Planet Neuroscience

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Median nerve stimulation based BCI: a new approach to detect intraoperative awareness during general anesthesia
Hundreds of millions of general anesthesia are performed each year on patients all over the world. Among these patients, 0.1-0.2 % are victims of Accidental Awareness during General Anesthesia (AAGA), i.e. an unexpected awakening during a surgical procedure under general anesthesia. Although anesthesiologists try to closely monitor patients using various techniques to prevent this terrifying phenomenon, there is currently no efficient solution to accurately detect its occurrence. We propose the conception of an innovative passive brain-computer interface (BCI) based on an intention of movement to prevent AAGA. Indeed, patients typically try to move to alert the medical staff during an AAGA, only to discover that they are unable to. First, we examine the challenges of such a BCI, i.e. the lack of a trigger to facilitate when to look for an intention to move, as well as the necessity for a high classification accuracy. Then, we present a solution that incorporates Median Nerve Stimulation (MNS). We investigate the specific modulations that MNS causes in the motor cortex and confirm that they can be altered by an intention of movement. Finally, we perform experiments on 16 healthy participants to assess whether an MI-based BCI using MNS is able to generate high classification accuracies. Our results show that MNS may provide a foundation for an innovative BCI that would allow the detection of AAGA.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on June 19, 2019 04:25 AM.
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Inferred successor maps for better transfer learning. (arXiv:1906.07663v1 [cs.AI])

Humans and animals show remarkable flexibility in adjusting their behaviour when their goals, or rewards in the environment change. While such flexibility is a hallmark of intelligent behaviour, these multi-task scenarios remain an important challenge for machine learning algorithms and neurobiological models alike. Factored representations can enable flexible behaviour by abstracting away general aspects of a task from those prone to change, while nonparametric methods provide a principled way of using similarity to past experiences to guide current behaviour. Here we combine the successor representation (SR), that factors the value of actions into expected outcomes and corresponding rewards, with evaluating task similarity through nonparametric inference and clustering the space of rewards. The proposed algorithm improves SR's transfer capabilities by inverting a generative model over tasks, while also explaining important neurobiological signatures of place cell representation in the hippocampus. It dynamically samples from a flexible number of distinct SR maps while accumulating evidence about the current reward context, and outperforms competing algorithms in settings with both known and unsignalled rewards changes. It reproduces the "flickering" behaviour of hippocampal maps seen when rodents navigate to changing reward locations, and gives a quantitative account of trajectory-dependent hippocampal representations (so-called splitter cells) and their dynamics. We thus provide a novel algorithmic approach for multi-task learning, as well as a common normative framework that links together these different characteristics of the brain's spatial representation.

in q-bio.NC updates on arXiv.org on June 19, 2019 01:30 AM.
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Quantized Three-Ion-Channel Neuron Model for Neural Action Potentials. (arXiv:1906.07570v1 [q-bio.NC])

The Hodgkin-Huxley model describes the conduction of the nervous impulse through the axon, whose membrane's electric response can be described employing multiple connected electric circuits containing capacitors, voltage sources, and conductances. These conductances depend on previous depolarizing membrane voltages, which can be identified with a memory resistive element called memristor. Inspired by the recent quantization of the memristor, a simplified Hodgkin-Huxley model including a single ion channel has been studied in the quantum regime. Here, we study the quantization of the complete Hodgkin-Huxley model, accounting for all three ion channels, and introduce a quantum source, together with an output waveguide as the connection to a subsequent neuron. Our system consists of two memristors and one resistor, describing potassium, sodium, and chloride ion channel conductances, respectively, and a capacitor to account for the axon's membrane capacitance. We study the behavior of both ion channel conductivities and the circuit voltage, and we compare the results with those of the single channel, for a given quantum state of the source. It is remarkable that, in opposition to the single-channel model, we are able to reproduce the voltage spike in an adiabatic regime. Arguing that the circuit voltage is a quantum variable, we find a purely quantum-mechanical contribution in the system voltage's second moment. This work represents a complete study of the Hodgkin-Huxley model in the quantum regime, establishing a recipe for constructing quantum neuron networks with quantum state inputs. This paves the way for advances in hardware-based neuromorphic quantum computing, as well as quantum machine learning, which might be more efficient resource-wise.

in q-bio.NC updates on arXiv.org on June 19, 2019 01:30 AM.
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Core language brain network for fMRI-language task used in clinical applications. (arXiv:1906.07546v1 [q-bio.NC])

Functional magnetic resonance imaging (fMRI) is widely used in clinical applications to highlight brain areas involved in specific cognitive processes. Brain impairments, such as tumors, suppress the fMRI activation of the anatomical areas they invade and, thus, brain-damaged functional networks present missing links/areas of activation. The identification of the missing circuitry components is of crucial importance to estimate the damage extent. The study of functional networks associated to clinical tasks but performed by healthy individuals becomes, therefore, of paramount concern. These `healthy' networks can, indeed, be used as control networks for clinical studies.In this work we investigate the functional architecture of 20 healthy individuals performing a language task designed for clinical purposes. We unveil a common architecture persistent across all subjects under study, which involves Broca's area, Wernicke's area, the Premotor area, and the pre-Supplementary motor area. We study the connectivity weight of this circuitry by using the k-core centrality measure and we find that three of these areas belong to the most robust structure of the functional language network for the specific task under study. Our results provide useful insight for clinical applications on primarily important functional connections which, thus, should be preserved through brain surgery.

in q-bio.NC updates on arXiv.org on June 19, 2019 01:30 AM.
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ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease. (arXiv:1906.07511v1 [q-bio.NC])

Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amy-loid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down-or up-regulation of ADAM30 expression triggered an increase/decrease in A$\beta$ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30 mut) did not affect A$\beta$ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered A$\beta$42 secretion in neuron primary cultures, soluble A$\beta$42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation.

in q-bio.NC updates on arXiv.org on June 19, 2019 01:30 AM.
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Bayesian fusion and multimodal DCM for EEG and fMRI. (arXiv:1906.07354v1 [q-bio.QM])

This paper asks whether integrating multimodal EEG and fMRI data offers a better characterisation of functional brain architectures than either modality alone. This evaluation rests upon a dynamic causal model that generates both EEG and fMRI data from the same neuronal dynamics. We introduce the use of Bayesian fusion to provide informative (empirical) neuronal priors - derived from dynamic causal modelling (DCM) of EEG data - for subsequent DCM of fMRI data. To illustrate this procedure, we generated synthetic EEG and fMRI timeseries for a mismatch negativity (or auditory oddball) paradigm, using biologically plausible model parameters (i.e., posterior expectations from a DCM of empirical, open access, EEG data). Using model inversion, we found that Bayesian fusion provided a substantial improvement in marginal likelihood or model evidence, indicating a more efficient estimation of model parameters, in relation to inverting fMRI data alone. We quantified the benefits of multimodal fusion with the information gain pertaining to neuronal and haemodynamic parameters - as measured by the Kullback-Leibler divergence between their prior and posterior densities. Remarkably, this analysis suggested that EEG data can improve estimates of haemodynamic parameters; thereby furnishing proof-of-principle that Bayesian fusion of EEG and fMRI is necessary to resolve conditional dependencies between neuronal and haemodynamic estimators. These results suggest that Bayesian fusion may offer a useful approach that exploits the complementary temporal (EEG) and spatial (fMRI) precision of different data modalities. We envisage the procedure could be applied to any multimodal dataset that can be explained by a DCM with a common neuronal parameterisation.

in q-bio.NC updates on arXiv.org on June 19, 2019 01:30 AM.
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Brain Maturation Study during Adolescence Using Graph Laplacian Learning Based Fourier Transform. (arXiv:1906.07211v1 [q-bio.NC])

Objective: Longitudinal neuroimaging studies have demonstrated that adolescence is the crucial developmental epoch of continued brain growth and change. A large number of researchers dedicate to uncovering the mechanisms about brain maturity during adolescence. Motivated by both achievement in graph signal processing and recent evidence that some brain areas act as hubs connecting functionally specialized systems, we proposed an approach to detect these regions from spectral analysis perspective. In particular, as human brain undergoes substantial development throughout adolescence, we addressed the challenge by evaluating the functional network difference among age groups from functional magnetic resonance imaging (fMRI) observations. Methods: We treated these observations as graph signals defined on the parcellated functional brain regions and applied graph Laplacian learning based Fourier Transform (GLFT) to transform the original graph signals into frequency domain. Eigen-analysis was conducted afterwards to study the behavior of the corresponding brain regions, which enables the characterization of brain maturation. Result: We first evaluated our method on the synthetic data and further applied the method to resting and task state fMRI imaging data from Philadelphia Neurodevelopmental Cohort (PNC) dataset, comprised of normally developing adolescents from 8 to 22. The model provided a highest accuracy of 95.69% in distinguishing different adolescence stages. Conclusion: We detected 13 hubs from resting state fMRI and 16 hubs from task state fMRI that are highly related to brain maturation process. Significance: The proposed GLFT method is powerful in extracting the brain connectivity patterns and identifying hub regions with a high prediction power

