investigate motor asymmetries in ecologically valid situations outside of the laboratory setting. Future research should focus on other lateralized behavioral phenotypes in real-life settings to provide more insights into lateralized motor functions.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on February 14, 2020 12:00 AM.

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    Editorial: Application of Neural Technology to Neuro-Management and Neuro-Marketing

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on February 14, 2020 12:00 AM.

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    Prediction of Pilot's Reaction Time Based on EEG Signals

    The main hypothesis of this work is that the time of delay in reaction to an unexpected event can be predicted on the basis of the brain activity recorded prior to that event. Such mental activity can be represented by electroencephalographic data. To test this hypothesis, we conducted a novel experiment involving 19 participants that took part in a 2-h long session of simulated aircraft flights. An EEG signal processing pipeline is proposed that consists of signal preprocessing, extracting bandpass features, and using regression to predict the reaction times. The prediction algorithms that are used in this study are the Least Absolute Shrinkage Operator and its Least Angle Regression modification, as well as Kernel Ridge and Radial Basis Support Vector Machine regression. The average Mean Absolute Error obtained across the 19 subjects was 114 ms. The present study demonstrates, for the first time, that it is possible to predict reaction times on the basis of EEG data. The presented solution can serve as a foundation for a system that can, in the future, increase the safety of air traffic.

    in Frontiers in Neuroinformatics | New and Recent Articles on February 14, 2020 12:00 AM.

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    The Relation Between Steroid Secretion Patterns and the Androgen Receptor Gene Polymorphism on Physical Health and Psychological Well-Being—Longitudinal Findings From the Men’s Health 40+ Study

    Research is increasingly focusing on promoting healthy aging and the related extension of the health span by targeting crucial biological processes responsible for age-related conditions. While age-related gradual changes in steroid hormones such as testosterone, estradiol, or cortisol are well described in men, their interactions among each other or with genetic markers have not been sufficiently investigated with regard to physical health or psychological well-being. More specifically, the examination of age-related alterations in hormone interactions and the androgen receptor polymorphism, which modulates androgen action on target cells, in relation to physical health and psychological well-being represents a promising avenue for research on healthy aging in men. A total of 97 healthy aging men provided complete data on psychometric health measures as well as hormonal and genetic parameters at baseline and a 4-year follow-up assessment. Fasting saliva samples were taken at 8:00 am under standardized laboratory conditions, while the androgen receptor gene polymorphism was analyzed from dried blood spots. Longitudinal analyses revealed that psychological well-being and physical health remained stable over time. Analyses indicated that E2 moderated the course of psychological well-being, while the androgen receptor gene polymorphism moderated the course of physical health. Further, T was a strong predictor of physical health. These results suggest that the hypothalamic-pituitary-gonadal (HPG) axis might be important for the maintenance of psychological well-being in men, while physical health depends more on interindividual differences in the androgen receptor gene and T.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Children With Unilateral Cerebral Palsy Utlilize More Cortical Resources for Similar Motor Output During Treadmill Gait

    Children with unilateral cerebral palsy (CP) walk independently although with an asymmetrical, more poorly coordinated pattern compared to their peers. While gait biomechanics in unilateral CP and their alteration from those without CP have been well documented, cortical mechanisms underlying gait remain inadequately understood. To the best of our knowledge, this is the first study utilizing electroencephalography (EEG) during treadmill gait in older children with and without CP. Lower limb surface electromyographic (EMG) data were collected and muscle synergy analyses performed to quantify motor output. Our primary goal was to evaluate the relationships between cortical and muscle activation within and across groups and hemispheres to provide novel insights into neural control of gait and how it may be disrupted by an early unilateral brain injury. Participants included 9 children with unilateral CP, mean age 16.0 ± 2.7 years, and 12 with typical development (TD), mean age 14.8 ± 3.0 years. EEG data were collected during a standing baseline and treadmill walking at self-selected speed. EMG of 16 lower limb muscles were also collected bilaterally and synchronized with EEG. No significant group differences were found in synergy number or structure across groups. Six cortical clusters were identified as having gait-related activation and all contained participants from both CP and TD groups; however, the percent of individuals per group appearing in different clusters varied. Notably, the cluster least represented in CP was the non-dominant motor region. Both groups showed mu-band ERD in the motor clusters during gait although sustained beta-band ERD was not evident in TD. The CP group showed greater cortical activation than TD during walking as measured by mu- and beta-ERD in the dominant and non-dominant motor and parietal regions and elevated low gamma-activity in the frontal and parietal areas, a unique finding in CP. CP showed greater bilateral motor EEG-EMG coherence in the gamma-band with the hallucis longus compared to TD. In summary, individuals with CP display increased cortical activation during gait possibly relating to differences in distal motor control of the more affected side. Strategies that iteratively reduce cortical activation while improving selective motor control are needed in CP.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Modulating Brain Networks With Transcranial Magnetic Stimulation Over the Primary Motor Cortex: A Concurrent TMS/fMRI Study

    Stimulating the primary motor cortex (M1) using transcranial magnetic stimulation (TMS) causes unique multisensory experience such as the targeted muscle activity, afferent/reafferent sensory feedback, tactile sensation over the scalp and “click” sound. Although the human M1 has been intensively investigated using TMS, the experience of the M1 stimulation has not been elucidated at the whole brain. Here, using concurrent TMS/fMRI, we investigated the acute effect of the M1 stimulation of functional brain networks during task and at rest. A short train of 1 Hz TMS pulses applied to individuals’ hand area in the M1 during motor execution or at rest. Employing the independent component analysis (ICA), we showed the M1 stimulation decreased the motor networks activity when the networks were engaged in the task and increased the deactivation of networks when the networks were not involved in the ongoing task. The M1 stimulation induced the activation in the key networks involved in bodily self-consciousness (BSC) including the insular and rolandic operculum systems regardless of states. The degree of activation in these networks was prominent at rest compared to task conditions, showing the state-dependent TMS effect. Furthermore, we demonstrated that the M1 stimulation modulated other domain-general networks such as the default mode network (DMN) and attention network and the inter-network connectivity between these networks. Our results showed that the M1 stimulation induced the widespread changes in the brain at the targeted system as well as non-motor, remote brain networks, specifically related to the BSC. Our findings shed light on understanding the neural mechanism of the complex and multisensory experience of the M1 stimulation.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Cerebellum, Basal Ganglia, and Cortex Mediate Performance of an Aerial Pursuit Task

    The affordance competition hypothesis is an ethologically inspired theory from cognitive neuroscience that provides an integrative neural account of continuous, real-time behavior, and will likely become increasingly relevant to the growing field of neuroergonomics. In the spirit of neuroergonomics in aviation, we designed a three-dimensional, first-person, continuous, and real-time fMRI task during which human subjects maneuvered a simulated airplane in pursuit of a target airplane along constantly changing headings. We introduce a pseudo-event-related, parametric fMRI analysis approach to begin testing the affordance competition hypothesis in neuroergonomic contexts, and attempt to identify regions of the brain that exhibit a linear metabolic relationship with the continuous variables of task performance and distance-from-target. In line with the affordance competition hypothesis, our results implicate the cooperation of the cerebellum, basal ganglia, and cortex in such a task, with greater involvement of the basal ganglia during good performance, and greater involvement of cortex and cerebellum during poor performance and when distance-from-target closes. We briefly review the somatic marker and dysmetria of thought hypotheses, in addition to the affordance competition hypothesis, to speculate on the intricacies of the cooperation of these brain regions in a task such as ours. In doing so, we demonstrate how the affordance competition hypothesis and other cognitive neuroscience theories are ready for testing in continuous, real-time tasks such as ours, and in other neuroergonomic settings more generally.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Editorial: How Do Motivational States Influence Motor Resonance?

    in Frontiers in Human Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Evaluation of EEG Headset Mounting for Brain-Computer Interface-Based Stroke Rehabilitation by Patients, Therapists, and Relatives

    Brain-computer interfaces (BCIs) have successfully been used for motor recovery training in stroke patients. However, the setup of BCI systems is complex and may be divided into (1) mounting the headset and (2) calibration of the BCI. One of the major problems is mounting the headset for recording brain activity in a stroke rehabilitation context, and usability testing of this is limited. In this study, the aim was to compare the translational aspects of mounting five different commercially available headsets from a user perspective and investigate the design considerations associated with technology transfer to rehabilitation clinics and home use. No EEG signals were recorded, so the effectiveness of the systems have not been evaluated. Three out of five headsets covered the motor cortex which is needed to pick up movement intentions of attempted movements. The other two were as control and reference for potential design considerations. As primary stakeholders, nine stroke patients, eight therapists and two relatives participated; the stroke patients mounted the headsets themselves. The setup time was recorded, and participants filled in questionnaires related to comfort, aesthetics, setup complexity, overall satisfaction, and general design considerations. The patients had difficulties in mounting all headsets except for a headband with a dry electrode located on the forehead (control). The therapists and relatives were able to mount all headsets. The fastest headset to mount was the headband, and the most preferred headsets were the headband and a behind-ear headset (control). The most preferred headset that covered the motor cortex used water-based electrodes. The patients reported that it was important that they could mount the headset themselves for them to use it every day at home. These results have implications for design considerations for the development of BCI systems to be used in rehabilitation clinics and in the patient’s home.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Altered Functional Connectivity in the Motor and Prefrontal Cortex for Children With Down's Syndrome: An fNIRS Study

    Children with Down's syndrome (DS) might exhibit disrupted brain functional connectivity in the motor and prefrontal cortex. To inspect the alterations in brain activation and functional connectivity for children with DS, the functional near-infrared spectroscopy (fNIRS) method was applied to examine the brain activation difference in the motor and prefrontal cortex between the DS and typically developing (TD) groups during a fine motor task. In addition, small-world analysis based on graph theory was also carried out to characterize the topological organization of functional brain networks. Interestingly, behavior data demonstrated that the DS group showed significantly long reaction time and low accuracy as compared to the TD group (p < 0.05). More importantly, significantly reduced brain activations in the frontopolar area, the pre-motor, and the supplementary motor cortex (p < 0.05) were identified in the DS group compared with the TD group. Meanwhile, significantly high global efficiency (Eg) and short average path length (Lp) were also detected for the DS group. This pilot study illustrated that the disrupted connectivity of frontopolar area, pre-motor, and supplementary motor cortex might be one of the core mechanisms associated with motor and cognitive impairments for children with DS. Therefore, the combination of the fNIRS technique with functional network analysis may pave a new avenue for improving our understanding of the neural mechanisms of DS.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Segmenting Brain Tumor Using Cascaded V-Nets in Multimodal MR Images

    In this work, we propose a novel cascaded V-Nets method to segment brain tumor substructures in multimodal brain magnetic resonance imaging. Although V-Net has been successfully used in many segmentation tasks, we demonstrate that its performance could be further enhanced by using a cascaded structure and ensemble strategy. Briefly, our baseline V-Net consists of four levels with encoding and decoding paths and intra- and inter-path skip connections. Focal loss is chosen to improve performance on hard samples as well as balance the positive and negative samples. We further propose three preprocessing pipelines for multimodal magnetic resonance images to train different models. By ensembling the segmentation probability maps obtained from these models, segmentation result is further improved. In other hand, we propose to segment the whole tumor first, and then divide it into tumor necrosis, edema, and enhancing tumor. Experimental results on BraTS 2018 online validation set achieve average Dice scores of 0.9048, 0.8364, and 0.7748 for whole tumor, tumor core and enhancing tumor, respectively. The corresponding values for BraTS 2018 online testing set are 0.8761, 0.7953, and 0.7364, respectively. We also evaluate the proposed method in two additional data sets from local hospitals comprising of 28 and 28 subjects, and the best results are 0.8635, 0.8036, and 0.7217, respectively. We further make a prediction of patient overall survival by ensembling multiple classifiers for long, mid and short groups, and achieve accuracy of 0.519, mean square error of 367240 and Spearman correlation coefficient of 0.168 for BraTS 2018 online testing set.

    in Frontiers in Computational Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling

    Pericytes are perivascular mural cells that enwrap brain capillaries and maintain blood-brain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously shown that congenital loss of pericytes leads over time to aberrant hemodynamic responses, the effects of acute global pericyte loss on neurovascular coupling have not been studied. To address this, we used our recently reported inducible pericyte-specific Cre mouse line crossed to iDTR mice carrying Cre-dependent human diphtheria toxin (DT) receptor, which upon DT treatment leads to acute pericyte ablation. As expected, DT led to rapid progressive loss of pericyte coverage of cortical capillaries up to 50% at 3 days post-DT, which correlated with approximately 50% reductions in stimulus-induced CBF responses measured with laser doppler flowmetry (LDF) and/or intrinsic optical signal (IOS) imaging. Endothelial response to acetylcholine, microvascular density, and neuronal evoked membrane potential responses remained, however, unchanged, as well as arteriolar smooth muscle cell (SMC) coverage and functional responses to adenosine, as we previously reported. Together, these data suggest that neurovascular uncoupling in this model is driven by pericyte loss, but not other vascular deficits or neuronal dysfunction. These results further support the role of pericytes in CBF regulation and may have implications for neurological conditions associated with rapid pericyte loss such as hypoperfusion and stroke, as well as conditions where the exact time course of global regional pericyte loss is less clear, such as Alzheimer’s disease (AD) and other neurogenerative disorders.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 14, 2020 12:00 AM.

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    Correction: A role for phagocytosis in inducing cell death during thymocyte negative selection

    in eLife: latest articles on February 14, 2020 12:00 AM.

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    Competition between kinesin-1 and myosin-V defines Drosophila posterior determination

    Local accumulation of oskar (osk) mRNA in the Drosophila oocyte determines the posterior pole of the future embryo. Two major cytoskeletal components, microtubules and actin filaments, together with a microtubule motor, kinesin-1, and an actin motor, myosin-V, are essential for osk mRNA posterior localization. In this study, we use Staufen, an RNA-binding protein that colocalizes with osk mRNA, as a proxy for osk mRNA. We demonstrate that posterior localization of osk/Staufen is determined by competition between kinesin-1 and myosin-V. While kinesin-1 removes osk/Staufen from the cortex along microtubules, myosin-V anchors osk/Staufen at the cortex. Myosin-V wins over kinesin-1 at the posterior pole due to low microtubule density at this site, while kinesin-1 wins at anterior and lateral positions because they have high density of cortically-anchored microtubules. As a result, posterior determinants are removed from the anterior and lateral cortex but retained at the posterior pole. Thus, posterior determination of Drosophila oocytes is defined by kinesin-myosin competition, whose outcome is primarily determined by cortical microtubule density.

    in eLife: latest articles on February 14, 2020 12:00 AM.

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    Determining the scale at which variation in a single gene changes population yields

    Plant trait diversity is known to influence population yield, but the scale at which this happens remains unknown: divergent individuals might change yields of immediate neighbors (neighbor scale) or of plants across a population (population scale). We use Nicotiana attenuata plants silenced in mitogen-activated protein kinase 4 (irMPK4) – with low water-use efficiency (WUE) – to study the scale at which water-use traits alter intraspecific population yields. In the field and glasshouse, we observed overyielding in populations with low percentages of irMPK4 plants, unrelated to water-use phenotypes. Paired-plant experiments excluded the occurrence of overyielding effects at the neighbor scale. Experimentally altering field arbuscular mycorrhizal fungal associations by silencing the Sym-pathway gene NaCCaMK did not affect reproductive overyielding, implicating an effect independent of belowground AMF interactions. Additionally, micro-grafting experiments revealed dependence on shoot-expressed MPK4 for N. attenuata to vary its yield per neighbor presence. We find that variation in a single-gene, MPK4, is responsible for population overyielding through a mechanism, independent of irMPK4's WUE phenotype, at the aboveground, population scale.

    in eLife: latest articles on February 14, 2020 12:00 AM.

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    Suppressing proteasome mediated processing of Topoisomerase II DNA-protein complexes preserves genome integrity

    Topoisomerase II (TOP2) relieves topological stress in DNA by introducing double-strand breaks (DSBs) via a transient, covalently linked TOP2 DNA-protein intermediate, termed TOP2 cleavage complex (TOP2cc). TOP2ccs are normally rapidly reversible, but can be stabilized by TOP2 poisons, such as the chemotherapeutic agent etoposide (ETO). TOP2 poisons have shown significant variability in their therapeutic effectiveness across different cancers for reasons that remain to be determined. One potential explanation for the differential cellular response to these drugs is in the manner by which cells process TOP2ccs. Cells are thought to remove TOP2ccs primarily by proteolytic degradation followed by DNA DSB repair. Here, we show that proteasome-mediated repair of TOP2cc is highly error-prone. Pre-treating primary splenic mouse B-cells with proteasome inhibitors prevented the proteolytic processing of trapped TOP2ccs, suppressed the DNA damage response (DDR) and completely protected cells from ETO-induced genome instability, thereby preserving cellular viability. When degradation of TOP2cc was suppressed, the TOP2 enzyme uncoupled itself from the DNA following ETO washout, in an error-free manner. This suggests a potential mechanism of developing resistance to topoisomerase poisons by ensuring rapid TOP2cc reversal.

    in eLife: latest articles on February 14, 2020 12:00 AM.

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    Functional heterogeneity of lymphocytic patterns in primary melanoma dissected through single-cell multiplexing

    In melanoma, the lymphocytic infiltrate is a prognostic parameter classified morphologically into 'brisk', 'non-brisk' and 'absent' entailing a functional association that has never been proved. Recently, it has been shown that lymphocytic populations can be very heterogeneous, and that anti-PD-1 immunotherapy supports activated T cells. Here, we characterize the immune landscape in primary melanoma by high-dimensional single cell multiplex analysis in tissue sections (MILAN technique) followed by image analysis, RT-PCR and shotgun proteomics. We observed that the brisk and non-brisk patterns are heterogeneous functional categories that can be further sub-classified into active, transitional or exhausted. The classification of primary melanomas based on the functional paradigm also shows correlation with spontaneous regression, and an improved prognostic value when compared to that of the brisk classification. Finally, the main inflammatory cell subpopulations that are present in the microenvironment associated with activation and exhaustion and their spatial relationships are described using neighbourhood analysis.

    in eLife: latest articles on February 14, 2020 12:00 AM.

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    Medial entorhinal cortex activates in a traveling wave in the rat

    Traveling waves are hypothesized to support the long-range coordination of anatomically distributed circuits. Whether separate strongly-interacting circuits exhibit traveling waves remains unknown. The hippocampus exhibits traveling 'theta' waves and interacts strongly with the medial entorhinal cortex (MEC). To determine whether the MEC also activates in a traveling wave, we performed extracellular recordings of LFP and multi-unit activity along the MEC. These recordings revealed progressive phase shifts in activity, indicating that the MEC also activates in a traveling wave. Variation in theta waveform along the region, generated by gradients in local physiology, contributed to the observed phase shifts. Removing waveform-related phase shifts left significant residual phase shifts. The residual phase shifts covaried with theta frequency in a manner consistent with those generated by weakly coupled oscillators. These results show that coordination of anatomically distributed circuits could be enabled by traveling waves but reveal heterogeneity in the mechanisms generating those waves.

    in eLife: latest articles on February 14, 2020 12:00 AM.

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    LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

    The Parkinson's Disease (PD)-associated gene leucine-rich repeat kinase (LRRK2) has been studied extensively in the brain. However, several studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection, suggesting LRRK2 also controls immunity. We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of type I interferons (IFN) and interferon stimulated genes (ISGs) and causes blunted interferon responses to mycobacterial pathogens and cytosolic nucleic acid agonists. Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combination of mitochondrial stresses, including oxidative stress from low levels of purine metabolites and DRP1-dependent mitochondrial fragmentation. Together, these defects promote mtDNA leakage into the cytosol and chronic cGAS engagement. While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mtb) replication, they have exacerbated inflammation and lower ISG expression in the lungs. These results demonstrate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling innate immune outcomes.

    in eLife: latest articles on February 14, 2020 12:00 AM.

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    Network efficiency predicts resilience to cognitive decline in elderly at risk for Alzheimer's

    To determine whether white matter network efficiency (WMNE) may be a surrogate marker of the physiological basis of resilience to cognitive decline in elderly persons without dementia and age and AD-related cerebral pathology, we quantified WMNE from baseline MRI scans and investigated its association with longitudinal neuropsychological assessments independent of baseline amyloid, tau and white matter hyperintensity volume. 85 cognitively normal elderly subjects and patients with mild cognitive impairment (MCI) with baseline diffusion imaging, CSF specimens, AV45-PET and longitudinal cognitive assessments were included. WMNE was calculated from reconstructed cerebral white matter networks for each individual. Mixed linear effects models were estimated to investigate the association of higher resilience to cognitive decline with higher WMNE and the modulation of this association by increased cerebral amyloid, CSF tau or WMHV. For the majority of cognitive outcome measures, higher WMNE was associated with higher resilience to cognitive decline independently of pathology measures (beta: .074 - .098; p: .011 - .039). Additionally, WMNE was consistently associated with higher resilience to cognitive decline in subjects with higher cerebral amyloid burden (beta: .024 - .276; p: .000 - .036) and with lower CSF tau (beta: -.030 - -.074; p: .015 - .002) across all cognitive outcome measures. The results of this study indicate that WMNE in particular and possibly white matter organization in general may be worthy targets of investigation to provide measures quantifying a patient's resilience to cognitive decline and thus provide an individual prognosis.

    in bioRxiv Subject Collection: Neuroscience on February 14, 2020 12:00 AM.

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    Visual Attention Through Uncertainty Minimization in Recurrent Generative Models

    Allocating visual attention through saccadic eye movements is a key ability of intelligent agents. Attention is both influenced through bottom-up stimulus properties as well as top-down task demands. The interaction of these two attention mechanisms is not yet fully understood. A parsimonious reconciliation posits that both processes serve the minimization of predictive uncertainty. We propose a recurrent generative neural network model that predicts a visual scene based on foveated glimpses. The model shifts its attention in order to minimize the uncertainty in its predictions. We show that the proposed model produces naturalistic eye movements focusing on informative stimulus regions. Introducing additional tasks modulates the saccade patterns towards task-relevant stimulus regions. The models saccade characteristics correspond well with previous experimental data in humans, providing evidence that uncertainty minimization could be a fundamental mechanisms for the allocation of visual attention.

    in bioRxiv Subject Collection: Neuroscience on February 14, 2020 12:00 AM.

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    Simultaneous human intracerebral stimulation and HD-EEG: ground-truth for source localization methods

    Precisely localizing the sources of brain activity as recorded by EEG is a fundamental procedure and a major challenge for both research and clinical practice. Even though many methods and algorithms have been proposed, their relative advantages and limitations are still not well established. Moreover, these methods involve tuning multiple parameters, for which no principled way of selection exists yet. These uncertainties are emphasized due to the lack of ground-truth for their validation and testing. Here we provide the first open dataset that comprises EEG recorded electrical activity originating from precisely known locations inside the brain of living humans. High-density EEG was recorded as single-pulse biphasic currents were delivered at intensities ranging from 0.1 to 5 mA through stereotactically implanted electrodes in diverse brain regions during pre-surgical evaluation of patients with drug-resistant epilepsy. The uses of this dataset range from the estimation of in vivo tissue conductivity to the development, validation and testing of forward and inverse solution methods.

    in bioRxiv Subject Collection: Neuroscience on February 14, 2020 12:00 AM.

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    Long-range correlation in protein dynamics: Confirmation by structural data and normal mode analysis

    by Qian-Yuan Tang, Kunihiko Kaneko

    Proteins in cellular environments are highly susceptible. Local perturbations to any residue can be sensed by other spatially distal residues in the protein molecule, showing long-range correlations in the native dynamics of proteins. The long-range correlations of proteins contribute to many biological processes such as allostery, catalysis, and transportation. Revealing the structural origin of such long-range correlations is of great significance in understanding the design principle of biologically functional proteins. In this work, based on a large set of globular proteins determined by X-ray crystallography, by conducting normal mode analysis with the elastic network models, we demonstrate that such long-range correlations are encoded in the native topology of the proteins. To understand how native topology defines the structure and the dynamics of the proteins, we conduct scaling analysis on the size dependence of the slowest vibration mode, average path length, and modularity. Our results quantitatively describe how native proteins balance between order and disorder, showing both dense packing and fractal topology. It is suggested that the balance between stability and flexibility acts as an evolutionary constraint for proteins at different sizes. Overall, our result not only gives a new perspective bridging the protein structure and its dynamics but also reveals a universal principle in the evolution of proteins at all different sizes.

    in PLOS Computational Biology: New Articles on February 13, 2020 10:00 PM.

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    Coding with transient trajectories in recurrent neural networks

    by Giulio Bondanelli, Srdjan Ostojic

    Following a stimulus, the neural response typically strongly varies in time and across neurons before settling to a steady-state. While classical population coding theory disregards the temporal dimension, recent works have argued that trajectories of transient activity can be particularly informative about stimulus identity and may form the basis of computations through dynamics. Yet the dynamical mechanisms needed to generate a population code based on transient trajectories have not been fully elucidated. Here we examine transient coding in a broad class of high-dimensional linear networks of recurrently connected units. We start by reviewing a well-known result that leads to a distinction between two classes of networks: networks in which all inputs lead to weak, decaying transients, and networks in which specific inputs elicit amplified transient responses and are mapped onto output states during the dynamics. Theses two classes are simply distinguished based on the spectrum of the symmetric part of the connectivity matrix. For the second class of networks, which is a sub-class of non-normal networks, we provide a procedure to identify transiently amplified inputs and the corresponding readouts. We first apply these results to standard randomly-connected and two-population networks. We then build minimal, low-rank networks that robustly implement trajectories mapping a specific input onto a specific orthogonal output state. Finally, we demonstrate that the capacity of the obtained networks increases proportionally with their size.

    in PLOS Computational Biology: New Articles on February 13, 2020 10:00 PM.

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    SuperFreq: Integrated mutation detection and clonal tracking in cancer

    by Christoffer Flensburg, Tobias Sargeant, Alicia Oshlack, Ian J. Majewski

    Analysing multiple cancer samples from an individual patient can provide insight into the way the disease evolves. Monitoring the expansion and contraction of distinct clones helps to reveal the mutations that initiate the disease and those that drive progression. Existing approaches for clonal tracking from sequencing data typically require the user to combine multiple tools that are not purpose-built for this task. Furthermore, most methods require a matched normal (non-tumour) sample, which limits the scope of application. We developed SuperFreq, a cancer exome sequencing analysis pipeline that integrates identification of somatic single nucleotide variants (SNVs) and copy number alterations (CNAs) and clonal tracking for both. SuperFreq does not require a matched normal and instead relies on unrelated controls. When analysing multiple samples from a single patient, SuperFreq cross checks variant calls to improve clonal tracking, which helps to separate somatic from germline variants, and to resolve overlapping CNA calls. To demonstrate our software we analysed 304 cancer-normal exome samples across 33 cancer types in The Cancer Genome Atlas (TCGA) and evaluated the quality of the SNV and CNA calls. We simulated clonal evolution through in silico mixing of cancer and normal samples in known proportion. We found that SuperFreq identified 93% of clones with a cellular fraction of at least 50% and mutations were assigned to the correct clone with high recall and precision. In addition, SuperFreq maintained a similar level of performance for most aspects of the analysis when run without a matched normal. SuperFreq is highly versatile and can be applied in many different experimental settings for the analysis of exomes and other capture libraries. We demonstrate an application of SuperFreq to leukaemia patients with diagnosis and relapse samples.

    in PLOS Computational Biology: New Articles on February 13, 2020 10:00 PM.

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    A generative growth model for thalamocortical axonal branching in primary visual cortex

    by Pegah Kassraian-Fard, Michael Pfeiffer, Roman Bauer

    Axonal morphology displays large variability and complexity, yet the canonical regularities of the cortex suggest that such wiring is based on the repeated initiation of a small set of genetically encoded rules. Extracting underlying developmental principles can hence shed light on what genetically encoded instructions must be available during cortical development. Within a generative model, we investigate growth rules for axonal branching patterns in cat area 17, originating from the lateral geniculate nucleus of the thalamus. This target area of synaptic connections is characterized by extensive ramifications and a high bouton density, characteristics thought to preserve the spatial resolution of receptive fields and to enable connections for the ocular dominance columns. We compare individual and global statistics, such as a newly introduced length-weighted asymmetry index and the global segment-length distribution, of generated and biological branching patterns as the benchmark for growth rules. We show that the proposed model surpasses the statistical accuracy of the Galton-Watson model, which is the most commonly employed model for biological growth processes. In contrast to the Galton-Watson model, our model can recreate the log-normal segment-length distribution of the experimental dataset and is considerably more accurate in recreating individual axonal morphologies. To provide a biophysical interpretation for statistical quantifications of the axonal branching patterns, the generative model is ported into the physically accurate simulation framework of Cx3D. In this 3D simulation environment we demonstrate how the proposed growth process can be formulated as an interactive process between genetic growth rules and chemical cues in the local environment.

    in PLOS Computational Biology: New Articles on February 13, 2020 10:00 PM.

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    Ischemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation

    Abstract

    Objective

    It is unknown whether patients with atrial fibrillation (AF) with ischaemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes and how ongoing secondary prevention should be managed.

    Methods

    We conducted an individual patient data pooled analysis of seven prospective cohort studies which recruited patients with AF and cerebral ischemia. We compared patients taking oral anticoagulants (Vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior) with those without prior anticoagulation (OACnaive). We further compared those who changed the type (i.e. from VKA or DOAC, vice versa or DOAC to DOAC) of anticoagulation (OACchanged) with those who continued the same anticoagulation as secondary prevention (OACunchanged). Time to recurrent ischaemic stroke (AIS) was analysed using multivariate competing risk Fine‐Gray models to calculate hazard ratios (HR) and 95% confidence intervals (95%CI).

    Results

    We included 5413 patients (median age 78years [IQR 71‐84years], 5136 [96.7%] had ischaemic stroke as the index event (median NIHSS‐on‐admission 6 [IQR 2‐12]). The median CHA2DS2‐Vasc score was 5 (IQR4‐6) and not different between OACprior (n=1195) and OACnaive (n=4119, p=0.103). During 6128 patient‐years of follow‐up, 289 patients had AIS (4.7%/year, 95%CI 4.2‐5.3%). OACprior was associated with an increased risk of AIS (HR 1.6, 95%CI 1.2‐2.3, p=0.005). OACchanged (n=307) was not associated with decreased risk of AIS (HR 1.2, 95%CI 0.7‐2.1, p=0.415) compared with OACunchanged (n=585).

    Interpretation

    Patients with AF who have a stroke despite oral anticoagulation once are at a higher risk for recurrent strokes despite a similar CHA2DS2‐Vasc score to those without prior oral anticoagulation. Better prevention strategies are needed for this high risk patient group.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 13, 2020 07:00 PM.

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    Dynamic microtubules at the synapse

    Publication date: August 2020

    Source: Current Opinion in Neurobiology, Volume 63

    Author(s): Erik W Dent

    Microtubules (MTs) are a fundamental cytoskeletal component that give neurons structure and are the primary polymer system for long distance transport of cargo throughout the cytoplasm. Although neurons are highly polarized and their structure is often maintained throughout the life of an organism, MTs can remain dynamic in axons and dendrites, undergoing bouts of polymerization and depolymerization, referred to as dynamic instability. Furthermore, MTs can be nucleated outside of the centrosome or MT organizing center (MTOC) that is located in the cell body, allowing dynamic formation and branching of MT polymers throughout the neuron. Together, these recent findings point to a much more dynamic landscape of microtubules in developing and mature neurons than was previously appreciated. Here we will focus on recent studies that show MT dynamics are playing a role at the synapse, both post-synaptically in dendrites and pre-synaptically in axons.

    in ScienceDirect Publication: Current Opinion in Neurobiology on February 13, 2020 07:00 PM.

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    Cannabinoid Signaling Recruits Astrocytes to Modulate Presynaptic Function in the Suprachiasmatic Nucleus

    Circadian rhythms are 24-h cycles in physiology regulated by the suprachiasmatic nucleus (SCN) in the brain, where daily cues act on SCN neurons to alter clock timing. Cannabinoid signaling modulates SCN neuronal activity, although the mechanism remains unclear. We propose that neuronal activity generates endocannabinoid release, activating astrocyte Ca2+ signaling, which releases adenosine and activates adenosine-1 receptors (A1Rs) on the presynaptic axon terminals, decreasing GABA release. We demonstrated, in mice, that activation of cannabinoid-1 receptors (CB1R) with the agonist WIN 55,212-2 (WIN) reduced the miniature GABA receptor-mediated postsynaptic current (mGPSC) frequency by a mechanism that requires astrocytes and A1R. WIN activated an intracellular Ca2+ signaling pathway in astrocytes. Activating this intracellular Ca2+ pathway with designer receptors exclusively activated by designer drugs (DREADDs) also decreased the mGPSC frequency and required A1R activation. The frequency of spontaneous Ca2+ events, including those induced by depolarization of a postsynaptic SCN neuron, was reduced by blocking CB1R activation with AM251, demonstrating neuronal endocannabinoid signaling modulates astrocytic Ca2+ signaling in the SCN. Finally, daytime application of WIN or adenosine phase advanced the molecular circadian clock, indicating that this cannabinoid signaling pathway is vital for the timing of circadian rhythms.

    in eNeuro current issue on February 13, 2020 05:30 PM.

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    Arousal-state dependent alterations in VTA-GABAergic neuronal activity

    Abstract

    Decades of research have implicated the ventral tegmental area (VTA) in motivation, learning and reward processing. We and others recently demonstrated that it also serves as an important node in sleep/wake regulation. Specifically, VTA-dopaminergic neuron activation is sufficient to drive wakefulness and necessary for the maintenance of wakefulness. However, the role of VTA-GABAergic neurons in arousal regulation is not fully understood. It is still unclear whether VTA-GABAergic neurons predictably alter their activity across arousal states, what is the nature of interactions between VTA-GABAergic activity and cortical oscillations, and how activity in VTA-GABAergic neurons relates to VTA-dopaminergic neurons in the context of sleep/wake regulation. To address these, we simultaneously recorded population activity from VTA-subpopulations and EEG/EMG signals during spontaneous sleep/wake states and in the presence of salient stimuli in freely-behaving mice. We found that VTA-GABAergic neurons exhibit robust arousal-state-dependent alterations in population activity, with high activity and transients during wakefulness and REM sleep. During wakefulness, population activity of VTA-GABAergic neurons, but not VTA-dopaminergic neurons, was positively correlated with EEG gamma power and negatively correlated with theta power. During NREM sleep, population activity in both VTA-GABAergic and VTA-dopaminergic neurons negatively correlated with delta, theta, and sigma power bands. Salient stimuli, with both positive and negative valence, activated VTA-GABAergic neurons. Together, our data indicate that VTA-GABAergic neurons, like their dopaminergic counterparts, drastically alter their activity across sleep-wake states. Changes in their activity predicts cortical oscillatory patterns reflected in the EEG, which are distinct from EEG spectra associated with dopaminergic neural activity.

    Statement of Significance Little is known about how ventral tegmental area (VTA) neural ensembles couple arousal to motivated behaviors. Using cell-type specific genetic tools, we investigated the population activity of GABAergic and dopaminergic neurons within the VTA across sleep/wake states and in the presence of salient stimuli. We demonstrate that coordinated neural activity within VTA-GABAergic neurons peaks during wakefulness and REM sleep. Furthermore, neuronal activity in VTA-GABAergic neurons is correlated with high frequency, low amplitude cortical oscillations during waking, but negatively correlated with high amplitude slower frequency oscillations during NREM sleep. Our results demonstrate that VTA-GABAergic neuronal activity is tightly linked to cortical arousal and highlight this population as a potential important node in sleep/wake regulation.

    in RSS PAP on February 13, 2020 05:30 PM.

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    NMDA receptor antibodies in autoimmune encephalopathy alter oligodendrocyte function

    Abstract

    Objective

    Antibodies against neuronal N‐methyl‐D‐aspartate receptors (NMDARs) in patients with anti‐NMDAR encephalitis alter neuronal synaptic function and plasticity, but the effects on other cells of the nervous system are unknown.

    Methods

    CSF of patients with anti‐NMDAR encephalitis (preabsorbed or not with GluN1) and a human NMDAR specific monoclonal antibody (SSM5) derived from plasma cells of a patient, along the corresponding controls, were used in the studies. To evaluate the activity of oligodendrocyte NMDARs and AMPARs in vitro after exposure to patients'CSF antibodies or SSM5 we used a functional assay based on cytosolic Ca2+ imaging. Expression of the glucose transporter (GLUT1) in oligodencrocytes was assessed by immunocytochemistry.

    Results

    NMDAR agonists responses were robustly reduced after pre‐incubation of oligodendrocytes with patients' CSF, or SSM5, but remained largely unaltered with the corresponding controls. These effects were NMDAR‐specific as patients' CSFs did not alter responses to AMPA receptor agonists and were abrogated by pre‐absorption of CSF with HEK cells expressing GluN1 subunit. Additionally, patients' CSF reduced oligodendrocyte expression of glucose transporter GLUT1 induced by NMDAR activity.

    Interpretation

    Antibodies from patients with anti‐NMDAR encephalitis specifically alter the function of NMDAR in oligodendrocytes causing a decrease of expression of GLUT1. Considering that normal GLUT1 expression in oligodendrocytes and myelin is needed to metabolically support axonal function, the findings suggest a link between antibody‐mediated dysfunction of NMDAR in oligodendrocytes and the white matter alterations reported in patients with this disorder.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 13, 2020 08:00 AM.

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    The Unreasonable Effectiveness of Deep Learning in Artificial Intelligence. (arXiv:2002.04806v1 [q-bio.NC])

    Deep learning networks have been trained to recognize speech, caption photographs and translate text between languages at high levels of performance. Although applications of deep learning networks to real world problems have become ubiquitous, our understanding of why they are so effective is lacking. These empirical results should not be possible according to sample complexity in statistics and non-convex optimization theory. However, paradoxes in the training and effectiveness of deep learning networks are being investigated and insights are being found in the geometry of high-dimensional spaces. A mathematical theory of deep learning would illuminate how they function, allow us to assess the strengths and weaknesses of different network architectures and lead to major improvements. Deep learning has provided natural ways for humans to communicate with digital devices and is foundational for building artificial general intelligence. Deep learning was inspired by the architecture of the cerebral cortex and insights into autonomy and general intelligence may be found in other brain regions that are essential for planning and survival, but major breakthroughs will be needed to achieve these goals.

    in q-bio.NC updates on arXiv.org on February 13, 2020 01:30 AM.

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    Social Network Analysis for Social Neuroscientists. (arXiv:1909.11894v2 [cs.SI] UPDATED)

    Although social neuroscience is concerned with understanding how the brain interacts with its social environment, prevailing research in the field has primarily considered the human brain in isolation, deprived of its rich social context. Emerging work in social neuroscience that leverages tools from network analysis has begun to pursue this issue, advancing knowledge of how the human brain influences and is influenced by the structures of its social environment. In this paper, we provide an overview of key theory and methods in network analysis (especially for social systems) as an introduction for social neuroscientists who are interested in relating individual cognition to the structures of an individual's social environments. We also highlight some exciting new work as examples of how to productively use these tools to investigate questions of relevance to social neuroscientists. We include tutorials to help with practical implementation of the concepts that we discuss. We conclude by highlighting a broad range of exciting research opportunities for social neuroscientists who are interested in using network analysis to study social systems.

    in q-bio.NC updates on arXiv.org on February 13, 2020 01:30 AM.

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    Eph/ephrin Function Contributes to the Patterning of Spinocerebellar Mossy Fibers Into Parasagittal Zones

    Purkinje cell microcircuits perform diverse functions using widespread inputs from the brain and spinal cord. The formation of these functional circuits depends on developmental programs and molecular pathways that organize mossy fiber afferents from different sources into a complex and precisely patterned map within the granular layer of the cerebellum. During development, Purkinje cell zonal patterns are thought to guide mossy fiber terminals into zones. However, the molecular mechanisms that mediate this process remain unclear. Here, we used knockout mice to test whether Eph/ephrin signaling controls Purkinje cell-mossy fiber interactions during cerebellar circuit formation. Loss of ephrin-A2 and ephrin-A5 disrupted the patterning of spinocerebellar terminals into discrete zones. Zone territories in the granular layer that normally have limited spinocerebellar input contained ectopic terminals in ephrin-A2−/−;ephrin-A5−/− double knockout mice. However, the overall morphology of the cerebellum, lobule position, and Purkinje cell zonal patterns developed normally in the ephrin-A2−/−;ephrin-A5−/− mutant mice. This work suggests that communication between Purkinje cell zones and mossy fibers during postnatal development allows contact-dependent molecular cues to sharpen the innervation of sensory afferents into functional zones.

    in Frontiers in Systems Neuroscience | New and Recent Articles on February 13, 2020 12:00 AM.

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    A Topological Cluster of Differentially Regulated Genes in Mice Lacking PER3

    Polymorphisms in the human circadian clock gene PERIOD3 (PER3) are associated with a wide variety of phenotypes such as diurnal preference, delayed sleep phase disorder, sleep homeostasis, cognitive performance, bipolar disorder, type 2 diabetes, cardiac regulation, cancer, light sensitivity, hormone and cytokine secretion, and addiction. However, the molecular mechanisms underlying these phenotypic associations remain unknown. Per3 knockout mice (Per3–/–) have phenotypes related to activity, sleep homeostasis, anhedonia, metabolism, and behavioral responses to light. Using a protocol that induces behavioral differences in response to light in wild type and Per3–/– mice, we compared genome-wide expression in the eye and hypothalamus in the two genotypes. Differentially expressed transcripts were related to inflammation, taste, olfactory and melatonin receptors, lipid metabolism, cell cycle, ubiquitination, and hormones, as well as receptors and channels related to sleep regulation. Differentially expressed transcripts in both tissues co-localized with Per3 on an ∼8Mbp region of distal chromosome 4. The most down-regulated transcript is Prdm16, which is involved in adipocyte differentiation and may mediate altered body mass accumulation in Per3–/– mice. eQTL analysis with BXD mouse strains showed that the expression of some of these transcripts and also others co-localized at distal chromosome 4, is correlated with brain tissue expression levels of Per3 with a highly significant linkage to genetic variation in that region. These data identify a cluster of transcripts on mouse distal chromosome 4 that are co-regulated with Per3 and whose expression levels correlate with those of Per3. This locus lies within a topologically associating domain island that contains many genes with functional links to several of the diverse non-circadian phenotypes associated with polymorphisms in human PER3.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 13, 2020 12:00 AM.

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    Neurovascular Coupling by Functional Near Infra-Red Spectroscopy and Sport-Related Concussion in Retired Rugby Players: The UK Rugby Health Project

    Aim: This study investigated cerebral hemodynamic responses to a neurovascular coupling (NVC) test in retired contact athletes with a history of repeated mild traumatic brain injury (mTBI) and in controls with no history of mTBI.

    Methods: Twenty-one retired rugby players (47.7 ± 12.9 year old; age at retirement: 38.5 ± 8.9 year; number of years playing rugby: 12.7 ± 3.7 year) with a history of three or more diagnosed concussions (8.9 ± 7.9 concussions per player) and 23 controls with no history of mTBI (46.5 ± 12.8 year old) performed a NVC test to detect task-orientated cerebral hemodynamic changes using functional near-infrared spectroscopy (fNIRS).

    Results: The NVC showed a statistically significant reduction in the cerebral hemodynamic response in comparison to the control group which had a greater relative increase of oxyhemoglobin (O2Hb). There were reductions in left middle frontal gyrus (MFG) O2Hb (−0.015 ± 0.258 μM) and relative increases in deoxyhemoglobin (HHb; −0.004 ± 0.159 μM) in the same region for the mTBI group in comparison to the control group (−0.160 ± 0.311 μM; −0.121 ± 0.076 μM for O2Hb and HHb, respectively). The mTBI group induced a greater rate of oxygen extraction compared to the control group.

    Conclusion: This was the first study to examine cerebral hemodynamic changes in retired rugby players in response to a NVC test, and we found reduced cerebral hemodynamic responses in participants with a history of mTBI compared to controls. These results suggest altered cerebral metabolic demands in participants with a history of multiple head injuries. Further research is needed to ascertain an understanding of the changes in hemodynamics from playing into retirement.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 13, 2020 12:00 AM.

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    The Similarity Between Chinese Five-Pattern and Eysenck’s Personality Traits: Evidence From Theory and Resting-State fMRI

    Chinese five-pattern and Eysenck’s personality traits are two types of personality theories based on different cultural backgrounds. The former is an indigenous theory, and the latter is a cross-cultural theory. In order to verify the relationship between two different personality traits from theory and neuropsychology, the current study recruited 170 healthy adults to calculate their five-Pattern Personality Inventory (FPPI) and Eysenck Personality Questionnaire-Revised (EPQ) scales and to scan their brains using functional magnetic resonance imaging (fMRI). Then, we performed stepwise-regression analysis and mediation-effect analysis to explore the association between brain regional homogeneity (ReHo) and two types of personality traits. The results showed that the ReHo of the right superior temporal gyrus (STG) positively correlated with TaiYang traits for FPPI and that there was a significant linear relationship with extraversion and neuroticism for EPQ. Besides, the ReHo of the right medial prefrontal cortex (mPFC) positively correlated with TaiYin for FPPI, and it also showed a significant linear relationship with neuroticism for EPQ. Furthermore, we found that extroversion and neuroticism partially mediated the relationship between five-pattern personality traits and the regional brain function, based on the mediation-effect analysis. Our findings suggest that Chinese five-pattern personality traits have a close relationship with Eysenck’s personality traits and that both may be engaged in similar neurobiological mechanisms in common brain regions to some extent. Hence, these findings first reveal a relationship between Chinese traditional personality traits and Western Eysenck’s personality traits in terms of both theoretical and neurobiological contexts.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 13, 2020 12:00 AM.

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    A Reappraisal of GAT-1 Localization in Neocortex

    γ-Aminobutyric acid (GABA) transporter (GAT)-1, the major GABA transporter in the brain, plays a key role in modulating GABA signaling and is involved in the pathophysiology of several neuropsychiatric diseases, including epilepsy. The original description of GAT-1 as a neuronal transporter has guided the interpretation of the findings of all physiological, pharmacological, genetic, or clinical studies. However, evidence published in the past few years, some of which is briefly reviewed herein, does not seem to be consistent with a neurocentric view of GAT-1 function and calls for more detailed analysis of its localization. We therefore performed a thorough systematic assessment of GAT-1 localization in neocortex and subcortical white matter. In line with earlier work, we found that GAT-1 was robustly expressed in axon terminals forming symmetric synapses and in astrocytic processes, whereas its astrocytic expression was more diffuse than expected and, even more surprisingly, immature and mature oligodendrocytes and microglial cells also expressed the transporter. These data indicate that the era of “neuronal” and “glial” GABA transporters has finally come to a close and provide a wider perspective from which to view GABA-mediated physiological phenomena. In addition, given the well-known involvement of astrocytes, oligodendrocytes, and microglial cells in physiological as well as pathological conditions, the demonstration of functional GAT-1 in these cells is expected to provide greater insight into the phenomena occurring in the diseased brain as well as to prompt a reassessment of earlier findings.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 13, 2020 12:00 AM.

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    Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson’s Disease

    The search for new disease-modifying drugs for Parkinson’s disease (PD) is a slow and highly expensive process, and the repurposing of drugs already approved for different medical indications is becoming a compelling alternative option for researchers. Genetic variables represent a predisposing factor to the disease and mutations in leucine-rich repeat kinase 2 (LRRK2) locus have been correlated to late-onset autosomal-dominant PD. The common fruit fly Drosophila melanogaster carrying the mutation LRRK2 loss-of-function in the WD40 domain (LRRK2WD40), is a simple in vivo model of PD and is a valid tool to first evaluate novel therapeutic approaches to the disease. Recent studies have suggested a neuroprotective activity of immunomodulatory agents in PD models. Here the immunomodulatory drug Pomalidomide (POM), a Thalidomide derivative, was examined in the Drosophila LRRK2WD40 genetic model of PD. Mutant and wild type flies received increasing POM doses (1, 0.5, 0.25 mM) through their diet from day 1 post eclosion, until postnatal day (PN) 7 or 14, when POM’s actions were evaluated by quantifying changes in climbing behavior as a measure of motor performance, the number of brain dopaminergic neurons and T-bars, mitochondria integrity. LRRK2WD40 flies displayed a spontaneous age-related impairment of climbing activity, and POM significantly and dose-dependently improved climbing performance both at PN 7 and PN 14. LRRK2WD40 fly motor disability was underpinned by a progressive loss of dopaminergic neurons in posterior clusters of the protocerebrum, which are involved in the control of locomotion, by a low number of T-bars density in the presynaptic bouton active zones. POM treatment fully rescued the cell loss in all posterior clusters at PN 7 and PN 14 and significantly increased the T-bars density. Moreover, several damaged mitochondria with dilated cristae were observed in LRRK2WD40 flies treated with vehicle but not following POM. This study demonstrates the neuroprotective activity of the immunomodulatory agent POM in a genetic model of PD. POM is an FDA-approved clinically available and well-tolerated drug used for the treatment of multiple myeloma. If further validated in mammalian models of PD, POM could rapidly be clinically tested in humans.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 13, 2020 12:00 AM.

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    Adipose-Derived Molecules–Untouched Horizons in Alzheimer’s Disease Biology

    The global incidence of Alzheimer’s disease (AD) is on the rise with the increase in obesity and metabolic disease epidemic. Obesity is co-morbid with the increase in mass of adipose tissue, which secretes numerous molecules that are biologically important. Obesity and its associated conditions are perhaps involved in the causative pathway of AD. Immunologically important cytokines such as IL-1β, IL-10, and IL-18, which are released by adipose tissue, are also found to be associated with AD. Besides, the expression of IL-6, IFNγ, and TNF alpha are also associated with AD. Ang-I and Ang-II are found to mediate the progression of AD. Complement factors B, C4b, and H are differentially expressed in AD. Overall, several adipocyte-derived cytokines are found to be dysregulated in AD, and their role in AD remains to be studied. The induction of autophagy is a very promising strategy in the treatment of AD. A variety of adipose-derived molecules have been shown to modulate autophagy. However, very little literature is available on the role of adipose-derived molecules in inducing autophagy in microglial cells of AD. Understanding the role of adipose-derived molecules in the development of AD, especially in the induction of autophagy, would open up new avenues in devising strategies for the treatment of AD.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 13, 2020 12:00 AM.

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    Moving proteins along in the cilium

    The structures of the bovine and human BBSome reveal that a conformational change is required to recruit the complex to the ciliary membrane.

    in eLife: latest articles on February 13, 2020 12:00 AM.

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    A large-scale resource for tissue-specific CRISPR mutagenesis in Drosophila

    Genetic screens are powerful tools for the functional annotation of genomes. In the context of multicellular organisms, interrogation of gene function is greatly facilitated by methods that allow spatial and temporal control of gene abrogation. Here, we describe a large-scale transgenic short guide (sg) RNA library for efficient CRISPR-based disruption of specific target genes in a constitutive or conditional manner. The library consists currently of more than 2600 plasmids and 1700 fly lines with a focus on targeting kinases, phosphatases and transcription factors, each expressing two sgRNAs under control of the Gal4/UAS system. We show that conditional CRISPR mutagenesis is robust across many target genes and can be efficiently employed in various somatic tissues, as well as the germline. In order to prevent artefacts commonly associated with excessive amounts of Cas9 protein, we have developed a series of novel UAS-Cas9 transgenes, which allow fine tuning of Cas9 expression to achieve high gene editing activity without detectable toxicity. Functional assays, as well as direct sequencing of genomic sgRNA target sites, indicates that the vast majority of transgenic sgRNA lines mediate efficient gene disruption. Furthermore, we conducted the so far largest fully transgenic CRISPR screen in any metazoan organism, which further supported the high efficiency and accuracy of our library and revealed many so far uncharacterized genes essential for development.

    in eLife: latest articles on February 13, 2020 12:00 AM.

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    Nodal β spectrins are required to maintain Na+ channel clustering and axon integrity

    Clustered ion channels at nodes of Ranvier are critical for fast action potential propagation in myelinated axons. Axon-glia interactions converge on ankyrin and spectrin cytoskeletal proteins to cluster nodal Na+ channels during development. However, how nodal ion channel clusters are maintained is poorly understood. Here, we generated mice lacking nodal spectrins in peripheral sensory neurons to uncouple their nodal functions from their axon initial segment functions. We demonstrate a hierarchy of nodal spectrins, where β4 spectrin is the primary spectrin and β1 spectrin can substitute; each is sufficient for proper node organization. Remarkably, mice lacking nodal β spectrins have normal nodal Na+ channel clustering during development, but progressively lose Na+ channels with increasing age. Loss of nodal spectrins is accompanied by an axon injury response and axon deformation. Thus, nodal spectrins are required to maintain nodal Na+ channel clusters and the structural integrity of axons.

    in eLife: latest articles on February 13, 2020 12:00 AM.

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    Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons

    In violation of Dale's principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter 3 and cholecystokinin expressing cortical interneurons (CCK+VGluT3+INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCK+VGluT3+INT mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCK+VGluT3+INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCK+VGluT3+INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK+ interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCK+VGluT3+INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.

    in eLife: latest articles on February 13, 2020 12:00 AM.

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    The speed of GTP hydrolysis determines GTP cap size and controls microtubule stability

    Microtubules are cytoskeletal polymers whose function depends on their property to switch between states of growth and shrinkage. Growing microtubules are thought to be stabilized by a GTP cap at their ends. The nature of this cap, however, is still poorly understood. End Binding proteins (EBs) recruit a diverse range of regulators of microtubule function to growing microtubule ends. Whether the EB binding region is identical to the GTP cap is unclear. Using mutated human tubulin with blocked GTP hydrolysis, we demonstrate that EBs bind with high affinity to the GTP conformation of microtubules. Slowing-down GTP hydrolysis leads to extended GTP caps. We find that cap length determines microtubule stability and that the microtubule conformation changes gradually in the cap as GTP is hydrolyzed. These results demonstrate the critical importance of the kinetics of GTP hydrolysis for microtubule stability and establish that the GTP cap coincides with the EB-binding region.

    in eLife: latest articles on February 13, 2020 12:00 AM.

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    Regulation of mRNA translation by a photoriboswitch

    Optogenetic tools have revolutionized the study of receptor-mediated processes, but such tools are lacking for RNA-controlled systems. In particular, light-activated regulatory RNAs are needed for spatiotemporal control of gene expression. To fill this gap, we used in vitro selection to isolate a novel riboswitch that selectively binds the trans isoform of a stiff-stilbene (amino-tSS)–a rapidly and reversibly photoisomerizing small molecule. Structural probing revealed that the RNA binds amino-tSS about 100-times stronger than the cis photoisoform (amino-cSS). In vitro and in vivo functional analysis showed that the riboswitch, termed Werewolf-1 (Were-1), inhibits translation of a downstream open reading frame when bound to amino-tSS. Photoisomerization of the ligand with a sub-millisecond pulse of light induced the protein expression. In contrast, amino-cSS supported protein expression, which was inhibited upon photoisomerization to amino-tSS. Reversible photoregulation of gene expression using a genetically encoded RNA will likely facilitate high-resolution spatiotemporal analysis of complex RNA processes.

    in eLife: latest articles on February 13, 2020 12:00 AM.

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    The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling in C. elegans and human cells

    The intracellular trafficking of growth factor receptors determines the activity of their downstream signaling pathways. Here, we show that he putative HSP-90 co-chaperone CHP-1 acts as a regulator of EGFR trafficking in C. elegans. Loss of chp-1 causes the retention of the EGFR in the ER and decreases MAPK signaling. CHP-1 is specifically required for EGFR trafficking, as the localization of other transmembrane receptors is unaltered in chp-1(lf) mutants, and the inhibition of hsp-90 or other co-chaperones does not affect EGFR localization. The role of the CHP-1 homolog CHORDC1 during EGFR trafficking is conserved in human cells. Analogous to C. elegans, the response of CHORDC1-deficient A431 cells to EGF stimulation is attenuated, the EGFR accumulates in the ER and ERK2 activity decreases. Although CHP-1 has been proposed to act as a co-chaperone for HSP90, our data indicate that CHP-1 plays an HSP90-independent function in controlling EGFR trafficking through the ER.

    in eLife: latest articles on February 13, 2020 12:00 AM.

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    A stochastic model for simulating ribosome kinetics <i>in vivo</i>

    by Eric Charles Dykeman

    Computational modelling of in vivo protein synthesis is highly complicated, as it requires the simulation of ribosomal movement over the entire transcriptome, as well as consideration of the concentration effects from 40+ different types of tRNAs and numerous other protein factors. Here I report on the development of a stochastic model for protein translation that is capable of simulating the dynamical process of in vivo protein synthesis in a prokaryotic cell containing several thousand unique mRNA sequences, with explicit nucleotide information for each, and report on a number of biological predictions which are beyond the scope of existing models. In particular, I show that, when the complex network of concentration dependent interactions between elongation factors, tRNAs, ribosomes, and other factors required for protein synthesis are included in full detail, several biological phenomena, such as the increasing peptide elongation rate with bacterial growth rate, are predicted as emergent properties of the model. The stochastic model presented here demonstrates the importance of considering the translational process at this level of detail, and provides a platform to interrogate various aspects of translation that are difficult to study in more coarse-grained models.

    in PLOS Computational Biology: New Articles on February 12, 2020 10:00 PM.

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    CovCopCan: An efficient tool to detect Copy Number Variation from amplicon sequencing data in inherited diseases and cancer

    by Paco Derouault, Jasmine Chauzeix, David Rizzo, Federica Miressi, Corinne Magdelaine, Sylvie Bourthoumieu, Karine Durand, Hélène Dzugan, Jean Feuillard, Franck Sturtz, Stéphane Mérillou, Anne-Sophie Lia

    Molecular diagnosis is an essential step of patient care. An increasing number of Copy Number Variations (CNVs) have been identified that are involved in inherited and somatic diseases. However, there are few existing tools to identify them among amplicon sequencing data generated by Next Generation Sequencing (NGS). We present here a new tool, CovCopCan, that allows the rapid and easy detection of CNVs in inherited diseases, as well as somatic data of patients with cancer, even with a low ratio of cancer cells to healthy cells. This tool could be very useful for molecular geneticists to rapidly identify CNVs in an interactive and user-friendly way.

    in PLOS Computational Biology: New Articles on February 12, 2020 10:00 PM.

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    Neurogranin stimulates Ca<sup>2+</sup>/calmodulin-dependent kinase II by suppressing calcineurin activity at specific calcium spike frequencies

    by Lu Li, Massimo Lai, Stephen Cole, Nicolas Le Novère, Stuart J. Edelstein

    Calmodulin sits at the center of molecular mechanisms underlying learning and memory. Its complex and sometimes opposite influences, mediated via the binding to various proteins, are yet to be fully understood. Calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) both bind open calmodulin, favoring Long-Term Potentiation (LTP) or Depression (LTD) respectively. Neurogranin binds to the closed conformation of calmodulin and its impact on synaptic plasticity is less clear. We set up a mechanistic computational model based on allosteric principles to simulate calmodulin state transitions and its interactions with calcium ions and the three binding partners mentioned above. We simulated calcium spikes at various frequencies and show that neurogranin regulates synaptic plasticity along three modalities. At low spike frequencies, neurogranin inhibits the onset of LTD by limiting CaN activation. At intermediate frequencies, neurogranin facilitates LTD, but limits LTP by precluding binding of CaMKII with calmodulin. Finally, at high spike frequencies, neurogranin promotes LTP by enhancing CaMKII autophosphorylation. While neurogranin might act as a calmodulin buffer, it does not significantly preclude the calmodulin opening by calcium. On the contrary, neurogranin synchronizes the opening of calmodulin’s two lobes and promotes their activation at specific frequencies. Neurogranin suppresses basal CaN activity, thus increasing the chance of CaMKII trans-autophosphorylation at high-frequency calcium spikes. Taken together, our study reveals dynamic regulatory roles played by neurogranin on synaptic plasticity, which provide mechanistic explanations for opposing experimental findings.

    in PLOS Computational Biology: New Articles on February 12, 2020 10:00 PM.

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    Topographic Mapping as a Basic Principle of Functional Organization for Visual and Prefrontal Functional Connectivity

    Abstract

    The organization of region-to-region functional connectivity has major implications for understanding information transfer and transformation between brain regions. We extended connective field mapping methodology to 3-D anatomic space to derive estimates of corticocortical functional organization. Using multiple publicly available human (both male and female) resting-state fMRI data samples for model testing and replication analysis, we have three main findings. First, we found that the functional connectivity between early visual regions maintained a topographic relationship along the anterior-posterior dimension, which corroborates previous research. Higher order visual regions showed a pattern of connectivity that supports convergence and biased sampling, which has implications for their receptive field properties. Second, we demonstrated that topographic organization is a fundamental aspect of functional connectivity across the entire cortex, with higher topographic connectivity between regions within a functional network than across networks. The principle gradient of topographic connectivity across the cortex resembled whole-brain gradients found in previous work. Last but not least, we showed that the organization of higher order regions such as the lateral prefrontal cortex demonstrate functional gradients of topographic connectivity and convergence. These organizational features of the lateral prefrontal cortex predict task-based activation patterns, particularly visual specialization and higher order rules. In sum, these findings suggest that topographic input is a fundamental motif of functional connectivity between cortical regions for information processing and transfer, with maintenance of topography potentially important for preserving the integrity of information from one region to another.

    in eNeuro current issue on February 12, 2020 05:30 PM.

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    Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid {beta}-Associated Alzheimer's Disease in Mice

    Alzheimer's disease (AD) is the most common neurodegenerative disorder, resulting in the progressive decline of cognitive function in patients. Familial forms of AD are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Inflammation and amyloidosis from amyloid β (Aβ) aggregates are implicated in neuron loss and cognitive decline. Inflammation activates the protein-tyrosine phosphatase 1B (PTP1B), and this could suppress many signaling pathways that activate glycogen synthase kinase 3β (GSK3β) implicated in neurodegeneration. However, the significance of PTP1B in AD pathology remains unclear. Here, we show that pharmacological inhibition of PTP1B with trodusquemine or selective ablation of PTP1B in neurons prevents hippocampal neuron loss and spatial memory deficits in a transgenic AD mouse model with Aβ pathology (hAPP-J20 mice of both sexes). Intriguingly, while systemic inhibition of PTP1B reduced inflammation in the hippocampus, neuronal PTP1B ablation did not. These results dissociate inflammation from neuronal loss and cognitive decline and demonstrate that neuronal PTP1B hastens neurodegeneration and cognitive decline in this model of AD. The protective effect of PTP1B inhibition or ablation coincides with the restoration of GSK3β inhibition. Neuronal ablation of PTP1B did not affect cerebral amyloid levels or plaque numbers, but reduced Aβ plaque size in the hippocampus. In summary, our preclinical study suggests that targeting PTP1B may be a new strategy to intervene in the progression of AD.

    SIGNIFICANCE STATEMENT Familial forms of Alzheimer's disease (AD) are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Here, we used a mouse model expressing human amyloid precursor protein bearing two familial mutations and asked whether activation of a phosphatase PTP1B participates in the disease process. Systemic inhibition of this phosphatase using a selective inhibitor prevented cognitive decline, neuron loss in the hippocampus, and attenuated inflammation. Importantly, neuron-targeted ablation of PTP1B also prevented cognitive decline and neuron loss but did not reduce inflammation. Therefore, neuronal loss rather than inflammation was critical for AD progression in this mouse model, and that disease progression could be ameliorated by inhibition of PTP1B.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    The Cumulative Effect of Transient Synchrony States on Motor Performance in Parkinson's Disease

    Bursts of beta frequency band activity in the basal ganglia of patients with Parkinson's disease (PD) are associated with impaired motor performance. Here we test in human adults whether small variations in the timing of movement relative to beta bursts have a critical effect on movement velocity and whether the cumulative effects of multiple beta bursts, both locally and across networks, matter. We recorded local field potentials from the subthalamic nucleus (STN) in 15 PD patients of both genders OFF-medication, during temporary lead externalization after deep brain stimulation surgery. Beta bursts were defined as periods exceeding the 75th percentile amplitude threshold. Subjects performed a visual cued joystick reaching task, with the visual cue being triggered in real time with different temporal relationships to bursts of STN beta activity. The velocity of actions made in response to cues prospectively triggered by STN beta bursts was slower than when responses were not time-locked to recent beta bursts. Importantly, slow movements were those that followed multiple bursts close to each other within a trial. In contrast, small differences in the delay between the last burst and movement onset had no significant impact on velocity. Moreover, when the overlap of bursts between the two STN was high, slowing was more pronounced. Our findings suggest that the cumulative, but recent, history of beta bursting, both locally and across basal ganglia networks, may impact on motor performance.

    SIGNIFICANCE STATEMENT Bursts of beta frequency band activity in the basal ganglia are associated with slowing of voluntary movement in patients with Parkinson's disease. We show that slow movements are those that follow multiple bursts close to each other and bursts that are coupled across regions. These results suggest that the cumulative, but recent, history of beta bursting, both locally and across basal ganglia networks, impacts on motor performance in this condition. The manipulation of burst dynamics may be a means of selectively improving motor impairment.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Divisively Normalized Integration of Multisensory Error Information Develops Motor Memories Specific to Vision and Proprioception

    Both visual and proprioceptive information contribute to the accuracy of limb movement, but the mechanism of integration of these different modality signals for movement control and learning remains controversial. We aimed to elucidate the mechanism of multisensory integration for motor adaptation by evaluating single-trial adaptation (i.e., aftereffect) induced by visual and proprioceptive perturbations while male and female human participants performed reaching movements. The force-channel method was used to precisely impose several combinations of visual and proprioceptive perturbations (i.e., error), including an instance when the directions of perturbation in both stimuli opposed each another. In the subsequent probe force-channel trial, the lateral force against the channel was quantified as the aftereffect to clarify the mechanism by which the motor adaptation system corrects movement in the event of visual and proprioceptive errors. We observed that the aftereffects had complex dependence on the visual and proprioceptive errors. Although this pattern could not be explained by previously proposed computational models based on the reliability of sensory information, we found that it could be reasonably explained by a mechanism known as divisive normalization, which was the reported mechanism underlying the integration of multisensory signals in neurons. Furthermore, we discovered evidence that the motor memory for each sensory modality developed separately in accordance with a divisive normalization mechanism and that the outputs of both memories were integrated. These results provide a novel view of the utilization and integration of different sensory modality signals in motor adaptation.

    SIGNIFICANCE STATEMENT The mechanism of utilization of multimodal sensory information by the motor control system to perform limb movements with accuracy is a fundamental question. However, the mechanism of integration of these different sensory modalities for movement control and learning remains highly debatable. Herein, we demonstrate that multisensory integration in the motor learning system can be reasonably explained by divisive normalization, a canonical computation, ubiquitously observed in the brain (Carandini and Heeger, 2011). Moreover, we provide evidence of a novel idea that integration does not occur at the sensory information processing level, but at the motor execution level, after the motor memory for each sensory modality is separately created.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Mating Behavioral Function of Preoptic Galanin Neurons Is Shared between Fish with Alternative Male Reproductive Tactics and Tetrapods

    Understanding the contribution of neuropeptide-containing neurons to variation in social behavior remains critically important. Galanin has gained increased attention because of the demonstration that galanin neurons in the preoptic area (POA) promote mating and parental care in mammals. How widespread these mechanisms are among vertebrates essentially remains unexplored, especially among teleost fishes, which comprise nearly one-half of living vertebrate species. Teleosts with alternative reproductive tactics exhibit stereotyped patterns of social behavior that diverge widely between individuals within a sex. This includes midshipman that have two male morphs. Type I males mate using either acoustic courtship to attract females to enter a nest they guard or cuckoldry during which they steal fertilizations from a nest-holding male using a sneak or satellite spawning tactic, whereas type II males only cuckold. Using the neural activity marker phospho-S6, we show increased galanin neuron activation in courting type I males during mating that is not explained by their courtship vocalizations, parental care of eggs, or nest defense against cuckolders. This increase is not observed during mating in cuckolders of either morph or females (none of which show parental care). Together with their role in mating in male mammals, the results demonstrate an unexpectedly specific and deep-rooted, phylogenetically shared behavioral function for POA galanin neurons. The results also point to galanin-dependent circuitry as a potential substrate for the evolution of divergent phenotypes within one sex and provide new functional insights into how POA populations in teleosts compare to the POA and anterior hypothalamus of tetrapods.

    SIGNIFICANCE STATEMENT Studies of neuropeptide regulation of vertebrate social behavior have mainly focused on the vasopressin-oxytocin family. Recently, galanin has received attention as a regulator of social behavior largely because of studies demonstrating that galanin neurons in the preoptic area (POA) promote mating and parental care in mammals. Species with alternative reproductive tactics (ARTs) exhibit robust, consistent differences in behavioral phenotypes between individuals within a sex. Taking advantage of this trait, we show POA galanin neurons are specifically active during mating in one of two male reproductive tactics, but not other mating-related behaviors in a fish with ARTs. The results demonstrate a deep, phylogenetically shared role for POA galanin neurons in reproductive-related social behaviors with implications for the evolution of ARTs.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Threat Prediction from Schemas as a Source of Bias in Pain Perception

    Our sensory impressions of pain are generally thought to represent the noxious properties of an agent but can be influenced by the predicted level of threat. Predictions can be sourced from higher-order cognitive processes, such as schemas, but the extent to which schemas can influence pain perception relative to bottom-up sensory inputs and the underlying neural underpinnings of such a phenomenon are unclear. Here, we investigate how threat predictions generated from learning a cognitive schema lead to inaccurate sensory impressions of the pain stimulus. Healthy male and female participants first detected a linear association between cue values and stimulus intensity and rated pain to reflect the linear schema when compared with uncued heat stimuli. The effect of bias on pain ratings was reduced when prediction errors (PEs) increased, but pain perception was only partially updated when measured against stepped increases in PEs. Cognitive, striatal, and sensory regions graded their responses to changes in predicted threat despite the PEs (p < 0.05, corrected). Individuals with more catastrophic thinking about pain and with low mindfulness were significantly more reliant on the schema than on the sensory evidence from the pain stimulus. These behavioral differences mapped to variability in responses of the striatum and ventromedial prefrontal cortex. Thus, this study demonstrates a significant role of higher-order schemas in pain perception and indicates that pain perception is biased more toward predictions and less toward nociceptive inputs in individuals who report less mindfulness and more fear of pain.

    SIGNIFICANCE STATEMENT This study demonstrates that threat predictions generated from cognitive schemas continue to influence pain perception despite increasing prediction errors arising in pain pathways. Individuals first formed a cognitive schema of linearity in the relationship between the cued threat value and the stimulus intensity. Subsequently, the linearity was reduced gradually, and participants partially updated their evaluations of pain in relation to the stepped increases in prediction errors. Individuals who continued to rate pain based more on the predicted threat than on changes in nociceptive inputs reported high pain catastrophizing and less mindful-awareness scores. These two affects mapped to activity in the ventral and dorsal striatum, respectively. These findings direct us to a significant role of top-down processes in pain perception.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Blockage of NMDA- and GABA(A) Receptors Improves Working Memory Selectivity of Primate Prefrontal Neurons

    The ongoing activity of prefrontal neurons after a stimulus has disappeared is considered a neuronal correlate of working memory. It depends on the delicate but poorly understood interplay between excitatory glutamatergic and inhibitory GABAergic receptor effects. We administered the NMDA receptor antagonist MK-801 and the GABA(A) receptor antagonist bicuculline methiodide while recording cellular activity in PFC of male rhesus monkeys performing a delayed decision task requiring working memory. The blockade of GABA(A) receptors strongly improved the selectivity of the neurons' delay activity, causing an increase in signal-to-noise ratio during working memory periods as well as an enhancement of the neurons' coding selectivity. The blockade of NMDA receptors resulted in a slight enhancement of selectivity and encoding capacity of the neurons. Our findings emphasize the delicate and more complex than expected interplay of excitatory and inhibitory transmitter systems in modulating working memory coding in prefrontal circuits.

    SIGNIFICANCE STATEMENT Ongoing delay activity of prefrontal neurons constitutes a neuronal correlate of working memory. However, how this delay activity is generated by the delicate interplay of synaptic excitation and inhibition is unknown. We probed the effects of excitatory neurotransmitter glutamate and inhibitory neurotransmitter GABA in regulating delay activity in rhesus monkeys performing a delayed decision task requiring working memory. Surprisingly, the blockade of both glutamatergic NMDA and GABA(A) receptors improved neuronal selectivity of delay activity, causing an increase in neuronal signal-to-noise ratio. Moreover, individual neurons were similarly affected by blockade of both receptors. This emphasizes the delicate and more complex than expected interplay of excitatory and inhibitory transmitter systems in modulating working memory coding in prefrontal circuits.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Maternal Experience-Dependent Cortical Plasticity in Mice Is Circuit- and Stimulus-Specific and Requires MECP2

    The neurodevelopmental disorder Rett syndrome is caused by mutations in the gene Mecp2. Misexpression of the protein MECP2 is thought to contribute to neuropathology by causing dysregulation of plasticity. Female heterozygous Mecp2 mutants (Mecp2het) failed to acquire a learned maternal retrieval behavior when exposed to pups, an effect linked to disruption of parvalbumin-expressing inhibitory interneurons (PV) in the auditory cortex. Nevertheless, how dysregulated PV networks affect the neural activity dynamics that underlie auditory cortical plasticity during early maternal experience is unknown. Here we show that maternal experience in WT adult female mice (WT) triggers suppression of PV auditory responses. We also observe concomitant disinhibition of auditory responses in deep-layer pyramidal neurons that is selective for behaviorally relevant pup vocalizations. These neurons further exhibit sharpened tuning for pup vocalizations following maternal experience. All of these neuronal changes are abolished in Mecp2het, suggesting that they are an essential component of maternal learning. This is further supported by our finding that genetic manipulation of GABAergic networks that restores accurate retrieval behavior in Mecp2het also restores maternal experience-dependent plasticity of PV. Our data are consistent with a growing body of evidence that cortical networks are particularly vulnerable to mutations of Mecp2 in PV neurons. Moreover, our work links, for the first time, impaired in vivo cortical plasticity in awake Mecp2 mutant animals to a natural, ethologically relevant behavior.

    SIGNIFICANCE STATEMENT Rett syndrome is a genetic disorder that includes language communication problems. Nearly all Rett syndrome is caused by mutations in the gene that produces the protein MECP2, which is important for changes in brain connectivity believed to underlie learning. We previously showed that female Mecp2 mutants fail to learn a simple maternal care behavior performed in response to their pups' distress cries. This impairment appeared to critically involve inhibitory neurons in the auditory cortex called parvalbumin neurons. Here we record from these neurons before and after maternal experience, and we show that they adapt their response to pup calls during maternal learning in nonmutants, but not in mutants. This adaptation is partially restored by a manipulation that improves learning.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Simultaneous Requirements for Hes1 in Retinal Neurogenesis and Optic Cup-Stalk Boundary Maintenance

    The bHLH transcription factor Hes1 is a key downstream effector for the Notch signaling pathway. During embryogenesis neural progenitors express low levels of Hes1 in an oscillating pattern, whereas glial brain boundary regions (e.g., isthmus) have high, sustained Hes1 levels that suppress neuronal fates. Here, we show that in the embryonic mouse retina, the optic nerve head and stalk express high Hes1, with the ONH constituting a boundary between the neural retina and glial cells that ultimately line the optic stalk. Using two Cre drivers with distinct spatiotemporal expression we conditionally inactivated Hes1, to delineate the requirements for this transcriptional repressor during retinal neurogenesis versus patterning of the optic cup and stalk. Throughout retinal neurogenesis, Hes1 maintains proliferation and blocks retinal ganglion cell formation, but surprisingly we found it also promotes cone photoreceptor genesis. In the postnatal eye, Hes1 inactivation with Rax-Cre resulted in increased bipolar neurons and a mispositioning of Müller glia. Our results indicate that Notch pathway regulation of cone genesis is more complex than previously assumed, and reveal a novel role for Hes1 in maintaining the optic cup–stalk boundary.

    SIGNIFICANCE STATEMENT The bHLH repressor Hes1 regulates the timing of neurogenesis, rate of progenitor cell division, gliogenesis, and maintains tissue compartment boundaries. This study expands current eye development models by showing Notch-independent roles for Hes1 in the developing optic nerve head (ONH). Defects in ONH formation result in optic nerve coloboma; our work now inserts Hes1 into the genetic hierarchy regulating optic fissure closure. Given that Hes1 acts analogously in the ONH as the brain isthmus, it prompts future investigation of the ONH as a signaling factor center, or local organizer. Embryonic development of the ONH region has been poorly studied, which is surprising given it is where the pan-ocular disease glaucoma is widely believed to inflict damage on RGC axons.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Blocking the Thrombin Receptor Promotes Repair of Demyelinated Lesions in the Adult Brain

    Myelin loss limits neurological recovery and myelin regeneration and is critical for restoration of function. We recently discovered that global knock-out of the thrombin receptor, also known as Protease Activated Receptor 1 (PAR1), accelerates myelin development. Here we demonstrate that knocking out PAR1 also promotes myelin regeneration. Outcomes in two unique models of myelin injury and repair, that is lysolecithin or cuprizone-mediated demyelination, showed that PAR1 knock-out in male mice improves replenishment of myelinating cells and remyelinated nerve fibers and slows early axon damage. Improvements in myelin regeneration in PAR1 knock-out mice occurred in tandem with a skewing of reactive astrocyte signatures toward a prorepair phenotype. In cell culture, the promyelinating effects of PAR1 loss of function are consistent with possible direct effects on the myelinating potential of oligodendrocyte progenitor cells (OPCs), in addition to OPC-indirect effects involving enhanced astrocyte expression of promyelinating factors, such as BDNF. These findings highlight previously unrecognized roles of PAR1 in myelin regeneration, including integrated actions across the oligodendrocyte and astroglial compartments that are at least partially mechanistically linked to the powerful BDNF-TrkB neurotrophic signaling system. Altogether, findings suggest PAR1 may be a therapeutically tractable target for demyelinating disorders of the CNS.

    SIGNIFICANCE STATEMENT Replacement of oligodendroglia and myelin regeneration holds tremendous potential to improve function across neurological conditions. Here we demonstrate Protease Activated Receptor 1 (PAR1) is an important regulator of the capacity for myelin regeneration across two experimental murine models of myelin injury. PAR1 is a G-protein-coupled receptor densely expressed in the CNS, however there is limited information regarding its physiological roles in health and disease. Using a combination of PAR1 knock-out mice, oligodendrocyte monocultures and oligodendrocyte-astrocyte cocultures, we demonstrate blocking PAR1 improves myelin production by a mechanism related to effects across glial compartments and linked in part to regulatory actions toward growth factors such as BDNF. These findings set the stage for development of new clinically relevant myelin regeneration strategies.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome

    During adult hippocampal neurogenesis, most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Here, we propose that phagocytosis is not merely passive corpse removal but has an active role in maintaining neurogenesis. First, we found that neurogenesis was disrupted in male and female mice chronically deficient for two phagocytosis pathways: the purinergic receptor P2Y12, and the tyrosine kinases of the TAM family Mer tyrosine kinase (MerTK)/Axl. In contrast, neurogenesis was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of the changes induced by phagocytosis in microglia in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro. Our data suggest that microglia act as a sensor of local cell death, modulating the balance between proliferation and survival in the neurogenic niche through the phagocytosis secretome, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.

    SIGNIFICANCE STATEMENT Microglia are the brain professional phagocytes and, in the adult hippocampal neurogenic niche, they remove newborn cells naturally undergoing apoptosis. Here we show that phagocytosis of apoptotic cells triggers a coordinated transcriptional program that alters their secretome, limiting neurogenesis both in vivo and in vitro. In addition, chronic phagocytosis disruption in mice deficient for receptors P2Y12 and MerTK/Axl reduces adult hippocampal neurogenesis. In contrast, inducible MerTK downregulation transiently increases neurogenesis, suggesting that microglial phagocytosis provides a negative feedback loop that is necessary for the long-term maintenance of adult hippocampal neurogenesis. Therefore, we speculate that the effects of promoting engulfment/degradation of cell debris may go beyond merely removing corpses to actively promoting regeneration in development, aging, and neurodegenerative diseases.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    The Temporal Neurogenesis Patterning of Spinal p3-V3 Interneurons into Divergent Subpopulation Assemblies

    Neuronal diversity provides the spinal cord with the functional flexibility required to perform complex motor tasks. Spinal neurons arise during early embryonic development with the establishment of spatially and molecularly discrete progenitor domains that give rise to distinct, but highly heterogeneous, postmitotic interneuron (IN) populations. Our previous studies have shown that Sim1-expressing V3 INs, originating from the p3 progenitor domain, are anatomically and physiologically divergent. However, the developmental logic guiding V3 subpopulation diversity remains elusive. In specific cases of other IN classes, neurogenesis timing can play a role in determining the ultimate fates and unique characteristics of distinctive subpopulations. To examine whether neurogenesis timing contributes to V3 diversity, we systematically investigated the temporal neurogenesis profiles of V3 INs in the mouse spinal cord. Our work uncovered that V3 INs were organized into either early-born [embryonic day 9.5 (E9.5) to E10.5] or late-born (E11.5–E12.5) neurogenic waves. Early-born V3 INs displayed both ascending and descending commissural projections and clustered into subgroups across dorsoventral spinal laminae. In contrast, late-born V3 INs became fate-restricted to ventral laminae and displayed mostly descending and local commissural projections and uniform membrane properties. Furthermore, we found that the postmitotic transcription factor, Sim1, although expressed in all V3 INs, exclusively regulated the dorsal clustering and electrophysiological diversification of early-born, but not late-born, V3 INs, which indicates that neurogenesis timing may enable newborn V3 INs to interact with different postmitotic differentiation pathways. Thus, our work demonstrates neurogenesis timing as a developmental mechanism underlying the postmitotic differentiation of V3 INs into distinct subpopulation assemblies.

    SIGNIFICANCE STATEMENT Interneuron (IN) diversity empowers the spinal cord with the computation flexibility required to perform appropriate sensorimotor control. As such, uncovering the developmental logic guiding spinal IN diversity is fundamental to understanding the development of movement. In our current work, through a focus on the cardinal spinal V3 IN population, we investigated the role of neurogenesis timing on IN diversity. We uncovered that V3 INs are organized into early-born [embryonic day 9.5 (E9.5) to E10.5] or late-born (E11.5–E12.5) neurogenic waves, where late-born V3 INs display increasingly restricted subpopulation fates. Next, to better understand the consequences of V3 neurogenesis timing, we investigated the time-dependent functions of the Sim1 transcription factor, which is expressed in postmitotic V3 INs. Interestingly, Sim1 exclusively regulated the diversification of early-born, but not late-born, V3 INs. Thus, our current work indicates neurogenesis timing can modulate the functions of early postmitotic transcription factors and, thus, subpopulation fate specifications.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Environmental Light Is Required for Maintenance of Long-Term Memory in Drosophila

    Long-term memory (LTM) is stored as functional modifications of relevant neural circuits in the brain. A large body of evidence indicates that the initial establishment of such modifications through the process known as memory consolidation requires learning-dependent transcriptional activation and de novo protein synthesis. However, it remains poorly understood how the consolidated memory is maintained for a long period in the brain, despite constant turnover of molecular substrates. Using the Drosophila courtship conditioning assay of adult males as a memory paradigm, here, we show that in Drosophila, environmental light plays a critical role in LTM maintenance. LTM is impaired when flies are kept in constant darkness (DD) during the memory maintenance phase. Because light activates the brain neurons expressing the neuropeptide pigment-dispersing factor (Pdf), we examined the possible involvement of Pdf neurons in LTM maintenance. Temporal activation of Pdf neurons compensated for the DD-dependent LTM impairment, whereas temporal knockdown of Pdf during the memory maintenance phase impaired LTM in light/dark cycles. Furthermore, we demonstrated that the transcription factor cAMP response element-binding protein (CREB) is required in the memory center, namely, the mushroom bodies (MBs), for LTM maintenance, and Pdf signaling regulates light-dependent transcription via CREB. Our results demonstrate for the first time that universally available environmental light plays a critical role in LTM maintenance by activating the evolutionarily conserved memory modulator CREB in MBs via the Pdf signaling pathway.

    SIGNIFICANCE STATEMENT Temporary memory can be consolidated into long-term memory (LTM) through de novo protein synthesis and functional modifications of neuronal circuits in the brain. Once established, LTM requires continual maintenance so that it is kept for an extended period against molecular turnover and cellular reorganization that may disrupt memory traces. How is LTM maintained mechanistically? Despite the critical importance of LTM maintenance, its molecular and cellular underpinnings remain elusive. This study using Drosophila is significant because it revealed for the first time in any organism that universally available environmental light plays an essential role in LTM maintenance. Interestingly, light does so by activating the evolutionarily conserved transcription factor cAMP response element-binding protein via peptidergic signaling.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    CREB Family Transcription Factors Are Major Mediators of BDNF Transcriptional Autoregulation in Cortical Neurons

    BDNF signaling via its transmembrane receptor TrkB has an important role in neuronal survival, differentiation, and synaptic plasticity. Remarkably, BDNF is capable of modulating its own expression levels in neurons, forming a transcriptional positive feedback loop. In the current study, we have investigated this phenomenon in primary cultures of rat cortical neurons using overexpression of dominant-negative forms of several transcription factors, including CREB, ATF2, C/EBP, USF, and NFAT. We show that CREB family transcription factors, together with the coactivator CBP/p300, but not the CRTC family, are the main regulators of rat BDNF gene expression after TrkB signaling. CREB family transcription factors are required for the early induction of all the major BDNF transcripts, whereas CREB itself directly binds only to BDNF promoter IV, is phosphorylated in response to BDNF-TrkB signaling, and activates transcription from BDNF promoter IV by recruiting CBP. Our complementary reporter assays with BDNF promoter constructs indicate that the regulation of BDNF by CREB family after BDNF-TrkB signaling is generally conserved between rat and human. However, we demonstrate that a nonconserved functional cAMP-responsive element in BDNF promoter IXa in humans renders the human promoter responsive to BDNF-TrkB-CREB signaling, whereas the rat ortholog is unresponsive. Finally, we show that extensive BDNF transcriptional autoregulation, encompassing all major BDNF transcripts, occurs also in vivo in the adult rat hippocampus during BDNF-induced LTP. Collectively, these results improve the understanding of the intricate mechanism of BDNF transcriptional autoregulation.

    SIGNIFICANCE STATEMENT Deeper understanding of stimulus-specific regulation of BDNF gene expression is essential to precisely adjust BDNF levels that are dysregulated in various neurological disorders. Here, we have elucidated the molecular mechanisms behind TrkB signaling-dependent BDNF mRNA induction and show that CREB family transcription factors are the main regulators of BDNF gene expression after TrkB signaling. Our results suggest that BDNF-TrkB signaling may induce BDNF gene expression in a distinct manner compared with neuronal activity. Moreover, our data suggest the existence of a stimulus-specific distal enhancer modulating BDNF gene expression.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Actin-Binding Protein Cortactin Promotes Pathogenesis of Experimental Autoimmune Encephalomyelitis by Supporting Leukocyte Infiltration into the Central Nervous System

    Leukocyte entry into the central nervous system (CNS) is essential for immune surveillance but is also the basis for the development of pathologic inflammatory conditions within the CNS, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). The actin-binding protein, cortactin, in endothelial cells is an important player in regulating the interaction of immune cells with the vascular endothelium. Cortactin has been shown to control the integrity of the endothelial barrier and to support neutrophil transendothelial migration in vitro and in vivo in the skin. Here we use cortactin gene-inactivated male and female mice to study the role of this protein in EAE. Inducing EAE by immunization with a myelin oligodendrocyte glycoprotein peptide (MOG35–55) revealed an ameliorated disease course in cortactin gene-deficient female mice compared with WT mice. However, proliferation capacity and expression of IL-17A and IFN by cortactin-deficient and WT splenocytes did not differ, suggesting that the lack of cortactin does not affect induction of the immune response. Rather, cortactin deficiency caused decreased vascular permeability and reduced leukocyte infiltration into the brains and spinal cords of EAE mice. Accordingly, cortactin gene-deficient mice had smaller numbers of proinflammatory cuffs, less extensive demyelination, and reduced expression levels of proinflammatory cytokines within the neural tissue compared with WT littermates. Thus, cortactin contributes to the development of neural inflammation by supporting leukocyte transmigration through the blood–brain barrier and, therefore, represents a potential candidate for targeting CNS autoimmunity.

    SIGNIFICANCE STATEMENT Multiple sclerosis is an autoimmune neuroinflammatory disorder, based on the entry of inflammatory leukocytes into the CNS where these cells cause demyelination and neurodegeneration. Here, we use a mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis, and show that gene inactivation of cortactin, an actin binding protein that modulates actin dynamics and branching, protects against neuroinflammation in experimental autoimmune encephalomyelitis. Leukocyte infiltration into the CNS was inhibited in cortactin-deficient mice, and lack of cortactin in cultured primary brain endothelial cells inhibited leukocyte transmigration. Expression levels of proinflammatory cytokines in the CNS and induction of vascular permeability were reduced. We conclude that cortactin represents a novel potential target for the treatment of multiple sclerosis.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Distinct P2Y Receptors Mediate Extension and Retraction of Microglial Processes in Epileptic and Peritumoral Human Tissue

    Microglia exhibit multiple, phenotype-dependent motility patterns often triggered by purinergic stimuli. However, little data exist on motility of human microglia in pathological situations. Here we examine motility of microglia stained with a fluorescent lectin in tissue slices from female and male epileptic patients diagnosed with mesial temporal lobe epilepsy or cortical glioma (peritumoral cortex). Microglial shape varied from ramified to amoeboid cells predominantly in regions of high neuronal loss or closer to a tumor. Live imaging revealed unstimulated or purine-induced microglial motilities, including surveillance movements, membrane ruffling, and process extension or retraction. At different concentrations, ADP triggered opposing motilities. Low doses triggered process extension. It was suppressed by P2Y12 receptor antagonists, which also reduced process length and surveillance movements. Higher purine doses caused process retraction and membrane ruffling, which were blocked by joint application of P2Y1 and P2Y13 receptor antagonists. Purinergic effects on motility were similar for all microglia tested. Both amoeboid and ramified cells from mesial temporal lobe epilepsy or peritumoral cortex tissue expressed P2Y12 receptors. A minority of microglia expressed the adenosine A2A receptor, which has been linked with process withdrawal of rodent cells. Laser-mediated tissue damage let us test the functional significance of these effects. Moderate damage induced microglial process extension, which was blocked by P2Y12 receptor antagonists. Overall, the purine-induced motility of human microglia in epileptic tissue is similar to that of rodent microglia in that the P2Y12 receptor initiates process extension. It differs in that retraction is triggered by joint activation of P2Y1/P2Y13 receptors.

    SIGNIFICANCE STATEMENT Microglial cells are brain-resident immune cells with multiple functions in healthy or diseased brains. These diverse functions are associated with distinct phenotypes, including different microglial shapes. In the rodent, purinergic signaling is associated with changes in cell shape, such as process extension toward tissue damage. However, there are little data on living human microglia, especially in diseased states. We developed a reliable technique to stain microglia from epileptic and glioma patients to examine responses to purines. Low-intensity purinergic stimuli induced process extension, as in rodents. In contrast, high-intensity stimuli triggered a process withdrawal mediated by both P2Y1 and P2Y13 receptors. P2Y1/P2Y13 receptor activation has not previously been linked to microglial morphological changes.

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    Microglia and Reactive Oxygen Species Are Required for Behavioral Susceptibility to Chronic Social Defeat Stress

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    This Week in The Journal

    in Journal of Neuroscience current issue on February 12, 2020 05:30 PM.

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    An Unexpected Dependence of Cortical Depth in Shaping Neural Responsiveness and Selectivity in Mouse Visual Cortex

    Abstract

    Two-photon imaging studies in mouse primary visual cortex (V1) consistently report that around half of the neurons respond to oriented grating stimuli. However, in cats and primates, nearly all neurons respond to such stimuli. Here we show that mouse V1 responsiveness and selectivity strongly depends on neuronal depth. Moving from superficial layer 2 down to layer 4, the percentage of visually responsive neurons nearly doubled, ultimately reaching levels similar to what is seen in other species. Over this span, the amplitude of neuronal responses also doubled. Moreover, stimulus selectivity was also modulated, not only with depth but also with response amplitude. Specifically, we found that orientation and direction selectivity were greater in stronger responding neurons, but orientation selectivity decreased with depth whereas direction selectivity increased. Importantly, these depth-dependent trends were found not just between layer 2/3 and layer four but at different depths within layer 2/3 itself. Thus, neuronal depth is an important factor to consider when pooling neurons for population analyses. Furthermore, the inability to drive the majority of cells in superficial layer 2/3 of mouse V1 with grating stimuli indicates that there may be fundamental differences in the micro-circuitry and role of V1 between rodents and other mammals.

    Significance Statement Studies frequently pool responses of neurons from different cortical depths in population analyses. Here we show that population neuronal response characteristics in mouse primary visual cortex vary dramatically across depth planes separated by just 50 μm. We also demonstrate that the stimulus selectivity of neuronal responses varies with both cortical depth and the response amplitude of neurons. These findings highlight the importance of considering cell depth and response amplitude as important factors contributing to the overall characteristics of neurons in sensory cortex.

    in RSS PAP on February 12, 2020 05:30 PM.

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    Synergistic information in a dynamical model implemented on the human structural connectome reveals spatially distinct associations with age. (arXiv:2002.04527v1 [q-bio.NC])

    We implement the dynamical Ising model on the large scale architecture of white matter connections of healthy subjects in the age range 4-85 years, and analyze the dynamics in terms of the synergy, a quantity measuring the extent to which the joint state of pairs of variables is projected onto the dynamics of a target one. We find that the amount of synergy in explaining the dynamics of the hubs of the structural connectivity (in terms of degree strength) peaks before the critical temperature, and can thus be considered as a precursor of a critical transition. Conversely the greatest amount of synergy goes into explaining the dynamics of more central nodes. We also find that the aging of the structural connectivity is associated to significant changes in the simulated dynamics: there are brain regions whose synergy decreases with age, in particular the frontal pole, the Subcallosal area and the Supplementary Motor area; these areas could then be more likely to show a decline in terms of the capability to perform higher order computation (if structural connectivity was the sole variable). On the other hand, several regions in the temporal cortex show a positive correlation with age in the first 30 years of life, i.e. during brain maturation.

    in q-bio.NC updates on arXiv.org on February 12, 2020 01:30 AM.

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    Some interesting observations on the free energy principle. (arXiv:2002.04501v1 [q-bio.NC])

    Biehl et al (2020) present some interesting observations on an early formulation of the free energy principle in (Friston, 2013). We use these observations to scaffold a discussion of the technical arguments that underwrite the free energy principle. This discussion focuses on solenoidal coupling between various (subsets of) states in sparsely coupled systems that possess a Markov blanket - and the distinction between exact and approximate Bayesian inference, implied by the ensuing Bayesian mechanics.

    in q-bio.NC updates on arXiv.org on February 12, 2020 01:30 AM.

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    A unifying framework for mean field theories of asymmetric kinetic Ising systems. (arXiv:2002.04309v1 [cond-mat.dis-nn])

    Kinetic Ising models are powerful tools for studying the non-equilibrium dynamics of complex discrete systems and analyzing their experimental recordings. However, the behaviour of the model is in general not tractable for large networks; therefore, mean field theories are frequently used to approximate its statistical properties. Many variants of the classical naive and TAP (i.e., second-order) mean field approximations have been proposed, each of which makes unique assumptions about time evolution of the system's correlation structure. This disparity of methods makes it difficult to systematically advance the mean field approach over previous contributions. Here, we propose a unified framework for mean field theories of the dynamics of asymmetric kinetic Ising systems based on information geometry. The framework is built on Plefka expansions of the model around a simplified model obtained by an orthogonal projection to a sub-manifold of tractable probability distributions. This approach not only unifies previous methods but allows us to define novel methods that, in contrast with traditional mean-field approaches, preserve correlations of the system, both in stationary and transient states. By comparing analytical approximations and exact numerical simulations, we show that the proposed methods provide more accurate estimates for the evolution of equal-time and delayed covariance structures than classical equations, and consequently outperform previous mean field theories for solving the inverse Ising problem. In sum, our framework unifies and extends current mean-field approximations of kinetic Ising model, constituting a powerful tool for studying non-equilibrium dynamics of complex systems.

    in q-bio.NC updates on arXiv.org on February 12, 2020 01:30 AM.

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    Early Effects of Aβ Oligomers on Dendritic Spine Dynamics and Arborization in Hippocampal Neurons

    Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to impaired memory and cognitive deficits. Spine loss as well as changes in spine morphology correlates with cognitive impairment in this neurological disorder. Many studies in animal models and ex vivo cultures indicate that amyloid β-peptide (Aβ) oligomers induce synaptic damage early during the progression of the disease. Here, in order to determine the events that initiate synaptic alterations, we acutely applied oligomeric Aβ to primary hippocampal neurons and an ex vivo model of organotypic hippocampal cultures from a mouse after targeted expression of EGFP to allow high-resolution imaging and algorithm-based evaluation of spine changes. Dendritic spines were classified as thin, stubby or mushroom, based on morphology. In vivo, time-lapse imaging showed that the three spine types were relatively stable, although their stability significantly decreased after treatment with Aβ oligomers. Unexpectedly, we observed that the density of total dendritic spines increased in organotypic hippocampal slices treated with Aβ compared to control cultures. Specifically, the fraction of stubby spines significantly increased, while mushroom and thin spines remained unaltered. Pharmacological tools revealed that acute Aβ oligomers induced spine changes through mechanisms involving CaMKII and integrin β1 activities. Additionally, analysis of dendritic complexity based on a 3D reconstruction of the whole neuron morphology showed an increase in the apical dendrite length and branching points in CA1 organotypic hippocampal slices treated with Aβ. In contrast to spines, the morphological changes were affected by integrin β1 but not by CaMKII inhibition. Altogether, these data indicate that the Aβ oligomers exhibit early dual effects by acutely enhancing dendritic complexity and spine density.

    in Frontiers in Synaptic Neuroscience | New and Recent Articles on February 12, 2020 12:00 AM.