in q-bio.NC updates on arXiv.org on June 19, 2019 01:30 AM.
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Classification of Subcortical Vascular Cognitive Impairment Using Single MRI Sequence and Deep Learning Convolutional Neural Networks
Deep learning has great potential for imaging classification by extracting low to high-level features. Our aim was to train a convolution neural network (CNN) with single T2-weighted FLAIR sequence to classify different cognitive performances in patients with subcortical ischemic vascular disease (SIVD). Totally 217 patients with SIVD (including 52 vascular dementia (VaD), 82 vascular mild cognitive impairment (VaMCI), 83 non-cognitive impairment (NCI)) and 46 matched healthy controls (HCs) underwent MRI scans and neuropsychological assessment. 2D and 3D CNNs were trained to classify VaD, VaMCI, NCI and HCs based on FLAIR data. For 3D-based model, loss curves of training set approached 0.017 after about 20 epochs, while the curves of testing set maintained at about 0.114. The accuracy of training set and testing set reached 99.7% and 96.9% after about 30 and 35 epochs, respectively. However, the accuracy of 2D-based model was only around 70%, which performed significantly worse than 3D-based model. This experiment suggests us that deep learning, is a powerful and convenient method to classify different cognitive performances in SIVD by extracting the shift and scale invariant features of neuroimaging data with single FLAIR sequence. 3D-CNN is superior to 2D-CNN which proposes clinical evaluation with MRI multiplanar reformation or volume scanning.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 19, 2019 12:00 AM.
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Impaired Motor Skill Acquisition Using Mirror Visual Feedback Improved by Transcranial Direct Current Stimulation (tDCS) in Patients With Parkinson’s Disease
Recent non-invasive brain stimulation techniques in combination with motor training can enhance neuroplasticity and learning. It is reasonable to assume that such neuroplasticity-based interventions constitute a useful rehabilitative tool for patients with Parkinson’s Disease (PD). Regarding motor skill training, many kinds of tasks that do not involve real motor movements have been applied to PD patients. The purpose of this study is to elucidate whether motor skill training using mirror visual feedback (MVF) is useful to patients with PD in order to improve untrained hand performance dependent on the time course of training; and whether MVF combined with anodal transcranial direct current stimulation (tDCS) over primary motor cortex (M1) causes an additional effect based on increased motor cortical excitability. Eighteen right-handed patients with PD in the off-medication state and 10 age-matched healthy subjects (HS) performed four sessions of right-hand ball rotation using MVF (intervention) on two separate days, one week apart (Day1 and Day2). HS subjects received only sham stimulation. The intervention included four sessions of motor-skill training using MVF for 20 minutes comprised of four sets of training for 30 seconds each. PD patients were randomly divided into two intervention groups without or with anodal tDCS over the right M1 contralateral to the untrained hand. As the behavior evaluation, the number of ball rotations of the left hand was counted before (pre) and immediately after (post) intervention on both days (pre Day1, post Day1, pre Day2, and post Day2). Motor evoked potential (MEP), input-output function, and cortical silent period were recorded to evaluate the motor cortical excitatory and inhibitory system in M1 pre Day1 and post Day2. The number of ball rotations of the left hand and the facilitation of MEP by intervention were significantly impaired in patients with PD compared to HS. In contrast, if anodal tDCS was applied to right M1 of patients with PD, the number of ball rotations in accordance with I-O function at 150% intensity was significantly increased after Day1 and retained until Day2. This finding may help provide a new strategy for neurorehabilitation improving task-specific motor memory without real motor movements in PD.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 19, 2019 12:00 AM.
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Non-pulsed Sinusoidal Electromagnetic Field Rescues Animals From Severe Ischemic Stroke via NO Activation
Despite the high prevalence and devastating outcome, only a few treatment options for cerebral ischemic stroke exist. Based on the nitric oxide (NO)-stimulating capacity of Non-Pulsed Sinusoidal Electromagnetic Field (NP-SEMF) and the possible neuroprotective role of NO in ischemic stroke, we hypothesized that NP-SEMF is able to enhance survival and neurological outcome in a rat model of cerebral ischemia. The animals in which ischemic injury was induced by occlusion of both common carotid arteries, received daily 20 minutes NP-SEMF of either 10 or 60 Hz for 4 days. NP-SEMF dramatically increased survival, reduced the size of the infarcted brain area and significantly improved the neurological score of the surviving rats. Corresponding to previous reports, NP-SEMF was able to induce NO production in vitro. The importance of NO as a key signaling molecule was highlighted by inhibition of the NP-SEMF beneficial effects in the rat stroke model after blocking NO synthase (NOS). Our results indicate for the first time that NP-SEMF exposure (13.5mT at 60 Hz and 10 Hz) improves the survival and neurological outcome of rats subjected to cerebral ischemia and that this effect is mediated by NO, underlining the great therapeutic potential of NP-SEMF as therapy for ischemic stroke.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 19, 2019 12:00 AM.
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Measuring Sharp Waves and Oscillatory Population Activity With the Genetically Encoded Calcium Indicator GCaMP6f
GCaMP6f is among the most widely used genetically-encoded calcium indicators for monitoring neuronal activity. Applications are at both the cellular and population levels. Here we explore two important and under-explored issues. First, we have tested if GCaMP6f is sensitive enough for the detection of population activity with sparse firing, similar to the sensitivity of the local field potential (LFP). Second, we have tested if GCaMP6f is fast enough for the detection of fast network oscillations critical for the encoding and consolidation of memory. We have focused this study on the activity of the hippocampal network including sharp waves (SWs), carbachol-induced theta oscillations, and interictal-like spikes. We compare simultaneous LFP and optical GCaMP6f fluorescent recordings in Thy1-GCaMP6f mouse hippocampal slices. We observe that SWs produce a clear population GCaMP6f signal above noise with an average magnitude of 0.3% ΔF/F. This population signal is highly correlated with the LFP, albeit with a delay of 40.3 ms (SD 10.8 ms). The population GCaMP6f signal follows the LFP evoked by 20 Hz stimulation with high fidelity, while electrically evoked oscillations up to 40 Hz were detectable with reduced amplitude. GCaMP6f and LFP signals showed a large amplitude discrepancy. The amplitude of GCaMP6f fluorescence increased by a factor of 28.9 (SD 13.5) between spontaneous SWs and carbachol-induced theta bursts, while the LFP amplitude increased by a factor of 2.4 (SD 1.0). Our results suggest that GCaMP6f is a useful tool for applications commonly considered beyond the scope of genetically-encoded calcium indicators. In particular, population GCaMP6f signals are sensitive enough for detecting synchronous network events with sparse firing and sub-threshold activity, as well as asynchronous events with only a nominal LFP. In addition, population GCaMP6f signals are fast enough for monitoring theta and beta oscillations (< 25 Hz). Faster calcium indicators (e.g., GCaMP7) will further improve the frequency response for the detection of gamma band oscillations. The advantage of population optical over LFP recordings are that they are non-contact and free from stimulation artifacts. These features may be particularly useful for high-throughput recordings and applications sensitive to stimulus artifact, such as monitoring responses during continuous stimulation.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 19, 2019 12:00 AM.
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Convergence of spectrums: neuronal gene network states in autism spectrum disorder

Publication date: December 2019
Source: Current Opinion in Neurobiology, Volume 59
Author(s): Josefa M Sullivan, Silvia De Rubeis, Anne Schaefer
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by social deficits and restrictive and/or repetitive behaviors. The breadth of ASD symptoms is paralleled by the multiplicity of genes that have been implicated in its etiology. Initial findings revealed numerous ASD risk genes that contribute to synaptic function. More recently, genomic and gene expression studies point to altered chromatin function and impaired transcriptional control as additional risk factors for ASD. The consequences of impaired transcriptional alterations in ASD involve consistent changes in synaptic gene expression and cortical neuron specification during brain development. The multiplicity of genetic and environmental factors associated with ASD risk and their convergence onto common molecular pathways in neurons point to ASD as a disorder of gene regulatory networks.

in ScienceDirect Publication: Current Opinion in Neurobiology on June 18, 2019 11:00 PM.
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Transcriptomic correlates of electrophysiological and morphological diversity within and across excitatory and inhibitory neuron classes

by Claire Bomkamp, Shreejoy J. Tripathy, Carolina Bengtsson Gonzales, Jens Hjerling-Leffler, Ann Marie Craig, Paul Pavlidis
In order to further our understanding of how gene expression contributes to key functional properties of neurons, we combined publicly accessible gene expression, electrophysiology, and morphology measurements to identify cross-cell type correlations between these data modalities. Building on our previous work using a similar approach, we distinguished between correlations which were “class-driven,” meaning those that could be explained by differences between excitatory and inhibitory cell classes, and those that reflected graded phenotypic differences within classes. Taking cell class identity into account increased the degree to which our results replicated in an independent dataset as well as their correspondence with known modes of ion channel function based on the literature. We also found a smaller set of genes whose relationships to electrophysiological or morphological properties appear to be specific to either excitatory or inhibitory cell types. Next, using data from PatchSeq experiments, allowing simultaneous single-cell characterization of gene expression and electrophysiology, we found that some of the gene-property correlations observed across cell types were further predictive of within-cell type heterogeneity. In summary, we have identified a number of relationships between gene expression, electrophysiology, and morphology that provide testable hypotheses for future studies.
in PLOS Computational Biology: New Articles on June 18, 2019 09:00 PM.
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Hierarchical Bayesian inference for concurrent model fitting and comparison for group studies

by Payam Piray, Amir Dezfouli, Tom Heskes, Michael J. Frank, Nathaniel D. Daw
Computational modeling plays an important role in modern neuroscience research. Much previous research has relied on statistical methods, separately, to address two problems that are actually interdependent. First, given a particular computational model, Bayesian hierarchical techniques have been used to estimate individual variation in parameters over a population of subjects, leveraging their population-level distributions. Second, candidate models are themselves compared, and individual variation in the expressed model estimated, according to the fits of the models to each subject. The interdependence between these two problems arises because the relevant population for estimating parameters of a model depends on which other subjects express the model. Here, we propose a hierarchical Bayesian inference (HBI) framework for concurrent model comparison, parameter estimation and inference at the population level, combining previous approaches. We show that this framework has important advantages for both parameter estimation and model comparison theoretically and experimentally. The parameters estimated by the HBI show smaller errors compared to other methods. Model comparison by HBI is robust against outliers and is not biased towards overly simplistic models. Furthermore, the fully Bayesian approach of our theory enables researchers to make inference on group-level parameters by performing HBI t-test.
in PLOS Computational Biology: New Articles on June 18, 2019 09:00 PM.
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Correction for Jang et al., Processing bodies control the selective translation for optimal development of Arabidopsis young seedlings [Correction]
PLANT BIOLOGY Correction for “Processing bodies control the selective translation for optimal development of Arabidopsis young seedlings,” by Geng-Jen Jang, Jun-Yi Yang, Hsu-Liang Hsieh, and Shu-Hsing Wu, which was first published March 8, 2019; 10.1073/pnas.1900084116 (Proc. Natl. Acad. Sci. U.S.A. 116, 6451–6456). The authors note that the grant numbers for...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Correction for Dutta et al., Regulation of myelin structure and conduction velocity by perinodal astrocytes [Correction]
NEUROSCIENCE Correction for “Regulation of myelin structure and conduction velocity by perinodal astrocytes,” by Dipankar J. Dutta, Dong Ho Woo, Philip R. Lee, Sinisa Pajevic, Olena Bukalo, William C. Huffman, Hiroaki Wake, Peter J. Basser, Shahriar SheikhBahaei, Vanja Lazarevic, Jeffrey C. Smith, and R. Douglas Fields, which was first published...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Correction for Li et al., Activation of RNase L is dependent on OAS3 expression during infection with diverse human viruses [Correction]
MICROBIOLOGY Correction for “Activation of RNase L is dependent on OAS3 expression during infection with diverse human viruses,” by Yize Li, Shuvojit Banerjee, Yuyan Wang, Stephen A. Goldstein, Beihua Dong, Christina Gaughan, Robert H. Silverman, and Susan R. Weiss, which was first published February 8, 2016; 10.1073/pnas.1519657113 (Proc. Natl. Acad....
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Correction for Lorenzo et al., Computer simulations suggest that prostate enlargement due to benign prostatic hyperplasia mechanically impedes prostate cancer growth [Correction]
ENGINEERING Correction for “Computer simulations suggest that prostate enlargement due to benign prostatic hyperplasia mechanically impedes prostate cancer growth,” by Guillermo Lorenzo, Thomas J. R. Hughes, Pablo Dominguez-Frojan, Alessandro Reali, and Hector Gomez, which was first published January 7, 2019; 10.1073/pnas.1815735116 (Proc. Natl. Acad. Sci. U.S.A. 116, 1152–1161). The authors...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Elephants have a nose for quantity [Psychological and Cognitive Sciences]
Animals often face situations that require making decisions based on quantity. Many species, including humans, rely on an ability to differentiate between more and less to make judgments about social relationships, territories, and food. Habitat-related choices require animals to decide between areas with greater and lesser quantities of food while...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Plant-derived coumarins shape the composition of an Arabidopsis synthetic root microbiome [Plant Biology]
The factors that contribute to the composition of the root microbiome and, in turn, affect plant fitness are not well understood. Recent work has highlighted a major contribution of the soil inoculum in determining the composition of the root microbiome. However, plants are known to conditionally exude a diverse array...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Engineering the phototropin photocycle improves photoreceptor performance and plant biomass production [Plant Biology]
The ability to enhance photosynthetic capacity remains a recognized bottleneck to improving plant productivity. Phototropin blue light receptors (phot1 and phot2) optimize photosynthetic efficiency in Arabidopsis thaliana by coordinating multiple light-capturing processes. In this study, we explore the potential of using protein engineering to improve photoreceptor performance and thereby plant...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Arabidopsis ABCG28 is required for the apical accumulation of reactive oxygen species in growing pollen tubes [Plant Biology]
Tip-focused accumulation of reactive oxygen species (ROS) is tightly associated with pollen tube growth and is thus critical for fertilization. However, it is unclear how tip-growing cells establish such specific ROS localization. Polyamines have been proposed to function in tip growth as precursors of the ROS, hydrogen peroxide. The ABC...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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The Cdk1/Cdk2 homolog CDKA;1 controls the recombination landscape in Arabidopsis [Plant Biology]
Little is known how patterns of cross-over (CO) numbers and distribution during meiosis are established. Here, we reveal that cyclin-dependent kinase A;1 (CDKA;1), the homolog of human Cdk1 and Cdk2, is a major regulator of meiotic recombination in Arabidopsis. Arabidopsis plants with reduced CDKA;1 activity experienced a decrease of class...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment [Neuroscience]
Aging drives a progressive decline in cognition and decreases synapse numbers and synaptic function in the brain, thereby increasing the risk for neurodegenerative disease. Pioneering studies showed that introduction of blood from young mice into aged mice reversed age-associated cognitive impairments and increased synaptic connectivity in brain, suggesting that young...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models [Neuroscience]
BACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer’s disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Routing information flow by separate neural synchrony frequencies allows for “functionally labeled lines” in higher primate cortex [Neuroscience]
Efficient transfer of sensory information to higher (motor or associative) areas in primate visual cortical areas is crucial for transforming sensory input into behavioral actions. Dynamically increasing the level of coordination between single neurons has been suggested as an important contributor to this efficiency. We propose that differences between the...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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UBE3A-mediated PTPA ubiquitination and degradation regulate PP2A activity and dendritic spine morphology [Neuroscience]
Deficiency in the E3 ubiquitin ligase UBE3A leads to the neurodevelopmental disorder Angelman syndrome (AS), while additional dosage of UBE3A is linked to autism spectrum disorder. The mechanisms underlying the downstream effects of UBE3A gain or loss of function in these neurodevelopmental disorders are still not well understood, and effective...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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ANO1/TMEM16A regulates process maturation in radial glial cells in the developing brain [Neuroscience]
Neural stem cells (NSCs) are primary progenitor cells in the early developmental stage in the brain that initiate a diverse lineage of differentiated neurons and glia. Radial glial cells (RGCs), a type of neural stem cell in the ventricular zone, are essential for nurturing and delivering new immature neurons to...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Stress transforms lateral habenula reward responses into punishment signals [Neuroscience]
Neuronal activity in the lateral habenula (LHb), a brain region implicated in depression [C. D. Proulx, O. Hikosaka, R. Malinow, Nat. Neurosci. 17, 1146–1152 (2014)], decreases during reward and increases during punishment or reward omission [M. Matsumoto, O. Hikosaka, Nature 447, 1111–1115 (2007)]. While stress is a major risk factor...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Primary structural differences at residue 226 of deer and elk PrP dictate selection of distinct CWD prion strains in gene-targeted mice [Microbiology]
Although the unifying hallmark of prion diseases is CNS neurodegeneration caused by conformational corruption of host prion protein (PrP) to its infective counterpart, contagious transmission of chronic wasting disease (CWD) results from shedding of prions produced at high titers in the periphery of diseased cervids. While deer and elk PrP...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Ammonia generation by tryptophan synthase drives a key genetic difference between genital and ocular Chlamydia trachomatis isolates [Microbiology]
A striking difference between genital and ocular clinical isolates of Chlamydia trachomatis is that only the former express a functional tryptophan synthase and therefore can synthesize tryptophan by indole salvage. Ocular isolates uniformly cannot use indole due to inactivating mutations within tryptophan synthase, indicating a selection against maintaining this enzyme...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Salmonella biofilms program innate immunity for persistence in Caenorhabditis elegans [Microbiology]
The adaptive in vivo mechanisms underlying the switch in Salmonella enterica lifestyles from the infectious form to a dormant form remain unknown. We employed Caenorhabditis elegans as a heterologous host to understand the temporal dynamics of Salmonella pathogenesis and to identify its lifestyle form in vivo. We discovered that Salmonella...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer [Medical Sciences]
Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α–positive (ERα+) breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here, we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer,...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors [Medical Sciences]
Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3)...
in Proceedings of the National Academy of Sciences Recent Issues on June 18, 2019 04:48 PM.
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Transcranial Direct Current Stimulation Effects on Memory Consolidation: Timing Matters
Abstract
Transcranial direct current stimulation (tDCS) is a promising tool for modulation of learning and memory, allowing to transiently change cortical excitability of specific brain regions with physiological and behavioral outcomes. A detailed exploration of factors that can moderate tDCS effects on episodic long-term memory (LTM) is of high interest due to the clinical potential for patients with traumatic or pathological memory deficits and with cognitive impairments. This commentary discusses findings by Marián et al. (2018) recently published in Cortex within a broad context of brain stimulation in memory research.