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    Reduction of Silent Information Regulator 1 Activates Interleukin-33/ST2 Signaling and Contributes to Neuropathic Pain Induced by Spared Nerve Injury in Rats

    Emerging studies have demonstrated that interleukin (IL)-33 and its receptor ST2 act as key factors in inflammatory diseases. Moreover, accumulating evidence has suggested that cytokines, including tumor necrosis factor (TNF)-α and IL-1β, trigger an inflammatory cascade. SIRT1 has been shown to suppress the expression of inflammatory cytokines. However, the effects of SIRT1 on IL-33/ST2 signaling and initiation of the inflammatory cascade via modulation of TNF-α and IL-1β by IL-33 remain unclear. In the present study, we found that the dorsal root ganglion (DRG) IL-33 and ST2 were upregulated in a rat model of spared nerve injury (SNI) and intrathecal injection of either IL-33 or ST2 antibodies alleviated mechanical allodynia and downregulated TNF-α and IL-1β induced by SNI. In addition, activation of SIRT1 decreased enhanced DRG IL-33/ST2 signaling in SNI rats. Artificial inactivation of SIRT1 via intrathecal injection of an SIRT1 antagonist could induce mechanical allodynia and upregulate IL-33 and ST2. These results demonstrated that reduction in SIRT1 could induce upregulation of DRG IL-33 and ST2 and contribute to mechanical allodynia induced by SNI in rats.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 12, 2020 12:00 AM.

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    Atypical Social Attention and Emotional Face Processing in Autism Spectrum Disorder: Insights From Face Scanning and Pupillometry

    Social attention deficits are a hallmark characteristic within autism spectrum disorder (ASD) and have been hypothesized to have cascading effects on emotion recognition. Eye-tracking methodology has emerged as a potentially reliable, feasible, and sensitive biomarker for examining core phenotypic features of ASD; however, these findings are mixed with regards to measuring treatment change in clinical trials. The present study aimed to assess the utility of an eye-tracking paradigm to discriminate between clinical groups in social attention and emotion recognition through face scanning and pupillometry. The present study also assessed the reliability of this paradigm within the ASD sample to further our understanding of the utility of eye-tracking for future clinical trials. Participants included 42 individuals with ASD, 29 developmental disability (DD) controls, and 62 typically developing (TD) controls between 3 and 25 years of age. An emotional faces eye-tracking paradigm was administered to all participants, with the ASD group completing the paradigm a second time approximately 2 months later. Participants’ average proportion of looking and number of fixations to specific areas of interest (AOI) were examined along with changes in pupil reactivity while viewing different emotional faces. Results suggest atypical face-scanning through a reduced proportion of looking and the number of fixations toward the eyes in the ASD group regardless of the emotion that was presented. Further, pupillometry measures were able to detect increases in pupil dilation to happy faces in the ASD group. Lastly, test-retest reliability coefficients varied between the poor and excellent range based on the mechanism assessed, with the proportion of looking demonstrating the highest reliability coefficients. These findings build on the promise of eye-tracking as a feasible and reliable biomarker for identifying social attention and emotion recognition deficits in ASD. Detecting differences in emotion recognition explicitly through facial scanning was not as clear. Specific mechanisms within the eye-tracking paradigm may be viable options for assessing treatment-specific outcomes.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on February 12, 2020 12:00 AM.

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    Fiber Connectivity Density in Cerebral Small-Vessel Disease Patients With Mild Cognitive Impairment and Cerebral Small-Vessel Disease Patients With Normal Cognition

    Abnormal structural connectivity of cerebral small-vessel disease (CSVD) is associated with cognitive impairment. But the different characteristics of structural connectivity have not been elucidated in early CSVD patients. The current study aimed to investigate the potential differences of structural connectivity in CSVD patients with mild cognitive impairment (MCI) and CSVD patients with normal cognition. Twenty-two CSVD patients with MCI, 34 CSVD patients with normal cognition, and 35 controls, who were age, sex, and education matched underwent diffusion tensor imaging and high resolution T1-weighted imaging. Clinical characteristics, lacunar infarct volume, white matter hyperintensity (WMH) volume, and global atrophy were quantitatively evaluated. Maps of fiber connectivity density (FiCD) were constructed and compared across groups in vertex levels. Pearson correlation was used to estimate the imaging–clinical relationships with control of general characteristics. CSVD patients with MCI had higher lesion load of WMH and lacunar infarcts, and correspondingly lower global FiCD value than CSVD patients with normal cognition (P < 0.01). Lacunar infarct (r = −0.318, P < 0.01) and WMH (r = −0.400, P < 0.01), but not global atrophy, age, or sex, were significantly correlated with the global FiCD value. CSVD patients with normal cognition showed decreased FiCD value mainly in the prefrontal areas (P < 0.01 with Monte Carlo correction). Compared with CSVD patients with normal cognition, CSVD patients with MCI showed significantly decreased FiCD value in enlarged frontal and parietal areas (P < 0.01 with Monte Carlo correction). Inter-group comparisons showed regional enhanced impairment of connectivity density in CSVD patients with MCI in the left superior frontal gyrus, the left precuneus, and the orbital part of the right inferior frontal gyrus (P < 0.01 with Monte Carlo correction). Regional FiCD value of frontal and parietal areas was associated with the cognitive function (P < 0.01). In conclusion, cognitively normal CSVD patients already have disruptions of structural connectivity. The extent and intensity of connectivity disruptions in frontal and parietal areas may underlie the mechanism of cognitive impairment in CSVD. Fiber connectivity density measurements may be helpful for quantitative description of structural cortical connectivity.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 12, 2020 12:00 AM.

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    Hypernetwork Construction and Feature Fusion Analysis Based on Sparse Group Lasso Method on Functional fMRI Dataset

    Recent works have shown that the resting-state brain functional connectivity hypernetwork, where multiple nodes can be connected, are an effective technique for brain disease diagnosis and classification research. The lasso method was used to construct hypernetworks by solving sparse linear regression models in previous research. But, constructing a hypernetwork based on the lasso method simply selects a single variable, in that it lacks the ability to interpret the grouping effect. Considering the group structure problem, the previous study proposed to create a hypernetwork based on the elastic net and the group lasso methods, and the results showed that the former method had the best classification performance. However, the highly correlated variables selected by the elastic net method were not necessarily in the active set in the group. Therefore, we extended our research to address this issue. Herein, we propose a new method that introduces the sparse group lasso method to improve the construction of the hypernetwork by solving the group structure problem of the brain regions. We used the traditional lasso, group lasso method, and sparse group lasso method to construct a hypernetwork in patients with depression and normal subjects. Meanwhile, other clustering coefficients (clustering coefficients based on pairs of nodes) were also introduced to extract features with traditional clustering coefficients. Two types of features with significant differences obtained after feature selection were subjected to multi-kernel learning for feature fusion and classification using each method, respectively. The network topology results revealed differences among the three networks, where hypernetwork using the lasso method was the strictest; the group lasso, most lenient; and the sgLasso method, moderate. The network topology of the sparse group lasso method was similar to that of the group lasso method but different from the lasso method. The classification results show that the sparse group lasso method achieves the best classification accuracy by using multi-kernel learning, which indicates that better classification performance can be achieved when the group structure exists and is properly extended.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on February 12, 2020 12:00 AM.

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    Editorial: Nanotechnologies in Neuroscience and Neuroengineering

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on February 12, 2020 12:00 AM.

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    Pre-frontal Cortex Oxygenation Changes During Aerobic Exercise in Elite Athletes Experiencing Sport-Related Concussion

    Aims: Recent research suggests that aerobic exercise can be performed safely within the first week following a concussion injury and that early initiation of exercise may speed recovery. To better understand the physiological changes during a concussion, we tested the hypothesis that mild-to-intense exercise testing can be performed within days immediately following injury, and can be used to discern differences between the concussed and normal healthy state. Thus, the purpose was to observe the cerebral hemodynamic responses to incremental exercise testing performed acutely post-concussion in high-performance athletes.

    Methods: This study was a within- and between-experimental design, with seven male university ice hockey teams participating. A subgroup of five players acted as control subjects (CON) and was tested at the same time as the 14 concussed (mTBI) players on Day 2, 4, and 7 post-concussion. A 5-min resting baseline and 5-min exercise bouts of mild (EX1), moderate (EX2), and high (EX3) intensity exercise were performed on a cycle ergometer. Near-infrared spectroscopy was used to monitor pre-frontal cortex oxy-haemoglobin (HbO2), deoxy-haemoglobin (HHb), and total blood volume (tHb) changes.

    Results: ANOVA compared differences between testing days and groups, and although large percentage changes in HbO2 (20–30%), HHb (30–40%), and tHb (30–40%) were recorded, no significant (p ≤ 0.05) differences in cerebral hemodynamics occurred between mTBI vs. CON during aerobic exercise testing on any day post-injury. Furthermore, there was a linear relationship between exercise intensity vs. cerebral hemodynamics during testing for each day (r2 = 0.83–0.99).

    Conclusion: These results demonstrate two novel findings: (1) mild-to-intense aerobic exercise testing can be performed safely as early as Day 2 post-concussion injury in a controlled laboratory environment; and (2) evidence-based objective measures such as cerebral hemodynamics can easily be collected using near-infrared spectroscopy (NIRS) to monitor physiological changes during the first-week post-injury. This research has important implications for monitoring physiological recovery post-injury and establishing new rehabilitation guidelines.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 12, 2020 12:00 AM.

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    A Layered Control Architecture of Sleep and Arousal

    Sleep and wakefulness are promoted not by a single neural pathway but via wake or sleep-promoting nodes distributed across layers of the brain. We equate each layer with a brain region in proposing a layered subsumption model for arousal based on a computational architecture. Beyond the brainstem the layers include the diencephalon (hypothalamus, thalamus), basal ganglia, and cortex. In light of existing empirical evidence, we propose that each layer have sleep and wake computations driven by similar high-level architecture and processing units. Specifically, an interconnected wake-promoting system is suggested as driving arousal in each brain layer with the processing converging to produce the features of wakefulness. In contrast, sleep-promoting GABAergic neurons largely project to and inhibit wake-promoting neurons. We propose a general pattern of caudal wake-promoting and sleep-promoting neurons having a strong effect on overall behavior. However, while rostral brain layers have less influence on sleep and wake, through descending projections, they can subsume the activity of caudal brain layers to promote arousal. The two models presented in this work will suggest computations for the layering and hierarchy. Through dynamic system theory several hypotheses are introduced for the interaction of controllers and systems that correspond to the different populations of neurons at each layer. The models will be drawn-upon to discuss future experiments to elucidate the structure of the hierarchy that exists among the sleep-arousal architecture.

    in Frontiers in Computational Neuroscience | New and Recent Articles on February 12, 2020 12:00 AM.

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    Dose-Dependent Microglial and Astrocytic Responses Associated With Post-ischemic Neuroprotection After Lipopolysaccharide-Induced Sepsis-Like State in Mice

    In contrast to lipopolysaccharide (LPS)-induced preconditioning, which has repeatedly been examined in the past, the effects of post-ischemic LPS-induced sepsis, although clinically considerably more important, have not systemically been studied. We exposed mice to transient intraluminal middle cerebral artery occlusion (MCAO) and examined the effects of intraperitoneal LPS (0.1 or 1 mg/kg) which was administered 24 h post-ischemia. Post-ischemic glial reactivity, neuronal survival and neurological outcome were differently modulated by the higher and the lower LPS dose. Although both doses promoted neuronal survival after 72 h, the underlying mechanisms were not similar. Mice receiving 1 mg/kg LPS exhibited transient hypothermia at 1 and 3 hours post sepsis (hps), followed by reduced focal neurological deficits at 24, 48 and 72 hps. The lower dose (0.1 mg/kg) did not induce hypothermia, but reduced microglia/macrophage activation with the appearance of an anti-inflammatory CD206 positive cell phenotype in the brain parenchyma. Together, our results indicate a novel, dose-dependent modulation of microglial cells that is intricately involved in brain protection.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 12, 2020 12:00 AM.

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    Identifying the pulsed neuron networks’ structures by a nonlinear Granger causality method

    It is a crucial task of brain science researches to explore functional connective maps of Biological Neural Networks (BNN). The maps help to deeply study the dominant relationship between the structures of the...

    in Most Recent Articles: BMC Neuroscience on February 12, 2020 12:00 AM.

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    Leveraging effect size distributions to improve polygenic risk scores derived from summary statistics of genome-wide association studies

    by Shuang Song, Wei Jiang, Lin Hou, Hongyu Zhao

    Genetic risk prediction is an important problem in human genetics, and accurate prediction can facilitate disease prevention and treatment. Calculating polygenic risk score (PRS) has become widely used due to its simplicity and effectiveness, where only summary statistics from genome-wide association studies are needed in the standard method. Recently, several methods have been proposed to improve standard PRS by utilizing external information, such as linkage disequilibrium and functional annotations. In this paper, we introduce EB-PRS, a novel method that leverages information for effect sizes across all the markers to improve prediction accuracy. Compared to most existing genetic risk prediction methods, our method does not need to tune parameters nor external information. Real data applications on six diseases, including asthma, breast cancer, celiac disease, Crohn’s disease, Parkinson’s disease and type 2 diabetes show that EB-PRS achieved 307.1%, 42.8%, 25.5%, 3.1%, 74.3% and 49.6% relative improvements in terms of predictive r2 over standard PRS method with optimally tuned parameters. Besides, compared to LDpred that makes use of LD information, EB-PRS also achieved 37.9%, 33.6%, 8.6%, 36.2%, 40.6% and 10.8% relative improvements. We note that our method is not the first method leveraging effect size distributions. Here we first justify our method by presenting theoretical optimal property over existing methods in this class of methods, and substantiate our theoretical result with extensive simulation results. The R-package EBPRS that implements our method is available on CRAN.

    in PLOS Computational Biology: New Articles on February 11, 2020 10:00 PM.

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    LRIT3 is Required for Nyctalopin Expression and Normal ON and OFF Pathway Signaling in the Retina

    Abstract

    The first retinal synapse, photoreceptor->bipolar cell (BC), is both anatomically and functionally complex. Within the same synaptic region, a change in presynaptic glutamate release is sensed by both ON BCs (DBCs) via the metabotropic glutamate receptor 6 (mGluR6), and OFF BCs (HBCs) via ionotropic glutamate receptors to establish parallel signaling pathways that preferentially encode light increments (ON) or decrements (OFF), respectively. The synaptic structural organization of ON and OFF-type BCs at the photoreceptor terminal differs. DBCs make an invaginating synapse that contains a diverse but incompletely understood complex of interacting proteins (signalplex). HBCs make primarily flat contacts that contain an apparent different set of proteins that is equally uncharacterized. LRIT3 is a synaptic protein known to be essential for ON pathway visual function. In both male and female mice, we demonstrate that LRIT3 interacts with and is required for expression of nyctalopin, and thus TRPM1 at all DBC dendritic tips, but DBC signalplex components are not required for LRIT3 expression. Using whole-cell and multielectrode array (MEA) electrophysiology and glutamate imaging, we demonstrate that the loss of LRIT3 impacts both ON and OFF signaling pathway function. Without LRIT3, excitatory input to type 1 BCs is reduced, as are the visually evoked responses of many OFF retinal ganglion cells (RGCs). We conclude that the absence of LRIT3 expression disrupts excitatory input to OFF BCs and, thus disrupts the normal function of OFF RGCs.

    in eNeuro current issue on February 11, 2020 05:30 PM.

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    A how-to-model guide for Neuroscience

    Abstract

    Within neuroscience, models have many roles, including driving hypotheses, making assumptions explicit, synthesizing knowledge, making experimental predictions, and facilitating applications to medicine. While specific modeling techniques are often taught, the process of constructing models for a given phenomenon or question is generally left opaque. Here, informed by guiding many students through modeling exercises at our CoSMo summer school we provide a practical ten step breakdown of the modeling process. This approach makes choices and criteria more explicit and replicable. Experiment design has long been taught in neuroscience; the modeling process should receive the same attention.

    Significance Modeling in Neuroscience is often perceived as a mysterious process and is hard to teach. Here we provide the first how-to-model guide that breaks down the modeling endeavor into a step-by-step process.

    in RSS PAP on February 11, 2020 05:30 PM.

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    Pericyte-mediated tissue repair through PDGFR{beta} promotes peri-infarct astrogliosis, oligodendrogenesis and functional recovery after acute ischemic stroke

    Abstract

    Post-stroke functional recovery can occur spontaneously during the subacute phase; however, how post-stroke fibrotic repair affects functional recovery is highly debated. Platelet derived growth factor receptor beta (PDGFRβ)-expressing pericytes are responsible for post-stroke fibrotic repair within infarct areas; therefore, we examined peri-infarct neural reorganization and functional recovery after permanent middle cerebral artery occlusion (pMCAO) using pericyte-deficient Pdgfrb+/– mice. Time-dependent reduction of infarct area sizes, i.e. repair, was significantly impaired in Pdgfrb+/– mice with recovery of cerebral blood flow in ischemic areas attenuated by defective leptomeningeal arteriogenesis and intra-infarct angiogenesis. Peri-infarct astrogliosis, accompanied by increased STAT3 phosphorylation, was attenuated in Pdgfrb+/– mice. Pericyte-conditioned medium (PCM), particularly when treated with platelet derived growth factor subunit B (PDGFB) homodimer (PDGF-BB) (PCM/PDGF-BB), activated STAT3 and enhanced the proliferation and activity of cultured astrocytes. Although peri-infarct proliferation of oligodendrocyte precursor cells (OPCs) was induced promptly after pMCAO regardless of intra-infarct repair, OPC differentiation and remyelination were significantly attenuated in Pdgfrb+/– mice. Consistently, astrocyte-conditioned medium promoted OPC differentiation and myelination, which were enhanced remarkably by adding PCM/PDGF-BB to the medium. Post-stroke functional recovery correlated well with the extent and process of intra-infarct repair and peri-infarct oligodendrogenesis. Overall, pericyte-mediated intra-infarct fibrotic repair through PDGFRβ may promote functional recovery through enhancement of peri-infarct oligodendrogenesis as well as astrogliosis after acute ischemic stroke.

    Significance Statement Pericyte-mediated fibrotic tissue repair is a major histological change within the infarct area during the subacute phase after ischemic stroke. Whether fibrotic repair is beneficial or detrimental to post-stroke functional recovery is highly debated. Here we demonstrate that inhibition of fibrotic repair in mice by heterozygous deletion of PDGFRβ (Pdgfrb+/–) significantly attenuates functional recovery after ischemic stroke. Pericyte-derived PDGFRβ-positive cells within the infarct area produced trophic factors that activated astrocytes, thereby enhancing peri-infarct astrogliosis. Furthermore, astrocytes, conditioned with PDGF-BB-stimulated pericyte culture medium, promoted oligodendrocyte differentiation and a myelinating response. Peri-infarct oligodendrogenesis and re-myelination within areas of astrogliosis was significantly attenuated in Pdgfrb+/– mice. Pericyte-mediated tissue repair is beneficial for post-stroke functional recovery and is a potential therapeutic target.

    in RSS PAP on February 11, 2020 05:29 PM.

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    Correction for Brutsaert et al., Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude [Correction]

    ANTHROPOLOGY Correction for “Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude,” by Tom D. Brutsaert, Melisa Kiyamu, Gianpietro Elias Revollendo, Jenna L. Isherwood, Frank S. Lee, Maria Rivera-Ch, Fabiola Leon-Velarde, Sudipta Ghosh, and Abigail W. Bigham, which was first published November 11, 2019; 10.1073/pnas.1906171116...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Correction for Hammond et al., Insights into the lower torso in late Miocene hominoid Oreopithecus bambolii [Correction]

    ANTHROPOLOGY Correction for “Insights into the lower torso in late Miocene hominoid Oreopithecus bambolii,” by Ashley S. Hammond, Lorenzo Rook, Alisha D. Anaya, Elisabetta Cioppi, Loïc Costeur, Salvador Moyà-Solà, and Sergio Almécija, which was first published December 23, 2019; 10.1073/pnas.1911896116 (Proc. Natl. Acad. Sci. U.S.A. 117, 278–284). The editors note...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Correction for Yu et al., Wildfire prevention through prophylactic treatment of high-risk landscapes using viscoelastic retardant fluids [Correction]

    APPLIED PHYSICAL SCIENCES Correction for “Wildfire prevention through prophylactic treatment of high-risk landscapes using viscoelastic retardant fluids,” by Anthony C. Yu, Hector Lopez Hernandez, Andrew H. Kim, Lyndsay M. Stapleton, Reuben J. Brand, Eric T. Mellor, Cameron P. Bauer, Gregory D. McCurdy, Albert J. Wolff III, Doreen Chan, Craig S....

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression [Systems Biology]

    Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Designing effective control of dengue with combined interventions [Systems Biology]

    Viruses transmitted by Aedes mosquitoes, such as dengue, Zika, and chikungunya, have expanding ranges and seem unabated by current vector control programs. Effective control of these pathogens likely requires integrated approaches. We evaluated dengue management options in an endemic setting that combine novel vector control and vaccination using an agent-based...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Reassessing enzyme kinetics: Considering protease-as-substrate interactions in proteolytic networks [Systems Biology]

    Enzymes are catalysts in biochemical reactions that, by definition, increase rates of reactions without being altered or destroyed. However, when that enzyme is a protease, a subclass of enzymes that hydrolyze other proteins, and that protease is in a multiprotease system, protease-as-substrate dynamics must be included, challenging assumptions of enzyme...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Genome-scale transcriptional dynamics and environmental biosensing [Systems Biology]

    Genome-scale technologies have enabled mapping of the complex molecular networks that govern cellular behavior. An emerging theme in the analyses of these networks is that cells use many layers of regulatory feedback to constantly assess and precisely react to their environment. The importance of complex feedback in controlling the real-time...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Uncertainty in learning, choice, and visual fixation [Psychological and Cognitive Sciences]

    Uncertainty plays a critical role in reinforcement learning and decision making. However, exactly how it influences behavior remains unclear. Multiarmed-bandit tasks offer an ideal test bed, since computational tools such as approximate Kalman filters can closely characterize the interplay between trial-by-trial values, uncertainty, learning, and choice. To gain additional insight...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    ARABIDOPSIS DEHISCENCE ZONE POLYGALACTURONASE 1 (ADPG1) releases latent defense signals in stems with reduced lignin content [Plant Biology]

    There is considerable interest in engineering plant cell wall components, particularly lignin, to improve forage quality and biomass properties for processing to fuels and bioproducts. However, modifying lignin content and/or composition in transgenic plants through down-regulation of lignin biosynthetic enzymes can induce expression of defense response genes in the absence...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Mapping proteome-wide targets of protein kinases in plant stress responses [Plant Biology]

    Protein kinases are major regulatory components in almost all cellular processes in eukaryotic cells. By adding phosphate groups, protein kinases regulate the activity, localization, protein–protein interactions, and other features of their target proteins. It is known that protein kinases are central components in plant responses to environmental stresses such as...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Central clock components modulate plant shade avoidance by directly repressing transcriptional activation activity of PIF proteins [Plant Biology]

    Light-environment signals, sensed by plant phytochrome photoreceptors, are transduced to target genes through direct regulation of PHYTOCHROME-INTERACTING FACTOR (PIF) transcription factor abundance and activity. Previous genome-wide DNA-binding and expression analysis has identified a set of genes that are direct targets of PIF transcriptional regulation. However, quantitative analysis of promoter occupancy...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Removing a single neuron in a vertebrate brain forever abolishes an essential behavior [Neuroscience]

    The giant Mauthner (M) cell is the largest neuron known in the vertebrate brain. It has enabled major breakthroughs in neuroscience but its ultimate function remains surprisingly unclear: An actual survival value of M cell-mediated escapes has never been supported experimentally and ablating the cell repeatedly failed to eliminate all...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Conservative and disruptive modes of adolescent change in human brain functional connectivity [Neuroscience]

    Adolescent changes in human brain function are not entirely understood. Here, we used multiecho functional MRI (fMRI) to measure developmental change in functional connectivity (FC) of resting-state oscillations between pairs of 330 cortical regions and 16 subcortical regions in 298 healthy adolescents scanned 520 times. Participants were aged 14 to...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Serotonergic afferents from the dorsal raphe decrease the excitability of pyramidal neurons in the anterior piriform cortex [Neuroscience]

    The olfactory system receives extensive serotonergic inputs from the dorsal raphe, a nucleus involved in control of behavior, regulation of mood, and modulation of sensory processing. Although many studies have investigated how serotonin modulates the olfactory bulb, few have focused on the anterior piriform cortex (aPC), a region important for...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Simple spike dynamics of Purkinje cells in the macaque vestibulo-cerebellum during passive whole-body self-motion [Neuroscience]

    Theories of cerebellar functions posit that the cerebellum implements internal models for online correction of motor actions and sensory estimation. As an example of such computations, an internal model resolves a sensory ambiguity where the peripheral otolith organs in the inner ear sense both head tilts and translations. Here we...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    A qualitative solution with quantitative potential for the mouse hippocampal cortex flatmap problem [Neuroscience]

    The hippocampal formation (HPF) is a focus of intense experimental investigation, particularly because of its roles in conscious memory consolidation, spatial navigation, emotion, and motivated behaviors. However, the HPF has a complex three-dimensional geometry resulting from extreme curvature of its layers, and this presents a challenge for investigators seeking to...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    SYNPLA, a method to identify synapses displaying plasticity after learning [Neuroscience]

    Which neural circuits undergo synaptic changes when an animal learns? Although it is widely accepted that changes in synaptic strength underlie many forms of learning and memory, it remains challenging to connect changes in synaptic strength at specific neural pathways to specific behaviors and memories. Here we introduce SYNPLA (synaptic...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Transformation of speech sequences in human sensorimotor circuits [Psychological and Cognitive Sciences]

    After we listen to a series of words, we can silently replay them in our mind. Does this mental replay involve a reactivation of our original perceptual dynamics? We recorded electrocorticographic (ECoG) activity across the lateral cerebral cortex as people heard and then mentally rehearsed spoken sentences. For each region,...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons [Neuroscience]

    The binding of GABA (γ-aminobutyric acid) to extrasynaptic GABAA receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes according to...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Antibiotic resistance by high-level intrinsic suppression of a frameshift mutation in an essential gene [Microbiology]

    A fundamental feature of life is that ribosomes read the genetic code in messenger RNA (mRNA) as triplets of nucleotides in a single reading frame. Mutations that shift the reading frame generally cause gene inactivation and in essential genes cause loss of viability. Here we report and characterize a +1-nt...

    in Proceedings of the National Academy of Sciences Recent Issues on February 11, 2020 05:21 PM.

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    Human Creativity and Consciousness: Unintended Consequences of the Brain's Extraordinary Energy Efficiency?. (arXiv:2002.03738v1 [q-bio.NC])

    It is proposed that both human creativity and human consciousness are (unintended) consequences of the human brain's extraordinary energy efficiency. The topics of creativity and consciousness are treated separately, though have a common sub-structure. It is argued that creativity arises from a synergy between two cognitive modes of the human brain (which broadly coincide with Kahneman's Systems 1 and 2). In the first, available energy is spread across a relatively large network of neurons. As such, the amount of energy per active neuron is so small that the operation of such neurons is susceptible to thermal (ultimately quantum decoherent) noise. In the second, available energy is focussed on a small enough subset of neurons to guarantee a deterministic operation. An illustration of how this synergy can lead to creativity with implications for computing in silicon are discussed. Starting with a discussion of the concept of free will, the notion of consciousness is defined in terms of an awareness of what are perceived to be nearby counterfactual worlds in state space. It is argued that such awareness arises from an interplay between our memories on the one hand, and quantum physical mechanisms (where, unlike in classical physics, nearby counterfactual worlds play an indispensable dynamical role) in the ion channels of neural networks. As with the brain's susceptibility to noise, it is argued that in situations where quantum physics plays a role in the brain, it does so for reasons of energy efficiency. As an illustration of this definition of consciousness, a novel proposal is outlined as to why quantum entanglement appears so counter-intuitive.

    in q-bio.NC updates on arXiv.org on February 11, 2020 01:30 AM.

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    A Spike in Performance: Training Hybrid-Spiking Neural Networks with Quantized Activation Functions. (arXiv:2002.03553v1 [cs.LG])

    The machine learning community has become increasingly interested in the energy efficiency of neural networks. The Spiking Neural Network (SNN) is a promising approach to energy-efficient computing, since its activation levels are quantized into temporally sparse, one-bit values (i.e., "spike" events), which additionally converts the sum over weight-activity products into a simple addition of weights (one weight for each spike). However, the goal of maintaining state-of-the-art (SotA) accuracy when converting a non-spiking network into an SNN has remained an elusive challenge, primarily due to spikes having only a single bit of precision. Adopting tools from signal processing, we cast neural activation functions as quantizers with temporally-diffused error, and then train networks while smoothly interpolating between the non-spiking and spiking regimes. We apply this technique to the Legendre Memory Unit (LMU) to obtain the first known example of a hybrid SNN outperforming SotA recurrent architectures---including the LSTM, GRU, and NRU---in accuracy, while reducing activities to at most 3.74 bits on average with 1.26 significant bits multiplying each weight. We discuss how these methods can significantly improve the energy efficiency of neural networks.

    in q-bio.NC updates on arXiv.org on February 11, 2020 01:30 AM.

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    Oriented Matroids and Combinatorial Neural Codes. (arXiv:2002.03542v1 [math.CO])

    A combinatorial neural code $\mathscr C\subseteq 2^{[n]}$ is convex if it arises as the intersection pattern of convex open subsets of $\mathbb R^d$. We relate the emerging theory of convex neural codes to the established theory of oriented matroids, both categorically and with respect to geometry and computational complexity. On the categorical side, we show that the map taking an acyclic oriented matroid to the code of positive parts of its topes is a faithful functor. We adapt the oriented matroid ideal introduced by Novik, Postnikov, and Sturmfels into a functor from the category of oriented matroids to the category of rings; then, we show that the resulting ring maps naturally to the neural ring of the matroid's neural code.

    For geometry and computational complexity, we show that a code has a realization with convex polytopes if and only if it lies below the code of a representable oriented matroid in the partial order of codes introduced by Jeffs. We show that previously published examples of non-convex codes do not lie below any oriented matroids, and we construct examples of non-convex codes lying below non-representable oriented matroids. By way of this construction, we can apply Mn\"{e}v-Sturmfels universality to show that deciding whether a combinatorial code is convex is NP-hard.

    in q-bio.NC updates on arXiv.org on February 11, 2020 01:30 AM.

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    A wave-pulse neural network for quasi-quantum coding. (arXiv:2002.03540v1 [q-bio.NC])

    We design a physical wave-pulse neural network (WPNN) for both wave and pulse propagation, which gives more degrees of freedom for neural coding than spike neural networks (SNN). We define the rules and the information entropy of this kind of neural network, where the signal speed, arrival time, and the length of connections between neurons all become crucial parameters for signal coding. We call it quasi-quantum coding (QQC) since the combination of wave and pulse signals here behaves like a classical mimic of quantum wave-particle duality, and can be studied by borrowing some concepts form quantum mechanics. We present that the quasi-quantum coding can give efficient methods for both sound and image recognitions. We also discuss the possibility of the wave-pulse neural network and the quasi-quantum coding methods running on it in biological brains where both neural oscillations and action potentials are important to cognition.

    in q-bio.NC updates on arXiv.org on February 11, 2020 01:30 AM.

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    Mapping low-dimensional dynamics to high-dimensional neural activity: A derivation of the ring model from the neural engineering framework. (arXiv:2002.03420v1 [q-bio.NC])

    Empirical estimates of the dimensionality of neural population activity are often much lower than the population size. Similar phenomena are also observed in trained and designed neural network models. These experimental and computational results suggest that mapping low-dimensional dynamics to high-dimensional neural space is a common feature of cortical computation. Despite the ubiquity of this observation, the constraints arising from such mapping are poorly understood. Here we consider a specific example of mapping low-dimensional dynamics to high-dimensional neural activity -- the neural engineering framework. We analytically solve the framework for the classic ring model -- a neural network encoding a static or dynamic angular variable. Our results provide a complete characterization of the success and failure modes for this model. Based on similarities between this and other frameworks, we speculate that these results could apply to more general scenarios.

    in q-bio.NC updates on arXiv.org on February 11, 2020 01:30 AM.

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    Appreciating the variety of goals in computational neuroscience. (arXiv:2002.03211v1 [q-bio.NC])

    Within computational neuroscience, informal interactions with modelers often reveal wildly divergent goals. In this opinion piece, we explicitly address the diversity of goals that motivate and ultimately influence modeling efforts. We argue that a wide range of goals can be meaningfully taken to be of highest importance. A simple informal survey conducted on the Internet confirmed the diversity of goals in the community. However, different priorities or preferences of individual researchers can lead to divergent model evaluation criteria. We propose that many disagreements in evaluating the merit of computational research stem from differences in goals and not from the mechanics of constructing, describing, and validating models. We suggest that authors state explicitly their goals when proposing models so that others can judge the quality of the research with respect to its stated goals.

    in q-bio.NC updates on arXiv.org on February 11, 2020 01:30 AM.

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    The Effects of Anesthetics on the Cortex—Lessons From Event-Related Potentials

    Consciousness while under general anesthesia is a dreadful condition. Various electroencephalogram (EEG)-based technologies have been developed, on the basis of empirical evidence, in order to identify this condition. However, certain electrophysiological phenomena, which seem strongly related with depth of anesthesia in some drugs, appear less consistent with those of other anesthetic drugs. There is a gap between the complexity of the phenomenon of consciousness and its behavioral manifestations, on the one hand, and the empirical nature of the reported electrophysiological markers, which are associated with it, on the other hand. In fact, such a gap might prevent us from progressing toward unified electrophysiological markers of consciousness while under anesthesia, which are applicable to all anesthetic drugs. We believe that there is a need to bridge this conceptual gap. Therefore, in this work, we will try to present a theoretical framework for such bridging. First, we suggest focusing on neuropsychological processes, which seem to have a clear role in the behavioral manifestations of consciousness while under anesthesia but seem, nevertheless, better defined than consciousness itself—such as perception and attention. Then, we suggest analyzing the effects of anesthesia upon these neuropsychological processes, as they are manifested in the EEG signal. Specifically, we will focus on the effects of anesthesia on event-related potentials (ERPs), which seem more easily associable with neuropsychological modeling.

    in Frontiers in Systems Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Unveiling the Synaptic Function and Structure Using Paired Recordings From Synaptically Coupled Neurons

    Synaptic transmission between neurons is the basic mechanism for information processing in cortical microcircuits. To date, paired recording from synaptically coupled neurons is the most widely used method which allows a detailed functional characterization of unitary synaptic transmission at the cellular and synaptic level in combination with a structural characterization of both pre- and postsynaptic neurons at the light and electron microscopic level. In this review, we will summarize the many applications of paired recordings to investigate synaptic function and structure. Paired recordings have been used to study the detailed electrophysiological and anatomical properties of synaptically coupled cell pairs within a synaptic microcircuit; this is critical in order to understand the connectivity rules and dynamic properties of synaptic transmission. Paired recordings can also be adopted for quantal analysis of an identified synaptic connection and to study the regulation of synaptic transmission by neuromodulators such as acetylcholine, the monoamines, neuropeptides, and adenosine etc. Taken together, paired recordings from synaptically coupled neurons will remain a very useful approach for a detailed characterization of synaptic transmission not only in the rodent brain but also that of other species including humans.

    in Frontiers in Synaptic Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor

    Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective and deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals’ has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Laminin and Integrin in LAMA2-Related Congenital Muscular Dystrophy: From Disease to Therapeutics

    Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a devastating neuromuscular disease caused by mutations in the LAMA2 gene. These mutations result in the complete absence or truncated expression of the laminin-α2 chain. The α2-chain is a major component of the laminin-211 and laminin-221 isoforms, the predominant laminin isoforms in healthy adult skeletal muscle. Mutations in this chain result in progressive skeletal muscle degeneration as early as neonatally. Laminin-211/221 is a ligand for muscle cell receptors integrin-α7β1 and α-dystroglycan. LAMA2 mutations are correlated with integrin-α7β1 disruption in skeletal muscle. In this review, we will summarize laminin-211/221 interactions with integrin-α7β1 in LAMA2-CMD muscle. Additionally, we will summarize recent developments using upregulation of laminin-111 in the sarcolemma of laminin-α2-deficient muscle. We will discuss potential mechanisms of action by which laminin-111 is able to prevent myopathy. These published studies demonstrate that laminin-111 is a disease modifier of LAMA2-CMD through different methods of delivery. Together, these studies show the potential for laminin-111 therapy as a novel paradigm for the treatment of LAMA2-CMD.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Multisensory Audiovisual Processing in Children With a Sensory Processing Disorder (I): Behavioral and Electrophysiological Indices Under Speeded Response Conditions

    Background

    Maladaptive reactivity to sensory inputs is commonly observed in neurodevelopmental disorders (e.g., autism, ADHD). Little is known, however, about the underlying neural mechanisms. For some children, atypical sensory reactivity is the primary complaint, despite absence of another identifiable neurodevelopmental diagnosis. Studying Sensory Processing Disorder (SPD) may well provide a window into the neuropathology of these symptoms. It has been proposed that a deficit in sensory integration underlies the SPD phenotype, but objective quantification of sensory integration is lacking. Here we used neural and behavioral measures of multisensory integration (MSI), which would be affected by impaired sensory integration and for which there are well accepted objective measures, to test whether failure to integrate across the senses is associated with atypical sensory reactivity in SPD. An autism group served to determine if observed differences were unique to SPD.

    Methods

    We tested whether children aged 6–16 years with SPD (N = 14) integrate multisensory inputs differently from age-matched typically developing controls (TD: N = 54), or from children with an autism spectrum disorder (ASD: N = 44). Participants performed a simple reaction-time task to the occurrence of auditory, visual, and audiovisual stimuli presented in random order, while high-density recordings of electrical brain activity were made.

    Results

    Children with SPD showed large reductions in the extent to which they benefited from multisensory inputs compared to TDs. The ASD group showed similarly reduced response speeding to multisensory relative to unisensory inputs. Neural evidence for MSI was seen across all three groups, with the multisensory response differing from the sum of the unisensory responses. Post hoc tests suggested the possibility of enhanced MSI in SPD in timeframes consistent with cortical sensory registration (∼60 ms), followed by reduced MSI during a timeframe consistent with object formation (∼130 ms). The ASD group also showed reduced MSI in the later timeframe.

    Conclusion

    Children with SPD showed reduction in their ability to benefit from redundant audio-visual inputs, similar to children with ASD. Neurophysiological recordings, on the other hand, showed that major indices of MSI were largely intact, although post hoc testing pointed to periods of potential differential processing. While these exploratory electrophysiological observations point to potential sensory-perceptual differences in multisensory processing in SPD, it remains equally plausible at this stage that later attentional processing differences may yet prove responsible for the multisensory behavioral deficits uncovered here.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Editorial: Neuromodulatory Control of Brainstem Function in Health and Disease

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on February 11, 2020 12:00 AM.

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    Examination of Structural Variations of the Circle of Willis by 3D Time-of-Flight Magnetic Resonance Angiography

    Objectives: To explore structural variations of the circle of Willis using three-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA), and to compare this modality with digital subtraction angiography (DSA).

    Methods: A total of 819 consecutive patients suspected of having cerebral vascular diseases underwent 3D-TOF-MRA, followed by DSA within 2 weeks. We report accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 3D-TOF-MRA compared with DSA.

    Results: The sensitivity and specificity of combined analyses were 90–100 and 98–100%, respectively. The sensitivity and NPV of 3D-TOF-MRA images for A-, C-, D-, and H-types of circle of Willis anomalies were 100%. The specificity, accuracy and sensitivity were all 100% for detecting absence of the anterior communicating artery (ACOA). Sensitivity, specificity, PPV, and NPV were all 100% for detecting F-type. The sensitivity and PPV of volume rendered (VR) images for the B-, E-, and G-types were relatively low (85.0, 86.2, and 73.8%, respectively). Maximum intensity projection (MIP) was somewhat better (88.3, 89.2, and 81.8%, respectively). Combined analyses were better still (95.8, 96.1, and 99.0%, respectively). Specificity and NPVs were high (99.3–100%).

    Conclusions: 3D-TOF-MRA compares well to DSA for evaluation of the structure of the circle of Willis. As 3D-TOF-MRA is a non-invasive modality, it may be preferred as a means to evaluate structural variations of the circle of Willis.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on February 11, 2020 12:00 AM.

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    A Connected Network of Interacting Proteins Is Involved in Human-Tau Toxicity in Drosophila

    Tauopathies are neurodegenerative diseases characterized by the presence of aggregates of abnormally phosphorylated Tau. Deciphering the pathophysiological mechanisms that lead from the alteration of Tau biology to neuronal death depends on the identification of Tau cellular partners. Combining genetic and transcriptomic analyses in Drosophila, we identified 77 new modulators of human Tau-induced toxicity, bringing to 301 the number of Tau genetic interactors identified so far in flies. Network analysis showed that 229 of these genetic modulators constitute a connected network. The addition of 77 new genes strengthened the network structure, increased the intergenic connectivity and brought up key hubs with high connectivities, namely Src64B/FYN, Src42A/FRK, kuz/ADAM10, heph/PTBP1, scrib/SCRIB, and Cam/CALM3. Interestingly, we established for the first time a genetic link between Tau-induced toxicity and ADAM10, a recognized Alzheimer Disease protective factor. In addition, our data support the importance of the presynaptic compartment in mediating Tau toxicity.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 11, 2020 12:00 AM.

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    Diffeomorphic Registration With Intensity Transformation and Missing Data: Application to 3D Digital Pathology of Alzheimer's Disease

    This paper examines the problem of diffeomorphic image registration in the presence of differing image intensity profiles and sparsely sampled, missing, or damaged tissue. Our motivation comes from the problem of aligning 3D brain MRI with 100-micron isotropic resolution to histology sections at 1 × 1 × 1,000-micron resolution with multiple varying stains. We pose registration as a penalized Bayesian estimation, exploiting statistical models of image formation where the target images are modeled as sparse and noisy observations of the atlas. In this injective setting, there is no assumption of symmetry between atlas and target. Cross-modality image matching is achieved by jointly estimating polynomial transformations of the atlas intensity. Missing data is accommodated via a multiple atlas selection procedure where several atlas images may be of homogeneous intensity and correspond to “background” or “artifact.” The two concepts are combined within an Expectation-Maximization algorithm, where atlas selection posteriors and deformation parameters are updated iteratively and polynomial coefficients are computed in closed form. We validate our method with simulated images, examples from neuropathology, and a standard benchmarking dataset. Finally, we apply it to reconstructing digital pathology and MRI in standard atlas coordinates. By using a standard convolutional neural network to detect tau tangles in histology slices, this registration method enabled us to quantify the 3D density distribution of tauopathy throughout the medial temporal lobe of an Alzheimer's disease postmortem specimen.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on February 11, 2020 12:00 AM.

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    An Automated Open-Source Workflow for Standards-Compliant Integration of Small Animal Magnetic Resonance Imaging Data

    Large-scale research integration is contingent on seamless access to data in standardized formats. Standards enable researchers to understand external experiment structures, pool results, and apply homogeneous preprocessing and analysis workflows. Particularly, they facilitate these features without the need for numerous potentially confounding compatibility add-ons. In small animal magnetic resonance imaging, an overwhelming proportion of data is acquired via the ParaVision software of the Bruker Corporation. The original data structure is predominantly transparent, but fundamentally incompatible with modern pipelines. Additionally, it sources metadata from free-field operator input, which diverges strongly between laboratories and researchers. In this article we present an open-source workflow which automatically converts and reposits data from the ParaVision structure into the widely supported and openly documented Brain Imaging Data Structure (BIDS). Complementing this workflow we also present operator guidelines for appropriate ParaVision data input, and a programmatic walk-through detailing how preexisting scans with uninterpretable metadata records can easily be made compliant after the acquisition.

    in Frontiers in Neuroinformatics | New and Recent Articles on February 11, 2020 12:00 AM.

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    Multimodal Recognition of Emotions in Music and Facial Expressions

    The aim of the study was to investigate the neural processing of congruent vs. incongruent affective audiovisual information (facial expressions and music) by means of ERPs (Event Related Potentials) recordings. Stimuli were 200 infant faces displaying Happiness, Relaxation, Sadness, Distress and 32 piano musical pieces conveying the same emotional states (as specifically assessed). Music and faces were presented simultaneously, and paired so that in half cases they were emotionally congruent or incongruent. Twenty subjects were told to pay attention and respond to infrequent targets (adult neutral faces) while their EEG was recorded from 128 channels. The face-related N170 (160–180 ms) component was the earliest response affected by the emotional content of faces (particularly by distress), while visual P300 (250–450 ms) and auditory N400 (350–550 ms) responses were specifically modulated by the emotional content of both facial expressions and musical pieces. Face/music emotional incongruence elicited a wide N400 negativity indicating the detection of a mismatch in the expressed emotion. A swLORETA inverse solution applied to N400 (difference wave Incong. – Cong.), showed the crucial role of Inferior and Superior Temporal Gyri in the multimodal representation of emotional information extracted from faces and music. Furthermore, the prefrontal cortex (superior and medial, BA 10) was also strongly active, possibly supporting working memory. The data hints at a common system for representing emotional information derived by social cognition and music processing, including uncus and cuneus.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Effects of Anodal tDCS on Arithmetic Performance and Electrophysiological Activity

    Arithmetic abilities are among the most important school-taught skills and form the basis for higher mathematical competencies. At the same time, their acquisition and application can be challenging. Hence, there is broad interest in methods to improve arithmetic abilities. One promising method is transcranial direct current stimulation (tDCS). In the present study, we compared two anodal tDCS protocols in their efficacy to improve arithmetic performance and working memory. In addition, we investigated stimulation-related electrophysiological changes. Three groups of participants solved arithmetic problems (additions and subtractions) and an n-back task before, during, and after receiving either frontal or parietal anodal tDCS (25 min; 1 mA) or sham stimulation. EEG was simultaneously recorded to assess stimulation effects on event-related (de-) synchronisation (ERS/ERD) in theta and alpha bands. Persons receiving frontal stimulation showed an acceleration of calculation speed in large subtractions from before to during and after stimulation. However, a comparable, but delayed (apparent only after stimulation) increase was also found in the sham stimulation group, while it was absent in the group receiving parietal stimulation. In additions and small subtractions as well as the working memory task, analyses showed no effects of stimulation. Results of ERS/ERD during large subtractions indicate changes in ERS/ERD patterns over time. In the left hemisphere there was a change from theta band ERD to ERS in all three groups, whereas a similar change in the right hemisphere was restricted to the sham group. Taken together, tDCS did not lead to a general improvement of arithmetic performance. However, results indicate that frontal stimulation accelerated training gains, while parietal stimulation halted them. The absence of general performance improvements, but acceleration of training effects might be a further indicator of the advantages of using tDCS as training or learning support over tDCS as a sole performance enhancer.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Three-Year Gait and Axial Outcomes of Bilateral STN and GPi Parkinson’s Disease Deep Brain Stimulation

    Objective: To examine the short- and long-term clinical outcomes of the bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) on gait and axial symptoms in Parkinson’s disease (PD) patients. Available data have been inconsistent and mostly short-term regarding the effect of both brain targets on gait and axial symptoms. We aimed to identify potential target specific differences at 3-year follow-up from a large single-center experience.

    Methods: We retrospectively reviewed short-term (6-month follow-up) and long-term (36-month follow-up) changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II and III total scores of 72 PD patients (53 with bilateral STN-DBS and 19 with bilateral GPi-DBS). An interdisciplinary team made target-specific decisions for each DBS patient. We analyzed changes in gait and axial subscores derived from UPDRS II and III.

    Results: In both the STN- and GPi-DBS cohorts, we observed no significant differences in gait and axial UPDRS derived subscores in the off-med/on stimulation state at long-term follow-up when compared to baseline. On-med axial scores remained similar in the short-term but worsened in both groups (STN, 2.23 ± 3.43, p < 0.001; GPi, 2.53 ± 2.37, p < 0.01) in the long-term possibly due to disease progression. At long-term follow-up, the UPDRS III off-med/on stimulation scores worsened but were persistently improved from baseline in both groups (−9.07 ± 13.9, p < 0.001).