in eNeuro current issue on June 18, 2019 04:32 PM.
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Slow NMDA-Mediated Excitation Accelerates Offset-Response Latencies Generated via a Post-Inhibitory Rebound Mechanism
Abstract
In neural circuits, action potentials (spikes) are conventionally caused by excitatory inputs whereas inhibitory inputs reduce or modulate neuronal excitability. We previously showed that neurons in the superior paraolivary nucleus (SPN) require solely synaptic inhibition to generate their hallmark offset response, a burst of spikes at the end of a sound stimulus, via a post-inhibitory rebound mechanism. In addition SPN neurons receive excitatory inputs, but their functional significance is not yet known. Here we used mice of both sexes to demonstrate that in SPN neurons, the classical roles for excitation and inhibition are switched, with inhibitory inputs driving spike firing and excitatory inputs modulating this response. Hodgkin–Huxley modeling suggests that a slow, NMDA receptor (NMDAR)-mediated excitation would accelerate the offset response. We find corroborating evidence from in vitro and in vivo recordings that lack of excitation prolonged offset-response latencies and rendered them more variable to changing sound intensity levels. Our results reveal an unsuspected function for slow excitation in improving the timing of post-inhibitory rebound firing even when the firing itself does not depend on excitation. This shows the auditory system employs highly specialized mechanisms to encode timing-sensitive features of sound offsets which are crucial for sound-duration encoding and have profound biological importance for encoding the temporal structure of speech.

in eNeuro current issue on June 18, 2019 04:30 PM.
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Molecular, Morphological, and Functional Characterization of Corticotropin-Releasing Factor Receptor 1-Expressing Neurons in the Central Nucleus of the Amygdala
Abstract
The central nucleus of the amygdala (CeA) is a brain region implicated in anxiety, stress-related disorders and the reinforcing effects of drugs of abuse. Corticotropin-releasing factor (CRF, Crh) acting at cognate type 1 receptors (CRF₁, Crhr1) modulates inhibitory and excitatory synaptic transmission in the CeA. Here, we used CRF₁:GFP reporter mice to characterize the morphological, neurochemical and electrophysiological properties of CRF₁-expressing (CRF₁+) and CRF₁-non-expressing (CRF₁–) neurons in the CeA. We assessed these two neuronal populations for distinctions in the expression of GABAergic subpopulation markers and neuropeptides, dendritic spine density and morphology, and excitatory transmission. We observed that CeA CRF₁+ neurons are GABAergic but do not segregate with calbindin (CB), calretinin (CR), parvalbumin (PV), or protein kinase C- (PKC). Among the neuropeptides analyzed, Penk and Sst had the highest percentage of co-expression with Crhr1 in both the medial and lateral CeA subdivisions. Additionally, CeA CRF₁+ neurons had a lower density of dendritic spines, which was offset by a higher proportion of mature spines compared to neighboring CRF₁– neurons. Accordingly, there was no difference in basal spontaneous glutamatergic transmission between the two populations. Application of CRF increased overall vesicular glutamate release onto both CRF₁+ and CRF₁– neurons and does not affect amplitude or kinetics of EPSCs in either population. These novel data highlight important differences in the neurochemical make-up and morphology of CRF₁+ compared to CRF₁– neurons, which may have important implications for the transduction of CRF signaling in the CeA.

in eNeuro current issue on June 18, 2019 04:30 PM.
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Rapid online learning and robust recall in a neuromorphic olfactory circuit. (arXiv:1906.07067v1 [cs.NE])

The mammalian olfactory system learns new odors rapidly, exhibits negligible interference among odor memories, and identifies known odors under challenging conditions. The mechanisms by which it does so are unknown. We here present a general theory for odor learning and identification under noise in the olfactory system, and demonstrate its efficacy using a neuromorphic model of the olfactory bulb. As with biological olfaction, the spike timing-based algorithm utilizes distributed, event-driven computations and rapid online learning. Localized spike timing-dependent plasticity rules are employed iteratively over sequential gamma-frequency packets to construct odor representations from the activity of chemosensor arrays mounted in a wind tunnel. Learned odors then are reliably identified despite strong destructive interference. Noise resistance is enhanced by neuromodulation and contextual priming. Lifelong learning capabilities are enabled by adult neurogenesis. The algorithm is applicable to any signal identification problem in which high-dimensional signals are embedded in unknown backgrounds.

in q-bio.NC updates on arXiv.org on June 18, 2019 01:30 AM.
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Brain Controllability: not a slam dunk yet. (arXiv:1906.06778v1 [q-bio.QM])

In our recent article (Tu et al., Warnings and caveats in brain controllability, arXiv:1705.08261) we provided quantitative evidence to show that there are warnings and caveats in the way Gu and collaborators (Gu et al. Controllability of structural brain networks. Nature communications 6 (2015): 8414) define brain controllability. The comment by Pasqualetti et al. (Pasqualetti et al. RE: Warnings and Caveats in Brain Controllability. NeuroImage 297 (2019), 586-588) confirms the need to go beyond the methodology and approach presented in Gu et al. original work. In fact, they recognize that the source of confusion is due to the fact that assessing controllability via numerical analysis typically leads to ill-conditioned problems, and thus often generates results that are difficult to interpret. This is indeed the first warning we discussed: our work was not meant to prove that brain networks are not controllable from one node, rather we wished to highlight that the one node controllability framework and all consequent results were not properly justified based on the methodology presented in Gu et al. We used in our work the same method of Gu et al. not because we believe it is the best methodology, but because we extensively investigated it with the aim of replicating, testing and extending their results. And the warning and caveats we have proposed are the results of this investigation.

in q-bio.NC updates on arXiv.org on June 18, 2019 01:30 AM.
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Agito ergo sum: correlates of spatiotemporal motion characteristics during fMRI. (arXiv:1906.06445v1 [q-bio.NC])

The impact of in-scanner motion on functional magnetic resonance imaging (fMRI) data has a notorious reputation in the neuroimaging community. State-ofthe-art guidelines advise to scrub out excessively corrupted frames as assessed by a composite framewise displacement (FD) score, to regress out models of nuisance variables, and to include average FD as a covariate in group-level analyses.

Here, we studied individual motion time courses at time points typically retained in fMRI analyses. We observed that even in this set of putatively clean time points, motion exhibited a very clear spatiotemporal structure, so that we could distinguish subjects into four groups of movers with varying characteristics

Then, we showed that this spatiotemporal motion cartography tightly relates to a broad array of anthropometric, behavioral and clinical factors. Convergent results were obtained from two different analytical perspectives: univariate assessment of behavioral differences across mover subgroups unraveled defining markers, while subsequent multivariate analysis broadened the range of involved factors and clarified that multiple motion/behavior modes of covariance overlap in the data.