    Conclusions: The study showed that long-term both STN- and GPi-DBS had a similar effect on gait and axial symptoms in UPDRS derived subscores at 36-month follow-up despite potential baseline differences in criteria for selection of each target. More sophisticated measures of gait and balance beyond the categorical UPDRS score will be needed for future studies.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Factors Influencing Manipulation of a Familiar Object in Patients With Limb Apraxia After Stroke

    Previous studies have shown that hand actions to visual objects are affected both by perceptual factors and by action goals. Our aim was to study how these processes affected hand actions in chronic stroke patients, based on whether they had limb apraxia. Twenty-two left hemisphere, chronic stroke patients were measured on neuropsychological tasks of limb apraxia, which was identified in a subgroup of 10 patients. All patients underwent testing on a separate task of making simple reach and grasp actions to a cup. Their performance was compared to a group of 18 healthy age-matched volunteers. Participants were instructed to grasp the top or bottom of a cup to either lift or turn it over so as to end with a hand position that was either comfortable or uncomfortable. This task tested the influence of the compatibility of hand–cup orientation, as well as goals driven by the end-state comfort of the hand, on action selection for object manipulation. Participants’ performance was measured in terms of error rates, and speed of initiation and reaching (movement time) to the object. The patients’ performance was significantly delayed, and error rates increased when reaching to grasp a cup under conditions of poor compatibility and end-state comfort. The subgroup of patients with apraxia showed a decreased influence of compatibility of hand interaction with the cup, with increased error rates and delayed response times, compared to patients with no apraxia and healthy volunteers. This is despite the fact they did not display significant deficits on neuropsychological tasks of real object use. The study shows that patients with apraxia have difficulties in selecting elements of object-directed actions, pertaining to both habitual and goal-directed factors.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    IRSp53 Deletion in Glutamatergic and GABAergic Neurons and in Male and Female Mice Leads to Distinct Electrophysiological and Behavioral Phenotypes

    IRSp53 (also known as BAIAP2) is an abundant excitatory postsynaptic scaffolding protein implicated in autism spectrum disorders (ASD), schizophrenia, and attention-deficit/hyperactivity disorder (ADHD). IRSp53 is expressed in different cell types across different brain regions, although it remains unclear how IRSp53 deletion in different cell types affects brain functions and behaviors in mice. Here, we deleted IRSp53 in excitatory and inhibitory neurons in mice and compared resulting phenotypes in males and females. IRSp53 deletion in excitatory neurons driven by Emx1 leads to strong social deficits and hyperactivity without affecting anxiety-like behavior, whereas IRSp53 deletion in inhibitory neurons driven by Viaat has minimal impacts on these behaviors in male mice. In female mice, excitatory neuronal IRSp53 deletion induces hyperactivity but moderate social deficits. Excitatory neuronal IRSp53 deletion in male mice induces an increased ratio of evoked excitatory and inhibitory synaptic transmission (E/I ratio) in layer V pyramidal neurons in the prelimbic region of the medial prefrontal cortex (mPFC), whereas the same mutation does not alter the E/I ratio in female neurons. These results suggest that IRSp53 deletion in excitatory and inhibitory neurons and in male and female mice has distinct impacts on behaviors and synaptic transmission.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

    Glial cells are multifunctional, non-neuronal components of the central nervous system with diverse phenotypes that have gained much attention for their close involvement in neuroinflammation and neurodegenerative diseases. Glial phenotypes are primarily characterized by their structural and functional changes in response to various stimuli, which can be either neuroprotective or neurotoxic. The reliance of neurons on glial cells is essential to fulfill the energy demands of the brain for its proper functioning. Moreover, the glial cells perform distinct functions to regulate their own metabolic activities, as well as work in close conjunction with neurons through various secreted signaling or guidance molecules, thereby constituting a complex network of neuron-glial interactions in health and disease. The emerging evidence suggests that, in disease conditions, the metabolic alterations in the glial cells can induce structural and functional changes together with neuronal dysfunction indicating the importance of neuron–glia interactions in the pathophysiology of neurological disorders. This review covers the recent developments that implicate the regulation of glial phenotypic changes and its consequences on neuron–glia interactions in neurological disorders. Finally, we discuss the possibilities and challenges of targeting glial metabolism as a strategy to treat neurological disorders.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Subarachnoid Hemorrhage Induces Dynamic Immune Cell Reactions in the Choroid Plexus

    Subarachnoid hemorrhage (SAH) is a specific form of hemorrhagic stroke that frequently causes intracranial hypertension. The choroid plexus (CP) of the brain ventricles is responsible for producing cerebrospinal fluid and forms the blood – cerebrospinal fluid barrier. The aim of the current study was to determine whether SAH induces an immune cell reaction in the CP and whether the resulting increase in intracranial pressure (ICP) itself can lead to cellular changes in the CP. SAH was induced by injecting non-heparinized autologous blood to the cisterna magna. Artificial cerebrospinal fluid (ACSF) instead of blood was used to assess influence of increased ICP alone. SAH and ACSF animals were left to survive for 1, 3, and 7 days. SAH induced significantly increased numbers of M1 (ED1+, CCR7+) and M2 (ED2+, CD206+) macrophages as well as MHC-II+ antigen presenting cells (APC) compared to naïve and ACSF animals. Increased numbers of ED1+ macrophages and APC were found in the CP only 3 and 7 days after ACSF injection, while ED2+ macrophage number did not increase. CD3+ T cells were not found in any of the animals. Following SAH, proliferation activity in the CP gradually increased over time while ACSF application induced higher cellular proliferation only 1 and 3 days after injection. Our results show that SAH induces an immune reaction in the CP resulting in an increase in the number of several macrophage types in the epiplexus position. Moreover, we also found that increased ICP due to ACSF application induced both an immune reaction and increased proliferation of epiplexus cells in the CP. These findings indicate that increased ICP, and not just blood, contributes to cellular changes in the CP following SAH.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Cellular Senescence in Neurodegenerative Diseases

    Cellular senescence is a homeostatic biological process characterized by a permanent state of cell cycle arrest that can contribute to the decline of the regenerative potential and function of tissues. The increased presence of senescent cells in different neurodegenerative diseases suggests the contribution of senescence in the pathophysiology of these disorders. Although several factors can induce senescence, DNA damage, oxidative stress, neuroinflammation, and altered proteostasis have been shown to play a role in its onset. Oxidative stress contributes to accelerated aging and cognitive dysfunction stages affecting neurogenesis, neuronal differentiation, connectivity, and survival. During later life stages, it is implicated in the progression of cognitive decline, synapse loss, and neuronal degeneration. Also, neuroinflammation exacerbates oxidative stress, synaptic dysfunction, and neuronal death through the harmful effects of pro-inflammatory cytokines on cell proliferation and maturation. Both oxidative stress and neuroinflammation can induce DNA damage and alterations in DNA repair that, in turn, can exacerbate them. Another important feature associated with senescence is altered proteostasis. Because of the disruption in the function and balance of the proteome, senescence can modify the proper synthesis, folding, quality control, and degradation rate of proteins producing, in some diseases, misfolded proteins or aggregation of abnormal proteins. There is an extensive body of literature that associates cellular senescence with several neurodegenerative disorders including Alzheimer’s disease (AD), Down syndrome (DS), and Parkinson’s disease (PD). This review summarizes the evidence of the shared neuropathological events in these neurodegenerative diseases and the implication of cellular senescence in their onset or aggravation. Understanding the role that cellular senescence plays in them could help to develop new therapeutic strategies.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Long Term Gene Expression in Human Induced Pluripotent Stem Cells and Cerebral Organoids to Model a Neurodegenerative Disease

    Human brain organoids (mini-brains) consist of self-organized three-dimensional (3D) neural tissue which can be derived from reprogrammed adult cells and maintained for months in culture. These 3D structures manifest substantial potential for the modeling of neurodegenerative diseases and pave the way for personalized medicine. However, as these 3D brain models can express the whole human genetic complexity, it is critical to have access to isogenic mini-brains that only differ in specific and controlled genetic variables. Genetic engineering based on retroviral vectors is incompatible with the long-term modeling needed here and implies a risk of random integration while methods using CRISPR-Cas9 are still too complex to adapt to stem cells. We demonstrate in this study that our strategy which relies on an episomal plasmid vector derived from the Epstein-Barr virus (EBV) offers a simple and robust approach, avoiding the remaining caveats of mini-brain models. For this proof-of-concept, we used a normal tau protein with a fluorescent tag and a mutant genetic form (P301S) leading to Fronto-Temporal Dementia. Isogenic cell lines were obtained which were stable for more than 30 passages expressing either form. We show that the presence of the plasmid in the cells does not interfere with the mini-brain differentiation protocol and obtain the development of a pathologically relevant phenotype in cerebral organoids, with pathological hyperphosphorylation of the tau protein. Such a simple and versatile genetic strategy opens up the full potential of human organoids to contribute to disease modeling, personalized medicine and testing of therapeutics.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Indoleamine-2,3-Dioxygenase Mediates Emotional Deficits by the Kynurenine/Tryptophan Pathway in the Ethanol Addiction/Withdrawal Mouse Model

    Objective

    Our study was designed to investigate whether the indoleamine-2,3-dioxygenase (IDO)-mediated kynurenine/tryptophan (KYN/TRP) pathway participates in the development of emotional deficits from ethanol addiction/withdrawal mice.

    Methods

    The expression of proinflammatory factors, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), was tested by enzyme-linked immunosorbent assay (ELISA). The IDO levels in the hippocampus, cerebral cortex, and amygdala were measured by polymerase chain reaction (PCR) and western blot, and the neurotransmitters were tested by high performance liquid chromatography (HPLC). Emotional deficits of mice were evaluated by behavioral tests.

    Results

    Expression levels of inflammatory factors (TNF-α, IL-1β, and IL-6) were increased in mice after 4 weeks of alcohol exposure. As for indoleamine 2,3-dioxygenase (IDO) expression, only the subtype IDO1 was found to increase at both mRNA level and protein level in all the tested brain regions of ethanol addiction/withdrawal mice. In behavioral tests, mice exposed to alcohol showed gradually declined memory function accompanied by anxiety-like and depressive-like behaviors. Meanwhile, increased expression of KYN, decreased expression of 5-HT, and abnormal expression of 3-HK and KA were found in the hippocampus, cerebral cortex, and amygdala of ethanol addiction/withdrawal mice. Interestingly, the IDO1 inhibitor, 1-methyl-L-tryptophan (1-MT), reversed all above alterations induced by ethanol in mice.

    Conclusion

    Our results suggested that the TRP/KYN pathway, medicated by IDO1, in the hippocampus, cerebral cortex, and amygdala, plays an important role in the development of emotional deficits caused by ethanol addiction and withdrawal.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    GABAA Receptor β2E155 Residue Located at the Agonist-Binding Site Is Involved in the Receptor Gating

    GABAA receptors (GABAARs) play a crucial role in mediating inhibition in the adult brain. In spite of progress in describing (mainly) the static structures of this receptor, the molecular mechanisms underlying its activation remain unclear. It is known that in the α1β2γ2L receptors, the mutation of the β2E155 residue, at the orthosteric binding site, strongly impairs the receptor activation, but the molecular and kinetic mechanisms of this effect remain elusive. Herein, we investigated the impact of the β2E155C mutation on binding and gating of the α1β2γ2L receptor. To this end, we combined the macroscopic and single-channel analysis, the use of different agonists [GABA and muscimol (MSC)] and flurazepam (FLU) as a modulator. As expected, the β2E155C mutation caused a vast right shift of the dose–response (for GABA and MSC) and, additionally, dramatic changes in the time course of current responses, indicative of alterations in gating. Mutated receptors showed reduced maximum open probability and enhanced receptor spontaneous activity. Model simulations for macroscopic currents revealed that the primary effect of the mutation was the downregulation of the preactivation (flipping) rate. Experiments with MSC and FLU further confirmed a reduction in the preactivation rate. Our single-channel analysis revealed the mutation impact mainly on the second component in the shut times distributions. Based on model simulations, this finding further confirms that this mutation affects mostly the preactivation transition, supporting thus the macroscopic data. Altogether, we provide new evidence that the β2E155 residue is involved in both binding and gating (primarily preactivation).

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Modulation of Hippocampal Gamma Oscillations by Dopamine in Heterozygous Reeler Mice in vitro

    The reelin haploinsufficient heterozygous reeler mice (HRM), an animal model of schizophrenia, have altered mesolimbic dopaminergic pathways and share similar neurochemical and behavioral properties with patients with schizophrenia. Dysfunctional neural circuitry with impaired gamma (γ) oscillation (30–80 Hz) has been implicated in abnormal cognition in patients with schizophrenia. However, the function of neural circuitry in terms of γ oscillation and its modulation by dopamine (DA) has not been reported in HRM. In this study, first, we recorded γ oscillations in CA3 from wild-type mice (WTM) and HRM hippocampal slices, and we studied the effects of DA on γ oscillations. We found that there was no difference in γ power between WTM and HRM and that DA increased γ power of WTM but not HRM, suggesting that DA modulations of network oscillations in HRM are impaired. Second, we found that N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 itself increased γ power and occluded DA-mediated enhancement of γ power in WTM but partially restored DA modulation of γ oscillations in HRM. Third, inhibition of phosphatidylinositol 3-kinase (PI3K), a downstream molecule of NMDAR, increased γ power and blocked the effects of DA on γ oscillation in WTM and had no significant effect on γ power but largely restored DA modulation of γ oscillations in HRM. Our results reveal that impaired DA function in HRM is associated with dysregulated NMDAR–PI3K signaling, a mechanism that may be relevant in the pathology of schizophrenia.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Zebrafish Astroglial Morphology in the Olfactory Bulb Is Altered With Repetitive Peripheral Damage

    Zebrafish do not possess the typical astrocytes that are found in mammalian systems. In some brain areas, this teleost has radial glia that appears to perform astrocyte-like functions, but these cells have not been described in the zebrafish olfactory bulb. Mammalian astrocytes facilitate neuroplasticity and undergo astrogliosis after insult. The role of these cells in the zebrafish olfactory system after the damage has been poorly explored. This is important to examine because zebrafish have a high degree of neuroplasticity and the olfactory bulb is a brain area renowned for plasticity. The goal of this study was to explore the potential role of zebrafish astrocytes in the olfactory bulb damage response, with a goal to exploit the high level of regeneration in this system. We found that anti-glial fibrillary acidic protein (GFAP) labels numerous processes in the zebrafish olfactory bulb that are concentrated in the nerve and glomerular layers (GL) and do not show radial glial-like morphology. We propose to term this astroglia, since their location and response to damage suggests that they are similar in function to the mammalian astrocyte. To induce repetitive peripheral damage to the olfactory organ, a wax plug was inserted into the nasal cavity of adult zebrafish every 12 h for up to 7 days; this crushes the olfactory organ and leads to degradation of olfactory sensory neuron axons that project to the olfactory bulb. After 1 day, we found a significant increase in astroglial labeling in the affected bulb when compared to the internal control bulb and astroglial branches appeared to increase in number and size. By the third day of plug insertions there was no significant difference in astroglial labeling between the affected bulb and the internal control bulb. These data lead us to believe that astrogliosis does occur in the presence of peripheral damage, but this process attenuates within 1 week and no glial scar is evident upon recovery from the damage. Further exploration of astrocytes in zebrafish, in particular this apparent attenuation of astrogliosis, has the potential to elucidate key differences in glial function between teleosts and mammals.

    in Frontiers in Neuroanatomy | New and Recent Articles on February 11, 2020 12:00 AM.

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    Stereotaxic Diffusion Tensor Imaging White Matter Atlas for the in vivo Domestic Feline Brain

    The cat brain is a useful model for neuroscientific research and with the increasing use of advanced neuroimaging techniques there is a need for an open-source stereotaxic white matter brain atlas to accompany the cortical gray matter atlas, currently available. A stereotaxic white matter atlas would facilitate anatomic registration and segmentation of the white matter to aid in lesion localization or standardized regional analysis of specific regions of the white matter. In this article, we document the creation of a stereotaxic feline white matter atlas from diffusion tensor imaging (DTI) data obtained from a population of eight mesaticephalic felines. Deterministic tractography reconstructions were performed to create tract priors for the major white matter projections of Corpus callosum (CC), fornix, cingulum, uncinate, Corona Radiata (CR), Corticospinal tract (CST), inferior longitudinal fasciculus (ILF), Superior Longitudinal Fasciculus (SLF), and the cerebellar tracts. T1-weighted, fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) population maps were generated. The volume, mean tract length and mean FA, MD, AD and RD values for each tract prior were documented. A structural connectome was then created using previously published cortical priors and the connectivity metrics for all cortical regions documented. The provided white matter atlas, diffusivity maps, tract priors and connectome will be a valuable resource for anatomical, pathological and translational neuroimaging research in the feline model. Multi-atlas population maps and segmentation priors are available at Cornell’s digital repository: https://ecommons.cornell.edu/handle/1813/58775.2.

    in Frontiers in Neuroanatomy | New and Recent Articles on February 11, 2020 12:00 AM.

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    The Density of Perineuronal Nets Increases With Age in the Inferior Colliculus in the Fischer Brown Norway Rat

    Age-related hearing loss, one of the most frequently diagnosed disabilities in industrialized countries, may result from declining levels of GABA in the aging inferior colliculus (IC). However, the mechanisms of aging and subsequent disruptions of temporal processing in elderly hearing abilities are still being investigated. Perineuronal nets (PNs) are a specialized form of the extracellular matrix and have been linked to GABAergic neurotransmission and to the regulation of structural and synaptic plasticity. We sought to determine whether the density of PNs in the IC changes with age. We combined Wisteria floribunda agglutinin (WFA) staining with immunohistochemistry to glutamic acid decarboxylase in three age groups of Fischer Brown Norway (FBN) rats. The density of PNs on GABAergic and non-GABAergic cells in the three major subdivisions of the IC was quantified. Results first demonstrate that the density of PNs in the FBN IC increase with age. The greatest increases of PN density from young to old age occurred in the central IC (67% increase) and dorsal IC (117% increase). Second, in the young IC, PNs surround non-GABAergic and GABAergic cells with the majority of PNs surrounding the former. The increase of PNs with age in the IC occurred on both non-GABAergic and GABAergic populations. The average density of PN-surrounded non-GABAergic cells increased from 84.9 PNs/mm2 in the young to 134.2 PNs/mm2 in the old. While the density of PN-surrounded GABAergic cells increased from 26 PNs/mm2 in the young to 40.6 PNs/mm2 in the old. The causality is unclear, but increases in PN density in old age may play a role in altered auditory processing in the elderly, or may lead to further changes in IC plasticity.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Vital Functions Contribute to the Spread of Extracellular Fluids in the Brain: Comparison Between Life and Death

    Vascular pulsations, contractions of vascular smooth muscle cells and breathing have been reported to foster movement and clearance of interstitial and cerebrospinal fluids from the brain. The aim of this study was to estimate the contribution of these vital functions. We compared the spread of an injected hydrophilic tracer (Fluoro-Emerald, a 10 kDa fluorescein-coupled dextran amine) in the brains of live anesthetized and sacrificed rats at 30 and 90 min after injection. To determine the overall pattern of distribution of tracers, we created 3D-reconstructions of the horizontal transections of the whole brain. Immunofluorescence staining with laminin and collagen IV was performed to determine the pattern of distribution of tracer in relation to the cerebrovascular basement membranes. We found that diffusion was widely restricted to the periventricular region in sacrificed rats with no spread to the contralateral hemisphere, while the bulk flow occurred along the vasculature and reached the surface and the contralateral hemisphere as soon as 30 min after injection in live anesthetized animals. The tracer appeared to be localized along the vascular basement membranes and along fiber tracts as reported previously. Thus, our data indicate that vital functions are essential for the remote movement of extracellular fluids within the cerebral parenchyma.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    Comparison of Gray Matter Atrophy in Behavioral Variant Frontal Temporal Dementia and Amyotrophic Lateral Sclerosis: A Coordinate-Based Meta-Analysis

    Background: There is growing evidence supporting behavioral variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS) as extreme points of a disease spectrum. The aim of this study was to delineate the common and different patterns of gray matter atrophy associated with bvFTD and with ALS by pooling together the results of previous voxel-based morphometry (VBM) studies.

    Methods: We retrieved VBM studies that investigated gray matter atrophy in bvFTD patients vs. controls and in ALS patients vs. controls. Stereotactic data were extracted from those studies and subsequently tested for convergence and differences using activation likelihood estimation (ALE). A behavioral analysis using the BrainMap database was performed to assess the functional roles of the regions affected by bvFTD and/or ALS.

    Results: Our study demonstrated a convergence of gray matter atrophy in the frontolimbic structures that involve the bilateral anterior insula and anterior cingulate cortex. Comparing the pattern of GM atrophy in bvFTD and ALS patients revealed greater atrophy in the frontomedial cortex, bilateral caudate, left anterior insula, and right thalamus in those with bvFTD and a higher degree of atrophy in the right motor cortex of those with ALS. Behavioral analysis revealed that the pattern of the affected regions contributed to the dysfunction of emotional and cognitive processing in bvFTD patients and the dysfunction of motor execution in ALS patients.

    Conclusion: Our results revealed a shared neural basis between bvFTD and ALS subjects, as well as a specific and distinct neural signature that underpinned the clinical manifestations of those two diseases. Those findings outlined the role of the frontomedial-caudate circuit in the development of bvFTD-like deficits in ALS patients.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    The Interaction of EphA4 With PDGFRβ Regulates Proliferation and Neuronal Differentiation of Neural Progenitor Cells in vitro and Promotes Neurogenesis in vivo

    Neural progenitor cells (NPCs) have great potentials in cell replacement therapy for neurodegenerative diseases, such as Alzheimer’s disease (AD), by promoting neurogenesis associated with hippocampal memory improvement. Ephrin receptors and angiogenic growth factor receptors have a marked impact on the proliferation and differentiation of NPCs. Although ephrin receptor A4 (EphA4) was shown to directly interact with platelet-derived growth factor receptor β (PDGFRβ), the functional effects of this interaction on neurogenesis in cultured NPCs and adult hippocampus have not yet been studied. Immunoprecipitation demonstrated that EphA4 directly interacted with PDGFRβ in NPCs under ligand stimulation. Ephrin-A1 and PDGF-platelet-derived growth factor BB (BB) significantly increased proliferation and neuronal differentiation of NPCs, which was further augmented by combined treatment of Ephrin-A1 and PDGF-BB. We also found that ligand-dependent proliferation and neuronal differentiation were inhibited by the dominant-negative EphA4 mutant or a PDGFR inhibitor. Most importantly, injection of ephrin-A1 and/or PDGF-BB promoted hippocampal NPC proliferation in the APP/PS1 mouse model of AD, indicating that direct interaction of EphA4 with PDGFRβ plays a functional role on neurogenesis in vivo. Finally, studies in NPCs showed that the EphA4/PDGFRβ/FGFR1/FRS2α complex formed by ligand stimulation is involved in neurogenesis via ERK signaling. The present findings provided a novel insight into the functional role of direct interaction of EphA4 and PDGFRβ in neurogenesis, implicating its potential use for treating neurodegenerative diseases.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 11, 2020 12:00 AM.

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    The role of spatial structure in the evolution of viral innate immunity evasion: A diffusion-reaction cellular automaton model

    by Ernesto Segredo-Otero, Rafael Sanjuán

    Most viruses have evolved strategies for preventing interferon (IFN) secretion and evading innate immunity. Recent work has shown that viral shutdown of IFN secretion can be viewed as a social trait, since the ability of a given virus to evade IFN-mediated immunity depends on the phenotype of neighbor viruses. Following this idea, we investigate the role of spatial structure in the evolution of innate immunity evasion. For this, we model IFN signaling and viral spread using a spatially explicit approximation that combines a diffusion-reaction model and cellular automaton. Our results indicate that the benefits of preventing IFN secretion for a virus are strongly determined by spatial structure through paracrine IFN signaling. Therefore, innate immunity evasion can evolve as a cooperative or even altruistic trait based on indirect fitness effects that IFN shutdown exerts on other members of the viral population. We identify key factors determining whether evasion from IFN-mediated immunity should evolve, such as population bottlenecks occurring during viral transmission, the relative speed of cellular infection and IFN secretion, and the diffusion properties of the medium.

    in PLOS Computational Biology: New Articles on February 10, 2020 10:00 PM.

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    A mechanism for epithelial-mesenchymal heterogeneity in a population of cancer cells

    by Shubham Tripathi, Priyanka Chakraborty, Herbert Levine, Mohit Kumar Jolly

    Epithelial-mesenchymal heterogeneity implies that cells within the same tumor can exhibit different phenotypes—epithelial, mesenchymal, or one or more hybrid epithelial-mesenchymal phenotypes. This behavior has been reported across cancer types, both in vitro and in vivo, and implicated in multiple processes associated with metastatic aggressiveness including immune evasion, collective dissemination of tumor cells, and emergence of cancer cell subpopulations with stem cell-like properties. However, the ability of a population of cancer cells to generate, maintain, and propagate this heterogeneity has remained a mystifying feature. Here, we used a computational modeling approach to show that epithelial-mesenchymal heterogeneity can emerge from the noise in the partitioning of biomolecules (such as RNAs and proteins) among daughter cells during the division of a cancer cell. Our model captures the experimentally observed temporal changes in the fractions of different phenotypes in a population of murine prostate cancer cells, and describes the hysteresis in the population-level dynamics of epithelial-mesenchymal plasticity. The model is further able to predict how factors known to promote a hybrid epithelial-mesenchymal phenotype can alter the phenotypic composition of a population. Finally, we used the model to probe the implications of phenotypic heterogeneity and plasticity for different therapeutic regimens and found that co-targeting of epithelial and mesenchymal cells is likely to be the most effective strategy for restricting tumor growth. By connecting the dynamics of an intracellular circuit to the phenotypic composition of a population, our study serves as a first step towards understanding the generation and maintenance of non-genetic heterogeneity in a population of cancer cells, and towards the therapeutic targeting of phenotypic heterogeneity and plasticity in cancer cell populations.

    in PLOS Computational Biology: New Articles on February 10, 2020 10:00 PM.

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    A model for time interval learning in the Purkinje cell

    by Daniel Majoral, Ajmal Zemmar, Raul Vicente

    Recent experimental findings indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. These findings add to the theoretical and experimental observations suggesting the presence of intra-cellular mechanisms for adaptation and processing. To account for these experimental results we propose a new biophysical model for time interval learning in a Purkinje cell. The numerical model focuses on a classical delay conditioning task (e.g. eyeblink conditioning) and relies on a few computational steps. In particular, the model posits the activation by the parallel fiber input of a local intra-cellular calcium store which can be modulated by intra-cellular pathways. The reciprocal interaction of the calcium signal with several proteins forming negative and positive feedback loops ensures that the timing of inhibition in the Purkinje cell anticipates the interval between parallel and climbing fiber inputs during training. We systematically test the model ability to learn time intervals at the 150-1000 ms time scale, while observing that learning can also extend to the multiple seconds scale. In agreement with experimental observations we also show that the number of pairings required to learn increases with inter-stimulus interval. Finally, we discuss how this model would allow the cerebellum to detect and generate specific spatio-temporal patterns, a classical theory for cerebellar function.

    in PLOS Computational Biology: New Articles on February 10, 2020 10:00 PM.

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    Host factor prioritization for pan-viral genetic perturbation screens using random intercept models and network propagation

    by Simon Dirmeier, Christopher Dächert, Martijn van Hemert, Ali Tas, Natacha S. Ogando, Frank van Kuppeveld, Ralf Bartenschlager, Lars Kaderali, Marco Binder, Niko Beerenwinkel

    Genetic perturbation screens using RNA interference (RNAi) have been conducted successfully to identify host factors that are essential for the life cycle of bacteria or viruses. So far, most published studies identified host factors primarily for single pathogens. Furthermore, often only a small subset of genes, e.g., genes encoding kinases, have been targeted. Identification of host factors on a pan-pathogen level, i.e., genes that are crucial for the replication of a diverse group of pathogens has received relatively little attention, despite the fact that such common host factors would be highly relevant, for instance, for devising broad-spectrum anti-pathogenic drugs. Here, we present a novel two-stage procedure for the identification of host factors involved in the replication of different viruses using a combination of random effects models and Markov random walks on a functional interaction network. We first infer candidate genes by jointly analyzing multiple perturbations screens while at the same time adjusting for high variance inherent in these screens. Subsequently the inferred estimates are spread across a network of functional interactions thereby allowing for the analysis of missing genes in the biological studies, smoothing the effect sizes of previously found host factors, and considering a priori pathway information defined over edges of the network. We applied the procedure to RNAi screening data of four different positive-sense single-stranded RNA viruses, Hepatitis C virus, Chikungunya virus, Dengue virus and Severe acute respiratory syndrome coronavirus, and detected novel host factors, including UBC, PLCG1, and DYRK1B, which are predicted to significantly impact the replication cycles of these viruses. We validated the detected host factors experimentally using pharmacological inhibition and an additional siRNA screen and found that some of the predicted host factors indeed influence the replication of these pathogens.

    in PLOS Computational Biology: New Articles on February 10, 2020 10:00 PM.

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    Ten simple rules for getting started on Twitter as a scientist

    by Veronika Cheplygina, Felienne Hermans, Casper Albers, Natalia Bielczyk, Ionica Smeets

    in PLOS Computational Biology: New Articles on February 10, 2020 10:00 PM.

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    Chromatin-enriched RNAs mark active and repressive <i>cis</i>-regulation: An analysis of nuclear RNA-seq

    by Xiangying Sun, Zhezhen Wang, Johnathon M. Hall, Carlos Perez-Cervantes, Alexander J. Ruthenburg, Ivan P. Moskowitz, Michael Gribskov, Xinan H. Yang

    Long noncoding RNAs (lncRNAs) localize in the cell nucleus and influence gene expression through a variety of molecular mechanisms. Chromatin-enriched RNAs (cheRNAs) are a unique class of lncRNAs that are tightly bound to chromatin and putatively function to locally cis-activate gene transcription. CheRNAs can be identified by biochemical fractionation of nuclear RNA followed by RNA sequencing, but until now, a rigorous analytic pipeline for nuclear RNA-seq has been lacking. In this study, we survey four computational strategies for nuclear RNA-seq data analysis and develop a new pipeline, Tuxedo-ch, which outperforms other approaches. Tuxedo-ch assembles a more complete transcriptome and identifies cheRNA with higher accuracy than other approaches. We used Tuxedo-ch to analyze benchmark datasets of K562 cells and further characterize the genomic features of intergenic cheRNA (icheRNA) and their similarity to enhancer RNAs (eRNAs). We quantify the transcriptional correlation of icheRNA and adjacent genes and show that icheRNA is more positively associated with neighboring gene expression than eRNA or cap analysis of gene expression (CAGE) signals. We also explore two novel genomic associations of cheRNA, which indicate that cheRNAs may function to promote or repress gene expression in a context-dependent manner. IcheRNA loci with significant levels of H3K9me3 modifications are associated with active enhancers, consistent with the hypothesis that enhancers are derived from ancient mobile elements. In contrast, antisense cheRNA (as-cheRNA) may play a role in local gene repression, possibly through local RNA:DNA:DNA triple-helix formation.

    in PLOS Computational Biology: New Articles on February 10, 2020 10:00 PM.

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    Corticotropin releasing factor receptor-1 neurons in the lateral amygdala display selective sensitivity to acute and chronic ethanol exposure

    ABSTRACT

    The lateral amygdala (LA) serves as the point of entry for sensory information within the amygdala complex, a structure that plays a critical role in emotional processes and has been implicated in alcohol use disorders. Within the amygdala, the corticotropin-releasing factor (CRF) system has been shown to mediate some of the effects of both stress and ethanol, but the effects of ethanol on specific CRF1 receptor circuits in the amygdala have not been fully established. We used male CRF1:GFP reporter mice to characterize CRF1-expressing (CRF1+) and non-expressing (CRF1-) LA neurons and investigate the effects of acute and chronic ethanol exposure on these populations. The CRF1+ population was found to be comprised predominantly of glutamatergic projection neurons with a minority subpopulation of interneurons. CRF1+ neurons exhibited a tonic conductance that was insensitive to acute ethanol. CRF1- neurons did not display a basal tonic conductance, but application of acute ethanol induced a GABAA receptor subunit-dependent tonic conductance and enhanced phasic GABA release onto these cells. Chronic ethanol increased CRF1+ neuronal excitability but did not significantly alter phasic or tonic GABA signaling in either CRF1+ or CRF1- cells. Chronic ethanol and withdrawal also did not alter basal extracellular GABA or glutamate transmitter levels in the LA/BLA and did not alter sensitivity of GABA or glutamate to acute ethanol-induced increases in transmitter release. Together, these results provide the first characterization of the CRF1+ population of LA neurons and suggest mechanisms for differential acute ethanol sensitivity within this region.

    SIGNIFICANCE STATEMENT The corticotropin releasing factor (CRF) system is a critical component of the stress network and has been implicated in psychiatric disorders including addiction, anxiety, and depression. The present study examines CRF receptor-1 (CRF1) lateral amygdala (LA) neurons and reports differential inhibitory control and acute ethanol effects of CRF1 LA neurons as compared to the unlabeled (CRF1-) population. An improved understanding of CRF1 amygdala circuitry and the selective sensitivity of that circuitry to ethanol represents an important step in identifying brain region-specific neuroadaptations that occur with ethanol exposure. The present findings also have broad implications, including potential relevance to the role of CRF1 circuitry in other contexts that may provide insight into other disorders involving amygdala dysfunction, including anxiety and depression.

    in RSS PAP on February 10, 2020 05:30 PM.

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    Zona incerta gabaergic output controls a signaled locomotor action in the midbrain tegmentum

    Abstract

    The zona incerta is a subthalamic nucleus proposed to link sensory stimuli with motor responses to guide behavior, but its functional role is not well established. Using mice of either sex, we studied the effect of manipulating zona incerta gabaergic cells on the expression of a signaled locomotor action, known as signaled active avoidance. We found that modulation of gabaergic zona incerta cells, but not of cells in the adjacent thalamic reticular nucleus, fully controls the expression of signaled active avoidance responses. Inhibition of zona incerta gabaergic cells drives active avoidance responses, while excitation of these cells blocks signaled active avoidance mainly by inhibiting cells in the midbrain pedunculopontine tegmentum (PPT). The zona incerta regulates signaled locomotion in the midbrain.

    Significance Statement The zona incerta is an enigmatic nucleus in the forebrain whose functional role is not well established. We found that gabaergic cells in the zona incerta, that project to the midbrain, control the ability of mice to avoid a threat signaled by a sensory stimulus. Inhibiting these cells drives avoidance responses, while exciting them blocks avoidance responses by inhibiting targets in the midbrain.

    in RSS PAP on February 10, 2020 05:30 PM.

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    TrkB Signaling Influences Gene Expression in Cortistatin-Expressing Interneurons

    Abstract

    Brain-derived neurotrophic factor (BDNF) signals through its cognate receptor tropomyosin receptor kinase B (TrkB) to promote the function of several classes of inhibitory interneurons. We previously reported that loss of BDNF–TrkB signaling in cortistatin (Cort)-expressing interneurons leads to behavioral hyperactivity and spontaneous seizures in mice. We performed bulk RNA sequencing (RNA-seq) from the cortex of mice with disruption of BDNF–TrkB signaling in cortistatin interneurons, and identified differential expression of genes important for excitatory neuron function. Using translating ribosome affinity purification and RNA-seq, we define a molecular profile for Cort-expressing inhibitory neurons and subsequently compare the translatome of normal and TrkB-depleted Cort neurons, revealing alterations in calcium signaling and axon development. Several of the genes enriched in Cort neurons and differentially expressed in TrkB-depleted neurons are also implicated in autism and epilepsy. Our findings highlight TrkB-dependent molecular pathways as critical for the maturation of inhibitory interneurons and support the hypothesis that loss of BDNF signaling in Cort interneurons leads to altered excitatory/inhibitory balance.

    in eNeuro current issue on February 10, 2020 05:30 PM.

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    Neurogenetics of the Human Adenosine Receptor Genes: Genetic Structures and Involvement in Brain Diseases. (arXiv:2002.02936v1 [q-bio.QM])

    Adenosine receptors are G-protein-coupled receptors involved in a wide range of physiological and pathological phenomena in most mammalian systems. All four receptors are widely expressed in the central nervous system, where they modulate neurotransmitter release and neuronal plasticity. A large number of gene association studies have shown that common genetic variants of the adenosine receptors (encoded by the ADORA1, ADORA2A, ADORA2B and ADORA3 genes) have a neuroprotective or neurodegenerative role in neurologic/psychiatric diseases. New genetic studies of rare variants and few novel associations with depression or epilepsy subtypes have recently been reported. Here, we review the literature on the genetics of adenosine receptors in neurologic and/or psychiatric diseases in humans, and discuss perspectives for further genetic research. We also provide an update on the genetic structures of the four human adenosine receptor genes and their regulation - a topic that has not been extensively addressed. Our review emphasizes the importance of (i) better characterizing the genetics of adenosine receptor genes and (ii) understanding how these genes are regulated.

    in q-bio.NC updates on arXiv.org on February 10, 2020 01:30 AM.

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    Adaptive control for hindlimb locomotion in a simulated mouse through temporal cerebellar learning. (arXiv:2002.02807v1 [q-bio.NC])

    Human beings and other vertebrates show remarkable performance and efficiency in locomotion, but the functioning of their biological control systems for locomotion is still only partially understood. The basic patterns and timing for locomotion are provided by a central pattern generator (CPG) in the spinal cord. The cerebellum is known to play an important role in adaptive locomotion. Recent studies have given insights into the error signals responsible for driving the cerebellar adaptation in locomotion. However, the question of how the cerebellar output influences the gait remains unanswered. We hypothesize that the cerebellar correction is applied to the pattern formation part of the CPG. Here, a bio-inspired control system for adaptive locomotion of the musculoskeletal system of the mouse is presented, where a cerebellar-like module adapts the step time by using the double support interlimb asymmetry as a temporal teaching signal. The control system is tested on a simulated mouse in a split-belt treadmill setup similar to those used in experiments with real mice. The results show adaptive locomotion behavior in the interlimb parameters similar to that seen in humans and mice. The control system adaptively decreases the double support asymmetry that occurs due to environmental perturbations in the split-belt protocol.

    in q-bio.NC updates on arXiv.org on February 10, 2020 01:30 AM.

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    Implementing Inductive bias for different navigation tasks through diverse RNN attractors. (arXiv:2002.02496v1 [q-bio.NC])

    Navigation is crucial for animal behavior and is assumed to require an internal representation of the external environment, termed a cognitive map. The precise form of this representation is often considered to be a metric representation of space. An internal representation, however, is judged by its contribution to performance on a given task, and may thus vary between different types of navigation tasks. Here we train a recurrent neural network that controls an agent performing several navigation tasks in a simple environment. To focus on internal representations, we split learning into a task-agnostic pre-training stage that modifies internal connectivity and a task-specific Q learning stage that controls the network's output. We show that pre-training shapes the attractor landscape of the networks, leading to either a continuous attractor, discrete attractors or a disordered state. These structures induce bias onto the Q-Learning phase, leading to a performance pattern across the tasks corresponding to metric and topological regularities. By combining two types of networks in a modular structure, we could get better performance for both regularities. Our results show that, in recurrent networks, inductive bias takes the form of attractor landscapes -- which can be shaped by pre-training and analyzed using dynamical systems methods. Furthermore, we demonstrate that non-metric representations are useful for navigation tasks, and their combination with metric representation leads to flexibile multiple-task learning.

    in q-bio.NC updates on arXiv.org on February 10, 2020 01:30 AM.

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    Criticality or Supersymmetry Breaking ?. (arXiv:1609.00001v3 [q-bio.NC] UPDATED)

    In many stochastic dynamical systems, ordinary chaotic behavior is preceded by a full-dimensional phase that exhibits 1/f-type power-spectra and/or scale-free statistics of (anti)instantons such as neuroavalanches, earthquakes, etc. In contrast with the phenomenological concept of self-organized criticality, the recently developed approximation-free supersymmetric theory of stochastic differential equations, or stochastics, (STS) identifies this phase as the noise-induced chaos (N-phase), i.e., the phase where the topological supersymmetry pertaining to all stochastic dynamical systems is broken spontaneously by the condensation of the noise-induced (anti-)instantons. Here, we support this picture in the context of neurodynamics. We study a 1D chain of neuron-like elements and find that the dynamics in the N-phase is indeed featured by positive stochastic Lyapunov exponents and dominated by (anti)instantonic processes of (creation)annihilation of kinks and antikinks, which can be viewed as predecessors of boundaries of neuroavalanches. We also construct the phase diagram of emulated stochastic neurodynamics on Spikey neuromorphic hardware and demonstrate that the width of the N-phase vanishes in the deterministic limit in accordance with STS. As a first result of the application of STS to neurodynamics comes the conclusion that a conscious brain can reside only in the N-phase.

    in q-bio.NC updates on arXiv.org on February 10, 2020 01:30 AM.

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    Myelin degeneration and diminished myelin renewal contribute to age-related deficits in memory

    Nature Neuroscience, Published online: 10 February 2020; doi:10.1038/s41593-020-0588-8

    Wang et al. show that myelination is greatly inhibited in aged brains. Enhancing myelination by ablation of M1R in OPCs or clemastine treatment promotes oligodendroglial differentiation and consequently rescues spatial memory decline during aging.

    in Nature Neuroscience - Issue - nature.com science feeds on February 10, 2020 12:00 AM.

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    Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke

    Nature Neuroscience, Published online: 10 February 2020; doi:10.1038/s41593-020-0585-y

    The authors establish inducible Cxcr4-CreER-based fate mapping as a universal means to identify bone-marrow-derived myeloid cells in the injured brain and demonstrate that Cxcr4 deficiency affects the innate immune response and outcome after stroke.

    in Nature Neuroscience - Issue - nature.com science feeds on February 10, 2020 12:00 AM.

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    Preservation of a remote fear memory requires new myelin formation

    Nature Neuroscience, Published online: 10 February 2020; doi:10.1038/s41593-019-0582-1

    Fear learning induces myelin formation. In the absence of new myelination, remote fear memory and neurophysiology of fear memory circuits are impaired. Conversely, administration of the pro-myelinating drug clemastine enhances remote fear memory.

    in Nature Neuroscience - Issue - nature.com science feeds on February 10, 2020 12:00 AM.

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    Improved tools to study astrocytes

    Nature Reviews Neuroscience, Published online: 10 February 2020; doi:10.1038/s41583-020-0264-8

    Much progress has been made in understanding astrocytes, but details on their functions and interactions remain difficult to determine. Yu, Nagai and Khakh give an overview of recent advances in the toolbox for molecular, genetic, morphological and physiological investigations into astrocytes.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on February 10, 2020 12:00 AM.

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    Immune cell regulation of glia during CNS injury and disease

    Nature Reviews Neuroscience, Published online: 10 February 2020; doi:10.1038/s41583-020-0263-9

    Interactions between immune cells and neurons are now widely believed to be important for the regulation of brain function. In their Review, Greenhalgh, David and Bennett highlight the importance of interactions between resident and infiltrating immune cells and the brain’s other major cellular population — glial cells — for brain function.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on February 10, 2020 12:00 AM.

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    Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories

    Nature Reviews Neuroscience, Published online: 10 February 2020; doi:10.1038/s41583-019-0260-z

    The dentate gyrus has an important role in memory formation in the hippocampus. In this Review, Thomas Hainmueller and Marlene Bartos examine the cells and circuits of the dentate gyrus, and discuss the evidence indicating that this brain region has multiple mnemonic functions.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on February 10, 2020 12:00 AM.

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    TLR4 signaling in neurons enhances calcium‐permeable AMPAR currents and drives post‐traumatic epileptogenesis

    Annals of Neurology TLR4 signaling in neurons enhances calcium‐permeable AMPAR currents and drives post‐traumatic epileptogenesis

    Graphic illustration of the effect of injury and early TLR4 antagonist treatment on early network excitability and the long‐term network state. The schematic neurons include TLR4 and AMPAR subunit expression profiles in the acute phase of sham or brain injury. The corresponding early effects on network excitability are depicted by schematic population response traces (inset on upper left). Note the increase in excitability of the uninjured neuron after TLR4 antagonism without changes in AMPAR expression. Note also the increase in TLR4, calcium permeable AMPARs and population excitability after injury and its reduction by TLR4 antagonist treatment. Ampakine enhancement of excitability during TLR4 antagonism is illustrated. The early phase responses and manipulations (including injury, treatments, and molecular responses) are superimposed on a two‐tone color‐coded network state topology where green indicates low‐normal network excitability, ensuring network stability and low risk for epilepsy (Inset on upper right). Note the correspondence between early excitability state (population response profile) and long‐term seizure susceptibility and the effects of pharmacological manipulations.


    Abstract

    Objective

    Traumatic brain injury is a major risk factor for acquired epilepsies and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor, toll‐like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury.

    Methods

    Slice and in vivo electrophysiology and western blots were conducted in rats subject to fluid percussion brain injury or sham injury.

    Results

    The studies identify that TLR4 signaling in neurons, augments dentate granule cell calcium‐permeable AMPA receptor (CP‐AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce post‐injury seizure susceptibility. Further, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls.

    Interpretation

    These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post‐traumatic neuronal excitability. Moreover, the TLR4‐dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4‐mediated increase in CP‐AMPAR signaling after injury may prevent epileptogenesis after brain trauma.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 09, 2020 08:00 AM.

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    Longitudinal neuroimaging over 30 days: Temporal Characteristics of Migraine

    Abstract

    Objective

    Although migraine is defined by the headache and headache associated symptoms, the true beginning of a migraine attack lies in the premonitory phase and to understand the generation of attacks one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well described complex of symptoms. Its duration, however, is not clearly defined and there are to date no biomarkers to help defining when this phase starts.

    Methods

    Here we used functional magnetic resonance imaging to elucidate the duration of the premonitory phase in spontaneous human migraine attacks. As migraine attacks are hardly predictable and thereby the premonitory phase difficult to catch, we scanned nine patients daily over a minimum period of 30 days using a well‐established paradigm for functional MRI of trigeminal nociception.

    Results

    Seven patients were included in the analysis thus providing cumulative data of 27 spontaneous human migraine attacks including scans before, during and after migraine pain as well as interictal scans. As a response to painful trigeminal stimulation activation of the hypothalamus was present within the last 48 hours before headache onset but not earlier.

    Conclusions

    Using hypothalamic activation as a potential marker for the premonitory phase of migraine in this unique data set, our data thus corroborate a duration of 48 hours for the premonitory phase of migraine and we suggest to apply this timely criterion in future studies when focussing on this particular phase of the migraine cycle.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 09, 2020 08:00 AM.

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    Coffee consumption and risk of stroke: a Mendelian randomization study

    Abstract

    Objective

    Observational epidemiological studies have reported a relationship between coffee intake and risk of stroke. However, evidence for this association is inconsistent and it remains uncertain whether the association is causal or due to confounding or reverse causality. To clarify this relationship, we adopted a Mendelian randomization (MR) approach to evaluate the effects of coffee consumption on the risk of stroke and its subtypes.

    Method

    A meta‐analysis of genome‐wide association studies (GWASs) including 91,462 coffee consumers was used to identify instruments for coffee consumption. Summary‐level data for stroke, intracerebral hemorrhage, ischemic stroke (IS) and IS subtypes were obtained from GWAS meta‐analyses conducted by the MEGASTROKE consortium. MR analyses were performed using the inverse‐variance‐weighted (IVW), weighted‐median, MR Pleiotropy RESidual Sum and Outlier (PRESSO) test and MR‐Egger regression. Sensitivity analyses were further performed using alternative instruments to test the robustness of our findings.

    Results

    Genetically predicted coffee consumption (high vs. infrequent/no) was not associated with risk of stroke. Similarly, among coffee consumers, MR analysis did not indicate causal associations between coffee consumption (cups/day) and risk of stroke. However, in the subgroup analysis, we found weak suggestive evidence for a potential protective effect of coffee consumption on risk of small vessel ischemic stroke (SV‐IS), though the association did not reach statistical significance after correction for multiple comparisons.

    Interpretation

    This study suggests that coffee consumption is not causally associated with risk of stroke or its subtypes. Further studies are warranted to elucidate the possible association between coffee intake and risk of SV‐IS, as well as its potential underlying mechanisms.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 09, 2020 08:00 AM.

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    Visual dysfunction of the superior colliculus in de novo Parkinsonian patients

    Abstract

    Objectives

    The dual hit hypothesis about the pathogenesis of Parkinson's disease suggests that the brainstem is a convergent area for the propagation of pathological α‐synuclein from the periphery to the brain. While brainstem structures are likely to be affected early in the course of the disease, detailed information regarding specific brainstem regions is lacking.

    The aim of our study was to investigate the function of the superior colliculus, a sensori‐motor brainstem structure, in de novo Parkinson's patients compared to controls using brain functional magnetic imaging and visual stimulation paradigms.

    Methods

    De novo Parkinson's patients and controls were recruited. PD subjects were imaged before and after starting PD medications. A recently developed functional magnetic resonance imaging protocol was used to stimulate and visualize the superior colliculus and two other visual structures: the lateral geniculate nucleus and the primary visual cortex.