Our results demonstrate that even the smaller episodes of motion typically retained in fMRI analyses carry structured, behaviorally relevant information. They call for further examinations of possible biases in current regression-based motion correction strategies.

in q-bio.NC updates on arXiv.org on June 18, 2019 01:30 AM.
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Blocking facial mimicry selectively alters early stages of facial expression processing. (arXiv:1906.06424v1 [q-bio.NC])

Simulation models of facial expressions suggest that posterior visual areas and brain areas underpinning sensorimotor simulations might interact to improve facial expression processing. According to these models, facial mimicry may contribute to the visual perceptual processing of facial expressions by influencing early stages of face processing, thus playing a crucial role in understanding the observed emotion. The aim of the present study was to assess whether and how early sensorimotor simulation influences face structural encoding/processing. A secondary aim was to investigate whether there is a relationship between alexithymic traits and sensorimotor simulation as a mechanism for fine facial expression discrimination. In order to examine the time-course of face processing, we monitored P1 and N170 components of the event-related potentials (ERP) in participants performing a fine discrimination task of facial expressions. An animal discrimination task was implemented as a control condition. In half of the experiment, participants could freely use their facial mimicry whereas, in the other half, they had their facial mimicry blocked by a gel. Our results revealed that the P1 ERP component was not modulated by the mimicry manipulation while the N170 amplitude was larger in the blocked mimicry condition when compared to the free mimicry condition selectively for the face stimuli. Interestingly, this modulation interacted with the alexithymic traits, with a reduction of the N170 amplitude modulation as a function of the facial mimicry manipulation for participants with the highest levels of alexithymic traits. These results demonstrate that sensorimotor simulation influences visual processing of facial expressions at early stages and that participants with higher alexithymic traits tend to underutilize the sensorimotor simulation system.

in q-bio.NC updates on arXiv.org on June 18, 2019 01:30 AM.
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Releasing the brake