    Results

    In the 22 parkinsonian patients, there was no modulation of the superior colliculus responses to the luminance contrasts compared to controls. This implies a hypersensitivity to low luminance contrast and abnormal rapid BOLD signal saturation to high luminance contrasts. The lateral geniculate nucleus was only modulated by 3%‐9% luminance contrasts, compared to controls. No major differences were found in the primary visual cortex between both groups.

    Interpretation

    Our findings suggest that pathological superior colliculus visual responses in de novo Parkinson's disease patients are present early on the course of the disease. Thus, changes in imaging the superior colliculus could play an important role as a preclinical biomarker of the disease.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 09, 2020 08:00 AM.

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    SmartPhase: Accurate and fast phasing of heterozygous variant pairs for genetic diagnosis of rare diseases

    by Paul Hager, Hans-Werner Mewes, Meino Rohlfs, Christoph Klein, Tim Jeske

    There is an increasing need to use genome and transcriptome sequencing to genetically diagnose patients suffering from suspected monogenic rare diseases. The proper detection of compound heterozygous variant combinations as disease-causing candidates is a challenge in diagnostic workflows as haplotype information is lost by currently used next-generation sequencing technologies. Consequently, computational tools are required to phase, or resolve the haplotype of, the high number of heterozygous variants in the exome or genome of each patient. Here we present SmartPhase, a phasing tool designed to efficiently reduce the set of potential compound heterozygous variant pairs in genetic diagnoses pipelines. The phasing algorithm of SmartPhase creates haplotypes using both parental genotype information and reads generated by DNA or RNA sequencing and is thus well suited to resolve the phase of rare variants. To inform the user about the reliability of a phasing prediction, it computes a confidence score which is essential to select error-free predictions. It incorporates existing haplotype information and applies logical rules to determine variants that can be excluded as causing a recessive, monogenic disease. SmartPhase can phase either all possible variant pairs in predefined genetic loci or preselected variant pairs of interest, thus keeping the focus on clinically relevant results. We compared SmartPhase to WhatsHap, one of the leading comparable phasing tools, using simulated data and a real clinical cohort of 921 patients. On both data sets, SmartPhase generated error-free predictions using our derived confidence score threshold. It outperformed WhatsHap with regard to the percentage of resolved pairs when parental genotype information is available. On the cohort data, SmartPhase enabled on average the exclusion of approximately 22% of the input variant pairs in each singleton patient and 44% in each trio patient. SmartPhase is implemented as an open-source Java tool and freely available at http://ibis.helmholtz-muenchen.de/smartphase/.

    in PLOS Computational Biology: New Articles on February 07, 2020 10:00 PM.

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    Multi-state design of flexible proteins predicts sequences optimal for conformational change

    by Marion F. Sauer, Alexander M. Sevy, James E. Crowe Jr., Jens Meiler

    Computational protein design of an ensemble of conformations for one protein–i.e., multi-state design–determines the side chain identity by optimizing the energetic contributions of that side chain in each of the backbone conformations. Sampling the resulting large sequence-structure search space limits the number of conformations and the size of proteins in multi-state design algorithms. Here, we demonstrated that the REstrained CONvergence (RECON) algorithm can simultaneously evaluate the sequence of large proteins that undergo substantial conformational changes. Simultaneous optimization of side chain conformations across all conformations increased sequence conservation when compared to single-state designs in all cases. More importantly, the sequence space sampled by RECON MSD resembled the evolutionary sequence space of flexible proteins, particularly when confined to predicting the mutational preferences of limited common ancestral descent, such as in the case of influenza type A hemagglutinin. Additionally, we found that sequence positions which require substantial changes in their local environment across an ensemble of conformations are more likely to be conserved. These increased conservation rates are better captured by RECON MSD over multiple conformations and thus multiple local residue environments during design. To quantify this rewiring of contacts at a certain position in sequence and structure, we introduced a new metric designated ‘contact proximity deviation’ that enumerates contact map changes. This measure allows mapping of global conformational changes into local side chain proximity adjustments, a property not captured by traditional global similarity metrics such as RMSD or local similarity metrics such as changes in φ and ψ angles.

    in PLOS Computational Biology: New Articles on February 07, 2020 10:00 PM.

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    Neuronal strategies for meeting the right partner during brain wiring

    Publication date: August 2020

    Source: Current Opinion in Neurobiology, Volume 63

    Author(s): Egemen Agi, Abhishek Kulkarni, Peter Robin Hiesinger

    Two neurons can only form a synapse if their axonal and dendritic projections meet at the same time and place. While spatiotemporal proximity is necessary for synapse formation, it remains unclear to what extent the underlying positional strategies are sufficient to ensure synapse formation between the right partners. Many neurons readily form synapses with wrong partners if they find themselves at the wrong place or time. Minimally, restricting spatiotemporal proximity can prevent incorrect synapses. Maximally, restricting encounters in time and space could be sufficient to ensure correct partnerships between neurons that can form synapses promiscuously. In this review we explore recent findings on positional strategies during developmental growth that contribute to precise outcomes in brain wiring.

    in ScienceDirect Publication: Current Opinion in Neurobiology on February 07, 2020 07:00 PM.

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    Longitudinal positron emission tomography of dopamine synthesis in subjects with GBA1 mutations

    Abstract

    Mutations in GBA1, the gene mutated in Gaucher disease, are a common genetic risk factor for Parkinson disease, although the penetrance is low. We performed [18F]‐Fluorodopa PET studies of 57 homozygous and heterozygous GBA1 mutation carriers (15 with parkinsonism) and 98 controls looking for early indications of dopamine loss using voxel‐wise analyses to identify group differences in striatal [18F]‐Fluorodopa uptake (Ki). Forty‐eight subjects were followed longitudinally. Cross‐sectional and longitudinal comparisons of Ki and Ki‐change found significant effects of Parkinson disease. However, at baseline and over time, striatal [18F]‐Fluorodopa uptake in mutation carriers without parkinsonism did not significantly differ from controls.

    This article is protected by copyright. All rights reserved.

    in Wiley: Annals of Neurology: Table of Contents on February 07, 2020 08:00 AM.

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    Locally-Induced CaMKII Translocation Requires Nucleotide Binding

    Calcium-calmodulin-dependent protein kinase (CaMKII) is a molecule involved in several cell processes including plasticity related to learning and memory. Activation of NMDA-type glutamate receptors results in translocation of CaMKII to synapses. However, there are at least two distinct mechanisms by which glutamate-dependent CaMKII translocation occurs: one well-studied process resulting from whole-cell glutamate stimulation and one resulting from brief, local glutamate application. Unlike the relatively fast CaMKII translocation seen following whole-cell glutamate delivery (seconds), local application results in CaMKII translocation that occurs gradually within 6–10 min. This locally-induced translocation of CaMKII requires L-type Ca2+ channel co-activation but does not rely on GluN2B receptor subunit expression, unlike translocation following whole-cell application of glutamate. The current study examined if nucleotide binding is necessary for locally-induced CaMKII translocation, similar to CaMKII translocation resulting from whole-cell glutamate application. Three different mechanisms of inhibition were employed: staurosporine (ATP inhibitor), CaMKII(281–302) peptide inhibitor and expression of the K42M mutation. Locally-induced CaMKII translocation was moderately suppressed in the presence of either the broad-spectrum kinase inhibitor staurosporine (100 nm) or the CaMKII(281–302) peptide inhibitor. However, expression of the catalytically dead K42M mutation that prevents ATP-binding to CaMKII, significantly inhibited locally-induced translocation. Thus, CaMKII translocation following brief, local glutamate application requires nucleotide binding, providing support for future research into the molecular mechanisms of this distinct form of CaMKII translocation.

    in Frontiers in Synaptic Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function

    The brainstem has traditionally been considered an area of the brain with autonomous control of mostly homeostatic functions such as heart rate, respiration, and the sleep and wakefulness state, which would preclude the necessity to exhibit the high degree of synaptic or cellular mechanisms of plasticity typical of regions of the brain responsible for flexible, executive control, such as the medial prefrontal cortex or the hippocampus. The perception that the brainstem does not share the same degree of flexibility to alter synaptic strength and/or wiring within local circuits makes intuitive sense, as it is not easy to understand how “soft wiring” would be an advantage when considering the importance of faithful and consistent performance of the homeostatic, autonomic functions that are controlled by the brainstem. However, many of the molecular and cellular requirements which underlie strengthening of synapses seen in brain regions involved in higher-level processing are present in brainstem nuclei, and recent research suggest that the view of the brainstem as “hard wired,” with rigid and static connectivity and with unchanging synaptic strength, is outdated. In fact, information from studies within the last decades, including work conducted in our group, leads us to propose that the brainstem can dynamically alter synaptic proteins, and change synaptic connections in response to prenatal or postnatal stimuli, and this would likely alter functionality and output. This article reviews recent research that has provided information resulting in our revision of the view of the brainstem as static and non-changing by using as example recent information gleaned from a brainstem pontine nucleus, the laterodorsal tegmentum (LDT). The LDT has demonstrated mechanisms underlying synaptic plasticity, and plasticity has been exhibited in the postnatal LDT following exposure to drugs of abuse. Further, exposure of the brain during gestation to drugs of abuse results in alterations in development of signaling pathways in the LDT. As the LDT provides a high degree of innervation of mesoaccumbal and mesocortical circuits involved in salience, as well as thalamocortical circuits involved in control of arousal and orientation, changes in synaptic strength would be expected to alter output, which would significantly impact behavioral state, motivated behavior and directed attention. Further, alterations in developmental trajectory within the LDT following prenatal exposure to drugs of abuse would be expected to impact on later life expression of motivation and arousal.

    in Frontiers in Synaptic Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Editorial: Shankopathies: Shank Protein Deficiency-Induced Synaptic Diseases

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Zebrafish as a Model System for the Study of Severe CaV2.1 (α1A) Channelopathies

    The P/Q-type CaV2.1 channel regulates neurotransmitter release at neuromuscular junctions (NMJ) and many central synapses. CACNA1A encodes the pore-containing α1A subunit of CaV2.1 channels. In humans, de novo CACNA1A mutations result in a wide spectrum of neurological, neuromuscular, and movement disorders, such as familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2), as well as a more recently discovered class of more severe disorders, which are characterized by ataxia, hypotonia, cerebellar atrophy, and cognitive/developmental delay. Heterologous expression of CaV2.1 channels has allowed for an understanding of the consequences of CACNA1A missense mutations on channel function. In contrast, a mechanistic understanding of how specific CACNA1A mutations lead in vivo to the resultant phenotypes is lacking. In this review, we present the zebrafish as a model to both study in vivo mechanisms of CACNA1A mutations that result in synaptic and behavioral defects and to screen for effective drug therapies to combat these and other CaV2.1 channelopathies.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Biomarker Acquisition and Quality Control for Multi-Site Studies: The Autism Biomarkers Consortium for Clinical Trials

    The objective of the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is to evaluate a set of lab-based behavioral video tracking (VT), electroencephalography (EEG), and eye tracking (ET) measures for use in clinical trials with children with autism spectrum disorder (ASD). Within the larger organizational structure of the ABC-CT, the Data Acquisition and Analytic Core (DAAC) oversees the standardization of VT, EEG, and ET data acquisition, data processing, and data analysis. This includes designing and documenting data acquisition and analytic protocols and manuals; facilitating site training in acquisition; data acquisition quality control (QC); derivation and validation of dependent variables (DVs); and analytic deliverables including preparation of data for submission to the National Database for Autism Research (NDAR). To oversee consistent application of scientific standards and methodological rigor for data acquisition, processing, and analytics, we developed standard operating procedures that reflect the logistical needs of multi-site research, and the need for well-articulated, transparent processes that can be implemented in future clinical trials. This report details the methodology of the ABC-CT related to acquisition and QC in our Feasibility and Main Study phases. Based on our acquisition metrics from a preplanned interim analysis, we report high levels of acquisition success utilizing VT, EEG, and ET experiments in a relatively large sample of children with ASD and typical development (TD), with data acquired across multiple sites and use of a manualized training and acquisition protocol.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Multiscale Imaging Approach for Studying the Central Nervous System: Methodology and Perspective

    Non-invasive imaging methods have become essential tools for understanding the central nervous system (CNS) in health and disease. In particular, magnetic resonance imaging (MRI) techniques provide information about the anatomy, microstructure, and function of the brain and spinal cord in vivo non-invasively. However, MRI is limited by its spatial resolution and signal specificity. In order to mitigate these shortcomings, it is crucial to validate MRI with an array of ancillary ex vivo imaging techniques. These techniques include histological methods, such as light and electron microscopy (EM), which can provide specific information on the tissue structure in healthy and diseased brain and spinal cord, at cellular and subcellular level. However, these conventional histological techniques are intrinsically two-dimensional (2D) and, as a result of sectioning, lack volumetric information of the tissue. This limitation can be overcome with genuine three-dimensional (3D) imaging approaches of the tissue. 3D highly resolved information of the CNS achievable by means of other imaging techniques can complement and improve the interpretation of MRI measurements. In this article, we provide an overview of different 3D imaging techniques that can be used to validate MRI. As an example, we introduce an approach of how to combine diffusion MRI and synchrotron X-ray phase contrast tomography (SXRPCT) data. Our approach paves the way for a new multiscale assessment of the CNS allowing to validate and to improve our understanding of in vivo imaging (such as MRI).

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on February 07, 2020 12:00 AM.

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    Systematic Evaluation of Image Tiling Adverse Effects on Deep Learning Semantic Segmentation

    Convolutional neural network (CNN) models obtain state of the art performance on image classification, localization, and segmentation tasks. Limitations in computer hardware, most notably memory size in deep learning accelerator cards, prevent relatively large images, such as those from medical and satellite imaging, from being processed as a whole in their original resolution. A fully convolutional topology, such as U-Net, is typically trained on down-sampled images and inferred on images of their original size and resolution, by simply dividing the larger image into smaller (typically overlapping) tiles, making predictions on these tiles, and stitching them back together as the prediction for the whole image. In this study, we show that this tiling technique combined with translationally-invariant nature of CNNs causes small, but relevant differences during inference that can be detrimental in the performance of the model. Here we quantify these variations in both medical (i.e., BraTS) and non-medical (i.e., satellite) images and show that training a 2D U-Net model on the whole image substantially improves the overall model performance. Finally, we compare 2D and 3D semantic segmentation models to show that providing CNN models with a wider context of the image in all three dimensions leads to more accurate and consistent predictions. Our results suggest that tiling the input to CNN models—while perhaps necessary to overcome the memory limitations in computer hardware—may lead to undesirable and unpredictable errors in the model's output that can only be adequately mitigated by increasing the input of the model to the largest possible tile size.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on February 07, 2020 12:00 AM.

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    Cynomolgus Monkeys With Spontaneous Type-2-Diabetes-Mellitus-Like Pathology Develop Alpha-Synuclein Alterations Reminiscent of Prodromal Parkinson’s Disease and Related Diseases

    Available evidence suggests that diabetes mellitus (DM) is a non-genetic risk factor for Parkinson’s disease (PD). PD and DM have shared similarities in pathogenetic mechanisms, including age, environmental factors, inflammatory reaction, and protein aggregation, etc. α-Synuclein is the primary protein component in the protein inclusions in PD, while islet amyloid polypeptide (IAPP) aggregates to form amyloid structures in β cells in type 2 diabetes mellitus (T2DM). Pancreatic and cerebral functions, pancreas and brain α-synuclein deposition as well as striatal alterations, were assessed in spontaneously developed T2DM monkeys and age-matched normal monkeys. We demonstrated increased accumulation, aggregation, and phosphorylation of α-synuclein, and IAPP in the pancreatic islets of spontaneously developed T2DM monkeys, compared to the age-matched normal subjects. Double immunofluorescence analyses showed complete overlap between α-synuclein and IAPP in the pancreatic islets. In addition, in T2DM monkeys’ brain, we observed concomitantly increased accumulation and phosphorylation of α-synuclein in the cortex, pre-commissural putamen and dopaminergic neurons in the substantia nigra, which interestingly showed high correlation with levels of fasting plasma glucose (FPG), triglyceride (TG), and high density lipoprotein (HDL). Our data indicates the close association between IAPP and α-synuclein and the potential link between T2DM and PD, which implies that T2DM may facilitate PD disease onset and progress by interfering with the pathological protein aggregation both in the pancreatic islets and the brain.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 07, 2020 12:00 AM.

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    Monitoring Depth of Anesthesia Based on Hybrid Features and Recurrent Neural Network

    Electroencephalogram (EEG) signals contain valuable information about the different physiological states of the brain, with a variety of linear and nonlinear features that can be used to investigate brain activity. Monitoring the depth of anesthesia (DoA) with EEG is an ongoing challenge in anesthesia research. In this paper, we propose a novel method based on Long Short-Term Memory (LSTM) and a sparse denoising autoencoder (SDAE) to combine the hybrid features of EEG to monitor the DoA. The EEG signals were preprocessed using filtering, etc., and then more than ten features including sample entropy, permutation entropy, spectra, and alpha-ratio were extracted from the EEG signal. We then integrated the optional features such as permutation entropy and alpha-ratio to extract the essential structure and learn the most efficient temporal model for monitoring the DoA. Compared with using a single feature, the proposed model could accurately estimate the depth of anesthesia with higher prediction probability (Pk). Experimental results evaluated on the datasets demonstrated that our proposed method provided better performance than the methods using permutation entropy, alpha-ratio, LSTM, and other traditional indices.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on February 07, 2020 12:00 AM.

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    Motion Biomarkers Showing Maximum Contrast Between Healthy Subjects and Parkinson's Disease Patients Treated With Deep Brain Stimulation of the Subthalamic Nucleus. A Pilot Study

    Background: Classic motion abnormalities in Parkinson's disease (PD), such as tremor, bradykinesia, or rigidity, are well-covered by standard clinical assessments such as the Unified Parkinson's Disease Rating Scale (UPDRS). However, PD includes motor abnormalities beyond the symptoms and signs as measured by UPDRS, such as the lack of anticipatory adjustments or compromised movement smoothness, which are difficult to assess clinically. Moreover, PD may entail motor abnormalities not yet known. All these abnormalities are quantifiable via motion capture and may serve as biomarkers to diagnose and monitor PD.

    Objective: In this pilot study, we attempted to identify motion features revealing maximum contrast between healthy subjects and PD patients with deep brain stimulation (DBS) of the nucleus subthalamicus (STN) switched off and on as the first step to develop biomarkers for detecting and monitoring PD patients' motor symptoms.

    Methods: We performed 3D gait analysis in 7 out of 26 PD patients with DBS switched off and on, and in 25 healthy control subjects. We computed feature values for each stride, related to 22 body segments, four time derivatives, left–right mean vs. difference, and mean vs. variance across stride time. We then ranked the feature values according to their distinguishing power between PD patients and healthy subjects.

    Results: The foot and lower leg segments proved better in classifying motor anomalies than any other segment. Higher degrees of time derivatives were superior to lower degrees (jerk > acceleration > velocity > displacement). The averaged movements across left and right demonstrated greater distinguishing power than left–right asymmetries. The variability of motion was superior to motion's absolute values.

    Conclusions: This small pilot study identified the variability of a smoothness measure, i.e., jerk of the foot, as the optimal signal to separate healthy subjects' from PD patients' gait. This biomarker is invisible to clinicians' naked eye and is therefore not included in current motor assessments such as the UPDRS. We therefore recommend that more extensive investigations be conducted to identify the most powerful biomarkers to characterize motor abnormalities in PD. Future studies may challenge the composition of traditional assessments such as the UPDRS.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 07, 2020 12:00 AM.

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    A Robust Model System for Retinal Hypoxia: Live Imaging of Calcium Dynamics and Gene Expression Studies in Primary Human Mixed Retinal Culture

    The detailed mechanisms underlying oxidative stress that leads to neuroinflammation and neurodegeneration in retinal vascular conditions, including diabetic retinopathy, retinopathy of prematurity etc., remain largely unexplored mainly due to a lack of suitable disease models that can simulate the inherent neuron–glia interactions in human retina. Specifically, establishment of a mixed retinal culture (MRC) containing both neuron and glial cell types remains a challenge due to different conditions required for their optimal growth and differentiation. Here, we establish a novel primary MRC model system containing neurons, astrocytes, Müller glia, and microglia from human donor retina that can be used to study the neuromodulatory effects of glial cells under the stress. The cell characterization based on immunostaining with individual cell type–specific markers and their presence in close vicinity to each other further underscores their utility for studying their cross talk. To the best of our knowledge, this is the first instance of an in vitro model obtained from human donor retina containing four major cell types. Next, we induce hypoxic stress to MRC to investigate if hypoxia activated neuroglia modulates altered gene expression for inflammatory, apoptotic, and angiogenic markers and Ca2+ transients by live cell imaging. Further, we performed k-means clustering of the Ca2+ responses to identify the modification of clustering pattern in stressed condition. Finally, we provide the evidence that the altered Ca2+ transient correlates to differential expression of genes shown to be involved in neuroinflammation, angiogenesis, and neurodegeneration under the hypoxic conditions as seen earlier in human cell lines and animal models of diabetic retinopathy. The major features of the hypoxic conditions in the proposed human MRC model included: increase in microglia activity, chemokine and cytokine expression, and percentage of cells having higher amplitude and frequency of Ca2+ transients. Thus, the proposed experimental system can potentially serve as an ideal in vitro model for studying the neuroinflammatory and neurodegenerative changes in the retina and identifying newer drug targets.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 07, 2020 12:00 AM.

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    Optimizing Computer–Brain Interface Parameters for Non-invasive Brain-to-Brain Interface

    A non-invasive, brain-to-brain interface (BBI) requires precision neuromodulation and high temporal resolution as well as portability to increase accessibility. A BBI is a combination of the brain–computer interface (BCI) and the computer–brain interface (CBI). The optimization of BCI parameters has been extensively researched, but CBI has not. Parameters taken from the BCI and CBI literature were used to simulate a two-class medical monitoring BBI system under a wide range of conditions. BBI function was assessed using the information transfer rate (ITR), measured in bits per trial and bits per minute. The BBI ITR was a function of classifier accuracy, window update rate, system latency, stimulation failure rate (SFR), and timeout threshold. The BCI parameters, including window length, update rate, and classifier accuracy, were kept constant to investigate the effects of varying the CBI parameters, including system latency, SFR, and timeout threshold. Based on passively monitoring BCI parameters, a base ITR of 1 bit/trial was used. The optimal latency was found to be 100 ms or less, with a threshold no more than twice its value. With the optimal latency and timeout parameters, the system was able to maintain near-maximum efficiency, even with a 25% SFR. When the CBI and BCI parameters are compared, the CBI’s system latency and timeout threshold should be reflected in the BCI’s update rate. This would maximize the number of trials, even at a high SFR. These findings suggested that a higher number of trials per minute optimizes the ITR of a non-invasive BBI. The delays innate to each BCI protocol and CBI stimulation method must also be accounted for. The high latencies in each are the primary constraints of non-invasive BBI for the foreseeable future.

    in Frontiers in Neuroinformatics | New and Recent Articles on February 07, 2020 12:00 AM.

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    Clustering of Brain Function Network Based on Attribute and Structural Information and Its Application in Brain Diseases

    At present, the diagnosis of brain disease is mainly based on the self-reported symptoms and clinical signs of the patient, which can easily lead to psychiatrists' bias. The purpose of this study is to develop a brain network clustering model to accurately identify brain diseases based on resting state functional magnetic resonance imaging (fMRI) in the absence of clinical information. We use cosine similarity and sub-network kernels to measure attribute similarity and structure similarity, respectively. By integrating the structure similarity and attribute similarity into one matrix, spectral clustering is used to achieve brain network clustering. Finally, we evaluate this method on three diseases: Alzheimer's disease, Bipolar disorder patients, and Schizophrenia. The performance of methods is evaluated by measuring clustering consistency. Clustering consistency is similar to clustering accuracy, which is used to evaluate the consistency between the clustering labels and clinical diagnostic labels of the subjects. The experimental results show that our proposed method can significantly improve clustering performance, with a consistency of 60.6% for Alzheimer's disease, with a consistency of 100% for Schizophrenia, with a consistency of 100% for Bipolar disorder patients.

    in Frontiers in Neuroinformatics | New and Recent Articles on February 07, 2020 12:00 AM.

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    The Effect of Visual Articulatory Information on the Neural Correlates of Non-native Speech Sound Discrimination

    Behavioral studies have shown that the ability to discriminate between non-native speech sounds improves after seeing how the sounds are articulated. This study examined the influence of visual articulatory information on the neural correlates of non-native speech sound discrimination. English speakers’ discrimination of the Hindi dental and retroflex sounds was measured using the mismatch negativity (MMN) event-related potential, before and after they completed one of three 8-min training conditions. In an audio-visual speech training condition (n = 14), each sound was presented with its corresponding visual articulation. In one control condition (n = 14), both sounds were presented with the same visual articulation, resulting in one congruent and one incongruent audio-visual pairing. In another control condition (n = 14), both sounds were presented with the same image of a still face. The control conditions aimed to rule out the possibility that the MMN is influenced by non-specific audio-visual pairings, or by general exposure to the dental and retroflex sounds over the course of the study. The results showed that audio-visual speech training reduced the latency of the MMN but did not affect MMN amplitude. No change in MMN amplitude or latency was observed for the two control conditions. The pattern of results suggests that a relatively short audio-visual speech training session (i.e., 8 min) may increase the speed with which the brain processes non-native speech sound contrasts. The absence of a training effect on MMN amplitude suggests a single session of audio-visual speech training does not lead to the formation of more discrete memory traces for non-native speech sounds. Longer and/or multiple sessions might be needed to influence the MMN amplitude.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    TEAMwork: Testing Emotional Attunement and Mutuality During Parent-Adolescent fMRI

    The parent-child relationship and family context influence the development of emotion regulation (ER) brain circuitry and related skills in children and adolescents. Although both parents’ and children’s ER neurocircuitry simultaneously affect how they interact with one another, neuroimaging studies of parent-child relationships typically include only one member of the dyad in brain imaging procedures. The current study examined brain activation related to parenting and ER in parent-adolescent dyads during concurrent fMRI scanning with a novel task – the Testing Emotional Attunement and Mutuality (TEAM) task. The TEAM task includes feedback trials indicating the other dyad member made an error, resulting in a monetary loss for both participants. Results indicate that positive parenting practices as reported by the adolescent were positively correlated with parents’ hemodynamic activation of the ventromedial prefrontal cortex, a region related to empathy, during these error trials. Additionally, during feedback conditions both parents and adolescents exhibited fMRI activation in ER-related regions, including the dorsolateral prefrontal cortex, anterior insula, fusiform gyrus, thalamus, caudate, precuneus, and superior parietal lobule. Adolescents had higher left amygdala activation than parents during the feedback condition. These findings demonstrate the utility of dyadic fMRI scanning for investigating relational processes, particularly in the parent-child relationship.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    A Curiosity-Based Learning Method for Spiking Neural Networks

    Spiking Neural Networks (SNNs) have shown favorable performance recently. Nonetheless, the time-consuming computation on neuron level and complex optimization limit their real-time application. Curiosity has shown great performance in brain learning, which helps biological brains grasp new knowledge efficiently and actively. Inspired by this leaning mechanism, we propose a curiosity-based SNN (CBSNN) model, which contains four main learning processes. Firstly, the network is trained with biologically plausible plasticity principles to get the novelty estimations of all samples in only one epoch; secondly, the CBSNN begins to repeatedly learn the samples whose novelty estimations exceed the novelty threshold and dynamically update the novelty estimations of samples according to the learning results in five epochs; thirdly, in order to avoid the overfitting of the novel samples and forgetting of the learned samples, CBSNN retrains all samples in one epoch; finally, step two and step three are periodically taken until network convergence. Compared with the state-of-the-art Voltage-driven Plasticity-centric SNN (VPSNN) under standard architecture, our model achieves a higher accuracy of 98.55% with only 54.95% of its computation cost on the MNIST hand-written digit recognition dataset. Similar conclusion can also be found out in other datasets, i.e., Iris, NETtalk, Fashion-MNIST, and CIFAR-10, respectively. More experiments and analysis further prove that such curiosity-based learning theory is helpful in improving the efficiency of SNNs. As far as we know, this is the first practical combination of the curiosity mechanism and SNN, and these improvements will make the realistic application of SNNs possible on more specific tasks within the von Neumann framework.

    in Frontiers in Computational Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Demystifying Brain Tumor Segmentation Networks: Interpretability and Uncertainty Analysis

    The accurate automatic segmentation of gliomas and its intra-tumoral structures is important not only for treatment planning but also for follow-up evaluations. Several methods based on 2D and 3D Deep Neural Networks (DNN) have been developed to segment brain tumors and to classify different categories of tumors from different MRI modalities. However, these networks are often black-box models and do not provide any evidence regarding the process they take to perform this task. Increasing transparency and interpretability of such deep learning techniques is necessary for the complete integration of such methods into medical practice. In this paper, we explore various techniques to explain the functional organization of brain tumor segmentation models and to extract visualizations of internal concepts to understand how these networks achieve highly accurate tumor segmentations. We use the BraTS 2018 dataset to train three different networks with standard architectures and outline similarities and differences in the process that these networks take to segment brain tumors. We show that brain tumor segmentation networks learn certain human-understandable disentangled concepts on a filter level. We also show that they take a top-down or hierarchical approach to localizing the different parts of the tumor. We then extract visualizations of some internal feature maps and also provide a measure of uncertainty with regards to the outputs of the models to give additional qualitative evidence about the predictions of these networks. We believe that the emergence of such human-understandable organization and concepts might aid in the acceptance and integration of such methods in medical diagnosis.

    in Frontiers in Computational Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Cell-Type-Specific Whole-Brain Direct Inputs to the Anterior and Posterior Piriform Cortex

    The piriform cortex (PC) is a key brain area involved in both processing and coding of olfactory information. It is implicated in various brain disorders, such as epilepsy, Alzheimer’s disease, and autism. The PC consists of the anterior (APC) and posterior (PPC) parts, which are different anatomically and functionally. However, the direct input networks to specific neuronal populations within the APC and PPC remain poorly understood. Here, we mapped the whole-brain direct inputs to the two major neuronal populations, the excitatory glutamatergic principal neurons and inhibitory γ-aminobutyric acid (GABA)-ergic interneurons within the APC and PPC using the rabies virus (RV)-mediated retrograde trans-synaptic tracing system. We found that for both types of neurons, APC and PPC share some similarities in input networks, with dominant inputs originating from the olfactory region (OLF), followed by the cortical subplate (CTXsp), isocortex, cerebral nuclei (CNU), hippocampal formation (HPF) and interbrain (IB), whereas the midbrain (MB) and hindbrain (HB) were rarely labeled. However, APC and PPC also show distinct features in their input distribution patterns. For both types of neurons, the input proportion from the OLF to the APC was higher than that to the PPC; while the PPC received higher proportions of inputs from the HPF and CNU than the APC did. Overall, our results revealed the direct input networks of both excitatory and inhibitory neuronal populations of different PC subareas, providing a structural basis to analyze the diverse PC functions.

    in Frontiers in Neural Circuits | New and Recent Articles on February 07, 2020 12:00 AM.

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    Functional and Metabolic Characterization of Microglia Culture in a Defined Medium

    Microglia are the endogenous immune cells of the brain and act as sensor of infection and pathologic injury to the brain, leading to a rapid plastic process of activation that culminates in the endocytosis and phagocytosis of damaged tissue. Microglia cells are the most plastic cells in the brain. Microglia isolation from their environment as well as culturing them in the presence of serum alter their function and lead to a rapid loss of their signature gene expression. Previous studies have identified pivotal factors allowing microglia culture in the absence of serum. Here, we have further characterized the function, expression of markers, metabolic status and response to pro and anti-inflammatory stimulus of microglia isolated by magnetic-activated cell sorting and cultured in a chemically defined medium. We have compared this new method with previous traditional protocols of culturing microglia that use high concentrations of serum.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    TTX-Resistant Sodium Channels Functionally Separate Silent From Polymodal C-nociceptors

    Pronounced activity-dependent slowing of conduction has been used to characterize mechano-insensitive, “silent” nociceptors and might be due to high expression of NaV1.8 and could, therefore, be characterized by their tetrodotoxin-resistance (TTX-r). Nociceptor-class specific differences in action potential characteristics were studied by: (i) in vitro calcium imaging in single porcine nerve growth factor (NGF)-responsive neurites; (ii) in vivo extracellular recordings in functionally identified porcine silent nociceptors; and (iii) in vitro patch-clamp recordings from murine silent nociceptors, genetically defined by nicotinic acetylcholine receptor subunit alpha-3 (CHRNA3) expression. Porcine TTX-r neurites (n = 26) in vitro had more than twice as high calcium transients per action potential as compared to TTX-s neurites (n = 18). In pig skin, silent nociceptors (n = 14) characterized by pronounced activity-dependent slowing of conduction were found to be TTX-r, whereas polymodal nociceptors were TTX-s (n = 12) and had only moderate slowing. Mechano-insensitive cold nociceptors were also TTX-r but showed less activity-dependent slowing than polymodal nociceptors. Action potentials in murine silent nociceptors differed from putative polymodal nociceptors by longer duration and higher peak amplitudes. Longer duration AP in silent murine nociceptors linked to increased sodium load would be compatible with a pronounced activity-dependent slowing in pig silent nociceptors and longer AP durations could be in line with increased calcium transients per action potential observed in vitro in TTX-resistant NGF responsive porcine neurites. Even though there is no direct link between slowing and TTX-resistant channels, the results indicate that axons of silent nociceptors not only differ in their receptive but also in their axonal properties.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Microbial BMAA and the Pathway for Parkinson’s Disease Neurodegeneration

    The neurotoxin β-N-methylamino-L-alanine (BMAA) is a natural non-proteinogenic diamino acid produced by several species of both prokaryotic (cyanobacteria) and eukaryotic (diatoms and dinoflagellates) microorganisms. BMAA has been shown to biomagnify through the food chain in some ecosystems, accumulating for example in seafood such as shellfish and fish, common dietary sources of BMAA whose ingestion may have possible neuronal consequences. In addition to its excitotoxic potential, BMAA has been implicated in protein misfolding and aggregation, inhibition of specific enzymes and neuroinflammation, all hallmark features of neurodegenerative diseases. However, the exact molecular mechanisms of neurotoxicity remain to be elucidated in detail. Although BMAA is commonly detected in its free form, complex BMAA-containing molecules have also been identified such as the paenilamicins, produced by an insect gut bacterial pathogen. On the other hand, production of BMAA or BMAA-containing molecules by members of the human gut microbiota, for example by non-photosynthetic cyanobacteria, the Melainabacteria, remains only hypothetical. In any case, should BMAA reach the gut it may interact with cells of the mucosal immune system and neurons of the enteric nervous system (ENS) and possibly target the mitochondria. Here, we review the available evidence and hint on possible mechanisms by which chronic exposure to dietary sources of this microbial neurotoxin may drive protein misfolding and mitochondrial dysfunction with concomitant activation of innate immune responses, chronic low-grade gut inflammation, and ultimately the neurodegenerative features observed across the gut-brain axis in Parkinson’s disease (PD).

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Electrophile Signaling and Emerging Immuno- and Neuro-modulatory Electrophilic Pharmaceuticals

    With a lipid-rich environment and elevated oxygen consumption, the central nervous system (CNS) is subject to intricate regulation by lipid-derived electrophiles (LDEs). Investigations into oxidative damage and chronic LDE generation in neural disorders have spurred the development of tools that can detect and catalog the gamut of LDE-adducted proteins. Despite these advances, deconstructing the precise consequences of individual protein-specific LDE modifications remained largely impossible until recently. In this perspective, we first overview emerging toolsets that can decode electrophile-signaling events in a protein/context-specific manner, and how the accumulating mechanistic insights brought about by these tools have begun to offer new means to modulate pathways relevant to multiple sclerosis (MS). By surveying the latest data surrounding the blockbuster MS drug dimethyl fumarate that functions through LDE-signaling-like mechanisms, we further provide a vision for how chemical biology tools probing electrophile signaling may be leveraged toward novel interventions in CNS disease.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 07, 2020 12:00 AM.

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    Modelling Parkinson disease

    Nature Reviews Neuroscience, Published online: 06 February 2020; doi:10.1038/s41583-020-0273-7

    Modelling Parkinson disease

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on February 06, 2020 12:00 AM.

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    Dendritic motors

    Nature Reviews Neuroscience, Published online: 06 February 2020; doi:10.1038/s41583-020-0272-8

    Dendritic motors

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on February 06, 2020 12:00 AM.

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    Astrocytic cueing of neuronal migration

    Nature Reviews Neuroscience, Published online: 06 February 2020; doi:10.1038/s41583-020-0271-9

    Astrocytic cueing of neuronal migration

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on February 06, 2020 12:00 AM.

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    Sodium intake regulation

    Nature Reviews Neuroscience, Published online: 06 February 2020; doi:10.1038/s41583-020-0270-x

    Sodium intake regulation

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on February 06, 2020 12:00 AM.

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    Macroscopic gradients of synaptic excitation and inhibition in the neocortex

    Nature Reviews Neuroscience, Published online: 06 February 2020; doi:10.1038/s41583-020-0262-x

    Certain biological properties vary across different areas of the cerebral cortex. In this Perspective, Xiao-Jing Wang proposes that macroscopic gradients in some properties align with functional hierarchy and can lead to qualitative differences in function.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on February 06, 2020 12:00 AM.

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    A Prototypical Template for Rapid Face Detection Is Embedded in the Monkey Superior Colliculus

    Human babies respond preferentially to faces or face-like images. It has been proposed that an innate and rapid face detection system is present at birth before the cortical visual pathway is developed in many species, including primates. However, in primates, the visual area responsible for this process is yet to be unraveled. We hypothesized that the superior colliculus (SC) that receives direct and indirect retinal visual inputs may serve as an innate rapid face-detection system in primates. To test this hypothesis, we examined the responsiveness of monkey SC neurons to first-order information of faces required for face detection (basic spatial layout of facial features including eyes, nose, and mouth), by analyzing neuronal responses to line drawing images of: (1) face-like patterns with contours and properly placed facial features; (2) non-face patterns including face contours only; and (3) nonface random patterns with contours and randomly placed face features. Here, we show that SC neurons respond stronger and faster to upright and inverted face-like patterns compared to the responses to nonface patterns, regardless of contrast polarity and contour shapes. Furthermore, SC neurons with central receptive fields (RFs) were more selective to face-like patterns. In addition, the population activity of SC neurons with central RFs can discriminate face-like patterns from nonface patterns as early as 50 ms after the stimulus onset. Our results provide strong neurophysiological evidence for the involvement of the primate SC in face detection and suggest the existence of a broadly tuned template for face detection in the subcortical visual pathway.

    in Frontiers in Systems Neuroscience | New and Recent Articles on February 06, 2020 12:00 AM.

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    Transcutaneous Electrical Spinal Cord Neuromodulator (TESCoN) Improves Symptoms of Overactive Bladder

    Neuromodulation is a therapeutic technique that is well-established in the treatment of idiopathic Lower urinary tract (LUT) dysfunction such as overactive bladder (OAB). We have recently developed a novel neuromodulation approach, Transcutaneous Electrical Spinal Cord Neuromodulation (TESCoN) and demonstrated its acute effects on LUT dysfunction after spinal cord injury (SCI) during urodynamic studies. We found that TESCoN can promote urinary storage and induce urinary voiding when delivered during urodynamic studies. The objective of this study was to determine whether TESCoN can retrain the spinal neural networks to induce chronic improvement in the LUT, such that positive changes can persist even in the absence of stimulation. In addition, we wished to examine the effect of TESCoN on LUT dysfunction due to multiple pathologies. To achieve this objective, 14 patients [SCI = 5, stroke = 5, multiple sclerosis (MS) = 3, and idiopathic OAB (iOAB) = 1] completed 24 sessions of TESCoN over the course of 8 weeks. Patients completed urodynamic studies before and after undergoing TESCoN therapy. Additionally, each subject completed a voiding diary and the Neurogenic Bladder Symptom Score questionnaire before and after receiving TESCoN therapy. We found that TESCoN led to decreased detrusor overactivity, improved continence, and enhanced LUT sensation across the different pathologies underlying LUT dysfunction. This study serves as a pilot in preparation for a rigorous randomized placebo-controlled trial designed to demonstrate the effect of TESCoN on LUT function in neurogenic and non-neurogenic conditions.

    New And Noteworthy

    Non-Surgical modality to reduce incidence of urinary incontinence and improve neurogenic bladder symptom scores (NBSS) in individuals with neurogenic bladder due to spinal cord injury or stroke.

    in Frontiers in Systems Neuroscience | New and Recent Articles on February 06, 2020 12:00 AM.

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    Lysophosphatidic Acid Induces Apoptosis of PC12 Cells Through LPA1 Receptor/LPA2 Receptor/MAPK Signaling Pathway

    Lysophosphatidic acid is a small extracellular signaling molecule, which is elevated in pathological conditions such as ischemic stroke and traumatic brain injury (TBI). LPA regulates the survival of neurons in various diseases. However, the molecular mechanisms underlying LPA-induced neuronal death remain unclear. Here we report that LPA activates LPA1 and LPA2 receptors, and the downstream MAPK pathway to induce the apoptosis of PC12 cells through mitochondrial dysfunction. LPA elicits the activation of ERK1/2, p38, and JNK pathways, decreases the expression of Bcl2, promotes the translocation of Bax, and enhances the activation of caspase-3, resulting in mitochondrial dysfunction and cell apoptosis. This process can be blocked by LPA1 receptor antagonist and LPA2 receptor antagonist and MAPK pathway inhibitors. Our results indicate that LPA1 receptor, LPA2 receptor and MAPK pathway play a critical role in LPA-induced neuronal injury. LPA receptors and MAPK pathways may be novel therapeutic targets for ischemic stroke and TBI, where excessive LPA signaling exist.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 06, 2020 12:00 AM.

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    Analyzing Event-Related Transients: Confidence Intervals, Permutation Tests, and Consecutive Thresholds

    Fiber photometry has enabled neuroscientists to easily measure targeted brain activity patterns in awake, freely behaving animal. A focus of this technique is to identify functionally-relevant changes in activity around particular environmental and/or behavioral events, i.e., event-related activity transients (ERT). A simple and popular approach to identifying ERT is to summarize peri-event signal [e.g., area under the curve (AUC), peak activity, etc.,] and perform standard analyses on this summary statistic. We highlight the various issues with this approach and overview straightforward alternatives: waveform confidence intervals (CIs) and permutation tests. We introduce the rationale behind these approaches, describe the results of Monte Carlo simulations evaluating their effectiveness at controlling Type I and Type II error rates, and offer some recommendations for selecting appropriate analysis strategies for fiber photometry experiments.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 06, 2020 12:00 AM.

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    Hierarchical Clustering Analyses of Plasma Proteins in Subjects With Cardiovascular Risk Factors Identify Informative Subsets Based on Differential Levels of Angiogenic and Inflammatory Biomarkers

    Agglomerative hierarchical clustering analysis (HCA) is a commonly used unsupervised machine learning approach for identifying informative natural clusters of observations. HCA is performed by calculating a pairwise dissimilarity matrix and then clustering similar observations until all observations are grouped within a cluster. Verifying the empirical clusters produced by HCA is complex and not well studied in biomedical applications. Here, we demonstrate the comparability of a novel HCA technique with one that was used in previous biomedical applications while applying both techniques to plasma angiogenic (FGF, FLT, PIGF, Tie-2, VEGF, VEGF-D) and inflammatory (MMP1, MMP3, MMP9, IL8, TNFα) protein data to identify informative subsets of individuals. Study subjects were diagnosed with mild cognitive impairment due to cerebrovascular disease (MCI-CVD). Through comparison of the two HCA techniques, we were able to identify subsets of individuals, based on differences in VEGF (p < 0.001), MMP1 (p < 0.001), and IL8 (p < 0.001) levels. These profiles provide novel insights into angiogenic and inflammatory pathologies that may contribute to VCID.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 06, 2020 12:00 AM.

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    Cortical and Striatal Circuits in Huntington’s Disease

    Huntington’s disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 06, 2020 12:00 AM.

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    Multi-Level Clustering of Dynamic Directional Brain Network Patterns and Their Behavioral Relevance

    Dynamic functional connectivity (DFC) obtained from resting state functional magnetic resonance imaging (fMRI) data has been shown to provide novel insights into brain function which may be obscured by static functional connectivity (SFC). Further, DFC, and by implication how different brain regions may engage or disengage with each other over time, has been shown to be behaviorally relevant and more predictive than SFC of behavioral performance and/or diagnostic status. DFC is not a directional entity and may capture neural synchronization. However, directional interactions between different brain regions is another putative mechanism by which neural populations communicate. Accordingly, static effective connectivity (SEC) has been explored as a means of characterizing such directional interactions. But investigation of its dynamic counterpart, i.e., dynamic effective connectivity (DEC), is still in its infancy. Of particular note are methodological insufficiencies in identifying DEC configurations that are reproducible across time and subjects as well as a lack of understanding of the behavioral relevance of DEC obtained from resting state fMRI. In order to address these issues, we employed a dynamic multivariate autoregressive (MVAR) model to estimate DEC. The method was first validated using simulations and then applied to resting state fMRI data obtained in-house (N = 21), wherein we performed dynamic clustering of DEC matrices across multiple levels [using adaptive evolutionary clustering (AEC)] – spatial location, time, and subjects. We observed a small number of directional brain network configurations alternating between each other over time in a quasi-stable manner akin to brain microstates. The dominant and consistent DEC network patterns involved several regions including inferior and mid temporal cortex, motor and parietal cortex, occipital cortex, as well as part of frontal cortex. The functional relevance of these DEC states were determined using meta-analyses and pertained mainly to memory and emotion, but also involved execution and language. Finally, a larger cohort of resting-state fMRI and behavioral data from the Human Connectome Project (HCP) (N = 232, Q1–Q3 release) was used to demonstrate that metrics derived from DEC can explain larger variance in 70 behaviors across different domains (alertness, cognition, emotion, and personality traits) compared to SEC in healthy individuals.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on February 06, 2020 12:00 AM.

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    Developmental Designs and Adult Functions of Cortical Maps in Multiple Modalities: Perception, Attention, Navigation, Numbers, Streaming, Speech, and Cognition

    This article unifies neural modeling results that illustrate several basic design principles and mechanisms that are used by advanced brains to develop cortical maps with multiple psychological functions. One principle concerns how brains use a strip map that simultaneously enables one feature to be represented throughout its extent, as well as an ordered array of another feature at different positions of the strip. Strip maps include circuits to represent ocular dominance and orientation columns, place-value numbers, auditory streams, speaker-normalized speech, and cognitive working memories that can code repeated items. A second principle concerns how feature detectors for multiple functions develop in topographic maps, including maps for optic flow navigation, reinforcement learning, motion perception, and category learning at multiple organizational levels. A third principle concerns how brains exploit a spatial gradient of cells that respond at an ordered sequence of different rates. Such a rate gradient is found along the dorsoventral axis of the entorhinal cortex, whose lateral branch controls the development of time cells, and whose medial branch controls the development of grid cells. Populations of time cells can be used to learn how to adaptively time behaviors for which a time interval of hundreds of milliseconds, or several seconds, must be bridged, as occurs during trace conditioning. Populations of grid cells can be used to learn hippocampal place cells that represent the large spaces in which animals navigate. A fourth principle concerns how and why all neocortical circuits are organized into layers, and how functionally distinct columns develop in these circuits to enable map development. A final principle concerns the role of Adaptive Resonance Theory top-down matching and attentional circuits in the dynamic stabilization of early development and adult learning. Cortical maps are modeled in visual, auditory, temporal, parietal, prefrontal, entorhinal, and hippocampal cortices.

    in Frontiers in Neuroinformatics | New and Recent Articles on February 06, 2020 12:00 AM.

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    Stimulus Onset Hub: an Open-Source, Low Latency, and Opto-Isolated Trigger Box for Neuroscientific Research Replicability and Beyond

    Accurate stimulus onset timing is critical to almost all behavioral research. Auditory, visual, or manual response time stimulus onsets are typically sent through wires to various machines that record data such as: eye gaze positions, electroencephalography, stereo electroencephalography, and electrocorticography. These stimulus onsets are collated and analyzed according to experimental condition. If there is variability in the temporal accuracy of the delivery of these onsets to external systems, the quality of the resulting data and scientific analyses will degrade. Here, we describe an approximately 200 dollar Arduino based system and associated open-source codebase that achieved a maximum of 4 microseconds of delay from the inputs to the outputs while electrically opto-isolating the connected external systems. Using an oscilloscope, the device is configurable for the different environmental conditions particular to each laboratory (e.g., light sensor type, screen type, speaker type, stimulus type, temperature, etc). This low-cost open-source project delivered electrically isolated digital stimulus onset Transistor-Transistor Logic triggers with an input/output delay of 4 μs, and was successfully tested with seven different external systems that record eye and neurological data.

    in Frontiers in Neuroinformatics | New and Recent Articles on February 06, 2020 12:00 AM.

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    Real-Time Eye-to-Eye Contact Is Associated With Cross-Brain Neural Coupling in Angular Gyrus

    Direct eye contact between two individuals is a salient social behavior known to initiate and promote interpersonal interaction. However, the neural processes that underlie these live interactive behaviors and eye-to-eye contact are not well understood. The Dynamic Neural Coupling Hypothesis presents a general theoretical framework proposing that shared interactive behaviors are represented by cross-brain signal coherence. Using functional near-infrared spectroscopy (fNIRS) adapted for hyper scanning, we tested this hypothesis specifically for neural mechanisms associated with eye-to-eye gaze between human participants compared to similar direct eye-gaze at a dynamic video of a face and predicted that the coherence of neural signals between the two participants during reciprocal eye-to-eye contact would be greater than coherence observed during direct eye-gaze at a dynamic video for those signals originating in social and face processing systems. Consistent with this prediction cross-brain coherence was increased for signals within the angular gyrus (AG) during eye-to-eye contact relative to direct eye-gaze at a dynamic face video (p < 0.01). Further, activity in the right temporal-parietal junction (TPJ) was increased in the real eye-to-eye condition (p < 0.05, FDR corrected). Together, these findings advance a functional and mechanistic understanding of the AG and cross-brain neural coupling associated with real-time eye-to-eye contact.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 06, 2020 12:00 AM.

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    Conserved Genoarchitecture of the Basal Hypothalamus in Zebrafish Embryos

    Analyses of genoarchitecture recently stimulated substantial revisions of anatomical models for the developing hypothalamus in mammalian and other vertebrate systems. The prosomeric model proposes the hypothalamus to be derived from the secondary prosencephalon, and to consist of alar and basal regions. The basal hypothalamus can further be subdivided into tuberal and mamillary regions, each with distinct subregions. Albeit being a widely used model system for neurodevelopmental studies, no detailed genoarchitectural maps exist for the zebrafish (Danio rerio) hypothalamus. Here, we compare expression domains of zebrafish genes, including arxa, shha, otpa, isl1, lhx5, nkx2.1, nkx2.2a, pax6, and dlx5a, the orthologs of which delimit specific subregions within the murine basal hypothalamus. We develop the highly conserved brain-specific homeobox (bsx) gene as a novel marker for genoarchitectural analysis of hypothalamic regions. Our comparison of gene expression patterns reveals that the genoarchitecture of the basal hypothalamus in zebrafish embryos 48 hours post fertilization is highly similar to mouse embryos at E13.5. We found the tuberal hypothalamus in zebrafish embryos to be relatively large and to comprise previously ill-defined regions around the posterior hypothalamic recess. The mamillary hypothalamus is smaller and concentrates to rather medial areas in proximity to the anterior end of the neural tube floor plate. Within the basal hypothalamus we identified longitudinal and transverse tuberal and mamillary subregions topologically equivalent to those previously described in other vertebrates. However, the hypothalamic diencephalic boundary region and the posterior tuberculum still provide a challenge. We applied the updated prosomeric model to the developing zebrafish hypothalamus to facilitate cross-species comparisons. Accordingly, we applied the mammalian nomenclature of hypothalamic organization to zebrafish and propose it to replace some controversial previous nomenclature.

    in Frontiers in Neuroanatomy | New and Recent Articles on February 06, 2020 12:00 AM.

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    Age-Dependent Effect of Transcranial Alternating Current Stimulation on Motor Skill Consolidation

    Transcranial alternating current stimulation (tACS) is the application of subthreshold, sinusoidal current to modulate ongoing brain rhythms related to sensory, motor and cognitive processes. Electrophysiological studies suggested that the effect of tACS applied at an alpha frequency (8–12 Hz) was state-dependent. The effects of tACS, that is, an increase in parieto-occipital electroencephalography (EEG) alpha power and magnetoencephalography (MEG) phase coherence, was only observed when the eyes were open (low alpha power) and not when the eyes were closed (high alpha power). This state-dependency of the effects of alpha tACS might extend to the aging brain characterized by general slowing and decrease in spectral power of the alpha rhythm. We additionally hypothesized that tACS will influence the motor cortex, which is involved in motor skill learning and consolidation. A group of young and old healthy adults performed a serial reaction time task (SRTT) with their right hand before and after the tACS stimulation. Each participant underwent three sessions of stimulation: sham, stimulation applied at the individual participant’s alpha peak frequency or individual alpha peak frequency (iAPF; α-tACS) and stimulation with iAPF plus 2 Hz (α2-tACS) to the left motor cortex for 10 min (1.5 mA). We measured the effect of stimulation on general motor skill (GMS) and sequence-specific skill (SS) consolidation. We found that α-tACS and α2-tACS improved GMS and SS consolidation in the old group. In contrast, α-tACS minimally improved GMS consolidation but impaired SS consolidation in the young group. On the other hand, α2-tACS was detrimental to the consolidation of both skills in the young group. Our results suggest that individuals with aberrant alpha rhythm such as the elderly could benefit more from tACS stimulation, whereas for young healthy individuals with intact alpha rhythm the stimulation could be detrimental.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 06, 2020 12:00 AM.

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    Electroacupuncture Ameliorates Cognitive Impairment by Inhibiting the JNK Signaling Pathway in a Mouse Model of Alzheimer’s Disease

    Electroacupuncture (EA) has become popular for its adjustable strength and frequency and easy quantification in the clinic and has demonstrated therapeutic potential for Alzheimer’s disease (AD). However, the mechanism remains unknown. Abnormally activated c-Jun N-terminal kinase (JNK) has been closely related to the pathological process of AD. The aim of this study was to investigate the effect of EA on cognitive impairment and the role of the JNK signaling pathway in AD model amyloid precursor protein (APP)/presenilin 1 (PS1) mice. The memory and learning ability of each group was assessed using the Morris Water Maze (MWM). Immunofluorescence, immunohistochemistry and Western blot were performed to measure the expression of APP, JNK, phosphorylated (P-)JNK, mitogen-activated protein kinase 4 (MKK4), MKK7, c-Jun and caspase-3 in hippocampal tissue samples in APP/PS1 mice after EA intervention. Obvious cognitive deficits were observed in the AD model APP/PS1 mice in the MWM test and were associated with JNK signaling pathway activation and APP upregulation. Four weeks of EA significantly ameliorated the cognitive impairments and inhibited JNK signaling pathway activation and APP upregulation. Taken together, the findings demonstrated that EA can reverse cognitive deficits and substantially lower the burden of APP in AD model APP/PS1 mice, at least partially through inhibiting the JNK signaling pathway and regulating apoptosis signals. Therefore, EA may offer an effective alternative therapeutic approach for AD.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 06, 2020 12:00 AM.

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    Corrigendum: Positive Allosteric Modulation of Alpha7 Nicotinic Acetylcholine Receptors Transiently Improves Memory but Aggravates Inflammation in LPS-Treated Mice

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 06, 2020 12:00 AM.

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    Erratum: Palenciano et al., "Representational Organization of Novel Task Sets during Proactive Encoding"

    in Journal of Neuroscience current issue on February 05, 2020 05:29 PM.

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    Erratum: Sartor et al., "Enhancement of BDNF Expression and Memory by HDAC Inhibition Requires BET Bromodomain Reader Proteins"

    in Journal of Neuroscience current issue on February 05, 2020 05:29 PM.

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    ICAM5 as a Novel Target for Treating Cognitive Impairment in Fragile X Syndrome

    Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, resulted from the silencing of the Fmr1 gene and the subsequent loss of fragile X mental retardation protein (FMRP). Spine dysgenesis and cognitive impairment have been extensively characterized in FXS; however, the underlying mechanism remains poorly understood. As an important regulator of spine maturation, intercellular adhesion molecule 5 (ICAM5) mRNA may be one of the targets of FMRP and involved in cognitive impairment in FXS. Here we show that in Fmr1 KO male mice, ICAM5 was excessively expressed during the late developmental stage, and its expression was negatively correlated with the expression of FMRP and positively related with the morphological abnormalities of dendritic spines. While in vitro reduction of ICAM5 normalized dendritic spine abnormalities in Fmr1 KO neurons, and in vivo knockdown of ICAM5 in the dentate gyrus rescued the impaired spatial and fear memory and anxiety-like behaviors in Fmr1 KO mice, through both granule cell and mossy cell with a relative rate of 1.32 ± 0.15. Furthermore, biochemical analyses showed direct binding of FMRP with ICAM5 mRNA, to the coding sequence of ICAM5 mRNA. Together, our study suggests that ICAM5 is one of the targets of FMRP and is implicated in the molecular pathogenesis of FXS. ICAM5 could be a therapeutic target for treating cognitive impairment in FXS.

    SIGNIFICANCE STATEMENT Fragile X syndrome (FXS) is characterized by dendritic spine dysgenesis and cognitive dysfunctions, while one of the FMRP latent targets, ICAM5, is well established for contributing both spine maturation and learning performance. In this study, we examined the potential link between ICAM5 mRNA and FMRP in FXS, and further investigated the molecular details and pathological consequences of ICAM5 overexpression. Our results indicate a critical role of ICAM5 in spine maturation and cognitive impairment in FXS and suggest that ICAM5 is a potential molecular target for the development of medication against FXS.

    in Journal of Neuroscience current issue on February 05, 2020 05:29 PM.

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    Characterizing Adult Cochlear Supporting Cell Transcriptional Diversity Using Single-Cell RNA-Seq: Validation in the Adult Mouse and Translational Implications for the Adult Human Cochlea

    Hearing loss is a problem that impacts a significant proportion of the adult population. Cochlear hair cell (HC) loss due to loud noise, chemotherapy and aging is the major underlying cause. A significant proportion of these individuals are dissatisfied with available treatment options which include hearing aids and cochlear implants. An alternative approach to restore hearing would be to regenerate HCs. Such therapy would require a recapitulation of the complex architecture of the organ of Corti, necessitating regeneration of both mature HCs and supporting cells (SCs). Transcriptional profiles of the mature cell types in the cochlea are necessary to can provide a metric for eventual regeneration therapies. To assist in this effort, we sought to provide the first single-cell characterization of the adult cochlear SC transcriptome. We performed single-cell RNA-Seq on FACS-purified adult cochlear SCs from the LfngEGFP adult mouse, in which SCs express GFP. We demonstrate that adult cochlear SCs are transcriptionally distinct from their perinatal counterparts. We establish cell-type-specific adult cochlear SC transcriptome profiles, and we validate these expression profiles through a combination of both fluorescent immunohistochemistry and in situ hybridization co-localization and quantitative polymerase chain reaction (qPCR) of adult cochlear SCs. Furthermore, we demonstrate the relevance of these profiles to the adult human cochlea through immunofluorescent human temporal bone histopathology. Finally, we demonstrate cell cycle regulator expression in adult SCs and perform pathway analyses to identify potential mechanisms for facilitating mitotic regeneration (cell proliferation, differentiation, and eventually regeneration) in the adult mammalian cochlea. Our findings demonstrate the importance of characterizing mature as opposed to perinatal SCs.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 05, 2020 12:00 AM.

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    Association of Hypomorphic P2X7 Receptor Genotype With Age

    One of the main risk factors for brain diseases is aging. Recent studies have shown that aging is a progressive degenerative process associated with chronic low-level inflammation. The ATP-gated P2X7 receptor (P2X7R) plays an important role in inflammation and has been associated with different brain (e.g., Alzheimer’s and Parkinson’s) or other age-related (osteoporosis, arthritis, cancer) diseases. Several single nucleotide polymorphisms (SNPs) in the P2RX7 gene have been identified, including the loss-of-function 1513A>C and 1405A>G SNPs, and the gain-of-function 489C>T and 1068G>A SNPs. We carried out a literature analysis to verify an association between P2RX7 SNPs’ frequency and age. In 34 worldwide eligible studies (11.858 subjects) no correlation between 1513CC genotype frequency and age emerged. On the contrary, analysis of European Caucasian cohorts (7.241 subjects) showed a significant increase in 1513CC frequency with age (P = 0.027). In agreement with these findings, analysis of two publicly available datasets, including USA Caucasian cohorts, unveiled an increased frequency of 1513CC and 489CC genotypes with age (P = 0.0055 and P = 0.0019, respectively). Thus, hypomorphic P2RX7 genotypes may be positively selected with age in European and North American Caucasian populations. We hypothesize that Caucasian individuals bearing an anti-inflammatory P2X7R phenotype and living in high-income countries may have a longer life expectancy.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 05, 2020 12:00 AM.

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    Complement System in Brain Architecture and Neurodevelopmental Disorders

    Current evidence indicates that certain immune molecules such as components of the complement system are directly involved in neurobiological processes related to brain development, including neurogenesis, neuronal migration, synaptic remodeling, and response to prenatal or early postnatal brain insults. Consequently, complement system dysfunction has been increasingly implicated in disorders of neurodevelopmental origin, such as schizophrenia, autism spectrum disorder (ASD) and Rett syndrome. However, the mechanistic evidence for a causal relationship between impaired complement regulation and these disorders varies depending on the disease involved. Also, it is still unclear to what extent altered complement expression plays a role in these disorders through inflammation-independent or -dependent mechanisms. Furthermore, pathogenic mutations in specific complement components have been implicated in the etiology of 3MC syndrome, a rare autosomal recessive developmental disorder. The aims of this review are to discuss the current knowledge on the roles of the complement system in sculpting brain architecture and function during normal development as well as after specific inflammatory insults, such as maternal immune activation (MIA) during pregnancy, and to evaluate the existing evidence associating aberrant complement with developmental brain disorders.

    in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on February 05, 2020 12:00 AM.

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    Response: Commentary: The Human Default Consciousness and Its Disruption: Insights From an EEG Study of Buddhist Jhāna Meditation

    in Frontiers in Human Neuroscience | New and Recent Articles on February 05, 2020 12:00 AM.

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    Bilateral Posterior Subthalamic Area Deep Brain Stimulation for Essential Tremor: A Case Series

    Background

    Deep brain stimulation (DBS) of the posterior subthalamic area (PSA) provides a potentially effective treatment for medication-refractory essential tremor (ET).

    Objective

    To study the clinical benefits and adverse-event profile of bilateral PSA-DBS for refractory ET.

    Methods

    Seven patients with refractory ET underwent bilateral PSA-DBS surgery under general anesthesia between September 2017 and May 2018. Clinical outcome assessments, using the Essential Tremor Rating Scale, were performed at 1-, 6-, and 12-month follow-up, except for the last assessment of one patient who was followed up to 9 months. Analysis was focused on changes in patients’ motor symptoms and quality of life following surgery as well as documenting the adverse-event profile associated with the surgical PSA-DBS treatment.

    Results

    After surgery, patients’ motor symptoms, including upper limb tremor and head tremor, were improved by 84.2% and their quality of life by 81.25% at 1-month follow-up. The clinical benefits to patients were maintained at 6-month and last follow-up. Adverse side effects included dysarthria (n = 4), balance disorder (n = 2), and paresthesia of the right limb (n = 1). No habituation effects were observed throughout the follow-up.

    Conclusion

    Bilateral PSA-DBS seems to offer an effective and safe alternative treatment for medically intractable ET, warranting further research into its clinical utility, adverse-event profile, and comparative effectiveness.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 05, 2020 12:00 AM.

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    Extremely Low Frequency Magnetic Fields Do Not Affect LTP-Like Plasticity in Healthy Humans

    Introduction

    Several studies explored the biological effects of extremely low-frequency magnetic fields (ELF-MFs) in vitro, reporting the induction of functional changes in neuronal activity. In particular, ELF-MFs can influence synaptic plasticity both in vitro and in animal models but some studies reported an increase in long-term potentiation (LTP) whereas others suggested its reduction. However, no specific study has investigated such effect on humans.

    Aims

    To evaluate whether ELF-MFs affect the propensity of the human cortex to undergo LTP-like plasticity.

    Methods

    We designed a randomized, single-blind, sham-controlled, cross-over study on 10 healthy subjects. Cortical plasticity was induced by intermittent theta burst stimulation (iTBS) before and after 45-min ELF-MFs (75 Hz; 1.8 mT) or sham exposure and was estimated by measuring the changes of motor evoked potentials (MEP) amplitude before and after each iTBS.

    Results

    No adverse events were reported. No significant effects of ELF-MFs on cortical plasticity were found.

    Conclusion

    Whole-brain exposure to ELF-MFs (75 Hz; 1.8 mT) is safe and does not seem to significantly affect LTP-like plasticity in human motor cortex.

    in Frontiers in Human Neuroscience | New and Recent Articles on February 05, 2020 12:00 AM.

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    Blebbistatin Inhibits Neomycin-Induced Apoptosis in Hair Cell-Like HEI-OC-1 Cells and in Cochlear Hair Cells

    Aging, noise, and ototoxic drug-induced hair cell (HC) loss are the major causes of sensorineural hearing loss. Aminoglycoside antibiotics are commonly used in the clinic, but these often have ototoxic side effects due to the accumulation of oxygen-free radicals and the subsequent induction of HC apoptosis. Blebbistatin is a myosin II inhibitor that regulates microtubule assembly and myosin–actin interactions, and most research has focused on its ability to modulate cardiac or urinary bladder contractility. By regulating the cytoskeletal structure and reducing the accumulation of reactive oxygen species (ROS), blebbistatin can prevent apoptosis in many different types of cells. However, there are no reports on the effect of blebbistatin in HC apoptosis. In this study, we found that the presence of blebbistatin significantly inhibited neomycin-induced apoptosis in HC-like HEI-OC-1 cells. We also found that blebbistatin treatment significantly increased the mitochondrial membrane potential (MMP), decreased ROS accumulation, and inhibited pro-apoptotic gene expression in both HC-like HEI-OC-1 cells and explant-cultured cochlear HCs after neomycin exposure. Meanwhile, blebbistatin can protect the synaptic connections between HCs and cochlear spiral ganglion neurons. This study showed that blebbistatin could maintain mitochondrial function and reduce the ROS level and thus could maintain the viability of HCs after neomycin exposure and the neural function in the inner ear, suggesting that blebbistatin has potential clinic application in protecting against ototoxic drug-induced HC loss.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 05, 2020 12:00 AM.

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    Cytoarchitectonic Characterization and Functional Decoding of Four New Areas in the Human Lateral Orbitofrontal Cortex

    A comprehensive concept of the biological basis of reward, social and emotional behavior, and language requires a deeper understanding of the microstructure and connectivity of the underlying brain regions. Such understanding could provide deeper insights into their role in functional networks, and form the anatomical basis of the functional segregation of this region as shown in recent in vivo imaging studies. Here, we investigated the cytoarchitecture of the lateral orbitofrontal cortex (lateral OFC) in serial histological sections of 10 human postmortem brains by image analysis and a statistically reproducible approach to detect borders between cortical areas. Profiles of the volume fraction of cell bodies were therefore extracted from digitized histological images, describing laminar changes from the layer I/layer II boundary to the white matter. As a result, four new areas, Fo4–7, were identified. Area Fo4 was mainly found in the anterior orbital gyrus (AOG), Fo5 anteriorly in the inferior frontal gyrus (IFG), Fo6 in the lateral orbital gyrus (LOG), and Fo7 in the lateral orbital sulcus. Areas differed in cortical thickness, abundance and size of pyramidal cells in layer III and degree of granularity in layer IV. A hierarchical cluster analysis was used to quantify cytoarchitectonic differences between them. The 3D-reconstructed areas were transformed into the single-subject template of the Montreal Neurological Institute (MNI), where probabilistic maps and a maximum probability map (MPM) were calculated as part of the JuBrain Cytoarchitectonic Atlas. These maps served as reference data to study the functional properties of the areas using the BrainMap database. The type of behavioral tasks that activated them was analyzed to get first insights of co-activation patterns of the lateral OFC and its contribution to cognitive networks. Meta-analytic connectivity modeling (MACM) showed that functional decoding revealed activation in gustatory perception in Fo4; reward and somesthetic perception in Fo5; semantic processing and pain perception in Fo6; and emotional processing and covert reading in Fo7. Together with existing maps of the JuBrain Cytoarchitectonic Atlas, the new maps can now be used as an open-source reference for neuroimaging studies, allowing to further decode brain function.

    in Frontiers in Neuroanatomy | New and Recent Articles on February 05, 2020 12:00 AM.

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    Revealing a Novel Landscape of the Association Between Blood Lipid Levels and Alzheimer's Disease: A Meta-Analysis of a Case-Control Study

    Objectives: Blood lipid profiles have been ambiguously reported as biomarkers of AD in recent years. This study was conducted to evaluate the correlation between blood lipid levels and AD in later-life and to explore the effectiveness and reliability of blood lipid profiles as biomarkers of AD.

    Methods: Database searching was conducted using PubMed, the Cochrane Library, EMBASE, and Medline. This study was designed following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) criteria. Review Manager 5.3 (RevMan 5.3) software was adopted to perform meta-analysis evaluating the standard mean difference (SMD) with its 95% confidence intervals (CI).

    Results: A total of 5,286 participants were enrolled from 27 case–control studies in this meta-analysis. The pooled results demonstrated that total cholesterol (TC) level was significantly associated with AD in late-life (SMD = 0.17, 95% CI: [0.01, 0.32], P = 0.03), especially in the subgroup under 70 years old (SMD: 0.45, 95% CI: [0.11, 0.79], P = 0.01) and the subgroup of Western population (SMD: 0.29, 95% CI: [0.04, 0.53], P = 0.02). In the subgroup under 70 years old, the high-density lipoprotein cholesterol (HDL-C) level (SMD = −0.50, 95% CI: [−0.76, −0.25], P = 0.0001) and the low-density lipoprotein cholesterol (LDL-C) level (SMD = 0.59, 95% CI: [0.02, 1.16], P = 0.04) in the AD group were significantly lower and higher than in the control group, respectively. In the subgroup with a sample size larger than 100 subjects, the LDL-C level was significantly higher in AD patients than in the control elderly group (SMD = 0.31, 95% CI: [0.05, 0.56], P = 0.02). There was no significant association between triglyceride (TG) levels and AD in later-life (SMD = −0.00, 95% CI: [−0.12, 0.12], P = 1.00).

    Conclusion: TC can be a new predictive biomarker of AD or cognitive decline in later-life. Increased TC levels are found to be associated with an elevated risk of AD. Decreased HDL-C levels and increased LDL-C levels may relate to an elevated risk of AD in subjects aged 60–70. Further comprehensive researches will be necessary in the future.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 05, 2020 12:00 AM.

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    Richard H. Masland (1942–2019)

    Richard H. Masland––Dick to all who knew him––died on December 13, 2019, from cancer, four years after his initial diagnosis. During this interval, while enduring major fluctuations in health, Dick managed to start and complete an approachable and reflective book, We Know It When We See It: What the Neurobiology of Vision Tells Us About How We Think (March 2020). We are gladdened, though not surprised, that his wife, Jean, reports, “Dick was truly amazing the way he faced his illness, never showing signs of depression or anger but soldiering on with a positive attitude toward life.”

    in Neuron on February 05, 2020 12:00 AM.

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    Artificial and Natural Intelligence: From Invention to Discovery

    An international group of researchers met in November 2019 in Beijing to explore the intersection of neuroscience and AI. The aim was to offer a fertile ground for stimulating discussions and ideas, including issues such as policy making and the future of neuroscience and AI across the globe.

    in Neuron on February 05, 2020 12:00 AM.

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    Photocontrol of Metabotropic Glutamate Receptors: When One Agonist Is Not Enough, Make It Two

    A current major challenge lies in controlling molecularly defined brain-receptor and channel populations to investigate their function in vivo. In this issue of Neuron, Acosta-Ruiz et al. (2020) developed a highly versatile molecular toolkit to efficiently manipulate specific metabotropic glutamate receptor subtypes in brain circuits with light.

    in Neuron on February 05, 2020 12:00 AM.

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    Vasomotion Drives Periarterial Drainage of Aβ from the Brain

    In this issue of Neuron, van Veluw et al. (2020) show that elimination of solutes from the brain along arterial walls is driven by low-frequency arteriolar oscillations and suggest that age-related reduction of this vasomotion may contribute to impaired clearance of Aβ.

    in Neuron on February 05, 2020 12:00 AM.

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    Lost in Translation: Cul3-Dependent Pathological Mechanisms in Psychiatric Disorders

    In this issue of Neuron, Dong et al. (2020) finds that deficiency of the psychiatric risk gene Cul3, which encodes an E3 ubiquitin ligase, leads to an upregulation of Cap-dependent protein translation. The resulting imbalance in protein synthesis and degradation is found to disrupt glutamatergic transmission and excitability in networks that underlie sociability and anxiety.

    in Neuron on February 05, 2020 12:00 AM.

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    High-Risk, High-Reward Genetics in ASD

    In a recent issue of Cell, Satterstrom et al. leverage de novo high-impact variants to identify 102 genes associated with autism spectrum disorder (ASD). Most of these genes have roles in regulation of gene expression or neuronal communication, implicating both developmental and functional changes in ASD.

    in Neuron on February 05, 2020 12:00 AM.

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    Neural Implementation of Behavioral Hierarchy

    A vast array of animal behavior—from locomotion to human speech—is thought to consist of different hierarchical levels, but its neural implementation remains poorly understood. In this issue of Neuron, Kaplan et al. (2020) identify neuronal circuit dynamics responsible for multiple levels and timescales of hierarchical locomotion control in Caenorhabditis elegans.

    in Neuron on February 05, 2020 12:00 AM.

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    Is Alpha Asymmetry a Byproduct or Cause of Spatial Attention? New Evidence Alpha Neurofeedback Controls Measures of Spatial Attention

    Cued spatial attention differentially modulates alpha power in attended relative to non-attended brain representations, termed the alpha asymmetry. Yet a causal role for alpha in attention is debated. In this issue of Neuron, Bagherzadeh et al., (2019) utilize neurofeedback to train alpha asymmetry and causally impact measures of spatial attention.

    in Neuron on February 05, 2020 12:00 AM.

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    Direct Fit to Nature: An Evolutionary Perspective on Biological and Artificial Neural Networks

    To guide adaptive behavior and support predictions in real-life contexts, the brain may rely on opaque, over-parameterized models capable of directly fitting to the multidimensional world, while being blind—like evolution—to the underlying rules and causes.

    in Neuron on February 05, 2020 12:00 AM.

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    Food, microbes, sex and old age: on the plasticity of gastrointestinal innervation

    Publication date: June 2020

    Source: Current Opinion in Neurobiology, Volume 62

    Author(s): Tomotsune Ameku, Hannah Beckwith, Laura Blackie, Irene Miguel-Aliaga

    The gastrointestinal tract is innervated by its own enteric nervous system and by extrinsic neurons that connect it with the central nervous system. Innervation allows the gastrointestinal tract to sense and respond to diverse stimuli, adjusting motility and secretion, but also affecting our physiology, behaviour and immunity. The mechanisms underlying the formation of gastrointestinal neurons are beginning to be elucidated; those that keep them plastic over an organism’s lifetime remain to be explored. Here, we review the effects of microbiota, nutrients, sex and ageing on the morphology and function of gastrointestinal innervation in mammals, and discuss how this plasticity shapes gut-brain crosstalk and whole-body physiology. We also highlight insights gained by nascent studies of the enteric innervation of Drosophila melanogaster.

    Graphical abstract

    Graphical abstract for this article

    in ScienceDirect Publication: Current Opinion in Neurobiology on February 04, 2020 07:00 PM.

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    A subcortical reorganizer

    Nature Reviews Neuroscience, Published online: 04 February 2020; doi:10.1038/s41583-020-0274-6

    In mice, inputs to the hippocampal CA1 region from the locus coeruleus have a key role in reorganizing place cell responses during spatial reward learning.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on February 04, 2020 12:00 AM.

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    Fibrogenesis in LAMA2-Related Muscular Dystrophy Is a Central Tenet of Disease Etiology

    LAMA2-related congenital muscular dystrophy, also known as MDC1A, is caused by loss-of-function mutations in the alpha2 chain of Laminin-211. Loss of this protein interrupts the connection between the muscle cell and its extracellular environment and results in an aggressive, congenital-onset muscular dystrophy characterized by severe hypotonia, lack of independent ambulation, and early mortality driven by respiratory complications and/or failure to thrive. Of the pathomechanisms of MDC1A, the earliest and most prominent is widespread and rampant fibrosis. Here, we will discuss some of the key drivers of fibrosis including TGF-beta and renin–angiotensin system signaling and consequences of these pathways including myofibroblast transdifferentiation and matrix remodeling. We will also highlight some of the differences in fibrogenesis in congenital muscular dystrophy (CMD) with that seen in Duchenne muscular dystrophy (DMD). Finally, we will connect the key signaling pathways in the pathogenesis of MDC1A to the current status of the therapeutic approaches that have been tested in the preclinical models of MDC1A to treat fibrosis.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on February 04, 2020 12:00 AM.

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    Corrigendum: The Lateralization of Speech-Brain Coupling Is Differentially Modulated by Intrinsic Auditory and Top-Down Mechanisms

    in Frontiers in Integrative Neuroscience | New and Recent Articles on February 04, 2020 12:00 AM.

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    Brain Structural Plasticity: From Adult Neurogenesis to Immature Neurons

    Brain structural plasticity is an extraordinary tool that allows the mature brain to adapt to environmental changes, to learn, to repair itself after lesions or disease, and to slow aging. A long history of neuroscience research led to fascinating discoveries of different types of plasticity, involving changes in the genetically determined structure of nervous tissue, up to the ultimate dream of neuronal replacement: a stem cell-driven “adult neurogenesis” (AN). Yet, this road does not seem a straight one, since mutable dogmas, conflicting results and conflicting interpretations continue to warm the field. As a result, after more than 10,000 papers published on AN, we still do not know its time course, rate or features with respect to other kinds of structural plasticity in our brain. The solution does not appear to be behind the next curve, as differences among mammals reveal a very complex landscape that cannot be easily understood from rodents models alone. By considering evolutionary aspects, some pitfalls in the interpretation of cell markers, and a novel population of undifferentiated cells that are not newly generated [immature neurons (INs)], we address some conflicting results and controversies in order to find the right road forward. We suggest that considering plasticity in a comparative framework might help assemble the evolutionary, anatomical and functional pieces of a very complex biological process with extraordinary translational potential.

    in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on February 04, 2020 12:00 AM.

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    Hemiparkinsonism or Hemidystonia With Hemiatrophy Syndrome: A Case Series With Follow-Up

    Hemiparkinsonism-hemiatrophy syndrome (HPHA) and hemidystonia-hemiatrophy syndrome (HDHA) are rare movement disorders composed of hemidystonia or hemiparkinsonism that present with unilateral limb, face, trunk, or cerebral hemiatrophy and mostly occur following head trauma or postanoxic events. However, relatively little is known about the pathogenesis of these conditions. In our case series, we present three HPHA patients and one HDHA patient who underwent detailed neuropsychological, radiological, motor, and non-motor functional assessments with a mean follow-up of 2 years. We followed two patients who showed differences in their progression for more than 2 years: one barely progressed with no treatment, and the other exhibited levodopa-induce dyskinesia (LID) and definitive progression while receiving multiple adjunctive therapies. In addition, we performed positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and 18F-dihydroxyphenylalanine (DOPA) in one HPHA patient who showed bilaterally symmetrical uptake of FDG with no significant increase or decrease in the cerebral hemispheres, including the striatum, but exhibited a significant reduction in the uptake of 18F-DOPA in the contralateral posterior striatum. In this study, we followed HPHA patients who showed different disease courses to explore the clinical characteristics and pathogenesis of HPHA and HDHA and illustrate the clinical heterogeneity of these diseases.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 04, 2020 12:00 AM.

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    Acute Treatment With Gleevec Does Not Promote Early Vascular Recovery Following Intracerebral Hemorrhage in Adult Male Rats

    Intracerebral hemorrhage (ICH) remains one of the most debilitating types of stroke and is characterized by a sudden bleeding from a ruptured blood vessel. ICH often results in high mortality and in survivors, permanent disability. Most studies have focused on neuroprotective strategies designed to minimize secondary consequences and prevent further pathology. Lacking is an understanding of how ICH acutely affects cerebrovascular components and their response to therapeutic interventions. We hypothesized that ICH alters cortical vessel complexity in the parenchyma adjacent to site of the initial vascular disruption and that vascular abnormalities would be mitigated by administration of the PDGFR inhibitor, Imatinib mesylate (Gleevec). Briefly, ICH was induced in male adult rats by injection of collagenase into basal ganglia, followed by Gleevec administration (60 mg/kg) 1 h after injury. Rats were then perfused using vessel painting methodology (Salehi et al., 2018b) to stain whole brain vascular networks at 1 day post-ICH. Axial and coronal wide field fluorescence microscopy was performed. Analyses for vascular features were undertaken and fractal analysis for vascular complexity. Data were collected from four groups of rats: Sham + Vehicle; Sham + Gleevec; ICH + Vehicle; ICH + Gleevec. Microscopy revealed that cortical vessels in both ipsi- and contralateral hemispheres exhibited significantly reduced density and branching by 22 and 34%, respectively. Fractal measures confirmed reduced complexity as well. Gleevec treatment further reduced vascular parameters, including reductions in vessel density in tissues adjacent to the ICH. The reductions in brain wide vascular networks after Gleevec in the current study after ICH is contrasted by previous reports of improved behavioral outcomes and decreased lCH lesion volumes Reductions in the vascular network after Gleevec may be involved in long-term repair mechanisms by pruning injured vessels to ultimately promote new vessel growth.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 04, 2020 12:00 AM.

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    Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

    Background

    The astrocytic phospholipase A2 (PLA2)-arachidonic acid (AA) pathway is crucial in understanding the reduction of cerebral blood flow (CBF) prior to cognitive deterioration. In complementary and alternative medicine, manual acupuncture (MA) is used as one of the most important therapies for Alzheimer’s disease (AD). The beneficial effects of MA on CBF were reported in our previous study. However, the underlying molecular mechanism remains largely elusive.

    Objective

    To investigate the effect of MA on the astrocytic PLA2-AA pathway in SAMP8 mice hippocampi.

    Methods

    SAMP8 mice were divided into the SAMP8 control (Pc) group, the SAMP8 MA (Pm) group and the SAMP8 donepezil (Pd) group. SAMR1 mice were used as the SAMRl control (Rc) group. Mice in the Pd group were treated with donepezil hydrochloride at 0.65 μg/g. In the Pm group, MA was applied at Baihui (GV20) and Yintang (GV29) for 20 min. The above treatments were administered once a day for 26 consecutive days. The Morris water maze was applied to assess spatial learning and memory. Immunofluorescence staining, western blot and liquid chromatography-tandem mass spectrometry were used to investigate the expression of related proteins and measure the contents of the metabolic intermediates of the PLA2-AA pathway.

    Results

    Compared with that in the Rc group, the escape latency in the Pc group significantly increased (p < 0.01); whereas, the platform crossover number and percentage of time and swimming distance in the platform quadrant decreased (p < 0.01). The hippocampal expression of PLA2, cyclooxygenase-1, cytochrome P450 proteins 2C23 and the levels of AA, prostaglandin E2 and epoxyeicosatrienoic acids of the Pc group was drastically higher than that in the Rc group (p < 0.01). These changes were reversed by MA and donepezil (p < 0.01 or p < 0.05).

    Conclusion

    MA can effectively improve the learning and memory abilities of SAMP8 mice and has a negative regulatory effect on the PLA2-AA pathway. We propose that the increase of the arterial tone, which is induced by the inhibition of vasodilatory pathway, may be a reason for the beneficial effect of MA on CBF.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on February 04, 2020 12:00 AM.

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    Magia: Robust Automated Image Processing and Kinetic Modeling Toolbox for PET Neuroinformatics

    Processing of positron emission tomography (PET) data typically involves manual work, causing inter-operator variance. Here we introduce the Magia toolbox that enables processing of brain PET data with minimal user intervention. We investigated the accuracy of Magia with four tracers: [11C]carfentanil, [11C]raclopride, [11C]MADAM, and [11C]PiB. We used data from 30 control subjects for each tracer. Five operators manually delineated reference regions for each subject. The data were processed using Magia using the manually and automatically generated reference regions. We first assessed inter-operator variance resulting from the manual delineation of reference regions. We then compared the differences between the manually and automatically produced reference regions and the subsequently obtained binding potentials and standardized-uptake-value-ratios. The results show that manually produced reference regions can be remarkably different from each other, leading to substantial differences also in outcome measures. While the Magia-derived reference regions were anatomically different from the manual ones, Magia produced outcome measures highly consistent with the average of the manually obtained estimates. For [11C]carfentanil and [11C]PiB there was no bias, while for [11C]raclopride and [11C]MADAM Magia produced 3–5% higher binding potentials. Based on these results and considering the high inter-operator variance of the manual method, we conclude that Magia can be reliably used to process brain PET data.

    in Frontiers in Neuroinformatics | New and Recent Articles on February 04, 2020 12:00 AM.

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    Modeling the Effect of Temperature on Membrane Response of Light Stimulation in Optogenetically-Targeted Neurons

    Optogenetics is revolutionizing Neuroscience, but an often neglected effect of light stimulation of the brain is the generation of heat. In extreme cases, light-generated heat kills neurons, but mild temperature changes alter neuronal function. To date, most in vivo experiments rely on light stimulation of neural tissue using fiber-coupled lasers of various wavelengths. Brain tissue is irradiated with high light power that can be deleterious to neuronal function. Furthermore, absorbed light generates heat that can lead to permanent tissue damage and affect neuronal excitability. Thus, light alone can generate effects in neuronal function that are unrelated to the genuine “optogenetic effect.” In this work, we perform a theoretical analysis to investigate the effects of heat transfer in rodent brain tissue for standard optogenetic protocols. More precisely, we first use the Kubelka-Munk model for light propagation in brain tissue to observe the absorption phenomenon. Then, we model the optothermal effect considering the common laser wavelengths (473 and 593 nm) used in optogenetic experiments approaching the time/space numerical solution of Pennes' bio-heat equation with the Finite Element Method. Finally, we then modeled channelrhodopsin-2 in a single and spontaneous-firing neuron to explore the effect of heat in light stimulated neurons. We found that, at commonly used light intensities, laser radiation considerably increases the temperature in the surrounding tissue. This effect alters action potential size and shape and causes an increase in spontaneous firing frequency in a neuron model. However, the shortening of activation time constants generated by heat in the single firing neuron model produces action potential failures in response to light stimulation. We also found changes in the power spectrum density and a reduction in the time required for synchronization in an interneuron network model of gamma oscillations. Our findings indicate that light stimulation with intensities used in optogenetic experiments may affect neuronal function not only by direct excitation of light sensitive ion channels and/or pumps but also by generating heat. This approach serves as a guide to design optogenetic experiments that minimize the role of tissue heating in the experimental outcome.

    in Frontiers in Computational Neuroscience | New and Recent Articles on February 04, 2020 12:00 AM.

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    Regulation of CSF and Brain Tissue Sodium Levels by the Blood-CSF and Blood-Brain Barriers During Migraine

    Cerebrospinal fluid (CSF) and brain tissue sodium levels increase during migraine. However, little is known regarding the underlying mechanisms of sodium homeostasis disturbance in the brain during the onset and propagation of migraine. Exploring the cause of sodium dysregulation in the brain is important, since correction of the altered sodium homeostasis could potentially treat migraine. Under the hypothesis that disturbances in sodium transport mechanisms at the blood-CSF barrier (BCSFB) and/or the blood-brain barrier (BBB) are the underlying cause of the elevated CSF and brain tissue sodium levels during migraines, we developed a mechanistic, differential equation model of a rat's brain to compare the significance of the BCSFB and the BBB in controlling CSF and brain tissue sodium levels. The model includes the ventricular system, subarachnoid space, brain tissue and blood. Sodium transport from blood to CSF across the BCSFB, and from blood to brain tissue across the BBB were modeled by influx permeability coefficients PBCSFB and PBBB, respectively, while sodium movement from CSF into blood across the BCSFB, and from brain tissue to blood across the BBB were modeled by efflux permeability coefficients PBCSFB′ and PBBB′, respectively. We then performed a global sensitivity analysis to investigate the sensitivity of the ventricular CSF, subarachnoid CSF and brain tissue sodium concentrations to pathophysiological variations in PBCSFB, PBBB, PBCSFB′ and PBBB′. Our results show that the ventricular CSF sodium concentration is highly influenced by perturbations of PBCSFB, and to a much lesser extent by perturbations of PBCSFB′. Brain tissue and subarachnoid CSF sodium concentrations are more sensitive to pathophysiological variations of PBBB and PBBB′ than variations of PBCSFB and PBCSFB′ within 30 min of the onset of the perturbations. However, PBCSFB is the most sensitive model parameter, followed by PBBB and PBBB′, in controlling brain tissue and subarachnoid CSF sodium levels within 3 h of the perturbation onset.

    in Frontiers in Computational Neuroscience | New and Recent Articles on February 04, 2020 12:00 AM.

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    Editorial: Purinergic Signaling in Health and Disease

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 04, 2020 12:00 AM.

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    Multiple Domains in the Kv7.3 C-Terminus Can Regulate Localization to the Axon Initial Segment

    The voltage-gated Kv7.2/Kv7.3 potassium channel is a critical regulator of neuronal excitability. It is strategically positioned at the axon initial segment (AIS) of neurons, where it effectively inhibits repetitive action potential firing. While the selective accumulation of Kv7.2/Kv7.3 channels at the AIS requires binding to the adaptor protein ankyrin G, it is currently unknown if additional molecular mechanisms contribute to the localization and fine-tuning of channel numbers at the AIS. Here, we utilized a chimeric approach to pinpoint regions within the Kv7.3 C-terminal tail with an impact upon AIS localization. This strategy identified two domains with opposing effects upon the AIS localization of Kv7.3 chimeras expressed in cultured hippocampal neurons. While a membrane proximal domain reduced AIS localization of Kv7.3 chimeras, helix D increased and stabilized chimera AIS localization. None of the identified domains were required for AIS localization. However, the domains modulated the relative efficiency of the localization raising the possibility that the two domains contribute to the regulation of Kv7 channel numbers and nanoscale organization at the AIS.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 04, 2020 12:00 AM.

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    Genetic Association of FERMT2, HLA-DRB1, CD2AP, and PTK2B Polymorphisms With Alzheimer’s Disease Risk in the Southern Chinese Population

    Objectives

    This study aimed to explore the relationship between 18 single nucleotide polymorphisms (SNPs) and Alzheimer’s disease (AD) within the southern Chinese population.

    Methods

    A total of 420 participants, consisting of 215 AD patients and 205 sex- and age-matched controls, were recruited. The SNaPshot technique and polymer chain reaction (PCR) were used to detect the 18 SNPs. Combined with the apolipoprotein E (APOE) ε4 allele and age at onset, we performed an association analysis between these SNPs and AD susceptibility. Furthermore, we analyzed SNP-associated gene expression using the expression quantitative trait loci analysis.

    Results

    Our study found that rs17125924 of FERMT2 was associated with the risk of developing AD in the dominant (P = 0.022, odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.07–2.32) and overdominant (P = 0.005, OR = 1.76, 95% CI: 1.18–2.61) models. Moreover, compared with APOE ε4 non-carriers, the frequency of the G-allele at rs17125924 was significantly higher among AD patients in APOE ε4 allele carriers (P = 0.029). The rs9271058 of HLA-DRB1 (dominant, overdominant, and additive models), rs9473117 of CD2AP (dominant and additive models), and rs73223431 of PTK2B (dominant, overdominant, and additive models) were associated with early onset AD (EOAD). Using the genotype-tissue expression (GTEx) and Braineac database, we found a significant association between rs9271058 genotypes and HLA-DRB1 expression levels, while the CC genotype at rs9473117 and the TT genotype of rs73223431 increased CD2AP and PTK2B gene expression, respectively.

    Conclusion

    Our study identifies the G-allele at rs17125924 as a risk factor for developing AD, especially in APOE ε4 carriers. In addition, we found that rs9271058 of HLA-DRB1, rs9473117 of CD2AP, and rs73223431 of PTK2B were associated with EOAD. Further studies with larger sample sizes are needed to confirm our results.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 04, 2020 12:00 AM.

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    Peripheral Routes to Neurodegeneration: Passing Through the Blood–Brain Barrier

    A bidirectional crosstalk between peripheral players of immunity and the central nervous system (CNS) exists. Hence, blood–brain barrier (BBB) breakdown is emerging as a participant mechanism of dysregulated peripheral–CNS interplay, promoting diseases. Here, we examine the implication of BBB damage in neurodegeneration, linking it to peripheral brain-directed autoantibodies and gut–brain axis mechanisms. As BBB breakdown is a factor contributing to, or even anticipating, neuronal dysfunction(s), we here identify contemporary pharmacological strategies that could be exploited to repair the BBB in disease conditions. Developing neurovascular, add on, therapeutic strategies may lead to a more efficacious pre-clinical to clinical transition with the goal of curbing the progression of neurodegeneration.

    in Frontiers in Aging Neuroscience | New and Recent Articles on February 04, 2020 12:00 AM.

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    Proximity ligation assay reveals both pre- and postsynaptic localization of the APP-processing enzymes ADAM10 and BACE1 in rat and human adult brain

    Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by...

    in Most Recent Articles: BMC Neuroscience on February 04, 2020 12:00 AM.

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    Phase separation at the synapse

    Nature Neuroscience, Published online: 03 February 2020; doi:10.1038/s41593-019-0579-9

    Phase separation is emerging as a versatile means for cellular sub-compartment formation. Chen et al. review recent advances of dense synaptic assembly formation via phase separation and discuss implications of phase separation in synaptic physiology.

    in Nature Neuroscience - Issue - nature.com science feeds on February 03, 2020 12:00 AM.

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    A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder

    Nature Neuroscience, Published online: 03 February 2020; doi:10.1038/s41593-019-0578-x

    The authors identify an impaired myelination signature from the brains of mouse models of Pitt–Hopkins syndrome and show that it is shared in the postmortem brains of people with autism.

    in Nature Neuroscience - Issue - nature.com science feeds on February 03, 2020 12:00 AM.

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    Corrigendum: An Inflammation-Centric View of Neurological Disease: Beyond the Neuron

    in Frontiers in Cellular Neuroscience | New and Recent Articles on February 03, 2020 12:00 AM.

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    Subscription and Copyright Information

    in Trends in Neurosciences on February 01, 2020 12:00 AM.

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    Editorial Board

    in Trends in Neurosciences on February 01, 2020 12:00 AM.

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    Author Correction: Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain

    Nature Neuroscience, Published online: 31 January 2020; doi:10.1038/s41593-020-0595-9

    Author Correction: Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain

    in Nature Neuroscience - Issue - nature.com science feeds on January 31, 2020 12:00 AM.

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    Reversing Hemianopia by Multisensory Training Under Anesthesia

    Hemianopia is characterized by blindness in one half of the visual field and is a common consequence of stroke and unilateral injury to the visual cortex. There are few effective rehabilitative strategies that can relieve it. Using the cat as an animal model of hemianopia, we found that blindness induced by lesions targeting all contiguous areas of the visual cortex could be rapidly reversed by a non-invasive, multisensory (auditory-visual) exposure procedure even while animals were anesthetized. Surprisingly few trials were required to reinstate vision in the previously blind hemisphere. That rehabilitation was possible under anesthesia indicates that the visuomotor behaviors commonly believed to be essential are not required for this recovery, nor are factors such as attention, motivation, reward, or the various other cognitive features that are generally thought to facilitate neuro-rehabilitative therapies.

    in Frontiers in Systems Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

    The mood disorders, major depression (MD) and bipolar disorder (BD), have a high lifetime prevalence in the human population and accordingly generate huge costs for health care. Efficient, rapidly acting, and side-effect-free pharmaceuticals are hitherto not available, and therefore, the identification of new therapeutic targets is an imperative task for (pre)clinical research. Such a target may be the purinergic P2X7 receptor (P2X7R), which is localized in the central nervous system (CNS) at microglial and neuroglial cells mediating neuroinflammation. MD and BD are due to neuroinflammation caused in the first line by the release of the pro-inflammatory cytokine interleukin-1β (IL-1β) from the microglia. IL-1β in turn induces the secretion of corticotropin-releasing hormone (CRH) and in consequence the secretion of adrenocorticotropic hormone (ACTH) and cortisol, which together with a plethora of further cytokines/chemokines lead to mood disorders. A number of biochemical/molecular biological measurements including the use of P2X7R- or IL-1β-deficient mice confirmed this chain of events. More recent studies showed that a decrease in the astrocytic release of ATP in the prefrontal cortex and hippocampus is a major cause of mood disorders. It is an attractive hypothesis that compensatory increases in P2X7Rs in these areas of the brain are the immediate actuators of MD and BD. Hence, blood-brain barrier-permeable P2X7R antagonists may be promising therapeutic tools to improve depressive disorders in humans.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Oligomers Are Promising Targets for Drug Development in the Treatment of Proteinopathies

    Currently, there is no effective treatment of proteinopathies, as well as their diagnosis in the early stages of the disease until the first clinical symptoms appear. The proposed model of fibrillation of the Aβ peptide and its fragments not only describes molecular rearrangements, but also offers models of processes that occur during the formation of amyloid aggregates. Since this model is also characteristic of other proteins and peptides, a new potential target for drug development in the treatment of Alzheimer’s disease (AD) and other proteinopathies is proposed on the basis of this model. In our opinion, it is oligomers that are promising targets for innovative developments in the treatment of these diseases.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Effects of Mongolian Warm Acupuncture on iNOS/NO and Inflammatory Cytokines in the Hippocampus of Chronic Fatigue Rats

    The inducible nitric oxide synthase/nitric oxide (iNOS/NO) signaling pathway and inflammatory cytokines play important roles in the pathogenesis of exercise-induced fatigue. Studies have found that Mongolian warm acupuncture (WA) could alleviate exercise-induced fatigue. However, the exact mechanisms underlying its effects remain unclear. In the present study, we investigated the effects of Mongolian WA on iNOS/NO signaling pathway and proinflammatory cytokines in a chronic exhaustive swimming-induced fatigue rat model. Animals were randomly divided into Control group, Ctrl + WA group, Model group, and Model + WA group. The body weight, exhaustive swimming time test, and Morris water maze test were performed before and after the chronic exhaustive swimming. The serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and iNOS were detected by enzyme linked immunosorbent assay (ELISA). The mRNA expressions of IL-1β, IL-6, TNF-α, IFN-γ, and iNOS in the hippocampus were measured by real-time polymerase chain reaction (RT-PCR). Moreover, the protein expression of iNOS in the hippocampus was measured by western blot, and the NO productions in the serum and hippocampus were detected by Griess reaction system. Chronic exhaustive exercise significantly reduced the body weight and exhaustive swimming time, and induced impairment in learning and memory, and which were reversed by WA treatment. Chronic exhaustive exercise also increased the expressions of iNOS and proinflammatory cytokines, while WA treatment significantly decreased the level of iNOS and proinflammatory cytokines. However, chronic exhaustive exercise did not affect the NO production. These findings demonstrated that WA could alleviate the chronic exhaustive swimming-induced fatigue and improve the learning and memory ability, and the actions might be related to the reduction of inflammatory response and iNOS expression.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Comparison of the ERP-Based BCI Performance Among Chromatic (RGB) Semitransparent Face Patterns

    Objective

    Previous studies have shown that combing with color properties may be used as part of the display presented to BCI users in order to improve performance. Build on this, we explored the effects of combinations of face stimuli with three primary colors (RGB) on BCI performance which is assessed by classification accuracy and information transfer rate (ITR). Furthermore, we analyzed the waveforms of three patterns.