Nature Reviews Neuroscience, Published online: 18 June 2019; doi:10.1038/s41583-019-0199-0
The encoding of salient events as memory traces involves the selective activation of specific neurons in the hippocampus and the inhibition of others, a process shown here to be regulated by GABAergic input from the nucleus incertus in the brainstem.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on June 18, 2019 12:00 AM.
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Shank3 Mice Carrying the Human Q321R Mutation Display Enhanced Self-Grooming, Abnormal Electroencephalogram Patterns, and Suppressed Neuronal Excitability and Seizure Susceptibility
Shank3, a postsynaptic scaffolding protein involved in regulating excitatory synapse assembly and function, has been implicated in several brain disorders, including autism spectrum disorders (ASD), Phelan-McDermid syndrome, schizophrenia, intellectual disability, and mania. Here we generated and characterized a Shank3 knock-in mouse line carrying the Q321R mutation (Shank3Q321R mice) identified in a human individual with ASD that affects the ankyrin repeat region (ARR) domain of the Shank3 protein. Homozygous Shank3Q321R/Q321R mice show a selective decrease in the level of Shank3a, an ARR-containing protein variant, but not other variants. CA1 pyramidal neurons in the Shank3Q321R/Q321R hippocampus show decreased neuronal excitability but normal excitatory and inhibitory synaptic transmission. Behaviorally, Shank3Q321R/Q321R mice show moderately enhanced self-grooming and anxiolytic-like behavior, but normal locomotion, social interaction, and object recognition and contextual fear memory. In addition, these mice show abnormal electroencephalogram (EEG) patterns and decreased susceptibility to induced seizures. These results indicate that the Q321R mutation alters Shank3 protein stability, neuronal excitability, repetitive and anxiety-like behavior, EEG patterns, and seizure susceptibility in mice.
in Frontiers in Molecular Neuroscience | New and Recent Articles on June 18, 2019 12:00 AM.
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A Critical Period for the Development of Schizophrenia-Like Pathology by Aberrant Postnatal Neurogenesis
Schizophrenia is a complex and serious mental disorder, and patients with schizophrenia are characterized by psychological hallucinations, deregulated emotionality, and cognitive impairment. Evidence indicated that postnatal neurogenesis in the hippocampus is profoundly impaired in schizophrenic individuals but the role of such dysregulated neurodevelopmental processing in the pathophysiological progress of schizophrenia has not been well investigated. Here in this study, by using the rodent model of schizophrenia through maternal immune activation of poly (I:C) injection, we aimed to examine whether the postnatal neurogenesis might be involved in the development of schizophrenia-like pathology. Through the comprehensive behavioral analyses of multiple core symptoms of schizophrenia at different developmental stages (six-, nine-, and twelve-weeks after birth) of the affected offspring, we found a delayed onset of schizophrenia-like behaviors in poly (I:C) animals through the development. Meanwhile, there is an age-dependent alteration of postnatal neurogenesis in the poly (I:C) animals along different development stages by which the aberrant dendritic elaboration functionally correlated with the schizophrenia-like symptoms in nine-week old of age for the animals. Interestingly, increase in the neurogenesis during a critical period of neurodevelopment exacerbates the schizophrenia-like pathology. Conversely, temporal suppression of aberrant postnatal neurogenesis during the same period of neurodevelopment ameliorates the occurrence of schizophrenia-like symptoms. Together, these findings strongly suggested the aberrant dendritic growth of postnatal neurogenesis during the critical time window of development is essential for controlling the pathophysiological progression of schizophrenia-like symptoms. And pharmacological treatments that adjust these abnormalities may provide potential therapeutic benefits toward patients with schizophrenia in clinic.
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on June 18, 2019 12:00 AM.
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Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway
Alzheimer’s disease (AD) and type 2 diabetes (T2D) are both diseases with increasing prevalence in aging populations. T2D, characterized by insulin resistance and defective insulin signaling, is a common co-morbidity and a risk factor for AD, increasing the risk approximately two- to four-fold. Insulin exerts a wide variety of effects as a growth factor as well as by regulating glucose, fatty acid and protein metabolism. Certain lifestyle factors, physical inactivity and typical Western diet (TWD) containing high fat and high sugar are strongly associated with insulin resistance and T2D. The PI3K-Akt signaling pathway is a major mediator of effects of insulin and plays a crucial role in T2D pathogenesis. Decreased levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) subunits as well as blunted Akt kinase phosphorylation have been observed in the AD brain, characterized by amyloid-β and tau pathologies. Furthermore, AD mouse models fed with TWD have shown to display altered levels of PI3K subunits. How impaired insulin-PI3K-Akt signaling in peripheral tissues or in the central nervous system (CNS) affects the development or progression of AD is currently poorly understood. Interestingly, enhancement of PI3K-Akt signaling in the CNS by intranasal insulin (IN) treatment has been shown to improve memory in vivo in mice and in human trials. Insulin is known to augment neuronal growth and synapse formation through the PI3K-Akt signaling pathway. However, PI3K-Akt pathway mediates signaling related to different functions also in other cell types, like microglia and astrocytes. In this review, we will discuss the most prominent molecular mechanisms related to the PI3K-Akt pathway in AD and how T2D and altered insulin signaling may affect the pathogenesis of AD.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 18, 2019 12:00 AM.
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Objective and Automated Detection of Diffuse White Matter Abnormality in Preterm Infants Using Deep Convolutional Neural Networks
Diffuse white matter abnormality (DWMA), or diffuse excessive high signal intensity is observed in 50-80% of very preterm infants at term-equivalent age. It is subjectively defined as higher than normal signal intensity in periventricular and subcortical white matter in comparison to normal unmyelinated white matter on T2-weighted MRI images. Despite the well-documented presence of DWMA, it remains debatable whether DWMA represents pathological tissue injury or a transient developmental phenomenon. Manual tracing of DWMA exhibits poor reliability and reproducibility and unduly increases image processing time. Thus, objective and ideally automatic assessment is critical to accurately elucidate the biologic nature of DWMA. We propose a deep learning approach to automatically identify DWMA regions on T2-weighted MRI images. Specifically, we formulated DWMA detection as an image voxel classification task; that is, the voxels on T2-weighted images are treated as samples and exclusively assigned as DWMA or normal white matter voxel classes. To utilize the spatial information of individual voxels, small image patches centered on the given voxels are retrieved. A deep convolutional neural networks (CNN) model was developed to differentiate DWMA and normal voxels. We tested our deep CNN in multiple validation experiments. First, we examined DWMA detection accuracy of our CNN model using computer simulations. This was followed by in vivo assessments in a cohort of very preterm infants (N=95) using cross-validation and holdout validation. Finally, we tested our approach on an independent preterm cohort (N=28) to externally validate our model. Our deep CNN model achieved Dice similarity index values ranging from 0.85 to 0.99 for DWMA detection in the aforementioned validation experiments. Our proposed deep CNN model exhibited significantly better performance than other popular machine learning models. We present an objective and automated approach for accurately identifying DWMA that may facilitate the clinical diagnosis of DWMA in very preterm infants.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 18, 2019 12:00 AM.
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New Neurons in the Post-ischemic and Injured Brain: Migrating or Resident?
The endogenous potential of adult neurogenesis is of particular interest for the development of new strategies for recovery after stroke and traumatic brain injury. These pathological conditions affect endogenous neurogenesis in two aspects. On the one hand, injury usually initiates the migration of neuronal precursors (NPCs) to the lesion area from the already existing, in physiological conditions, neurogenic niche – the ventricular-subventricular zone (V-SVZ) near the lateral ventricles. On the other hand, recent studies have convincingly demonstrated the local generation of new neurons near lesion areas in different brain locations. The striatum, cortex, and hippocampal CA1 region are considered to be locations of such new neurogenic zones in the damaged brain. This review focuses on the relative contribution of two types of NPCs of different origin, resident population in new neurogenic zones and cells migrating from the lateral ventricles, to post-stroke or post-traumatic enhancement of neurogenesis. The migratory pathways of NPCs have also been considered. In addition, the review highlights the advantages and limitations of different methodological approaches to the definition of NPC location and tracking of new neurons. In general, we suggest that despite the considerable number of studies, we still lack a comprehensive understanding of neurogenesis in the damaged brain. We believe that the advancement of methods for in vivo visualization and longitudinal observation of neurogenesis in the brain could fundamentally change the current situation in this field.
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on June 18, 2019 12:00 AM.
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Prion-Like Mechanisms in Parkinson’s Disease
Formation and aggregation of misfolded proteins in the central nervous system (CNS) is a key hallmark of several age-related neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). These diseases share key biophysical and biochemical characteristics with prion diseases. It is believed that PD is characterized by abnormal protein aggregation, mainly that of α-synuclein (α-syn). Of particular importance, there is growing evidence indicating that abnormal α-syn can spread to neighboring brain regions and cause aggregation of endogenous α-syn in these regions as seeds, in a “prion-like” manner. Abundant studies in vitro and in vivo have shown that α-syn goes through a templated conformational change, propagates from the original region to neighboring regions, and eventually cause neuron degeneration in the substantia nigra and striatum. The objective of this review is to summarize the mechanisms involved in the aggregation of abnormal intracellular α-syn and its subsequent cell-to-cell transmission. According to these findings, we look forward to effective therapeutic perspectives that can block the progression of neurodegenerative diseases.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 18, 2019 12:00 AM.
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Interpreting Prefrontal Recruitment During Walking After Stroke: Influence of Individual Differences in Mobility and Cognitive Function
Background: Functional near-infrared spectroscopy (fNIRS) is a valuable neuroimaging approach for studying cortical contributions to walking function. Recruitment of prefrontal cortex during walking has been a particular area of focus in the literature. The present study investigated whether task-related change in prefrontal recruitment measured by fNIRS is affected by individual differences in people post-stroke. The primary hypotheses were that poor mobility function would contribute to prefrontal over-recruitment during typical walking, and that poor cognitive function would contribute to a ceiling in prefrontal recruitment during dual-task walking (i.e., walking with a cognitive task). Methods: Thirty-three adults with chronic post-stroke hemiparesis performed three tasks: typical walking at preferred speed (Walk), serial-7 subtraction (Serial7), and walking combined with serial-7 subtraction (Dual-Task). Prefrontal recruitment was measured with fNIRS and quantified as the change in oxygenated hemoglobin concentration (ΔO2Hb) between resting and active periods for each task. Spatiotemporal gait parameters were measured on an electronic walkway. Stepwise regression was used to assess how prefrontal recruitment was affected by individual differences including age, sex, stroke region, injured hemisphere, stroke chronicity, 10 meter walking speed, balance confidence measured by Activities-specific Balance Confidence (ABC) Scale, sensorimotor impairment measured by Fugl-Meyer Assessment, and cognitive function measured by Mini-Mental State Exam (MMSE). Results: For Walk, poor balance confidence (ABC Scale score) significantly predicted greater prefrontal recruitment (ΔO2Hb; R2 = 0.25, p = 0.003). For Dual-Task poor cognitive function (MMSE score) significantly predicted lower prefrontal recruitment (ΔO2Hb; R2 = 0.25, p = 0.002). Conclusions: Poor mobility function predicted higher prefrontal recruitment during typical walking, consistent with compensatory over-recruitment. Poor cognitive function predicted lower prefrontal recruitment during dual-task walking, consistent with a recruitment ceiling effect. These findings indicate that interpretation of prefrontal recruitment should carefully consider the characteristics of the person and demands of the task.
in Frontiers in Human Neuroscience | New and Recent Articles on June 18, 2019 12:00 AM.
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Abnormal Interactions of the Salience Network, Central Executive Network, and Default-Mode Network in Patients With Different Cognitive Impairment Loads Caused by Leukoaraiosis
Leukoaraiosis (LA) is considered to be associated with cognitive impairment in the older people. This alteration can be reflected in functional connectivity (FC) based on resting-state functional MRI (rs-fMRI). In this study, we used the triple brain network model to investigate altered changes in FC for LA with different cognitive impairment loads determined by the Mini Mental State Exam (MMSE) and Clinical Dementia Rating (CDR). Eighty-three subjects were divided into four groups based on their clinical diagnosis: the LA-normal cognition group (LA-NC) (n=14, 6 males), LA with mild cognitive impairment (LA-MCI) group (n=27, 13 males), LA with vascular dementia (LA-VD) group (n=12, 6 males) and matched healthy controls (HC) (n=30, 11 males). The triple brain network model includes the default-mode network (DMN), salience networks (SN) and the central executive network (CEN), which were extracted with independent components analysis (ICA) and region of interest (ROI) based analysis using the REST toolbox. LA group presented decreased FC for all these three brain networks, compared with matched healthy controls. For inter-brain network analysis, there were decreased negative FC between the SN and DMN in LA group. While there were enhanced inter-brain network FC between the SN and CEN as well as within the SN. The decrease of FC between SN and DMN may reflect the damage mechanism of cognitive impairment of LA, which can compensate with the enhanced inter-brain network between SN and CEN and intra-brain network FC within the SN.
in Frontiers in Neural Circuits | New and Recent Articles on June 18, 2019 12:00 AM.
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Secretion of Mast Cell Inflammatory Mediators Is Enhanced by CADM1-Dependent Adhesion to Sensory Neurons