    Methods

    We compared three patterns in which semitransparent face is overlaid three primary colors as stimuli: red semitransparent face (RSF), green semitransparent face (GSF), and blue semitransparent face (BSF). Bayesian linear discriminant analysis (BLDA) was used to construct the individual classifier model. In addition, a Repeated-measures ANOVA (RM-ANOVA) and Bonferroni correction were chosen for statistical analysis.

    Results

    The results indicated that the RSF pattern achieved the highest online averaged accuracy with 93.89%, followed by the GSF pattern with 87.78%, while the lowest performance was caused by the BSF pattern with an accuracy of 81.39%. Furthermore, significant differences in classification accuracy and ITR were found between RSF and GSF (p < 0.05) and between RSF and BSF patterns (p < 0.05).

    Conclusion

    The semitransparent faces colored red (RSF) pattern yielded the best performance of the three patterns. The proposed patterns based on ERP-BCI system have a clinically significant impact by increasing communication speed and accuracy of the P300-speller for patients with severe motor impairment.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 31, 2020 12:00 AM.

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    Structural Variants May Be a Source of Missing Heritability in sALS

    The underlying genetic and molecular mechanisms that drive amyotrophic lateral sclerosis (ALS) remain poorly understood. Structural variants within the genome can play a significant role in neurodegenerative disease risk, such as the repeat expansion in C9orf72 and the tri-nucleotide repeat in ATXN2, both of which are associated with familial and sporadic ALS. Many such structural variants reside in uncharacterized regions of the human genome, and have been under studied. Therefore, characterization of structural variants located in and around genes associated with ALS could provide insight into disease pathogenesis, and lead to the discovery of highly informative genetic tools for stratification in clinical trials. Such genomic variants may provide a deeper understanding of how gene expression can affect disease etiology, disease severity and trajectory, patient response to treatment, and may hold the key to understanding the genetics of sporadic ALS. This article outlines the current understanding of amyotrophic lateral sclerosis genetics and how structural variations may underpin some of the missing heritability of this disease.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 31, 2020 12:00 AM.

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    An Informant-Based Simple Questionnaire for Visuospatial Dysfunction Assessment in Dementia

    Objectives

    Visuospatial dysfunction (VSD) is one of the most important symptoms for the diagnosis of dementia with Lewy bodies (DLB). The aim of this study was to validate a novel VSD questionnaire and determine the cutoff score for the screening for VSD in DLB.

    Methods

    This is a retrospective analysis of data from a project of the History-based Artificial Intelligent Clinical Dementia Diagnostic System (HAICDDS). VSD of non-demented control (NDC), Alzheimer’s disease (AD), and DLB participants were analyzed and compared using the visuospatial questionnaire in the HAICDDS (HAI-VSQ), the Draw subscale in the Cognitive Abilities Screening Instrument (CASI-Draw), and the visuospatial subscale in Montreal Cognitive Assessment (MoCA-VS).

    Results

    A total of 440 individuals were studied, including 154 NDC, 229 AD, and 57 DLB participants. Compared to NDC or AD participants, DLB participants showed a higher total score on HAI-VSQ after adjustment for age. Using HAI-VSQ, a cutoff score ≥ 2 was useful for the screening for VSD in DLB with a sensitivity of 0.77 and a specificity of 0.94. Compared with CASI-Draw or MoCA-VS, HAI-VSQ was least influenced by gender, age, and education and had the highest correlation with the sum of boxes of the Clinical Dementia Rating scale. After adjustment for age, education, gender, and global cognitive function, HAI-VSQ significantly discriminated DLB from AD and NDC whereas MoCA-VS or CASI-Draw did not.

    Conclusion

    Our study showed that the newly designed simple questionnaire was a practical screening tool for VSD in DLB that can be applied in clinical practice as well as on a registration platform.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 31, 2020 12:00 AM.

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    Subcortical Intermittent Theta-Burst Stimulation (iTBS) Increases Theta-Power in Dorsolateral Prefrontal Cortex (DLPFC)

    Introduction

    Cognitive symptoms from Parkinson’s disease cause severe disability and significantly limit quality of life. Little is known about mechanisms of cognitive impairment in PD, although aberrant oscillatory activity in basal ganglia-thalamo-prefrontal cortical circuits likely plays an important role. While continuous high-frequency deep brain stimulation (DBS) improves motor symptoms, it is generally ineffective for cognitive symptoms. Although we lack robust treatment options for these symptoms, recent studies with transcranial magnetic stimulation (TMS), applying intermittent theta-burst stimulation (iTBS) to dorsolateral prefrontal cortex (DLPFC), suggest beneficial effects for certain aspects of cognition, such as memory or inhibitory control. While TMS is non-invasive, its results are transient and require repeated application. Subcortical DBS targets have strong reciprocal connections with prefrontal cortex, such that iTBS through the permanently implanted lead might represent a more durable solution. Here we demonstrate safety and feasibility for delivering iTBS from the DBS electrode and explore changes in DLPFC electrophysiology.

    Methods

    We enrolled seven participants with medically refractory Parkinson’s disease who underwent DBS surgery targeting either the subthalamic nucleus (STN) or globus pallidus interna (GPi). We temporarily placed an electrocorticography strip over DLPFC through the DBS burr hole. After placement of the DBS electrode into either GPi (n = 3) or STN (n = 4), awake subjects rested quietly during iTBS (three 50-Hz pulses delivered at 5 Hz for 2 s, followed by 8 s of rest). We contrasted power spectra in DLPFC local field potentials during iTBS versus at rest, as well as between iTBS and conventional high-frequency stimulation (HFS).

    Results

    Dominant frequencies in DLPFC at rest varied among subjects and along the subdural strip electrode, though they were generally localized in theta (3–8 Hz) and/or beta (10–30 Hz) ranges. Both iTBS and HFS were well-tolerated and imperceptible. iTBS increased theta-frequency activity more than HFS. Further, GPi stimulation resulted in significantly greater theta-power versus STN stimulation in our sample.

    Conclusion

    Acute subcortical iTBS from the DBS electrode was safe and well-tolerated. This novel stimulation pattern delivered from the GPi may increase theta-frequency power in ipsilateral DLPFC. Future studies will confirm these changes in DLPFC activity during iTBS and evaluate whether they are associated with improvements in cognitive or behavioral symptoms from PD.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 31, 2020 12:00 AM.

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    The Hemodynamic Mass Action of a Central Pattern Generator

    The hemodynamic response is a neurovascular and metabolic process in which there is rapid delivery of blood flow to a neuronal tissue in response to neuronal activation. The functional magnetic resonance imaging (fMRI) and the functional near-infrared spectroscopy (fNIRS), for instance, are based on the physiological principles of such hemodynamic responses. Both techniques allow the mapping of active neuronal regions in which the neurovascular and metabolic events are occurring. However, although both techniques have revolutionized the neurosciences, they are mostly employed for neuroimaging of the human brain but not for the spinal cord during functional tasks. Moreover, little is known about other techniques measuring the hemodynamic response in the spinal cord. The purpose of the present study was to show for the first time that a simple optical system termed direct current photoplethysmography (DC-PPG) can be employed to detect hemodynamic responses of the spinal cord and the brainstem during the functional activation of the spinal central pattern generator (CPG). In particular, we positioned two DC-PPG systems directly on the brainstem and spinal cord during fictive scratching in the cat. The optical DC-PPG systems allowed the trial-by-trial recording of massive hemodynamic signals. We found that the “strength” of the flexor-plus-extensor motoneuron activities during motor episodes of fictive scratching was significantly correlated to the “strengths” of the brainstem and spinal DC-PPG signals. Because the DC-PPG was robustly detected in real-time, we claim that such a functional signal reflects the hemodynamic mass action of the brainstem and spinal cord associated with the CPG motor action. Our findings shed light on an unexplored hemodynamic observable of the spinal CPGs, providing a proof of concept that the DC-PPG can be used for the assessment of the integrity of the human CPGs.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 31, 2020 12:00 AM.

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    Resting-State Functional Connectivity Estimated With Hierarchical Bayesian Diffuse Optical Tomography

    Resting-state functional connectivity (RSFC) has been generally assessed with functional magnetic resonance imaging (fMRI) thanks to its high spatial resolution. However, fMRI has several disadvantages such as high cost and low portability. In addition, fMRI may not be appropriate for people with metal or electronic implants in their bodies, with claustrophobia and who are pregnant. Diffuse optical tomography (DOT), a method of neuroimaging using functional near-infrared spectroscopy (fNIRS) to reconstruct three-dimensional brain activity images, offers a non-invasive alternative, because fNIRS as well as fMRI measures changes in deoxygenated hemoglobin concentrations and, in addition, fNIRS is free of above disadvantages. We recently proposed a hierarchical Bayesian (HB) DOT algorithm and verified its performance in terms of task-related brain responses. In this study, we attempted to evaluate the HB DOT in terms of estimating RSFC. In 20 healthy males (21–38 years old), 10 min of resting-state data was acquired with 3T MRI scanner or high-density NIRS on different days. The NIRS channels consisted of 96 long (29-mm) source-detector (SD) channels and 56 short (13-mm) SD channels, which covered bilateral frontal and parietal areas. There were one and two resting-state runs in the fMRI and fNIRS experiments, respectively. The reconstruction performances of our algorithm and the two currently prevailing algorithms for DOT were evaluated using fMRI signals as a reference. Compared with the currently prevailing algorithms, our HB algorithm showed better performances in both the similarity to fMRI data and inter-run reproducibility, in terms of estimating the RSFC.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 31, 2020 12:00 AM.

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    Altered Amplitude of Low-Frequency Fluctuations and Functional Connectivity in Excessive Daytime Sleepiness in Parkinson Disease

    Object

    Excessive daytime sleepiness (EDS) is common in Parkinson disease (PD), but the neural basis of EDS in PD is unclear. We aim to analyze the neural activity changes in PD-related EDS.

    Methods

    In the present study, 38 PD patients and 19 healthy controls underwent clinical assessments and resting state functional magnetic resonance imaging (MRI) at 3T. Patients were further classified into PD patients with EDS (n = 17) and PD patients without EDS (n = 21), according to the Epworth Sleepiness Scale (ESS) cutoff score with greater than 10 or less than 3. We evaluated all patients using PD-related motor and non-motor clinical scales. An analysis of covariance and post hoc two-sample t-tests were performed to examine between-groups differences of the amplitude of low-frequency fluctuations (ALFF) and functional connectivity (FC).

    Results

    We found that, all PD-EDS subjects in our study were male. Compared with the control subjects, PD patients with EDS had decreased ALFF in the Pons and increased ALFF in the Frontal_Mid_Orb_L (p < 0.01, corrected). Moreover, PD patients with EDS showed decreased ALFF in the left posterior cingulate cortex (PCC) relative to PD without EDS, which was negatively correlated with the ESS score (p < 0.001). After that, the FC analysis with the left PCC region of interest showed reduced FC of the right PCC and right precuneus in PD with EDS compared with PD without EDS (p < 0.01, corrected).

    Conclusion

    We hypothesized the wake-promoting pathways and the default mode network dysfunction underlying the EDS in male PD patients.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 31, 2020 12:00 AM.

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    Corrigendum: Alterations of the Gut Microbiota in Multiple System Atrophy Patients

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 31, 2020 12:00 AM.

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    A Sparse EEG-Informed fMRI Model for Hybrid EEG-fMRI Neurofeedback Prediction

    Measures of brain activity through functional magnetic resonance imaging (fMRI) or electroencephalography (EEG), two complementary modalities, are ground solutions in the context of neurofeedback (NF) mechanisms for brain rehabilitation protocols. While NF-EEG (in which real-time neurofeedback scores are computed from EEG signals) has been explored for a very long time, NF-fMRI (in which real-time neurofeedback scores are computed from fMRI signals) appeared more recently and provides more robust results and more specific brain training. Using fMRI and EEG simultaneously for bi-modal neurofeedback sessions (NF-EEG-fMRI, in which real-time neurofeedback scores are computed from fMRI and EEG) is very promising for the design of brain rehabilitation protocols. However, fMRI is cumbersome and more exhausting for patients. The original contribution of this paper concerns the prediction of bi-modal NF scores from EEG recordings only, using a training phase where EEG signals as well as the NF-EEG and NF-fMRI scores are available. We propose a sparse regression model able to exploit EEG only to predict NF-fMRI or NF-EEG-fMRI in motor imagery tasks. We compared different NF-predictors stemming from the proposed model. We showed that predicting NF-fMRI scores from EEG signals adds information to NF-EEG scores and significantly improves the correlation with bi-modal NF sessions compared to classical NF-EEG scores.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 31, 2020 12:00 AM.

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    Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach

    Inflammation is a complex biological response to injuries, metabolic disorders or infections. In the brain, astrocytes play an important role in the inflammatory processes during neurodegenerative diseases. Recent studies have shown that the increase of free saturated fatty acids such as palmitic acid produces a metabolic inflammatory response in astrocytes generally associated with damaging mechanisms such as oxidative stress, endoplasmic reticulum stress, and autophagic defects. In this aspect, the synthetic neurosteroid tibolone has shown to exert protective functions against inflammation in neuronal experimental models without the tumorigenic effects exerted by sexual hormones such as estradiol and progesterone. However, there is little information regarding the specific mechanisms of tibolone in astrocytes during inflammatory insults. In the present study, we performed a genome-scale metabolic reconstruction of astrocytes that was used to study astrocytic response during an inflammatory insult by palmitate through Flux Balance Analysis methods and data mining. In this aspect, we assessed the metabolic fluxes of human astrocytes under three different scenarios: healthy (normal conditions), induced inflammation by palmitate, and tibolone treatment under palmitate inflammation. Our results suggest that tibolone reduces the L-glutamate-mediated neurotoxicity in astrocytes through the modulation of several metabolic pathways involved in glutamate uptake. We also identified a set of reactions associated with the protective effects of tibolone, including the upregulation of taurine metabolism, gluconeogenesis, cPPAR and the modulation of calcium signaling pathways. In conclusion, the different scenarios studied in our model allowed us to identify several metabolic fluxes perturbed under an inflammatory response and the protective mechanisms exerted by tibolone.

    in Frontiers in Neuroscience | Systems Biology section | New and Recent Articles on January 31, 2020 12:00 AM.

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    Simplified Model of PKCγ Signaling Dysregulation and Cytosol-to-Membrane Translocation Kinetics During Neurodegenerative Spinocerebellar Ataxia Type 14 (SCA14)

    Spinocerebellar ataxia type 14 (SCA14) is an autosomal neurodegenerative disease clinically characterized by progressive ataxia in the patient’s gait, accompanied by slurred speech and abnormal eye movements. These symptoms are linked to the loss of Purkinje cells (PCs), which leads to cerebellar neurodegeneration. PC observations link the mutations in PRKCG gene encoding protein kinase C γ (PKCγ) to SCA14. Observations also show that the link between PKCγ and SCA14 relies on a gain-of-function mechanism, and, in fact, both positive and negative regulation of PKCγ expression and activity may result in changes in cellular number, size, and complexity of the dendritic arbors in PCs. Here, through a systems biology approach, we investigate a key question relating to this system: why is PKCγ membrane residence time reduced in SCA14 mutant PCs compared to wild-type (WT) PCs? In this study, we investigate this question through two contrasting PKCγ signaling models in PCs. The first model proposed in this study describes the mechanism through which PKCγ signaling activity may be regulated in WT PCs. In contrast, the second model explores how mutations in PKCγ signaling affect the state of SCA14 in PCs. Numerical simulations of both models show that, in response to extracellular stimuli-induced depolarization of the membrane compartment, PKCγ and diacylglycerol kinase γ (DGKγ) translocate to the membrane. Results from our computational approach indicate that, for the same set of parameters, PKCγ membrane residence time is shorter in the SCA14 mutant model compared to the WT model. These results show how PKCγ membrane residence time is regulated by diacylglycerol (DAG), causing translocated PKCγ to return to the cytosol as DAG levels drop. This study shows that, when the strength of the extracellular signal is held constant, the membrane lifetime of mutant PKCγ is reduced. This reduction is due to the presence of constitutively active mutant PKCγ in the cytosol. Cytosolic PKCγ, in turn, leads to phosphorylation and activation of DGKγ while it is still residing in the cytosol. This effect occurs even during the resting conditions. Thus, the SCA14 mutant model explains that, when both DAG effector molecules are active in the cytosol, their interactions in the membrane compartment are reduced, critically influencing PKCγ membrane residence time.

    in Frontiers in Neuroscience | Systems Biology section | New and Recent Articles on January 31, 2020 12:00 AM.

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    Editorial: Shaping the Brain by Neuronal Cytoskeleton: From Development to Disease and Degeneration

    in Frontiers in Cellular Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Plasmacytoid Dendritic Cells Protect Against Middle Cerebral Artery Occlusion Induced Brain Injury by Priming Regulatory T Cells

    Regulatory T cells (Tregs) play an anti-inflammatory effect to protect against ischemic stroke. Plasmacytoid dendritic cells (pDCs) can induce regulatory T cells tolerance in sterile-inflammation conditions. However, whether and how pDCs-mediated Tregs response play a part in the pathology of ischemic stroke remains unclear. In this study, we showed that pDCs were increased in the brain of middle cerebral artery occlusion (MCAO) mice. Depletion of pDCs with 120G8 exacerbated MCAO-induced brain injury, peripheral pro-inflammation response and decreased the systemic Tregs in mice. Furthermore, the data of mixed lymphocyte reaction (MLR) in vitro demonstrate that splenic pDCs from MCAO mice can significantly promote Tregs proliferation, accompanying with the increased expression of indoleamine 2,3-dioxygenase 1 (IDO1) on pDCs. Taken together, the findings here suggested that under the pathologic state of stroke, pDCs protect against MCAO-induced brain injury by priming Tregs, illustrating that pDCs represented as a therapeutic target for the prevention of ischemic brain injury.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Increased Presence of Cerebral Microbleeds Correlates With Ventricular Enlargement and Increased White Matter Hyperintensities in Alzheimer’s Disease

    Objective: To investigate whether the number of cerebral microbleeds (CMB) could be a useful indicator to predict glymphatic system dysfunction in Alzheimer’s disease (AD) patients, by comparing the degree of cerebral spinal fluid (CSF) and interstitial fluid (ISF) stasis.

    Methods: Forty probable AD patients were included, with those exhibiting two or more CMB were included in the multiple CMB group (mCMB, n = 21, mean = 11.1), and none or one CMB included in the non-multiple CMB group (nmCMB, n = 19, mean = 0.84). CMB was defined in axial gradient recalled echo (GRE) T2*-weighted images. Evans index (EI) was calculated to measure lateral ventricle enlargement, Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) software was used to determine the extent of gray and white matter atrophy, and Fazekas scale (FS) was used to determine white matter hyperintensities (WMH).

    Results: EI was significantly larger in mCMB than in nmCMB, while the gray and white matter volume was not different between groups. Thus, the difference in lateral ventricle enlargement between AD with and without multiple CMB reflects a combination of the degree of brain atrophy and the extent of CSF stasis. FS was higher in mCMB than in the nmCMB, suggesting the failure of ISF elimination was more severe in mCMB cases.

    Conclusion: The difference in lateral ventricle enlargement and WMH between AD with or without multiple CMB may reflect a difference in the degree of CSF/ISF stagnation.

    in Frontiers in Aging Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Functional Connectivity of the Anterior and Posterior Hippocampus: Differential Effects of Glucose in Younger and Older Adults

    The hippocampus features structurally and functionally distinct anterior and posterior segments. Relatively few studies have examined how these change during aging or in response to pharmacological interventions. Alterations in hippocampal connectivity and changes in glucose regulation have each been associated with cognitive decline in aging. A distinct line of research suggests that administration of glucose can lead to a transient improvement in hippocampus-dependent memory. Here, we probe age, glucose and human cognition with a special emphasis on resting-state functional connectivity (rsFC) of the hippocampus along its longitudinal axis to the rest of the brain. Using a randomized, placebo-controlled, double-blind, crossover design 32 healthy adults (16 young and 16 older) ingested a drink containing 25 g glucose or placebo across two counter balanced sessions. They then underwent resting-state functional magnetic resonance imaging (rs-fMRI) and cognitive testing. There was a clear dissociation in the effects of glucose by age. Magnitude change in rsFC from posterior hippocampus (pHPC) to medial frontal cortex (mPFC) was correlated with individual glucose regulation and gains in performance on a spatial navigation task. Our results demonstrate that glucose administration can attenuate cognitive performance deficits in older adults with impaired glucose regulation and suggest that increases in pHPC-mPFC rsFC are beneficial for navigation task performance in older participants.

    in Frontiers in Aging Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

    Parkinson’s disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.

    in Frontiers in Aging Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    The Decline in Intrinsic Connectivity Between the Salience Network and Locus Coeruleus in Older Adults: Implications for Distractibility

    We examined functional connectivity between the locus coeruleus (LC) and the salience network in healthy young and older adults to investigate why people become more prone to distraction with age. Recent findings suggest that the LC plays an important role in focusing processing on salient or goal-relevant information from multiple incoming sensory inputs (Mather et al., 2016). We hypothesized that the connection between LC and the salience network declines in older adults, and therefore the salience network fails to appropriately filter out irrelevant sensory signals. To examine this possibility, we used resting-state-like fMRI data, in which all task-related activities were regressed out (Fair et al., 2007; Elliott et al., 2019) and performed a functional connectivity analysis based on the time-course of LC activity. Older adults showed reduced functional connectivity between the LC and salience network compared with younger adults. Additionally, the salience network was relatively more coupled with the frontoparietal network than the default-mode network in older adults compared with younger adults, even though all task-related activities were regressed out. Together, these findings suggest that reduced interactions between LC and the salience network impairs the ability to prioritize the importance of incoming events, and in turn, the salience network fails to initiate network switching (e.g., Menon and Uddin, 2010; Uddin, 2015) that would promote further attentional processing. A chronic lack of functional connection between LC and salience network may limit older adults’ attentional and executive control resources.

    in Frontiers in Aging Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Prefrontal Consolidation and Compensation as a Function of Wearing Denture in Partially Edentulous Elderly Patients

    Background

    The cognitive effects of wearing a denture are not well understood. This study was conducted to clarify the effects of denture use on prefrontal and chewing muscle activities, occlusal state, and subjective chewing ability in partially edentulous elderly individuals.

    Methods

    A total of 16 partially edentulous patients were enrolled. Chewing-related prefrontal cortex and jaw muscle activities were simultaneously examined using a functional near-infrared spectroscopy (fNIRS) device and electromyography, under the conditions of unwearing, and wearing a denture. Occlusal state and masticatory score were also determined under both conditions. Using multiple linear regression analysis, associations between prefrontal and chewing activities with wearing were examined using change rates.

    Results

    Chewing rhythmicity was maintained under both conditions. As compared with unwearing, the wearing condition was associated with improved prefrontal cortex and chewing muscle activities, occlusal state in regard to force and area, and masticatory score. Also, prefrontal activities were positively associated with burst duration and peak amplitude in masseter (Mm) and temporal muscle activities, as well as masticatory scores. In contrast, prefrontal activities were negatively associated with occlusal force.

    Conclusion

    Wearing a denture induced a positive association between burst duration and peak amplitude in Mm and temporal muscle activities and prefrontal activity, which may indicate a parallel consolidation of prefrontal cortex and rhythmical chewing activities, as well as masticatory scores. On the other hand, denture use induced a negative association of occlusal force with prefrontal activities, which might suggest that prefrontal compensative associations for the physiocognitive acquisition depended on biomechanical efficacy gained by wearing a denture.

    in Frontiers in Aging Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer’s Disease Mice

    Introduction

    Alzheimer’s disease (AD) is a progressive neurodegenerative dementia with the key pathological hallmarks amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau. microRNAs (miRNAs) are small non-coding RNAs that contribute to the pathogenesis of AD. In this study, we investigated the effect of the loss of miR-369 on the phosphorylation of tau protein and the activation of the kinases Fyn and serine/threonine-protein kinase 2 (SRPK2) as the upstream molecules facilitating tau phosphorylation in miR-369 knockout 3xTg-AD mice.

    Methods

    We generated miR-369 knockout 3xTg-AD mice and investigated their cognitive behaviors by maze tests. Real-time qPCR, western blot, and immunohistochemistry were performed to evaluate the expression of the miR-369 gene, phosphorylation of tau protein, and activation of Fyn and SRPK2. Luciferase reporter assays were applied to confirm the predicted targets of miR-369.

    Results

    Knocking out miR-369 in 3xTg AD mice aggravated cognitive impairment, promoted hyperphosphorylation of tau, and upregulated Fyn and SRPK2. Restoring miR-369 reversed the hyperphosphorylation of tau and downregulated Fyn and SRPK2. Additionally, miR-369 was shown to target the 3′UTRs of Fyn and SRPK2 to regulate their expression levels.

    Conclusion

    Loss of miR-369 promotes tau phosphorylation by targeting the Fyn and SRPK2 signaling pathways in AD mice, and supplementation with miR-369 might be a valuable option for AD therapeutic studies.

    in Frontiers in Aging Neuroscience | New and Recent Articles on January 31, 2020 12:00 AM.

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    Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human

    Objective

    Aging is a major risk factor for numerous neurological disorders, and the mechanisms underlying brain aging remain elusive. Recent animal studies demonstrated a tight relationship between impairment of the glymphatic pathway, meningeal lymphatic vessels, and aging. However, the relationship in the human brain remains uncertain.

    Methods

    In this observational cohort study, patients underwent magnetic resonance imaging before and at multiple time points after intrathecal administration of a contrast agent. Head T1‐weighted imaging was performed to assess the function of the glymphatic pathway and head high‐resolution T2–fluid attenuated inversion recovery imaging to visualize putative meningeal lymphatic vessels (pMLVs). We measured the signal unit ratio (SUR) of 6 locations in the glymphatic pathway and pMLVs, defined the percentage change in SUR from baseline to 39 hours as the clearance of the glymphatic pathway and pMLVs, and then analyzed their relationships with aging.

    Results

    In all patients (N = 35), the SUR of the glymphatic pathway and pMLVs changed significantly after intrathecal injection of the contrast agent. The clearance of both the glymphatic pathway and pMLVs was related to aging (all p < 0.05). The clearance of pMLVs was significantly related to the clearance of the glymphatic pathway (all p < 0.05), and the clearance of the glymphatic pathway was significantly faster in patients with early filling of pMLVs than those with late filling (all p < 0.05).

    Interpretation

    We revealed that both the glymphatic pathway and pMLVs might be impaired in the aging human brain through the novel, clinically available method to simultaneously visualize their clearance. Our findings also support that in humans, pMLVs are the downstream of the glymphatic pathway. Ann Neurol 2020;87:357–369

    in Wiley: Annals of Neurology: Table of Contents on January 30, 2020 12:17 PM.

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    ANA Investigates: Pioneering Unbiased Diagnostics

    in Wiley: Annals of Neurology: Table of Contents on January 30, 2020 10:55 AM.

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    Excessive Treadmill Training Enhances Brain-Specific MicroRNA-34a in the Mouse Hippocampus

    Background: An imbalance between total training load and total recovery may cause overtraining (OT). The purpose of the present study was to verify the effects of OT on the expression of brain-derived neurotrophic factor (BDNF), its receptor tropomyosin receptor kinase B (TrkB) and p75 and the dynamic expression patterns of brain-specific miR-34a and miR-124 or inflammation-related miR-21 and miR-132 in the mouse hippocampus.

    Method: Eight weeks old C57BL/6J mice were randomly assigned to the control (CON), normal training (NT) and OT groups. An 8-week OT training protocol was applied to evaluate the phenotype of mice endurance (incremental load test, ILT) and cognitive capacity (Morris water maze test). We used qRT-PCR and immunoblotting to detect changes in the molecular level of hippocampal samples.

    Result: Compared with the CON, both NT and OT decreased bodyweight after 8-week training. After 8-week of training, NT increased the exhaustion velocity (EV) while the EV of OT was lower than NT. Mice in NT decreased the escape latency than CON. The percentage of time spent in the probe quadrant and the number of crossing platform times in NT were higher than CON and OT. The BDNF, p75 and TrkB mRNA levels were increased in NT than CON, only the p75 mRNA was increased in OT. The NT exhibited increased protein levels of BDNF and TrkB compared to CON. The protein expression of BDNF was decreased in OT than NT and CON. The protein level of p75 in the OT was higher than in NT and CON. In addition, the phosphorylation level of TrkB in OT was higher than CON and NT. Only the miR-34a level was increased in the OT. Moreover, the expression of miR-34a was found to be negatively correlated with the expression of BDNF, and the increase in miR-34a level was accompanied by a decrease in performance.

    Conclusion: In summary, the training-evoked increase in the BDNF level may help to improve performance, whereas this conditioning is lost after OT. Moreover, miR-34a potentially mediated changes in the expression of BDNF and may reflect the decrease in performance after OT.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on January 30, 2020 12:00 AM.

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    Using Neural Circuit Interrogation in Rodents to Unravel Human Speech Decoding

    The neural circuits responsible for social communication are among the least understood in the brain. Human studies have made great progress in advancing our understanding of the global computations required for processing speech, and animal models offer the opportunity to discover evolutionarily conserved mechanisms for decoding these signals. In this review article, we describe some of the most well-established speech decoding computations from human studies and describe animal research designed to reveal potential circuit mechanisms underlying these processes. Human and animal brains must perform the challenging tasks of rapidly recognizing, categorizing, and assigning communicative importance to sounds in a noisy environment. The instructions to these functions are found in the precise connections neurons make with one another. Therefore, identifying circuit-motifs in the auditory cortices and linking them to communicative functions is pivotal. We review recent advances in human recordings that have revealed the most basic unit of speech decoded by neurons is a phoneme, and consider circuit-mapping studies in rodents that have shown potential connectivity schemes to achieve this. Finally, we discuss other potentially important processing features in humans like lateralization, sensitivity to fine temporal features, and hierarchical processing. The goal is for animal studies to investigate neurophysiological and anatomical pathways responsible for establishing behavioral phenotypes that are shared between humans and animals. This can be accomplished by establishing cell types, connectivity patterns, genetic pathways and critical periods that are relevant in the development and function of social communication.

    in Frontiers in Neural Circuits | New and Recent Articles on January 30, 2020 12:00 AM.

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    Unsuspected Involvement of Spinal Cord in Alzheimer Disease

    Objective: Brain atrophy is an established biomarker for dementia, yet spinal cord involvement has not been investigated to date. As the spinal cord is relaying sensorimotor control signals from the cortex to the peripheral nervous system and vice-versa, it is indeed a very interesting question to assess whether it is affected by atrophy due to a disease that is known for its involvement of cognitive domains first and foremost, with motor symptoms being clinically assessed too. We, therefore, hypothesize that in Alzheimer’s disease (AD), severe atrophy can affect the spinal cord too and that spinal cord atrophy is indeed an important in vivo imaging biomarker contributing to understanding neurodegeneration associated with dementia.

    Methods: 3DT1 images of 31 AD and 35 healthy control (HC) subjects were processed to calculate volume of brain structures and cross-sectional area (CSA) and volume (CSV) of the cervical cord [per vertebra as well as the C2-C3 pair (CSA23 and CSV23)]. Correlated features (ρ > 0.7) were removed, and the best subset identified for patients’ classification with the Random Forest algorithm. General linear model regression was used to find significant differences between groups (p ≤ 0.05). Linear regression was implemented to assess the explained variance of the Mini-Mental State Examination (MMSE) score as a dependent variable with the best features as predictors.

    Results: Spinal cord features were significantly reduced in AD, independently of brain volumes. Patients classification reached 76% accuracy when including CSA23 together with volumes of hippocampi, left amygdala, white and gray matter, with 74% sensitivity and 78% specificity. CSA23 alone explained 13% of MMSE variance.

    Discussion: Our findings reveal that C2-C3 spinal cord atrophy contributes to discriminate AD from HC, together with more established features. The results show that CSA23, calculated from the same 3DT1 scan as all other brain volumes (including right and left hippocampi), has a considerable weight in classification tasks warranting further investigations. Together with recent studies revealing that AD atrophy is spread beyond the temporal lobes, our result adds the spinal cord to a number of unsuspected regions involved in the disease. Interestingly, spinal cord atrophy explains also cognitive scores, which could significantly impact how we model sensorimotor control in degenerative diseases with a primary cognitive domain involvement. Prospective studies should be purposely designed to understand the mechanisms of atrophy and the role of the spinal cord in AD.

    in Frontiers in Cellular Neuroscience | New and Recent Articles on January 30, 2020 12:00 AM.

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    CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

    Objective

    Evidence for a role of microglia in the pathogenesis of multiple sclerosis (MS) is growing. We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity (relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients.

    Methods

    In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia‐related proteins, chitotriosidase (CHIT1), chitinase‐3–like protein 1 (CHI3L1 or YKL‐40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme‐linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia‐related markers in publicly available RNA expression data from postmortem brain tissue.

    Results

    CHIT1 levels at diagnostic LP correlated with 2 aspects of long‐term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E‐04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E‐04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL.

    Interpretation

    CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity. ANN NEUROL 2020

    in Wiley: Annals of Neurology: Table of Contents on January 29, 2020 05:41 PM.

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    Independent Functional Outcomes after Prolonged Coma following Cardiac Arrest: A Mechanistic Hypothesis

    Objective

    Survivors of prolonged (>2 weeks) post–cardiac arrest (CA) coma are expected to remain permanently disabled. We aimed to investigate 3 outlier patients who ultimately achieved independent functional outcomes after prolonged post‐CA coma to identify electroencephalographic (EEG) markers of their recovery potential. For validation purposes, we also aimed to evaluate these markers in an independent cohort of post‐CA patients.

    Methods

    We identified 3 patients with late recovery from coma (17–37 days) following CA who recovered to functionally independent behavioral levels. We performed spectral power analyses of available EEGs during prominent burst suppression patterns (BSP) present in all 3 patients. Using identical methods, we also assessed the relationship of intraburst spectral power and outcomes in a prospectively enrolled cohort of post‐CA patients. We performed chart reviews of common clinical, imaging, and EEG prognostic variables and clinical outcomes for all patients.

    Results

    All 3 patients with late recovery from coma lacked evidence of overwhelming cortical injury but demonstrated prominent BSP on EEG. Spectral analyses revealed a prominent theta (~4–7Hz) feature dominating the bursts during BSP in these patients. In the prospective cohort, similar intraburst theta spectral features were evident in patients with favorable outcomes; patients with BSP and unfavorable outcomes showed either no features, transient burst features, or decreasing intraburst frequencies with time.

    Interpretation

    BSP with theta (~4–7Hz) peak intraburst spectral power after CA may index a recovery potential. We discuss our results in the context of optimizing metabolic substrate availability and stimulating the corticothalamic system during recovery from prolonged post‐CA coma. ANN NEUROL 2020

    in Wiley: Annals of Neurology: Table of Contents on January 29, 2020 10:50 AM.

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    Natural History of Adult Patients with GM2 Gangliosidosis

    Objective

    GM2 gangliosidoses are lysosomal diseases due to biallelic mutations in the HEXA (Tay–Sachs disease [TS]) or HEXB (Sandhoff disease [SD]) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2 gangliosidosis.

    Methods

    We retrospectively described 12 patients from a French cohort and 45 patients from the literature.

    Results

    We observed 4 typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above 3 manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging feature was cerebellar atrophy, even in patients without cerebellar symptoms. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users.

    Interpretation

    Improved knowledge of GM2 gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. ANN NEUROL 2020

    in Wiley: Annals of Neurology: Table of Contents on January 29, 2020 10:40 AM.

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    Withdrawn support

    Nature Reviews Neuroscience, Published online: 29 January 2020; doi:10.1038/s41583-020-0268-4

    In a mouse model of prion disease, blocking a major branch of the unfolded protein response selectively in astrocytes was highly neuroprotective, reducing neurodegeneration, reducing astrocyte reactivity and increasing longevity.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 29, 2020 12:00 AM.

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    A stand-out loop

    Nature Reviews Neuroscience, Published online: 29 January 2020; doi:10.1038/s41583-020-0267-5

    One of two anatomically and functionally characterized subpopulations of neurons in the mouse paraventricular thalamus forms a thalamo-corticothalamic loop with the infralimbic cortex that regulates arousal.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 29, 2020 12:00 AM.

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    Reward memories extinguish fear

    Nature Reviews Neuroscience, Published online: 29 January 2020; doi:10.1038/s41583-020-0266-6

    Fear extinction memories are formed and stored within a population of reward-encoding neurons in the basolateral amygdala.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 29, 2020 12:00 AM.

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    Soluble Epoxide Hydrolase and Brain Cholesterol Metabolism

    The bifunctional enzyme soluble epoxide hydrolase (sEH) is found in all regions of the brain. It has two different catalytic activities, each assigned to one of its terminal domains: the C-terminal domain presents hydrolase activity, whereas the N-terminal domain exhibits phosphatase activity. The enzyme’s C-terminal domain has been linked to cardiovascular protective and anti-inflammatory effects. Cholesterol-related disorders have been associated with sEH, which plays an important role in the metabolism of cholesterol precursors. The role of sEH’s phosphatase activity has been so far poorly investigated in the context of the central nervous system physiology. Given that brain cholesterol disturbances play a role in the onset of Alzheimer’s disease (AD) as well as of other neurodegenerative diseases, understanding the functions of this enzyme could provide pivotal information on the pathophysiology of these conditions. Moreover, the sEH phosphatase domain could represent an underexplored target for drug design and therapeutic strategies to improve symptoms related to neurodegenerative diseases. This review discusses the function of sEH in mammals and its protein structure and catalytic activities. Particular attention was given to the distribution and expression of sEH in the human brain, deepening into the enzyme’s phosphatase activity and its participation in brain cholesterol synthesis. Finally, this review focused on the metabolism of cholesterol and its association with AD.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on January 29, 2020 12:00 AM.

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    Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

    The physical continuity of axons over long cellular distances poses challenges for their maintenance. One organelle that faces this challenge is endoplasmic reticulum (ER); unlike other intracellular organelles, this forms a physically continuous network throughout the cell, with a single membrane and a single lumen. In axons, ER is mainly smooth, forming a tubular network with occasional sheets or cisternae and low amounts of rough ER. It has many potential roles: lipid biosynthesis, glucose homeostasis, a Ca2+ store, protein export, and contacting and regulating other organelles. This tubular network structure is determined by ER-shaping proteins, mutations in some of which are causative for neurodegenerative disorders such as hereditary spastic paraplegia (HSP). While axonal ER shares many features with the tubular ER network in other contexts, these features must be adapted to the long and narrow dimensions of axons. ER appears to be physically continuous throughout axons, over distances that are enormous on a subcellular scale. It is therefore a potential channel for long-distance or regional communication within neurons, independent of action potentials or physical transport of cargos, but involving its physiological roles such as Ca2+ or organelle homeostasis. Despite its apparent stability, axonal ER is highly dynamic, showing features like anterograde and retrograde transport, potentially reflecting continuous fusion and breakage of the network. Here we discuss the transport processes that must contribute to this dynamic behavior of ER. We also discuss the model that these processes underpin a homeostatic process that ensures both enough ER to maintain continuity of the network and repair breaks in it, but not too much ER that might disrupt local cellular physiology. Finally, we discuss how failure of ER organization in axons could lead to axon degenerative diseases, and how a requirement for ER continuity could make distal axons most susceptible to degeneration in conditions that disrupt ER continuity.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 29, 2020 12:00 AM.

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    Transcranial Direct Current Stimulation Ameliorates Cognitive Impairment via Modulating Oxidative Stress, Inflammation, and Autophagy in a Rat Model of Vascular Dementia

    To investigate the potential applications and the molecular mechanisms of transcranial direct current stimulation (tDCS) on cognitive impairment in a vascular dementia (VD) animal model. Sprague-Dawley rats were used in this study. VD rat model was induced by modified permanent bilateral common carotid artery occlusion (2-VO) approach. Anodal tDCS was applied to the animals. Morris water maze was used to analyze spatial memory and navigation ability. The pathological changes in the hippocampal CA1 region and cerebral cortex were examined via Hematoxylin-Eosin staining. The rats were sacrificed for the measurement of the level of superoxide (SOD), glutathione (GSH), reactive oxidative species (ROS), malondialdehyd (MDA), Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α level in the hippocampus. Western blot was carried out to measure the hippocampal expression of microtubule-associated protein 1 light chain 3 (LC-3) and p62. Rats with VD have decreased number of neurons in the hippocampus and cerebral cortex, as well as worse cognitive impairment. The proliferation of activated microglia and astroglia, accompanied with attenuation of myelination were observed in the white matter about 1 month after 2-VO operation. These abnormalities were significantly ameliorated by tDCS treatment. Further study revealed that anodal tDCS could suppress the MDA and ROS level, while enhance the SOD and GSH level to reduce the oxidative stress. Anodal tDCS could inhibit hypoperfusion-induced IL-1β, IL-6, and TNF-α expression to attenuate inflammatory response in hippocampus. Moreover, anodal tDCS treatment could alleviate autophagy level. The study has demonstrated a possible therapeutic role of tDCS in the treatment of cognitive impairment in VD.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 29, 2020 12:00 AM.

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    Early Maternal and Social Deprivation Expands Neural Stem Cell Population Size and Reduces Hippocampus/Amygdala-Dependent Fear Memory

    Early life stress can exert detrimental or beneficial effects on neural development and postnatal behavior depending on the timing, duration, strength, and ability to control the stressors. In this study, we utilized a maternal and social deprivation (MSD) model to investigate the effects of early life stress on neural stem cells (NSCs) and neurogenesis in the adult brain. We found that MSD during the stress-hyporesponsive period (SHRP) (early-MSD), when corticosterone secretion is suppressed, increased the size of the NSC population, whereas the same stress beyond the SHRP abrogated these effects. Early-MSD enhanced neurogenesis not only in the dentate gyrus of the hippocampus, one of the classic neurogenic regions, but also in the amygdala. In addition, mice exposed to early-MSD exhibited a reduction in amygdala/hippocampus-dependent fear memory. These results suggest that animals exposed to early life stress during the SHRP have reinforced stress resilience to cope with perceived stressors to maintain a normal homeostatic state.

    in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on January 29, 2020 12:00 AM.

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    A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles

    α-Synuclein (αS) is a presynaptic protein whose aggregation is associated with Parkinson’s disease (PD). Although the physiological function of αS is still unclear, several lines of evidence indicate that this protein may play a role in the trafficking of synaptic vesicles (SVs) during neurotransmitter release, a task associated with its ability to bind SVs and promote their clustering. It is therefore crucial to identify the cellular factors that modulate this process. To address this question, using nuclear magnetic resonance (NMR) spectroscopy we have characterized the role of cholesterol, a major component of the membrane of SVs, in the binding of αS with synaptic-like vesicles. Our results indicate that cholesterol can act as a modulator of the overall affinity of αS for SVs by reducing the local affinity of the region spanning residues 65–97 in the non-amyloid-β component (NAC) of the protein. The increased population of bound states that expose the region 65–97 to the solvent was found to induce stronger vesicle-vesicle interactions by αS. These results provide evidence that cholesterol modulates the clustering of synaptic vesicles induced by (α)S, and supports the role of the disorder-to-order equilibrium of the NAC region in the modulation of the biological properties of the membrane-bound state of αS.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 29, 2020 12:00 AM.

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    Environmental Tobacco Smoke During the Early Postnatal Period of Mice Interferes With Brain 18 F-FDG Uptake From Infancy to Early Adulthood – A Longitudinal Study

    Exposure to environmental tobacco smoke (ETS) is associated with high morbidity and mortality, mainly in childhood. Our aim was to evaluate the effects of postnatal ETS exposure in the brain 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake of mice by positron emission tomography (PET) neuroimaging in a longitudinal study. C57BL/6J mice were exposed to ETS that was generated from 3R4F cigarettes from postnatal day 3 (P3) to P14. PET analyses were performed in male and female mice during infancy (P15), adolescence (P35), and adulthood (P65). We observed that ETS exposure decreased 18F-FDG uptake in the whole brain, both left and right hemispheres, and frontal cortex in both male and female infant mice, while female infant mice exposed to ETS showed decreased 18F-FDG uptake in the cerebellum. In addition, all mice showed reduced 18F-FDG uptake in infancy, compared to adulthood in all analyzed VOIs. In adulthood, ETS exposure during the early postnatal period decreased brain 18F-FDG uptake in adult male mice in the cortex, striatum, hippocampus, cingulate cortex, and thalamus when compared to control group. ETS induced an increase in 18F-FDG uptake in adult female mice when compared to control group in the brainstem and cingulate cortex. Moreover, male ETS-exposed animals showed decreased 18F-FDG uptake when compared to female ETS-exposed in the whole brain, brainstem, cortex, left amygdala, striatum, hippocampus, cingulate cortex, basal forebrain and septum, thalamus, hypothalamus, and midbrain. The present study shows that several brain regions are vulnerable to ETS exposure during the early postnatal period and these effects on 18F-FDG uptake are observed even a long time after the last exposure. This study corroborates our previous findings, strengthening the idea that exposure to tobacco smoke in a critical period interferes with brain development of mice from late infancy to early adulthood.

    in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on January 29, 2020 12:00 AM.

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    Interplay Between Mitochondrial Oxidative Disorders and Proteostasis in Alzheimer’s Disease

    Although the basis of Alzheimer’s disease (AD) etiology remains unknown, oxidative stress (OS) has been recognized as a prodromal factor associated to its progression. OS refers to an imbalance between oxidant and antioxidant systems, which usually consist in an overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which overwhelms the intrinsic antioxidant defenses. Due to this increased production of ROS and RNS, several biological functions such as glucose metabolism or synaptic activity are impaired. In AD, growing evidence links the ROS-mediated damages with molecular targets including mitochondrial dynamics and function, protein quality control system, and autophagic pathways, affecting the proteostasis balance. In this scenario, OS should be considered as not only a major feature in the pathophysiology of AD but also a potential target to combat the progression of the disease. In this review, we will discuss the role of OS in mitochondrial dysfunction, protein quality control systems, and autophagy associated to AD and suggest innovative therapeutic strategies based on a better understanding of the role of OS and proteostasis.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 29, 2020 12:00 AM.

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    Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

    Iron is an essential transition metal for numerous biologic processes in mammals. Iron metabolism is regulated via several coordination mechanisms including absorption, utilization, recycling, and storage. Iron dyshomeostasis can result in intracellular iron retention, thereby damaging cells, tissues, and organs through free oxygen radical generation. Numerous studies have shown that brain iron overload is involved in the pathological mechanism of neurodegenerative disease including Alzheimer’s disease (AD). However, the underlying mechanisms have not been fully elucidated. Ferroptosis, a newly defined iron-dependent form of cell death, which is distinct from apoptosis, necrosis, autophagy, and other forms of cell death, may provide us a new viewpoint. Here, we set out to summarize the current knowledge of iron metabolism and ferroptosis, and review the contributions of iron and ferroptosis to AD.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 29, 2020 12:00 AM.