Neuroimmune interactions are important in the pathophysiology of many chronic inflammatory diseases, particularly those associated with alterations in sensory processing and pain. Mast cells and sensory neuron nerve endings are found in areas of the body exposed to the external environment; both are specialized to sense potential damage by injury or pathogens and signal to the immune system and nervous system respectively, to elicit protective responses. Cell adhesion molecule 1 (CADM1), also known as SynCAM1, has previously been identified as an adhesion molecule which may couple mast cells to sensory neurons however, whether this molecule exerts a functional as well as structural role in neuroimmune cross-talk is unknown. Here we show, using a newly developed in vitro co-culture system consisting of murine bone marrow derived mast cells (BMMC) and adult sensory neurons isolated from dorsal root ganglions (DRG), that CADM1 is expressed in mast cells and adult sensory neurons and mediates strong adhesion between the two cell types. Non-neuronal cells in the DRG cultures did not express CADM1, and mast cells did not adhere to them. The interaction of BMMCs with sensory neurons was found to induce mast cell degranulation and IL-6 secretion and to enhance responses to antigen stimulation and activation of FcRI receptors. Secretion of TNF in contrast was not affected, nor was secretion evoked by compound 48/80. Co-cultures of BMMCs with HEK 293 cells, which also express CADM1, while also leading to adhesion did not replicate the effects of sensory neurons on mast cells, indicative of a neuron-specific interaction. Application of a CADM1 blocking peptide or knockdown of CADM1 in BMMCs significantly decreased BMMC attachment to sensory neurites and abolished the enhanced secretory responses of mast cells. In conclusion, CADM1 is necessary and sufficient to drive mast cell-sensory neuron adhesion and promote the development of a microenvironment in which neurons enhance mast cell responsiveness to antigen; this interaction could explain why the incidence of painful neuroinflammatory disorders such as irritable bowel syndrome (IBS) are increased in atopic patients.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 18, 2019 12:00 AM.
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Distinct Brain Regions in Physiological and Pathological Brain Aging
Background: Studying structural brain aging is important to understand age-related pathologies, as well as to identify the early manifestations of the Alzheimer’s disease (AD) continuum. In this study, we investigated the long-term trajectory of physiological and pathological brain aging in a large number of participants ranging from the 50s to over 80 years of age. Objective: To explore the distinct brain regions that distinguish pathological brain aging from physiological brain aging using sophisticated measurements of cortical thickness. Methods: A total of 2,823 cognitively normal (CN) individuals and 2,675 patients with AD continuum (874 with subjective memory impairments [SMI], 954 with amnestic mild cognitive impairments [aMCI], and 847 with AD dementia) who underwent a high-resolution 3.0-tesla MRI were included in this study. To investigate pathological brain aging, we further classified patients with aMCI and AD according to the severity of cognitive impairment. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age, diagnostic groups, and cortical thickness. Results: Aging extensively affected cortical thickness not only in CN individuals but also in AD continuum patients; however, the precuneus and inferior temporal regions were relatively preserved against age-related cortical thinning. Compared to CN individuals, AD continuum patients including those with SMI showed a decreased cortical thickness in the perisylvian region. However, widespread cortical thinning including the precuneus and inferior temporal regions were found from the late-stage aMCI to the moderate to severe AD. Unlike the other age groups, AD continuum patients aged over 80 years showed prominent cortical thinning in the medial temporal region with relative sparing of the precuneus. Conclusion: Our findings suggested that the precuneus and inferior temporal regions are the key regions in distinguishing between physiological and pathological brain aging. Attempts to differentiate age-related pathology from physiological brain aging at a very early stage would be important in terms of establishing new strategies for preventing accelerated pathological brain aging.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 18, 2019 12:00 AM.
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Effects of tDCS of Dorsolateral Prefrontal Cortex on Dual-Task Performance Involving Manual Dexterity and Cognitive Task in Healthy Older Adults
Healthy aging limits the activities of daily living and personal independence. Furthermore, cognitive-motor interference in dual-task (e.g., walking while talking) appears to be more pronounced in the elderly. Transcranial direct current stimulation (tDCS), a form of the non-invasive brain stimulation technique, is known to modify cortical excitability and has been investigated as a tool for enhancing learning in health and disease. The present study examined the effects of the dorsolateral prefrontal cortex (DLPFC), applied while dual-tasking (on-line), improves performance in healthy older humans. Anodal, cathodal, bilateral or sham tDCS targeting left DLPFC was applied while performing the grooved pegboard test (GPT) and serial seven subtraction test (SSST) alone or together (dual-tasking). The number of pegs and the number of correct subtractions were recorded before, during and 30 minutes after tDCS. The dual-task performance was measured as the percent change from single to the dual-task condition (dual-task cost DTC). Only bilateral, anode left tDCS, induced a significant increase in subtracted numbers while dual-tasking, i.e., it reduced the DTC of manual dexterity (GPT) to a cognitive task. Significant changes 30 minutes after the stimulation were only present after bilateral anode right tDCS on GPT dual-task costs. These findings suggest that anodal tDCS applied online interacts with a dual-task performance involving demanding cognitive and manual dexterity tasks. The results support the potential use of non-invasive brain stimulation for improvement of cognitive functioning in daily activities in older individuals.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 18, 2019 12:00 AM.
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The Gut-Brain Axis in Neurodegenerative Diseases and Relevance of the Canine Model: A Review
Identifying appropriate animal models is critical in developing translatable in vitro and in vivo systems for therapeutic drug development and investigating disease pathophysiology. These animal models should have direct biological and translational relevance to the underlying disease they are supposed to mimic. Aging dogs not only naturally develop a cognitive decline in many aspects including learning and memory deficits, but they also exhibit human-like individual variability in the aging process. Neurodegenerative processes that can be observed in both human and canine brains include the progressive accumulation of β-amyloid (Aβ) found as diffuse plaques in the prefrontal cortex (PFC), including the gyrus proreus (i.e., medial orbital PFC), as well as the hippocampus and the cerebral vasculature. Tau pathology, a marker of neurodegeneration and dementia progression, was also found in canine hippocampal synapses. Various epidemiological data show that human patients with neurodegenerative diseases have concurrent intestinal lesions, and histopathological changes in the gastrointestinal (GI) tract occurs decades before neurodegenerative changes. Gut microbiome alterations have also been reported in many neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases, as well as inflammatory central nervous system (CNS) diseases. Interestingly, the dog gut microbiome more closely resembles human gut microbiome in composition and functional overlap compared to rodent models. This article reviews the physiology of the gut-brain axis (GBA), and its involvement with neurodegenerative diseases in humans. Additionally, we outline the advantages and weaknesses of current in vitro and in vivo models and discuss future research directions investigating major human neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases using dogs.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 18, 2019 12:00 AM.
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Seizing an opportunity
As the techniques available to neuroscientists to probe the inner workings of the brain become more powerful, the volume of data generated increases exponentially and the tools used to analyze these data become ever more sophisticated. Alongside this feverish press into the future comes a growing interest in the use of new data technologies to study old literary and philosophical texts. And as researchers develop new methods to unearth patterns hidden within complex data, it is natural to think of these old texts as simply more data reflecting the intricacies of the human mind, waiting to succumb to the powerful, objective, and reliable perception of machines. Here we argue that historical texts are more than prone booty to be exploited: rather, they offer researchers in neuroscience, philosophy, and literature the opportunity to work together, to learn from and enrich each other’s methodologies. Using the study of human curiosity as an illustration, we describe our vision for a collaborative approach to exploring the mysteries of the mind and human behavior.
in eLife: latest articles on June 18, 2019 12:00 AM.
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A lesson in homology
The same genes and signaling pathways control the formation of limbs in vertebrates, arthropods and cuttlefish.
in eLife: latest articles on June 18, 2019 12:00 AM.
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Structure of the Helicobacter pylori Cag Type IV secretion system
Bacterial type IV secretion systems (T4SSs) are molecular machines that can mediate interbacterial DNA transfer through conjugation and delivery of effector molecules into host cells. The Helicobacter pylori Cag T4SS translocates CagA, a bacterial oncoprotein, into gastric cells, contributing to gastric cancer pathogenesis. We report the structure of a membrane-spanning Cag T4SS complex, which contains three sub-complexes: a 14-fold symmetric outer membrane core complex (OMCC), 17-fold symmetric periplasmic ring complex (PRC), and stalk domain. Features that differ markedly from those of prototypical T4SSs include an expanded OMCC and unexpected symmetry mismatch between the OMCC and PRC. This structure is one of the largest bacterial secretion system complexes ever reported and illustrates the remarkable structural diversity that exists among bacterial T4SSs.
in eLife: latest articles on June 18, 2019 12:00 AM.
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Variable opportunities for outcrossing result in hotspots of novel genetic variation in a pathogen metapopulation
Many pathogens possess the capacity for sex through outcrossing, despite being able to reproduce also asexually and/or via selfing. Given that sex is assumed to come at a cost, these mixed reproductive strategies typical of pathogens have remained puzzling. While the ecological and evolutionary benefits of outcrossing are theoretically well-supported, support for such benefits in pathogen populations are still scarce. Here, we analyze the epidemiology and genetic structure of natural populations of an obligate fungal pathogen, Podosphaera plantaginis. We find that the opportunities for outcrossing vary spatially. Populations supporting high levels of coinfection -a prerequisite of sex - result in hotspots of novel genetic diversity. Pathogen populations supporting coinfection also have a higher probability of surviving winter. Jointly our results show that outcrossing has direct epidemiological consequences as well as a major impact on pathogen population genetic diversity, thereby providing evidence of ecological and evolutionary benefits of outcrossing in pathogens.
in eLife: latest articles on June 18, 2019 12:00 AM.
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Cretaceous dinosaur bone contains recent organic material and provides an environment conducive to microbial communities
Fossils were thought to lack original organic molecules, but chemical analyses show that some can survive. Dinosaur bone has been proposed to preserve collagen, osteocytes, and blood vessels. However, proteins and labile lipids are diagenetically unstable, and bone is a porous open system, allowing microbial/molecular flux. These ‘soft tissues’ have been reinterpreted as biofilms. Organic preservation versus contamination of dinosaur bone was examined by freshly excavating, with aseptic protocols, fossils and sedimentary matrix, and chemically/biologically analyzing them. Fossil ‘soft tissues’ differed from collagen chemically and structurally; while degradation would be expected, the patterns observed did not support this. 16S rRNA amplicon sequencing revealed that dinosaur bone hosted an abundant microbial community different from lesser abundant communities of surrounding sediment. Subsurface dinosaur bone is a relatively fertile habitat, attracting microbes that likely utilize inorganic nutrients and complicate identification of original organic material. There exists potential post-burial taphonomic roles for subsurface microorganisms.
in eLife: latest articles on June 18, 2019 12:00 AM.
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Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors
In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.
in eLife: latest articles on June 18, 2019 12:00 AM.
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Cryo-EM structures of remodeler-nucleosome intermediates suggest allosteric control through the nucleosome
The SNF2h remodeler slides nucleosomes most efficiently as a dimer, yet how the two protomers avoid a tug-of-war is unclear. Furthermore, SNF2h couples histone octamer deformation to nucleosome sliding, but the underlying structural basis remains unknown. Here we present cryo-EM structures of SNF2h-nucleosome complexes with ADP-BeF_x that capture two reaction intermediates. In one structure, histone residues near the dyad and in the H2A-H2B acidic patch, distal to the active SNF2h protomer, appear disordered. The disordered acidic patch is expected to inhibit the second SNF2h protomer, while disorder near the dyad is expected to promote DNA translocation. The other structure doesn't show octamer deformation, but surprisingly shows a 2bp translocation. FRET studies indicate that ADP-BeF_x predisposes SNF2h-nucleosome complexes for an elemental translocation step. We propose a model for allosteric control through the nucleosome, where one SNF2h protomer promotes asymmetric octamer deformation to inhibit the second protomer, while stimulating directional DNA translocation.
in eLife: latest articles on June 18, 2019 12:00 AM.
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A FRET sensor of C-terminal movement reveals VRAC activation by plasma membrane DAG signaling rather than ionic strength
Volume-regulated anion channels (VRACs) are central to cell volume regulation. Recently identified as hetero-hexamers formed by LRRC8 proteins, their activation mechanism remains elusive. Here we measured Förster resonance energy transfer (FRET) between fluorescent proteins fused to the C-termini of LRRC8 subunits. Inter-subunit FRET from LRRC8 complexes tracked VRAC activation. With patch-clamp fluorometry, we confirmed that the cytoplasmic domains rearrange during VRAC opening. With these FRET reporters, we determined VRAC activation, non-invasively, in live cells and their subcompartments. Reduced intracellular ionic strength did not directly activate VRACs, and VRACs were not activated on endomembranes. Instead, pharmacological manipulation of diacylglycerol (DAG), and protein kinase D (PKD) activity, activated or inhibited plasma membrane-localized VRACs. Finally, we resolved previous contradictory reports concerning VRAC activation, using FRET to detect robust activation by PMA that was absent during whole-cell patch clamp. Overall, non-invasive VRAC measurement by FRET is an essential tool for unravelling its activation mechanism.
in eLife: latest articles on June 18, 2019 12:00 AM.
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Evolution of limb development in cephalopod mollusks
Cephalopod mollusks evolved numerous anatomical novelties, including arms and tentacles, but little is known about the developmental mechanisms underlying cephalopod limb evolution. Here we show that all three axes of cuttlefish limbs are patterned by the same signaling networks that act in vertebrates and arthropods, although they evolved limbs independently. In cuttlefish limb buds, Hedgehog is expressed anteriorly. Posterior transplantation of Hedgehog-expressing cells induced mirror-image limb duplications. Bmp and Wnt signals, which establish dorsoventral polarity in vertebrate and arthropod limbs, are similarly polarized in cuttlefish. Inhibition of Bmp2/4 dorsally caused ectopic expression of Notum, which marks the ventral sucker field, and ectopic sucker development. Cuttlefish also show proximodistal regionalization of Hth, Exd, Dll, Dac, Sp8/9, and Wnt expression, which delineates arm and tentacle sucker fields. These results suggest that cephalopod limbs evolved by parallel activation of a genetic program for appendage development that was present in the bilaterian common ancestor.
in eLife: latest articles on June 18, 2019 12:00 AM.
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Neuromodulation Leads to a Burst-Tonic Switch in a Subset of VIP Neurons in Mouse Primary Somatosensory (Barrel) Cortex