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    A Machine Learning Approach to the Differentiation of Functional Magnetic Resonance Imaging Data of Chronic Fatigue Syndrome (CFS) From a Sedentary Control

    Chronic Fatigue Syndrome (CFS) is a debilitating condition estimated to impact at least 1 million individuals in the United States, however there persists controversy about its existence. Machine learning algorithms have become a powerful methodology for evaluating multi-regional areas of fMRI activation that can classify disease phenotype from sedentary control. Uncovering objective biomarkers such as an fMRI pattern is important for lending credibility to diagnosis of CFS. fMRI scans were evaluated for 69 patients (38 CFS and 31 Control) taken before (Day 1) and after (Day 2) a submaximal exercise test while undergoing the n-back memory paradigm. A predictive model was created by grouping fMRI voxels into the Automated Anatomical Labeling (AAL) atlas, splitting the data into a training and testing dataset, and feeding these inputs into a logistic regression to evaluate differences between CFS and control. Model results were cross-validated 10 times to ensure accuracy. Model results were able to differentiate CFS from sedentary controls at a 80% accuracy on Day 1 and 76% accuracy on Day 2 (Table 3). Recursive features selection identified 29 ROI's that significantly distinguished CFS from control on Day 1 and 28 ROI's on Day 2 with 10 regions of overlap shared with Day 1 (Figure 3). These 10 shared regions included the putamen, inferior frontal gyrus, orbital (F3O), supramarginal gyrus (SMG), temporal pole; superior temporal gyrus (T1P) and caudate ROIs. This study was able to uncover a pattern of activated neurological regions that differentiated CFS from Control. This pattern provides a first step toward developing fMRI as a diagnostic biomarker and suggests this methodology could be emulated for other disorders. We concluded that a logistic regression model performed on fMRI data significantly differentiated CFS from Control.

    in Frontiers in Computational Neuroscience | New and Recent Articles on January 29, 2020 12:00 AM.

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    An Information Theoretic Approach to Reveal the Formation of Shared Representations

    Modality-invariant categorical representations, i.e., shared representation, is thought to play a key role in learning to categorize multi-modal information. We have investigated how a bimodal autoencoder can form a shared representation in an unsupervised manner with multi-modal data. We explored whether altering the depth of the network and mixing the multi-modal inputs at the input layer affect the development of the shared representations. Based on the activation of units in the hidden layers, we classified them into four different types: visual cells, auditory cells, inconsistent visual and auditory cells, and consistent visual and auditory cells. Our results show that the number and quality of the last type (i.e., shared representation) significantly differ depending on the depth of the network and are enhanced when the network receives mixed inputs as opposed to separate inputs for each modality, as occurs in typical two-stage frameworks. In the present work, we present a way to utilize information theory to understand the abstract representations formed in the hidden layers of the network. We believe that such an information theoretic approach could potentially provide insights into the development of more efficient and cost-effective ways to train neural networks using qualitative measures of the representations that cannot be captured by analyzing only the final outputs of the networks.

    in Frontiers in Computational Neuroscience | New and Recent Articles on January 29, 2020 12:00 AM.

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    A Step-by-Step Protocol for Optogenetic Kindling

    Electrical kindling, repeated brain stimulation eventually resulting in seizures, is widely used as an animal model of epileptogenesis and epilepsy. However, the stimulation electrode used for electric kindling targets unknown neuronal populations and may introduce tissue damage and inflammation. Optogenetics can be used to circumvent these shortcomings by permitting millisecond control of activity in genetically defined neurons without gross injury or inflammation. Here we describe an easy step-by-step protocol for optogenetic kindling – optokindling – by which seizures are eventually elicited in initially healthy mice through repeated light stimulation of neurons expressing Channelrhodopsin-2 (ChR2). Chronic EEG recordings may be performed over large time scales to monitor activity while video camera monitoring may be used to assess the behavioral severity of seizures. In conclusion, with optokindling, neuroscientists can elucidate the circuit changes that underpin epilepsy while minimizing the contribution of confounding factors such as brain damage and inflammation.

    in Frontiers in Neural Circuits | New and Recent Articles on January 29, 2020 12:00 AM.

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    Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury

    Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecu...

    in Most Recent Articles: BMC Neuroscience on January 29, 2020 12:00 AM.

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    Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4

    Objective

    To determine the clinical and molecular features in patients with amyotrophic lateral sclerosis 4 (ALS4) due to mutations in the senataxin (SETX) gene and to develop tools for evaluating SETX variants.

    Methods

    Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual‐energy x‐ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function.

    Results

    We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlates with disease duration (thigh fat fraction R 2 = 0.35, p = 0.01; lower leg fat fraction R 2 = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than upper extremities (average fat z scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function.

    Interpretation

    We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R‐loop levels in patient‐derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. ANN NEUROL 2020

    in Wiley: Annals of Neurology: Table of Contents on January 28, 2020 02:13 PM.

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    A need for input

    Nature Reviews Neuroscience, Published online: 28 January 2020; doi:10.1038/s41583-020-0265-7

    In mice, temporally patterned inputs to the motor cortex that controls the forelimb are required for a well-trained reaching behaviour.

    in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 28, 2020 12:00 AM.

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    The Molecular Organization of Self-awareness: Paralimbic Dopamine-GABA Interaction

    The electrophysiology of the paralimbic network (“default mode”) for self-awareness has drawn much attention in the past couple of decades. In contrast, knowledge of the molecular organization of conscious experience has only lately come into focus. We here review newer data on dopaminergic control of awareness in humans, particularly in self-awareness. These results implicate mainly dopaminergic neurotransmission and the control of GABAergic function directly in the paralimbic network. The findings are important for understanding addiction, developmental disorders, and dysfunctional consciousness.

    in Frontiers in Systems Neuroscience | New and Recent Articles on January 28, 2020 12:00 AM.

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    Decreased Density of Perineuronal Net in Prelimbic Cortex Is Linked to Depressive-Like Behavior in Young-Aged Rats

    Perineuronal nets (PNNs) are condensed extracellular matrix (ECM) structures regulating developmental plasticity and protecting neurons against oxidative stress. PNN abnormalities have been observed in various psychiatric disorders such as schizophrenia and bipolar disorder, but the relationship between PNN density and depression still remains unclear. In the present study, we examined the density and components of PNNs including aggrecan, neurocan and Tenascin-R in the prelimbic cortex (PrL) after chronic unpredictable mild stress (CUMS). We found that depressive-like behaviors were induced after 30 days of CUMS accompanied by decreases in PNN+ cell density and aggrecan expression in the PrL. In addition, rats subjected to 20 days of CUMS were separated into vulnerable and resilient subpopulations that differ along several behavioral domains. Consistently, the density of PNNs and the expression level of neurocan in the vulnerable group were decreased compared to control and resilient groups. Finally, we examined individual differences based on locomotion in a novel context and classified rats as high responding (HR) and low responding (LR) phenotypes. The density of PNNs and the expression level of neurocan in the LR group were lower than the HR group. Moreover, the LR rats were more susceptible to depressive-like behaviors compared with HR rats. Altogether, these results suggest that the density of PNNs in the PrL is associated with depressive-like behaviors in young-aged rats, and it may serve as a potential endophenotype or therapeutic target for depression.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on January 28, 2020 12:00 AM.

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    Systematic Review on Fractal Dimension of the Retinal Vasculature in Neurodegeneration and Stroke: Assessment of a Potential Biomarker

    Introduction: Ocular manifestations in several neurological pathologies accentuate the strong relationship between the eye and the brain. Retinal alterations in particular can serve as surrogates for cerebral changes. Offering a “window to the brain,” the transparent eye enables non-invasive imaging of these changes in retinal structure and vasculature. Fractal dimension (FD) reflects the overall complexity of the retinal vasculature. Changes in FD could reflect subtle changes in the cerebral vasculature that correspond to preclinical stages of neurodegenerative diseases. In this review, the potential of this retinal vessel metric to serve as a biomarker in neurodegeneration and stroke will be explored.

    Methods: A literature search was conducted, following the PRISMA Statement 2009 criteria, in four large bibliographic databases (Pubmed, Embase, Web Of Science and Cochrane Library) up to 12 October 2019. Articles have been included based upon their relevance. Wherever possible, level of evidence (LOE) has been assessed by means of the Oxford Centre for Evidence-based Medicine Level of Evidence classification.

    Results: Twenty-one studies were included for qualitative synthesis. We performed a narrative synthesis and produced summary tables of findings of included papers because methodological heterogeneity precluded a meta-analysis. A significant association was found between decreased FD and neurodegenerative disease, mainly addressing cognitive impairment (CI) and dementia. In acute, subacute as well as chronic settings, decreased FD seems to be associated with stroke. Differences in FD between subtypes of ischemic stroke remain unclear.

    Conclusions: This review provides a summary of the scientific literature regarding the association between retinal FD and neurodegenerative disease and stroke. Central pathology is associated with a decreased FD, as a measure of microvascular network complexity. As retinal FD reflects the global integrity of the cerebral microvasculature, it is an attractive parameter to explore. Despite obvious concerns, mainly due to a lack of methodological standardization, retinal FD remains a promising non-invasive and low-cost diagnostic biomarker for neurodegenerative and cerebrovascular disease. Before FD can be implemented in clinic as a diagnostic biomarker, the research community should strive for uniformization and standardization.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 28, 2020 12:00 AM.

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    Neural Correlates of Learning Pure Tones or Natural Sounds in the Auditory Cortex

    Associative learning of pure tones is known to cause tonotopic map expansion in the auditory cortex (ACx), but the function this plasticity sub-serves is unclear. We developed an automated training platform called the “Educage,” which was used to train mice on a go/no-go auditory discrimination task to their perceptual limits, for difficult discriminations among pure tones or natural sounds. Spiking responses of excitatory and inhibitory parvalbumin (PV+) L2/3 neurons in mouse ACx revealed learning-induced overrepresentation of the learned frequencies, as expected from previous literature. The coordinated plasticity of excitatory and inhibitory neurons supports a role for PV+ neurons in homeostatic maintenance of excitation–inhibition balance within the circuit. Using a novel computational model to study auditory tuning curves, we show that overrepresentation of the learned tones does not necessarily improve discrimination performance of the network to these tones. In a separate set of experiments, we trained mice to discriminate among natural sounds. Perceptual learning of natural sounds induced “sparsening” and decorrelation of the neural response, consequently improving discrimination of these complex sounds. This signature of plasticity in A1 highlights its role in coding natural sounds.

    in Frontiers in Neural Circuits | New and Recent Articles on January 28, 2020 12:00 AM.

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    Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

    Objective

    Leucine‐rich glioma‐inactivated 1 (LGI1) encephalitis is the second most common antibody‐mediated encephalopathy, but insight into the intrathecal B‐cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited.

    Methods

    We cloned, expressed, and tested antibodies from 90 antibody‐secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis.

    Results

    Eighty‐four percent of the ASCs and 21% of the memory B cells encoded LGI1‐reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non–ADAM22‐competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures.

    Interpretation

    Our data show that the patients’ intrathecal B‐cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N‐methyl‐D‐aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405–418

    in Wiley: Annals of Neurology: Table of Contents on January 27, 2020 08:00 PM.

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    Face Representations via Tensorfaces of Various Complexities

    Neural Computation, Volume 32, Issue 2, Page 281-329, February 2020.

    in MIT Press: Neural Computation: Table of Contents on January 25, 2020 01:29 AM.

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    Synaptic Scaling Improves the Stability of Neural Mass Models Capable of Simulating Brain Plasticity

    Neural Computation, Volume 32, Issue 2, Page 424-446, February 2020.

    in MIT Press: Neural Computation: Table of Contents on January 25, 2020 01:29 AM.

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    Improving Generalization via Attribute Selection on Out-of-the-Box Data

    Neural Computation, Volume 32, Issue 2, Page 485-514, February 2020.

    in MIT Press: Neural Computation: Table of Contents on January 25, 2020 01:29 AM.

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    Transition Scale-Spaces: A Computational Theory for the Discretized Entorhinal Cortex

    Neural Computation, Volume 32, Issue 2, Page 330-394, February 2020.

    in MIT Press: Neural Computation: Table of Contents on January 25, 2020 01:28 AM.

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    Scaled Coupled Norms and Coupled Higher-Order Tensor Completion

    Neural Computation, Volume 32, Issue 2, Page 447-484, February 2020.

    in MIT Press: Neural Computation: Table of Contents on January 25, 2020 01:28 AM.

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    From Synaptic Interactions to Collective Dynamics in Random Neuronal Networks Models: Critical Role of Eigenvectors and Transient Behavior

    Neural Computation, Volume 32, Issue 2, Page 395-423, February 2020.

    in MIT Press: Neural Computation: Table of Contents on January 25, 2020 01:28 AM.

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    Publisher Correction: Predictive and reactive reward signals conveyed by climbing fiber inputs to cerebellar Purkinje cells

    Nature Neuroscience, Published online: 24 January 2020; doi:10.1038/s41593-020-0594-x

    Publisher Correction: Predictive and reactive reward signals conveyed by climbing fiber inputs to cerebellar Purkinje cells

    in Nature Neuroscience - Issue - nature.com science feeds on January 24, 2020 12:00 AM.

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    Plasticity in Limbic Regions at Early Time Points in Experimental Models of Tinnitus

    Tinnitus is one of the most prevalent auditory disorders worldwide, manifesting in both chronic and acute forms. The pathology of tinnitus has been mechanistically linked to induction of harmful neural plasticity stemming from traumatic noise exposure, exposure to ototoxic medications, input deprivation from age-related hearing loss, and in response to injuries or disorders damaging the conductive apparatus of the ears, the cochlear hair cells, the ganglionic cells of the VIIIth cranial nerve, or neurons of the classical auditory pathway which link the cochlear nuclei through the inferior colliculi and medial geniculate nuclei to auditory cortices. Research attempting to more specifically characterize the neural plasticity occurring in tinnitus have used a wide range of techniques, experimental paradigms, and sampled at different windows of time to reach different conclusions about why and which specific brain regions are crucial in the induction or ongoing maintenance of tinnitus-related plasticity. Despite differences in experimental methodologies, evidence reveals similar findings that strongly suggest that immediate and prolonged activation of non-classical auditory structures (i.e., amygdala, hippocampus, and cingulate cortex) may contribute to the initiation and development of tinnitus in addition to the ongoing maintenance of this devastating condition. The overarching focus of this review, therefore, is to highlight findings from the field supporting the hypothesis that abnormal early activation of non-classical sensory limbic regions are involved in tinnitus induction, with activation of these regions continuing to occur at different temporal stages. Since initial/early stages of tinnitus are difficult to control and to quantify in human clinical populations, a number of different animal paradigms have been developed and assessed in experimental investigations. Reviews of traumatic noise exposure and ototoxic doses of sodium salicylate, the most prevalently used animal models to induce experimental tinnitus, indicate early limbic system plasticity (within hours, minutes, or days after initial insult), supports subsequent plasticity in other auditory regions, and contributes to the pathophysiology of tinnitus. Understanding this early plasticity presents additional opportunities for intervention to reduce or eliminate tinnitus from the human condition.

    in Frontiers in Systems Neuroscience | New and Recent Articles on January 24, 2020 12:00 AM.

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    Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management

    Opioid drugs are the gold standard for the management of pain, but their use is severely limited by dangerous and unpleasant side effects. All clinically available opioid analgesics bind to and activate the mu-opioid receptor (MOR), a heterotrimeric G-protein-coupled receptor, to produce analgesia. The activity of these receptors is modulated by a family of intracellular RGS proteins or regulators of G-protein signaling proteins, characterized by the presence of a conserved RGS Homology (RH) domain. These proteins act as negative regulators of G-protein signaling by serving as GTPase accelerating proteins or GAPS to switch off signaling by both the Gα and βγ subunits of heterotrimeric G-proteins. Consequently, knockdown or knockout of RGS protein activity enhances signaling downstream of MOR. In this review we discuss current knowledge of how this activity, across the different families of RGS proteins, modulates MOR activity, as well as activity of other members of the opioid receptor family, and so pain and analgesia in animal models, with particular emphasis on RGS4 and RGS9 families. We discuss inhibition of RGS proteins with small molecule inhibitors that bind to sensitive cysteine moieties in the RH domain and the potential for targeting this family of intracellular proteins as adjuncts to provide an opioid sparing effect or as standalone analgesics by promoting the activity of endogenous opioid peptides. Overall, we conclude that RGS proteins may be a novel drug target to provide analgesia with reduced opioid-like side effects, but that much basic work is needed to define the roles for specific RGS proteins, particularly in chronic pain, as well as a need to develop newer inhibitors.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on January 24, 2020 12:00 AM.

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    Herpes Simplex Virus 1-Induced Blood-Brain Barrier Damage Involves Apoptosis Associated With GM130-Mediated Golgi Stress

    Herpes simplex encephalitis (HSE) caused by herpes simplex virus 1 (HSV-1) infection can lead to a high mortality rate and severe neurological sequelae. The destruction of the blood-brain barrier (BBB) is an important pathological mechanism for the development of HSE. However, the specific mechanism underlying the BBB destruction remains unclear. Our previous study found that the Golgi apparatus (GA) plays a crucial role in maintaining the integrity of the BBB. Therefore, this present study aimed to investigate the role of the GA in the destruction of the BBB and its underlying mechanisms. Mouse brain endothelial cells (Bend.3) were cultured to establish a BBB model in vitro, and then infected with HSV-1. The results showed that HSV-1 infection caused downregulation of the Golgi-associated protein GM130, accompanied by Golgi fragmentation, cell apoptosis, and downregulation of tight junction proteins occludin and claudin 5. Knockdown of GM130 with small interfering RNA in uninfected Bend.3 cells triggered Golgi fragmentation, apoptosis, and downregulation of occludin and claudin 5. However, overexpression of GM130 in HSV-1 infected Bend.3 cells by transient transfection partially attenuated the aforementioned damage caused by HSV-1 infection. When the pan-caspase inhibitor Z-VAD-fmk was used after HSV-1 infection to inhibit apoptosis, the protein levels of GM130, occludin and claudin 5 were partially restored. Taken together, these observations indicate that HSV-1 infection of Bend.3 cells triggers a GM130-mediated Golgi stress response that is involved in apoptosis, which in turn results in downregulation of occludin and claudin 5 protein levels. Meanwhile, GM130 downregulation is partially due to apoptosis triggered by HSV-1 infection. Our findings reveal an association between the GA and the BBB during HSV-1 infection and identify potentially novel targets for protecting the BBB and therapeutic approaches for patients with HSE.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on January 24, 2020 12:00 AM.

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    Low and High Molecular Weight FGF-2 Have Differential Effects on Astrocyte Proliferation, but Are Both Protective Against Aβ-Induced Cytotoxicity

    Astrocytes are the most abundant type of glial cells in the brain, and they play a key role in Alzheimer’s disease (AD). Fibroblast Growth Factor-2 (FGF-2) has been implicated as a potential therapeutic agent for treating AD. In the present study, we investigated the protective effects of low molecular weight (LMW; 17 KDa) and high molecular weight (HMW; 23 KDa) forms of FGF-2 on Aβ1–42-induced toxicity, and proliferation in astrocytes. We show that both isoforms of FGF-2 have similar protective effects against Aβ1–42-induced cytotoxicity in primary cultured cortical astrocytes as measured by Lactate Dehydrogenase (LDH) release assay. Additionally, 17 KDa FGF-2 significantly promoted astrocyte proliferation as measured by Trypan Blue, DRAQ5 and 5-ethynyl-2’-deoxyuridine (EdU) staining, but not 23 kDa FGF-2. Furthermore, our results demonstrated that AKT signaling pathway was required for the protective and proliferative effects of FGF-2. Downstream effector studies indicated that 17 kDa FGF-2 promoted astrocyte proliferation by enhanced expression of c-Myc, Cyclin D1, Cyclin E. Furthermore, our data suggested that Cyclin D1 was required for the proliferative effect of LMW FGF2 in astrocytes. Taken together, our findings provide important information for the similarities and differences between 23 kDa and17 kDa isoforms of FGF-2 on astrocyte survival and proliferation.

    in Frontiers in Molecular Neuroscience | New and Recent Articles on January 24, 2020 12:00 AM.

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    Afterdischarges of Spinal Interneurons Following a Brief High-Frequency Stimulation of Ia Afferents in the Cat

    Spinal motoneurons exhibit sustained afterdischarges and plateau potentials following a brief high-frequency stimulation of Ia afferents. Also, there is evidence that spinal cord interneurons exhibit plateau potentials. However, to our knowledge, there are no reports about the possible afterdischarge behavior of lumbar spinal interneurons activated by Ia afferents. Given that there are spinal interneurons receiving monosynaptic inputs from Ia afferents, these cells could then be activated in parallel to motoneurons after repetitive muscle stretch. We explored this possibility in cats with a precollicular-postmammillary decerebration. We found that a brief high-frequency stimulation of Ia afferents produces afterdischarges that are highly correlated to a DC slow potential recorded at the cord dorsum. We conclude that in the cat spinal cord, not only the motoneurons but also the interneurons from the superficial and deep dorsal horn produce sustained afterdischarges, thus highlighting the importance of interneurons in the spinal neuronal circuitry. The significance of our finding is that it opens the possibility that the spinal cord interneurons activated by Ia afferents could also exhibit bistability, a relevant phenomenon well-characterized in the motoneurons.

    in Frontiers in Integrative Neuroscience | New and Recent Articles on January 24, 2020 12:00 AM.

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    Shape Information Improves the Cross-Cohort Performance of Deep Learning-Based Segmentation of the Hippocampus

    Performing an accurate segmentation of the hippocampus from brain magnetic resonance images is a crucial task in neuroimaging research, since its structural integrity is strongly related to several neurodegenerative disorders, including Alzheimer’s Disease (AD). Some automatic segmentation tools are already being used, but, in recent years, new deep learning (DL) based methods have been proven to be much more accurate in various medical image segmentation tasks. In this work, we propose a DL-based hippocampus segmentation framework that embeds statistical shape of the hippocampus as context information into the deep neural network (DNN). The inclusion of shape information is achieved with three main steps: (1) a U-Net based segmentation, (2) a shape model estimation and (3) a second U-Net based segmentation which uses both the original input data and the fitted shape model. The trained DL architectures were tested on image data of three diagnostic groups (AD patients, subjects with mild cognitive impairment and controls) from two cohorts (ADNI and AddNeuroMed). Both intra-cohort validation and cross-cohort validation were performed and compared with the conventional U-net architecture and some variations with other types of context information (i.e. autocontext and tissue-class context). Our results suggest that adding shape information can improve the segmentation accuracy in cross-cohort validation, i.e. when DNNs are trained on one cohort and applied to another. However, no significant benefit is observed in intra-cohort validation, i.e. training and testing DNNs on images from the same cohort. Moreover, compared to other types of context information, the use of shape context was shown to be the most successful in increasing the accuracy, while keeping the computational time in the order of a few minutes.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 24, 2020 12:00 AM.

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    Efficacy of Self-Management Smartphone-Based Apps for Post-traumatic Stress Disorder Symptoms: A Systematic Review and Meta-Analysis

    Post-traumatic stress disorder (PTSD) symptoms are prevalent in both civilian and military service members. As the number of smartphone-based applications (apps) grows rapidly in health care, apps are also increasingly used to help individuals with subthreshold PTSD or full PTSD. Yet, if the apps are self-managed, the feasibility and efficacy of such interventions are still rather unclear in these two populations with PTSD symptoms. Hence, the present meta-analysis set out to evaluate the effect of self-management smartphone-based apps on PTSD and depressive symptoms in populations with subthreshold PTSD or full PTSD. Studies were included if they conducted randomized controlled trials or pre-post comparisons. Six studies (n = 2 randomized controlled trials) were identified for meta-analysis. In pre-post comparisons, N = 209 participants were included in the analyses. In randomized controlled trials, N = 87 participants received smartphone-based self-management interventions and N = 82 participants were in waitlist control conditions. Meta-analysis for pre-post comparisons concluded an effect of g = 0.55 (p < 0.001) regarding the overall reduction in PTSD symptoms (n = 6) and g = 0.45 (p < 0.001) for reduction in depressive symptoms (n = 5). Yet, in randomized controlled trials, no significant difference was found between app-based treatment and waitlist control groups (g = 0.09, p = 0.574). The duration of the interventions did not significantly influence the results. Overall, despite positive pre-post effects, current results indicate that smartphone-apps for PTSD patients are not significantly more effective than waitlist control conditions. Nevertheless, a combined smartphone and standard therapy approach may be a fruitful field for future research.

    in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 24, 2020 12:00 AM.

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    Improving Patch-Based Convolutional Neural Networks for MRI Brain Tumor Segmentation by Leveraging Location Information

    The manual brain tumor annotation process is time consuming and resource consuming, therefore, an automated and accurate brain tumor segmentation tool is greatly in demand. In this paper, we introduce a novel method to integrate location information with the state-of-the-art patch-based neural networks for brain tumor segmentation. This is motivated by the observation that lesions are not uniformly distributed across different brain parcellation regions and that a locality-sensitive segmentation is likely to obtain better segmentation accuracy. Toward this, we use an existing brain parcellation atlas in the Montreal Neurological Institute (MNI) space and map this atlas to the individual subject data. This mapped atlas in the subject data space is integrated with structural Magnetic Resonance (MR) imaging data, and patch-based neural networks, including 3D U-Net and DeepMedic, are trained to classify the different brain lesions. Multiple state-of-the-art neural networks are trained and integrated with XGBoost fusion in the proposed two-level ensemble method. The first level reduces the uncertainty of the same type of models with different seed initializations, and the second level leverages the advantages of different types of neural network models. The proposed location information fusion method improves the segmentation performance of state-of-the-art networks including 3D U-Net and DeepMedic. Our proposed ensemble also achieves better segmentation performance compared to the state-of-the-art networks in BraTS 2017 and rivals state-of-the-art networks in BraTS 2018. Detailed results are provided on the public multimodal brain tumor segmentation (BraTS) benchmarks.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 24, 2020 12:00 AM.

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    Assessing Brain Networks by Resting-State Dynamic Functional Connectivity: An fNIRS-EEG Study

    The coordination of brain activity between disparate neural populations is highly dynamic. Investigations into intrinsic brain organization by evaluating dynamic resting-state functional connectivity (dRSFC) have attracted great attention in recent years. However, there are few dRSFC studies based on functional near-infrared spectroscopy (fNIRS) even though it has some advantages for studying the temporal evolution of brain function. In this research, we recruited 20 young adults and measured their resting-state brain fluctuations in several areas of the frontal, parietal, temporal, and occipital lobes using fNIRS-electroencephalography (EEG) simultaneous recording. Based on a sliding-window approach, we found that the variability of the dRSFC within any region of interest was significantly lower than the connections between region of interests but noticeably greater than the correlation between the channels with a short interoptode distance, which mainly consist of physiological fluctuations occurring in the superficial layers. Furthermore, based on a time-resolved k-means clustering analysis, the temporal evolution was extracted for three dominant functional networks. These networks were roughly consistent between different subject subgroups and in varying sliding time window lengths of 20, 30, and 60 s. Between these three functional networks, there were obvious time-varied and system-specific synchronous relationships. In addition, the oscillation of the frontal-parietal-temporal network showed significant correlation with the switching of one EEG microstate, a finding which is consistent with a previous functional MRI-EEG study. All this evidence implies the functional significance of fNIRS-dRSFC and demonstrates the feasibility of fNIRS for extracting the dominant functional networks based on RSFC dynamics.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 24, 2020 12:00 AM.

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    Novel Volumetric Sub-region Segmentation in Brain Tumors

    A novel deep learning based model called Multi-Planar Spatial Convolutional Neural Network (MPS-CNN) is proposed for effective, automated segmentation of different sub-regions viz. peritumoral edema (ED), necrotic core (NCR), enhancing and non-enhancing tumor core (ET/NET), from multi-modal MR images of the brain. An encoder-decoder type CNN model is designed for pixel-wise segmentation of the tumor along three anatomical planes (axial, sagittal, and coronal) at the slice level. These are then combined, by incorporating a consensus fusion strategy with a fully connected Conditional Random Field (CRF) based post-refinement, to produce the final volumetric segmentation of the tumor and its constituent sub-regions. Concepts, such as spatial-pooling and unpooling are used to preserve the spatial locations of the edge pixels, for reducing segmentation error around the boundaries. A new aggregated loss function is also developed for effectively handling data imbalance. The MPS-CNN is trained and validated on the recent Multimodal Brain Tumor Segmentation Challenge (BraTS) 2018 dataset. The Dice scores obtained for the validation set for whole tumor (WT :NCR/NE +ET +ED), tumor core (TC:NCR/NET +ET), and enhancing tumor (ET) are 0.90216, 0.87247, and 0.82445. The proposed MPS-CNN is found to perform the best (based on leaderboard scores) for ET and TC segmentation tasks, in terms of both the quantitative measures (viz. Dice and Hausdorff). In case of the WT segmentation it also achieved the second highest accuracy, with a score which was only 1% less than that of the best performing method.

    in Frontiers in Computational Neuroscience | New and Recent Articles on January 24, 2020 12:00 AM.

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    Corrigendum: Analgesic Effects of Compression at Trigger Points Are Associated With Reduction of Frontal Polar Cortical Activity as Well as Functional Connectivity Between the Frontal Polar Area and Insula in Patients With Chronic Low Back Pain: A Randomized Trial

    in Frontiers in Systems Neuroscience | New and Recent Articles on January 23, 2020 12:00 AM.

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    Probabilistic Template of the Lateral Parabrachial Nucleus, Medial Parabrachial Nucleus, Vestibular Nuclei Complex, and Medullary Viscero-Sensory-Motor Nuclei Complex in Living Humans From 7 Tesla MRI

    The lateral parabrachial nucleus, medial parabrachial nucleus, vestibular nuclei complex, and medullary viscero-sensory-motor (VSM) nuclei complex (the latter including among others the solitary nucleus, vagus nerve nucleus, and hypoglossal nucleus) are anatomically and functionally connected brainstem gray matter structures that convey signals across multiple modalities between the brain and the spinal cord to regulate vital bodily functions. It is remarkably difficult to precisely extrapolate the location of these nuclei from ex vivo atlases to conventional 3 Tesla in vivo images; thus, a probabilistic brainstem template in stereotaxic neuroimaging space in living humans is needed. We delineated these nuclei using single-subject high contrast 1.1 mm isotropic resolution 7 Tesla MRI images. After precise coregistration of nuclei labels to stereotaxic space, we generated a probabilistic template of their anatomical locations. Finally, we validated the nuclei labels in the template by assessing their inter-rater agreement, consistency across subjects and volumes. We also performed a preliminary comparison of their location and microstructural properties to histologic sections of a postmortem human brainstem specimen. In future, the resulting probabilistic template of these brainstem nuclei in stereotaxic space may assist researchers and clinicians in evaluating autonomic, vestibular and VSM nuclei structure, function and connectivity in living humans using conventional 3 Tesla MRI scanners.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 23, 2020 12:00 AM.

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    Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

    Alpha-synuclein (α-syn) is localized in cellular organelles of most neurons, but many of its physiological functions are only partially understood. α-syn accumulation is associated with Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy as well as other synucleinopathies; however, the exact pathomechanisms that underlie these neurodegenerative diseases remain elusive. In this review, we describe what is known about α-syn function and pathophysiological changes in different cellular structures and organelles, including what is known about its behavior as a prion-like protein. We summarize current knowledge of α-syn and its pathological forms, covering its effect on each organelle, including aggregation and toxicity in different model systems, with special interest on the mitochondria due to its relevance during the apoptotic process of dopaminergic neurons. Moreover, we explore the effect that α-syn exerts by interacting with chromatin remodeling proteins that add or remove histone marks, up-regulate its own expression, and resume the impairment that α-syn induces in vesicular traffic by interacting with the endoplasmic reticulum. We then recapitulate the events that lead to Golgi apparatus fragmentation, caused by the presence of α-syn. Finally, we report the recent findings about the accumulation of α-syn, indirectly produced by the endolysosomal system. In conclusion, many important steps into the understanding of α-syn have been made using in vivo and in vitro models; however, the time is right to start integrating observational studies with mechanistic models of α-syn interactions, in order to look at a more complete picture of the pathophysiological processes underlying α-synucleinopathies.

    in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 23, 2020 12:00 AM.

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    Effects of Cholinergic Neuromodulation on Thalamocortical Rhythms During NREM Sleep: A Model Study

    It has been suggested that cholinergic neurons shape the oscillatory activity of the thalamocortical (TC) network in behavioral and electrophysiological experiments. However, theoretical modeling demonstrating how cholinergic neuromodulation of thalamocortical rhythms during non-rapid eye movement (NREM) sleep might occur has been lacking. In this paper, we first develop a novel computational model (TC-ACH) by incorporating a cholinergic neuron population (CH) into the classical thalamo-cortical circuitry, where connections between populations are modeled in accordance with existing knowledge. The neurotransmitter acetylcholine (ACH) released by neurons in CH, which is able to change the discharge activity of thalamocortical neurons, is the primary focus of our work. Simulation results with our TC-ACH model reveal that the cholinergic projection activity is a key factor in modulating oscillation patterns in three ways: (1) transitions between different patterns of thalamocortical oscillations are dramatically modulated through diverse projection pathways; (2) the model expresses a stable spindle oscillation state with certain parameter settings for the cholinergic projection from CH to thalamus, and more spindles appear when the strength of cholinergic input from CH to thalamocortical neurons increases; (3) the duration of oscillation patterns during NREM sleep including K-complexes, spindles, and slow oscillations is longer when cholinergic input from CH to thalamocortical neurons becomes stronger. Our modeling results provide insights into the mechanisms by which the sleep state is controlled, and provide a theoretical basis for future experimental and clinical studies.

    in Frontiers in Computational Neuroscience | New and Recent Articles on January 23, 2020 12:00 AM.

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    Equilibrium States and Their Stability in the Head-Direction Ring Network

    Head-direction cells have been found in several areas in the mammalian brains. The firing rate of an ideal head-direction cell reaches its peak value only when the animal's head points in a specific direction, and this preferred direction stays the same regardless of spatial location. In this paper we combine mathematical analytical techniques and numerical simulations to fully analyze the equilibrium states of a generic ring attractor network, which is a widely used modeling framework for the head-direction system. Under specific conditions, all solutions of the ring network are bounded, and there exists a Lyapunov function that guarantees the stability of the network for any given inputs, which may come from multiple sources in the biological system, including self-motion information for inertially based updating and landmark information for calibration. We focus on the first few terms of the Fourier series of the ring network to explicitly solve for all possible equilibrium states, followed by a stability analysis based on small perturbations. In particular, these equilibrium states include the standard single-peaked activity pattern as well as double-peaked activity pattern, whose existence is unknown but has testable experimental implications. To our surprise, we have also found an asymmetric equilibrium activity profile even when the network connectivity is strictly symmetric. Finally we examine how these different equilibrium solutions depend on the network parameters and obtain the phase diagrams in the parameter space of the ring network.

    in Frontiers in Computational Neuroscience | New and Recent Articles on January 23, 2020 12:00 AM.

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    Structural Neural Connectivity Analysis in Zebrafish With Restricted Anterograde Transneuronal Viral Labeling and Quantitative Brain Mapping

    The unique combination of small size, translucency, and powerful genetic tools makes larval zebrafish a uniquely useful vertebrate system to investigate normal and pathological brain structure and function. While functional connectivity can now be assessed by optical imaging (via fluorescent calcium or voltage reporters) at the whole-brain scale, it remains challenging to systematically determine structural connections and identify connectivity changes during development or disease. To address this, we developed Tracer with Restricted Anterograde Spread (TRAS), a novel vesicular stomatitis virus (VSV)-based neural circuit labeling approach. TRAS makes use of replication-incompetent VSV (VSVΔG) and a helper virus (lentivirus) to enable anterograde transneuronal spread between efferent axons and their direct postsynaptic targets but restricts further spread to downstream areas. We integrated TRAS with the Z-Brain zebrafish 3D atlas for quantitative connectivity analysis and identified targets of the retinal and habenular efferent projections, in patterns consistent with previous reports. We compared retinofugal connectivity patterns between wild-type and down syndrome cell adhesion molecule-like 1 (dscaml1) mutant zebrafish and revealed differences in topographical distribution. These results demonstrate the utility of TRAS for quantitative structural connectivity analysis that would be valuable for detecting novel efferent targets and mapping connectivity changes underlying neurological or behavioral deficits.

    in Frontiers in Neural Circuits | New and Recent Articles on January 23, 2020 12:00 AM.

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    Facilitation of Crossmodal Integration During Emotional Prediction in Methamphetamine Dependents

    Methamphetamine (meth) can greatly damage the prefrontal cortex of the brain and trigger dysfunction of the cognitive control loop, which triggers not only drug dependence but also emotional disorders. The imbalance between the cognitive and emotional systems will lead to crossmodal emotional deficits. Until now, the negative impact of meth dependence on crossmodal emotional processing has not received attention. Therefore, the present study firstly examined the differences in crossmodal emotional processing between healthy controls and meth dependents (MADs) and then investigated the role of visual- or auditory-leading cues in the promotion of crossmodal emotional processing. Experiment 1 found that MADs made a visual–auditory integration disorder for fearful emotion, which may be related to the defects in information transmission between the auditory and auditory cortex. Experiment 2 found that MADs had a crossmodal disorder pertaining to fear under visual-leading cues, but the fearful sound improved the detection of facial emotions for MADs. Experiment 3 reconfirmed that, for MADs, A-leading cues could induce crossmodal integration immediately more easily than V-leading ones. These findings provided sufficient quantitative indicators and evidences that meth dependence was associated with crossmodal integration disorders, which in turn was associated with auditory-leading cues that enhanced the recognition ability of MADs for complex emotions (all results are available at: https://osf.io/x6rv5/). These results provided a better understanding for individuals using drugs in order to enhance the cognition for the complex crossmodal emotional integration.

    in Frontiers in Neural Circuits | New and Recent Articles on January 23, 2020 12:00 AM.

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    QC-Automator: Deep Learning-Based Automated Quality Control for Diffusion MR Images

    Quality assessment of diffusion MRI (dMRI) data is essential prior to any analysis, so that appropriate pre-processing can be used to improve data quality and ensure that the presence of MRI artifacts do not affect the results of subsequent image analysis. Manual quality assessment of the data is subjective, possibly error-prone, and infeasible, especially considering the growing number of consortium-like studies, underlining the need for automation of the process. In this paper, we have developed a deep-learning-based automated quality control (QC) tool, QC-Automator, for dMRI data, that can handle a variety of artifacts such as motion, multiband interleaving, ghosting, susceptibility, herringbone, and chemical shifts. QC-Automator uses convolutional neural networks along with transfer learning to train the automated artifact detection on a labeled dataset of ∼332,000 slices of dMRI data, from 155 unique subjects and 5 scanners with different dMRI acquisitions, achieving a 98% accuracy in detecting artifacts. The method is fast and paves the way for efficient and effective artifact detection in large datasets. It is also demonstrated to be replicable on other datasets with different acquisition parameters.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 22, 2020 12:00 AM.

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    A Review of ex vivo Elemental Mapping Methods to Directly Image Changes in the Homeostasis of Diffusible Ions (Na+, K+, Mg2 +, Ca2 +, Cl–) Within Brain Tissue

    Diffusible ions (Na+, K+, Mg2+, Ca2+, Cl) are vital for healthy function of all cells, especially brain cells. Unfortunately, the diffusible nature of these ions renders them difficult to study with traditional microscopy in situ within ex vivo brain tissue sections. This mini-review examines the recent progress in the field, using direct elemental mapping techniques to study ion homeostasis during normal brain physiology and pathophysiology, through measurement of ion distribution and concentration in ex vivo brain tissue sections. The mini-review examines the advantages and limitations of specific techniques: proton induced X-ray emission (PIXE), X-ray fluorescence microscopy (XFM), secondary ion mass spectrometry (SIMS), laser-ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), and the sample preparation requirements to study diffusible ions with these methods.

    in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 22, 2020 12:00 AM.

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    Animal Functional Magnetic Resonance Imaging: Trends and Path Toward Standardization

    Animal whole-brain functional magnetic resonance imaging (fMRI) provides a non-invasive window into brain activity. A collection of associated methods aims to replicate observations made in humans and to identify the mechanisms underlying the distributed neuronal activity in the healthy and disordered brain. Animal fMRI studies have developed rapidly over the past years, fueled by the development of resting-state fMRI connectivity and genetically encoded neuromodulatory tools. Yet, comparisons between sites remain hampered by lack of standardization. Recently, we highlighted that mouse resting-state functional connectivity converges across centers, although large discrepancies in sensitivity and specificity remained. Here, we explore past and present trends within the animal fMRI community and highlight critical aspects in study design, data acquisition, and post-processing operations, that may affect the results and influence the comparability between studies. We also suggest practices aimed to promote the adoption of standards within the community and improve between-lab reproducibility. The implementation of standardized animal neuroimaging protocols will facilitate animal population imaging efforts as well as meta-analysis and replication studies, the gold standards in evidence-based science.

    in Frontiers in Neuroinformatics | New and Recent Articles on January 22, 2020 12:00 AM.

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    Spectro-Temporal Processing in a Two-Stream Computational Model of Auditory Cortex

    Neural processing of sounds in the dorsal and ventral streams of the (human) auditory cortex is optimized for analyzing fine-grained temporal and spectral information, respectively. Here we use a Wilson and Cowan firing-rate modeling framework to simulate spectro-temporal processing of sounds in these auditory streams and to investigate the link between neural population activity and behavioral results of psychoacoustic experiments. The proposed model consisted of two core (A1 and R, representing primary areas) and two belt (Slow and Fast, representing rostral and caudal processing respectively) areas, differing in terms of their spectral and temporal response properties. First, we simulated the responses to amplitude modulated (AM) noise and tones. In agreement with electrophysiological results, we observed an area-dependent transition from a temporal (synchronization) to a rate code when moving from low to high modulation rates. Simulated neural responses in a task of amplitude modulation detection suggested that thresholds derived from population responses in core areas closely resembled those of psychoacoustic experiments in human listeners. For tones, simulated modulation threshold functions were found to be dependent on the carrier frequency. Second, we simulated the responses to complex tones with missing fundamental stimuli and found that synchronization of responses in the Fast area accurately encoded pitch, with the strength of synchronization depending on number and order of harmonic components. Finally, using speech stimuli, we showed that the spectral and temporal structure of the speech was reflected in parallel by the modeled areas. The analyses highlighted that the Slow stream coded with high spectral precision the aspects of the speech signal characterized by slow temporal changes (e.g., prosody), while the Fast stream encoded primarily the faster changes (e.g., phonemes, consonants, temporal pitch). Interestingly, the pitch of a speaker was encoded both spatially (i.e., tonotopically) in Slow area and temporally in Fast area. Overall, performed simulations showed that the model is valuable for generating hypotheses on how the different cortical areas/streams may contribute toward behaviorally relevant aspects of auditory processing. The model can be used in combination with physiological models of neurovascular coupling to generate predictions for human functional MRI experiments.

    in Frontiers in Computational Neuroscience | New and Recent Articles on January 22, 2020 12:00 AM.

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    A Computational Model of Interactions Between Neuronal and Astrocytic Networks: The Role of Astrocytes in the Stability of the Neuronal Firing Rate

    Recent research in neuroscience indicates the importance of tripartite synapses and gliotransmission mediated by astrocytes in neuronal system modulation. Although the astrocyte and neuronal network functions are interrelated, they are fundamentally different in their signaling patterns and, possibly, the time scales at which they operate. However, the exact nature of gliotransmission and the effect of the tripartite synapse function at the network level are currently elusive. In this paper, we propose a computational model of interactions between an astrocyte network and a neuron network, starting from tripartite synapses and spanning to a joint network level. Our model focuses on a two-dimensional setup emulating a mixed in vitro neuron-astrocyte cell culture. The model depicts astrocyte-released gliotransmitters exerting opposing effects on the neurons: increasing the release probability of the presynaptic neuron while hyperpolarizing the post-synaptic one at a longer time scale. We simulated the joint networks with various levels of astrocyte contributions and neuronal activity levels. Our results indicate that astrocytes prolong the burst duration of neurons, while restricting hyperactivity. Thus, in our model, the effect of astrocytes is homeostatic; the firing rate of the network stabilizes to an intermediate level independently of neuronal base activity. Our computational model highlights the plausible roles of astrocytes in interconnected astrocytic and neuronal networks. Our simulations support recent findings in neurons and astrocytes in vivo and in vitro suggesting that astrocytic networks provide a modulatory role in the bursting of the neuronal network.

    in Frontiers in Computational Neuroscience | New and Recent Articles on January 22, 2020 12:00 AM.

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    Reactive, Proactive, and Inductive Agents: An Evolutionary Path for Biological and Artificial Spiking Networks

    Complex environments provide structured yet variable sensory inputs. To best exploit information from these environments, organisms must evolve the ability to anticipate consequences of new stimuli, and act on these predictions. We propose an evolutionary path for neural networks, leading an organism from reactive behavior to simple proactive behavior and from simple proactive behavior to induction-based behavior. Based on earlier in-vitro and in-silico experiments, we define the conditions necessary in a network with spike-timing dependent plasticity for the organism to go from reactive to proactive behavior. Our results support the existence of specific evolutionary steps and four conditions necessary for embodied neural networks to evolve predictive and inductive abilities from an initial reactive strategy.

    in Frontiers in Computational Neuroscience | New and Recent Articles on January 22, 2020 12:00 AM.

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    Editorial: Neuromodulatory Control of Spinal Function in Health and Disease

    in Frontiers in Neural Circuits | New and Recent Articles on January 22, 2020 12:00 AM.

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    Multiple Morphometric Assessment of Microglial Cells in Deafferented Spinal Trigeminal Nucleus

    Microglia (MG) are the first cells to react to the abnormal incoming signals that follow an injury of sensory nerves and play a critical role in the development and maintenance of neuropathic pain, a common sequel of nerve injuries. Here we present population data on cell number, soma size, and length of processes of MG in the caudal division of the spinal trigeminal nucleus (Sp5C) in control mice and at the peak of microgliosis (7 days) following unilateral transection of the infraorbital nerve (IoN). The study is performed combining several bias- and assumption-free imaging and stereological approaches with different immunolabeling procedures, with the objective of tackling some hard problems that often hinder proper execution of MG morphometric studies. Our approach may easily be applied to low-density MG populations, but also works, with limited biases, in territories where MG cell bodies and processes form dense meshworks. In controls, and contralaterally to the deafferented side, MG cell body size and shape and branching pattern matched well the descriptions of “resting” or “surveillant” MG described elsewhere, with only moderate intersubject variability. On the superficial laminae of the deafferented side, however, MG displayed on average larger somata and remarkable diversity in shape. The number of cells and the length of MG processes per mm3 increased 5 and 2.5 times, respectively, indicating a net 50% decrease in the mean length of processes per cell. By using specific immunolabeling and cell sorting of vascular macrophages, we found only a negligible fraction of these cells in Sp5C, with no differences between controls and deafferented animals, suggesting that blood-borne monocytes play at most a very limited role in the microgliosis occurring following sensory nerve deafferentation. In sum, here we present reliable morphometric data on MG in control and deafferented trigeminal nuclei using efficient methods that we propose may equally be applied to any morphometric population analysis of these cells under different physiological or pathological conditions.

    in Frontiers in Neuroanatomy | New and Recent Articles on January 22, 2020 12:00 AM.

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    International Brain Initiative: An Innovative Framework for Coordinated Global Brain Research Efforts

    The International Brain Initiative (IBI) has been established to coordinate efforts across existing and emerging national and regional brain initiatives. This NeuroView describes how to be involved and the new opportunities for global collaboration that are emerging between scientists, scientific societies, funders, industry, government, and society.

    in Neuron on January 22, 2020 12:00 AM.

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    Aβ Puts the Alpha in Synuclein

    Neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease are characterized pathologically by aberrant protein accumulation, such as Aβ or α-synuclein deposition. In this issue of Neuron, Bassil et al. (2020) observed an exacerbation of α-syn pathology in the presence of Aβ plaques in vivo, with comorbid pathologies associated with greater neurodegeneration.

    in Neuron on January 22, 2020 12:00 AM.

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    Deciphering Pyramidal Neuron Diversity: Delineating Perceptual Functions of Projection-Defined Neuronal Types

    Axonal projection patterns are increasingly recognized as a defining feature for neuronal classification. How could such structural distinctions be linked to functions? In this issue of Neuron, Tang and Higley (2020) disambiguate behavior-level functions of two projection-defined subtypes of cortical projection neurons.

    in Neuron on January 22, 2020 12:00 AM.

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    Thomas Blanpied

    In an interview with Neuron, Dr. Thomas Blanpied talks about why he became a neuroscientist, what inspires him to investigate protein organization at synapses, politicization being one of the biggest challenges for science, and why passion is important for driving science forward.

    in Neuron on January 22, 2020 12:00 AM.

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