Abstract
Neocortical GABAergic interneurons expressing vasoactive intestinal polypeptide (VIP) contribute to sensory processing, sensorimotor integration, and behavioral control. In contrast to other major subpopulations of GABAergic interneurons, VIP neurons show a remarkable diversity. Studying morphological and electrophysiological properties of VIP cells, we found a peculiar group of neurons in layer II/III of mouse primary somatosensory (barrel) cortex, which showed a highly dynamic burst firing behavior at resting membrane potential that switched to tonic mode at depolarized membrane potentials. Furthermore, we demonstrate that burst firing depends on T-type calcium channels. The burst-tonic switch could be induced by acetylcholine (ACh) and serotonin. ACh mediated a depolarization via nicotinic receptors whereas serotonin evoked a biphasic depolarization via ionotropic and metabotropic receptors in 48% of the population and a purely monophasic depolarization via metabotropic receptors in the remaining cells. These data disclose an electrophysiologically defined subpopulation of VIP neurons that via neuromodulator-induced changes in firing behavior is likely to regulate the state of cortical circuits in a profound manner.
in Cerebral Cortex Open Access on June 18, 2019 12:00 AM.
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Unusual Physiological Properties of Smooth Monostratified Ganglion Cell Types in Primate Retina
Rhoades et al. find the smooth monostratified retinal ganglion cells in the primate retina have unusual receptive fields consisting of multiple hotspots. This differs from classic center-surround receptive field models and suggests a role in nonlinear visual computation.
in Neuron on June 18, 2019 12:00 AM.
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Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation
Zerbi et al. selectively activate the mouse locus coeruleus, which provides norepinephrine to the brain. This induces anxiety and rapidly shifts network connectivity toward salience and fear processing. This appears to be mediated by the spatial distribution of adrenergic receptors.
in Neuron on June 18, 2019 12:00 AM.
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Neural, functional, and aesthetic impacts of spatially heterogeneous flicker: A potential role of natural flicker
Spatially heterogeneous flicker, characterized by probabilistic and locally independent luminance modulations, abounds in nature. It is generated by flames, water surfaces, rustling leaves, and so on, and it is pleasant to the senses. It affords spatiotemporal multistability that allows sensory activation conforming to the biases of the visual system, thereby generating the perception of spontaneous motion and likely facilitating the calibration of motion detectors. One may thus hypothesize that spatially heterogeneous flicker might potentially provide restoring stimuli to the visual system that engage fluent (requiring minimal top-down control) and self-calibrating processes. Here, we present some converging behavioral and electrophysiological evidence consistent with this idea. Spatially heterogeneous (multistable) flicker (relative to controls matched in temporal statistics) reduced posterior EEG (electroencephalography) beta power implicated in long-range neural interactions that impose top-down influences on sensory processing. Further, the degree of spatiotemporal multistability, the amount of posterior beta-power reduction, and the aesthetic responses to flicker were closely associated. These results are consistent with the idea that the pleasantness of natural flicker may derive from its spatiotemporal multistability that affords fluent and self-calibrating visual processing.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Exploratory Data Analysis in The Vallecas Project: A six years longitudinal study in healthy brain aging
Alzheimer's Disease (AD) is a complex, multifactorial and comorbid condition. The asymptomatic behavior in early stages of the disease is a paramount obstacle to formulate a preclinical and predictive model of AD. Not surprisingly, the AD drug approval rate is one of the lowest in the industry, an exiguous 0.4%. The identification of risk factors, preferably obtained by the subject herself, is sorely needed given that the incidence of Alzheimer's disease grows exponentially with age. Since the end of 2011, researchers at The Vallecas Project have collected information about the project's volunteers, aged 70 or more. The Vallecas Project dataset includes information about a wide range of factors including magnetic resonance imaging, genetic, demographic, socioeconomic, cognitive performance, subjective memory complains, neuropsychiatric disorders, cardiovascular, sleep, diet, physical exercise and self assessed quality of life. The subjects in each visit were diagnosed as healthy, mild cognitive impairment (MCI) or dementia. In this study we perform Exploratory Data Analysis to summarize the main characteristics of this unique longitudinal dataset. The objective is to characterize the evolution of the collected features over time and most importantly, how their dynamics are related to cognitive decline. We show that the longitudinal dataset of The Vallecas Project, if conveniently exploited, holds promise to identifying either factors promoting healthy aging and risk factors related to cognitive decline.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Physical activity, aerobic fitness and brain white matter: their role for executive functions in adolescence
Physical activity and exercise beneficially link to brain properties and cognitive functions in older adults, but it is unclear how these results generalise to other age groups. During adolescence, the brain undergoes significant changes, which are especially pronounced in white matter. Existing studies provide contradictory evidence regarding the influence of physical activity or aerobic-exercise on executive functions in youth. Little is also known about the link between both aerobic fitness and physical activity with white matter during puberty. For this reason, we investigated the connection between both aerobic fitness (20-m shuttle run) and physical activity (moderate-to-vigorous intensity physical activity) with white matter in 59 adolescents (12.7-16.2 years). We further determined whether white matter interacts with the connection of fitness or physical activity with three core executive functions (sustained attention, spatial working memory and response inhibition). Our results showed that only the level of aerobic fitness, but not of physical activity was related to white matter properties. Furthermore, the white matter of specific tracts also moderated the links of aerobic fitness and physical activity with working memory. Our results suggest that aerobic fitness and physical activity have an unequal contribution to the properties of white matter in adolescent brains. We propose that the differences in white matter properties could underlie the variations in the relationship between either physical activity or aerobic fitness with working memory.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Serotonin Neurons in the Dorsal and Medial Raphe Nuclei: from Single-Cell Transcriptomes to Whole-Brain Projections
Serotonin neurons of the dorsal and medial raphe nuclei (DR and MR) collectively innervate the entire forebrain and midbrain, modulating diverse physiology and behavior. To gain a fundamental understanding of their molecular heterogeneity, we used plate-based single-cell RNA-sequencing to generate a comprehensive dataset comprising eleven transcriptomically distinct serotonin neuron clusters. Systematic in situ hybridization mapped specific clusters to the principal DR, caudal DR, or MR. These transcriptomic clusters differentially express a rich repertoire of neuropeptides, receptors, ion channels, and transcription factors. We generated novel intersectional viral-genetic tools to access specific subpopulations. Whole-brain axonal projection mapping revealed that DR serotonin neurons co-expressing vesicular glutamate transporter-3 preferentially innervate the cortex, whereas those co-expressing thyrotropin-releasing hormone innervate subcortical regions in particular the hypothalamus. Reconstruction of 50 individual DR serotonin neurons revealed segregated axonal projection patterns at the single-cell level. Together, these results provide a molecular foundation of the heterogenous serotonin neuronal phenotypes.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Nucleus Basalis Stimulation Stabilizes Attractor Networks and Enhances Task Representation in Prefrontal Cortex
The action of acetylcholine in the neocortex is critical for executive function. Cholinergic drugs can improve cognitive function in patient populations and normal adults. How endogenous cholinergic action affects neuronal activity in higher cortical areas is unknown. Here we tested the effects of electrical stimulation of the cortical source of acetylcholine in primates, the Nucleus Basalis of Meynert, on neural activity while monkeys performed working memory tasks. Stimulation delivered in an intermittent fashion improved behavioral performance and increased neuronal activity during the delay period of the task but not to the phasic responses of visual stimuli. Selectivity of neuronal responses broadened, rendering the bump of activity in an attractor network more stable, and filtering distracting stimuli more effectively. These neural results show that acetylcholine has effects on neural activity and selectivity in the prefrontal cortex opposing those of dopamine and fine tuning aggregate neural ensemble activity based on neuromodulatory tone.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Altered dorsal CA1 neuronal population coding in the APP/PS1 mouse model of Alzheimer\'s disease
While the link between amyloid beta accumulation and synaptic degradation in Alzheimer's disease is known, the consequences of this pathology on coding remain unknown. We found that the entropy across neural ensembles was lower in the CA1 region in the APP/PS1 mouse model of a-beta, thereby reducing the population's coding capacity. Our results reveal a network level signature of the deficits a-beta accumulation causes to the computations performed by neural circuits.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Chronic Stability of Single-Channel Neurophysiological Correlates of Gross and Fine Reaching Movements in the Rat
Following injury to motor cortex, reorganization occurs throughout spared brain regions and is thought to underlie motor recovery. Unfortunately, the standard neurophysiological and neuroanatomical measures of post-lesion plasticity are only indirectly related to observed changes in motor execution. While substantial task-related neural activity has been observed during motor tasks in rodent primary motor cortex and premotor cortex, the long-term stability of these responses in healthy rats is uncertain, limiting the interpretability of longitudinal changes in the specific patterns of neural activity during motor recovery following injury. This study examined the stability of task-related neural activity associated with execution of reaching movements in healthy rodents. Rats were trained to perform a novel reaching task combining a gross lever press and a fine pellet retrieval. In each animal, two chronic microelectrode arrays were implanted in motor cortex spanning the caudal forelimb area (rodent primary motor cortex) and the rostral forelimb area (rodent premotor cortex). We recorded multiunit spiking and local field potential activity from 10 days to 7-10 weeks post-implantation to characterize the patterns of neural activity observed during each task component and analyzed the consistency of channel-specific task-related neural activity. Task-related changes in neural activity were observed on the majority of channels. While the task-related changes in multi-unit spiking and local field potential spectral power were consistent over several weeks, spectral power changes were more stable, despite the trade-off of decreased spatial and temporal resolution. These results show that rodent primary and premotor cortex are both involved in reaching movements with stable patterns of task-related activity across time, establishing the relevance of the rodent for future studies designed to examine changes in task-related neural activity during recovery from focal cortical lesions.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Maximizing the coding capacity of neuronal networks
Information in neuronal networks is encoded as spatiotemporal patterns of activity. The capacity of a network may thus be thought of as the number of stable spatiotemporal patterns it can generate. To understand what structural attributes of a network enable it to generate a profusion of stable patterns, we simulated an array of 9 x 9 neurons modelled as pulse-coupled oscillators. The structure of the network was inspired by the popular puzzle Sudoku such that its periodic responses mapped to solutions of the puzzle. Given that there are nearly a 109 possible Sudokus, this networks could possibly generate 109 spatiotemporal patterns. We show that the number of stable patterns were maximized when excitatory and inhibitory inputs to each neuron were balanced. When this balance was disrupted, only a subset of patterns with certain symmetries survived.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn
The passage of nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate neurons that contain the calcium-binding protein calretinin (CR). We show that CR+ interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relays signals to lamina I projection neurons. In vivo photoactivation of CR+ interneurons resulted in a significant nocifensive behavior that was morphine sensitive and cause a conditioned place aversion. Furthermore, halorhodopsin-mediated inhibition of CR+ interneurons elevated sensory thresholds. These results suggest that neuronal circuits in the superficial dorsal horn that involve excitatory CR+ neurons are important for the generation and amplification of pain, and identify these interneurons as a future analgesic target.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Highly Accelerated Vessel-Selective Arterial Spin Labelling Angiography using Sparsity and Smoothness Constraints
Purpose: To demonstrate that vessel-selectivity in arterial spin labeling angiography can be achieved without any scan time penalty or noticeable loss of image quality compared to conventional arterial spin labeling angiography. Methods: Simulations on a numerical phantom were used to assess whether the increased sparsity of vessel-encoded angiograms compared to non-vessel-encoded angiograms alone can improve reconstruction results in a compressed sensing framework. Further simulations were performed to study whether the difference in relative sparsity between non-selective and vessel-selective dynamic angiograms were sufficient to achieve similar image quality at matched scan times in the presence of noise. Finally, data were acquired from 5 healthy volunteers to validate the technique in vivo. All data, both simulated and in vivo, were sampled in 2D using a golden angle radial trajectory and reconstructed by enforcing both image domain sparsity and temporal smoothness on the angiograms in a parallel imaging and compressed sensing framework. Results: Relative sparsity was established as a primary factor governing the reconstruction fidelity. Using the proposed reconstruction scheme, differences between vessel-selective and non-selective angiography were negligible compared to the dominant factor of total scan time in both simulations and in vivo experiments at acceleration factors up to R = 34. The reconstruction quality was not heavily dependent on hand-tuning the parameters of the reconstruction. Conclusion: The increase in relative sparsity of vessel-selective angiograms compared to non-selective angiograms can be leveraged to achieve higher acceleration without loss of image quality, resulting in the acquisition of vessel-selective information at no scan time cost.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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PET and CSF amyloid-β status are differently predicted by patient features: Information from discordant cases
Background: Amyloid-{beta} PET and CSF A{beta}42 yield discordant results in 10-20% of patients, possibly providing unique information. Although the predictive power of demographic, clinical, genetic and imaging features for amyloid-positivity has previously been investigated, it is unknown whether these features differentially predict amyloid-{beta} status based on PET or CSF, or whether this differs by disease stage. Methods: We included 768 patients (subjective cognitive decline (SCD, n=194), mild cognitive impairment (MCI, n=127), dementia (AD and non-AD, n=447) with amyloid-{beta} PET and CSF A{beta}42 measurement within one year. 97(13%) patients had discordant PET/CSF amyloid-{beta}; status. We performed parallel random forest models predicting separately PET and CSF status using 17 patient features (demographics, APOE4 positivity, CSF (p)tau, cognitive performance, and MRI visual ratings) in the total patient group and stratified by syndrome diagnosis. Thereafter, we selected features with the highest variable importance measure (VIM) as input for logistic regression models, where amyloid status on either PET or CSF was predicted by (i) the selected patient feature, and (ii) the patient feature adjusted for the status of the other amyloid modality. Results: APOE4, CSF tau and p-tau had highest VIM for PET and CSF in all groups. In the amyloid-adjusted logistic regression models, p-tau was a significant predictor for PET-amyloid in SCD (OR=1.02[1.01-1.04], pFDR=0.03), MCI (OR=1.05[1.02-1.07], pFDR<0.01) and dementia (OR=1.04[1.03-1.05], pFDR<0.001), but not for CSF-amyloid. APOE4 (OR=3.07[1.33-7.07], punc<0.01) was associated with CSF-amyloid in SCD, while it was only predictive for PET-amyloid in MCI (OR=9.44[2.93,30.39], pFDR<0.01). Worse MMSE scores (OR=1.21[1.03-1.41], punc=0.02) were associated to CSF-amyloid status in SCD, whereas worse memory (OR=1.17[1.05-1.31], pFDR=0.02) only predicted PET positivity in dementia. Conclusion: Amyloid status based on either PET or CSF was predicted by different patient features and this varied by disease stage, suggesting that PET-CSF discordance yields unique information. The stronger associations of both APOE4 carriership and worse memory z-scores with CSF-amyloid in SCD suggests that CSF-amyloid is more sensitive early in the disease course. The higher predictive value of CSF p-tau for a positive PET scan suggests that PET is more specific to AD pathology. These findings can influence the choice between amyloid biomarkers in future studies or trials.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Cervical spinal cord atrophy and Alzheimer\'s disease.
Objective: Brain atrophy is an established biomarker for dementia. We hypothesise that spinal cord atrophy is an important in vivo imaging biomarker for neurodegeneration associated with dementia. Methods: 3DT1 images of 31 Alzheimer's disease (AD) and 35 healthy control (HC) subjects were processed to calculate volumes 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 ({rho}>0.7) were removed, and 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 dependent variable with 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 grey 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. Results show that CSA23 has a considerable weight in classification tasks warranting further investigations.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Functions of ventral visual cortex after bilateral hippocampal loss
Repeated stimuli elicit attenuated responses in visual cortex relative to novel stimuli. This adaptation phenomenon can be considered a form of rapid learning and a signature of perceptual memory. Adaptation occurs not only when a stimulus is repeated immediately, but also when there is a lag in terms of time and other intervening stimuli before the repetition. But how does the visual system keep track of which stimuli are repeated, especially after long delays and many intervening stimuli? We hypothesized that the hippocampus supports long-lag adaptation, given that it learns from single experiences, maintains information over delays, and sends feedback to visual cortex. We tested this hypothesis with fMRI in an amnesic patient, LSJ, who has encephalitic damage to the medial temporal lobe resulting in complete bilateral hippocampal loss. We measured adaptation at varying time lags between repetitions in functionally localized visual areas that were intact in LSJ. We observed that these areas track information over a few minutes even when the hippocampus is unavailable. Indeed, LSJ and controls were identical when attention was directed away from the repeating stimuli: adaptation occurred for lags up to three minutes, but not six minutes. However, when attention was directed toward stimuli, controls now showed an adaptation effect at six minutes but LSJ did not. These findings suggest that visual cortex can support one-shot perceptual memories lasting for several minutes but that the hippocampus is necessary for adaptation in visual cortex after longer delays when stimuli are task-relevant.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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High Throughput Evolution of Near Infrared Serotonin Nanosensors
Release and reuptake of neuromodulator serotonin is central to mood regulation and neuropsychiatric disorders, whereby imaging serotonin is of fundamental importance to study the brain serotonin signaling system. We introduce a reversible near infrared nanosensor for serotonin (nIRHT), for which synthetic molecular recognition toward serotonin is systematically evolved from ssDNA-carbon nanotube constructs generated from large libraries of 6.9e10 unique ssDNA sequences. nIRHT produces a 200% fluorescence enhancement upon exposure to serotonin with a Kd = 6.3 M affinity. nIRHT shows selective responsivity towards serotonin over serotonin analogs, metabolites, and receptor-targeting drugs, and a 5-fold increased affinity for serotonin over dopamine. Further, nIRHT can be introduced into the brain extracellular space in acute slice, and can be used to image exogenous serotonin reversibly. Our results suggest evolution of nanosensors could be generically implemented to rapidly develop other neuromodulator probes, and that these probes can image neuromodulator dynamics at spatiotemporal scales compatible with endogenous neuromodulation.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Reconstruction of in-vivo subthreshold activity of single neurons from large-scale spiking recordings
Current developments in the manufacturing of silicon probes allow recording of spikes from large populations of neurons from several brain structures in freely moving animals. It is still, however, technically challenging to record the membrane potential from awake behaving animals. Routine access to the subthreshold activity of neurons would be of great value in order to understand the role of, for example, neuronal integration, oscillations, and excitability. Here we have developed a framework for reconstructing the subthreshold activity of single neurons using the spiking activity from large neuronal populations. The reconstruction accuracy and reliability have been evaluated with ground truth data provided from simultaneous patch clamp membrane potential recordings in-vivo. Given the abundance of large-scale spike recordings in the contemporary systems neuroscience society, this approach provides a general access to the subthreshold activity and hence could shed light on the intricate mechanisms of the genesis of spiking activity.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Subcortical brain volume, regional cortical thickness and cortical surface area across attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD): findings from the ENIGMA-ADHD, -ASD, and -OCD working groups
Objective: Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods: Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results: We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion: Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Towards an Objective Evaluation of EEG/MEG Source Estimation Methods: The Linear Tool Kit
The question "What is the spatial resolution of EEG/MEG?" can only be answered with many ifs and buts, as the answer depends on a large number of parameters. Here, we describe a framework for resolution analysis of EEG/MEG source estimation, focusing on linear methods. The spatial resolution of linear methods can be evaluated using the resolution matrix, which contains the point-spread and cross-talk functions (PSFs and CTFs), respectively. Both of them have to be taken into account for a full characterization of spatial resolution. They can be used to compute a range of quantitative resolution metrics, which should cover at the last three aspects of those functions: localization accuracy, spatial extent, and relative amplitude. Here, we first provide a tutorial-style introduction to resolution analysis of linear source estimation methods. We then apply these concepts to evaluate the benefit of combining EEG and MEG measurements, and to compare weighted and normalized L2-minimum-norm estimation and spatial filters. We confirm and extend previous results, showing that adding EEG to MEG improves spatial resolution, and that different methods offer different compromises among different resolution criteria. We hope that our approach will help EEG/MEG researchers in the interpretation of source estimation results, the design of new experiments, and the development of new MEG systems.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Paying Attention to Speech: The Role of Cognitive Capacity and Acquired Experience
Managing attention in multi-speaker environments is a challenging feat that is critical for human performance. However, why some people are better than others in allocating attention appropriately, remains highly unknown. Here we investigated the contribution of two factors - Cognitive Capacity and Acquired Experience - to performance on two different types of Attention task: Selective Attention to one speaker and Distributed Attention among multiple concurrent speakers. We compared performance across three groups: Individuals with low (n=20) and high cognitive capacity (n=26), and Aircraft Pilots (n=25), who have gained extensive experience on both Selective and Distributed attention to speech through their training and profession. Results indicate that both types of Attention benefit from higher Cognitive Capacity, suggesting reliance on common capacity-limited resources. However, only Selective Attention was further improved in the Pilots, pointing to its flexible and trainable nature, whereas Distributed Attention seems to suffer from more fixed and hard-wired processing-bottlenecks.
in bioRxiv Subject Collection: Neuroscience on June 18, 2019 12:00 AM.
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Correction: Path Similarity Analysis: A Method for Quantifying Macromolecular Pathways

by Sean L. Seyler, Avishek Kumar, M. F. Thorpe, Oliver Beckstein

in PLOS Computational Biology: New Articles on June 17, 2019 09:00 PM.
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Correction: Recentrifuge: Robust comparative analysis and contamination removal for metagenomics

by Jose Manuel Martí

in PLOS Computational Biology: New Articles on June 17, 2019 09:00 PM.
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A multi-scale model of gas transport in the lung to study heterogeneous lung ventilation during the multiple-breath washout test

by David Hasler, Pinelopi Anagnostopoulou, Sylvia Nyilas, Philipp Latzin, Johannes Schittny, Dominik Obrist
The multiple-breath washout (MBW) is a lung function test that measures the degree of ventilation inhomogeneity (VI). The test is used to identify small airway impairment in patients with lung diseases like cystic fibrosis. However, the physical and physiological factors that influence the test outcomes and differentiate health from disease are not well understood. Computational models have been used to better understand the interaction between anatomical structure and physiological properties of the lung, but none of them has dealt in depth with the tracer gas washout test in a whole. Thus, our aim was to create a lung model that simulates the entire MBW and investigate the role of lung morphology and tissue mechanics on the tracer gas washout procedure. To this end, we developed a multi-scale lung model to simulate the inert gas transport in airways of all size. We then applied systematically different modifications to geometrical and mechanical properties of the lung model (compliance, residual airway volume and flow resistance) which have been associated with VI. The modifications were applied to distinct parts of the model, and their effects on the gas distribution within the lung and on the gas concentration profile were assessed. We found that variability in compliance and residual volume of the airways, as well as the spatial distribution of this variability in the lung had a direct influence on gas distribution among airways and on the MBW pattern (washout duration, characteristic concentration profile during each expiration), while the effects of variable flow resistance were negligible. Based on these findings, it is possible to classify different types of inhomogeneities in the lung and relate them to specific features of the MBW pattern, which builds the basis for a more detailed association of lung function and structure.
in PLOS Computational Biology: New Articles on June 17, 2019 09:00 PM.
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Rational discovery of dual-indication multi-target PDE/Kinase inhibitor for precision anti-cancer therapy using structural systems pharmacology

by Hansaim Lim, Di He, Yue Qiu, Patrycja Krawczuk, Xiaoru Sun, Lei Xie
Many complex diseases such as cancer are associated with multiple pathological manifestations. Moreover, the therapeutics for their treatments often lead to serious side effects. Thus, it is needed to develop multi-indication therapeutics that can simultaneously target multiple clinical indications of interest and mitigate the side effects. However, conventional one-drug-one-gene drug discovery paradigm and emerging polypharmacology approach rarely tackle the challenge of multi-indication drug design. For the first time, we propose a one-drug-multi-target-multi-indication strategy. We develop a novel structural systems pharmacology platform 3D-REMAP that uses ligand binding site comparison and protein-ligand docking to augment sparse chemical genomics data for the machine learning model of genome-scale chemical-protein interaction prediction. Experimentally validated predictions systematically show that 3D-REMAP outperforms state-of-the-art ligand-based, receptor-based, and machine learning methods alone. As a proof-of-concept, we utilize the concept of drug repurposing that is enabled by 3D-REMAP to design dual-indication anti-cancer therapy. The repurposed drug can demonstrate anti-cancer activity for cancers that do not have effective treatment as well as reduce the risk of heart failure that is associated with all types of existing anti-cancer therapies. We predict that levosimendan, a PDE inhibitor for heart failure, inhibits serine/threonine-protein kinase RIOK1 and other kinases. Subsequent experiments and systems biology analyses confirm this prediction, and suggest that levosimendan is active against multiple cancers, notably lymphoma, through the direct inhibition of RIOK1 and RNA processing pathway. We further develop machine learning models to predict cancer cell-line’s and a patient’s response to levosimendan. Our findings suggest that levosimendan can be a promising novel lead compound for the development of safe, effective, and precision multi-indication anti-cancer therapy. This study demonstrates the potential of structural systems pharmacology in designing polypharmacology for precision medicine. It may facilitate transforming the conventional one-drug-one-gene-one-disease drug discovery process and single-indication polypharmacology approach into a new one-drug-multi-target-multi-indication paradigm for complex diseases.
in PLOS Computational Biology: New Articles on June 17, 2019 09:00 PM.
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How Do You Treat Traumatic Brain Injury? One Symptom at a Time

in Wiley: Annals of Neurology: Table of Contents on June 17, 2019 06:49 PM.
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Deoxynucleoside Therapy for Thymidine Kinase 2–Deficient Myopathy

Objective

Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies.

Methods

We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2‐deficient patients under a compassionate use program.

Results

In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe independently. In motor functional scales, improvements were observed in the 6‐minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 15 levels decreased with treatment in all 7 patients tested. A side effect observed in 8 of the 16 patients was dose‐dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy.

Interpretation

This open‐label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 17, 2019 06:03 PM.
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Intellectual and Developmental Disabilities Research Centers: 50 Years of Scientific Accomplishments

Abstract

Progress in addressing the origins of intellectual and developmental disabilities accelerated with the establishment 50 years ago of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health and associated Intellectual and Developmental Disabilities Research Centers. Investigators at these Centers have made seminal contributions to understand human brain and behavioral development, and to define mechanisms and treatments of disorders of the developing brain.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on June 17, 2019 05:07 PM.
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Cyfip1 haploinsufficiency does not alter GABAA receptor {delta}-subunit expression and tonic inhibition in dentate gyrus PV+ interneurons and granule cells
Abstract
Copy number variation at chromosomal region 15q11.2 is linked to increased risk of neurodevelopmental disorders including autism and schizophrenia. A significant gene at this locus is cytoplasmic fragile X mental retardation protein (FMRP) interacting protein 1 (CYFIP1). CYFIP1 protein interacts with FMRP, whose monogenic absence causes Fragile X syndrome. FMRP knock-out has been shown to reduce tonic GABAergic inhibition by interacting with the -subunit of the GABA_A receptor. Using in situ hybridization, qPCR, western blot techniques and patch clamp electrophysiology in brain slices from a Cyfip1 haploinsufficient mouse, we examined -subunit mediated tonic inhibition in the dentate gyrus. In wild-type mice, dentate gyrus granule cells (DGGC) responded to the -subunit selective agonist THIP with significantly increased tonic currents. In heterozygous mice, no significant difference was observed in THIP evoked currents in DGGC. Phasic GABAergic inhibition in DGGC was also unaltered with no difference in properties of spontaneous inhibitory post synaptic currents (IPSCs). Additionally, we demonstrate that dentate gyrus granule cell layer PV⁺-interneurons (PV⁺-IN) have functional -subunit mediated tonic GABAergic currents which, unlike DGGC, are also modulated by the α₁ selective drug zolpidem. Similar to DGGC, both IPSCs and THIP-evoked currents in PV⁺-IN were not different between Cyfip1 heterozygous and wild-type mice. Supporting our electrophysiological data, we found no significant change in hippocampal -subunit mRNA expression or protein level and no change in α₁/α₄ subunit mRNA expression. Thus, Cyfip1 haploinsufficiency, mimicking human 15q11.2 microdeletion syndrome, does not alter hippocampal phasic or tonic GABAergic inhibition, substantially differing from the FMRP knock-out mouse model.
Significance StatementCYFIP1 is a candidate risk gene for neurodevelopmental and neuropsychiatric disorders. CYFIP1 protein interacts with FMRP whose loss downregulates tonic GABAergic inhibition via interaction with the -subunit of the GABA_A receptor. Here, however, we report that reduced Cyfip1 dosage in mice does not alter tonic GABAergic inhibition in granule cells and PV⁺-interneurons of the dentate gyrus, a region rich in -subunit expression. Despite these negative findings, our data does demonstrate that PV⁺-interneurons of the DG granule cell layer are functionally regulated by tonic GABAergic inhibition, and in contrast to granule cells, this involves receptors incorporating both and α₁-subunits. Thus, granule cell layer excitatory neurons and PV⁺-interneurons may be differentially modulated by subunit selective GABA receptor targeting drugs.

in RSS PAP on June 17, 2019 04:30 PM.
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Temporal dynamics of inhalation-linked activity across defined subpopulations of mouse olfactory bulb neurons imaged in vivo
ABSTRACT
In mammalian olfaction, inhalation drives the temporal patterning of neural activity that underlies early olfactory processing. It remains poorly understood how the neural circuits that process incoming olfactory information are engaged in the context of inhalation-linked dynamics. Here, we used artificial inhalation and two-photon calcium imaging to compare the dynamics of activity evoked by odorant inhalation across major cell types of the mouse olfactory bulb (OB). We expressed GCaMP6f or jRGECO1a in mitral and tufted cell subpopulations, olfactory sensory neurons, and two major juxtaglomerular interneuron classes, and imaged responses to a single inhalation of odorant. Activity in all cell types was strongly linked to inhalation, and all cell types showed some variance in the latency, rise-times, and durations of their inhalation-linked response. Juxtaglomerular interneuron dynamics closely matched that of sensory inputs, while mitral and tufted cells showed the highest diversity in responses, with a range of latencies and durations that could not be accounted for by heterogeneity in sensory input dynamics. Diversity was apparent even among 'sister' tufted cells innervating the same glomerulus. Surprisingly, inhalation-linked responses of mitral and tufted cells were highly overlapping and could not be distinguished on the basis of their inhalation-linked dynamics, with the exception of a subpopulation of superficial tufted cells expressing cholecystokinin. Our results are consistent with a model in which diversity in inhalation-linked patterning of OB output arises first at the level of sensory input and is enhanced by feedforward inhibition from juxtaglomerular interneurons which differentially impact different subpopulations of OB output neurons.
SIGNIFICANCE STATEMENT Inhalation drives the temporal patterning of neural activity that underlies olfactory processing and rapid odor perception, yet the dynamics of the neural circuit elements mediating this processing are poorly understood. By comparing inhalation-linked dynamics of major olfactory bulb subpopulations, we find that diversity in the timing of neural activation arises at the level of sensory input, which is then mirrored by inhibitory interneurons in the glomerular layer. Temporal diversity is higher among olfactory bulb output neurons, with different subpopulations showing distinct but nonetheless highly overlapping ranges of inhalation-linked dynamics. These results implicate feedforward inhibition by glomerular-layer interneurons in diversifying temporal responses among output neurons, which may be important for generating and shaping timing-based odor representations during natural odor sampling.

in RSS PAP on June 17, 2019 04:30 PM.
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The scientific case for brain simulations. (arXiv:1906.06189v1 [q-bio.NC])

A key element of the European Union's Human Brain Project (HBP) and other large-scale brain research projects is simulation of large-scale model networks of neurons. Here we argue why such simulations will likely be indispensable for bridging the scales between the neuron and system levels in the brain, and a set of brain simulators based on neuron models at different levels of biological detail should thus be developed. To allow for systematic refinement of candidate network models by comparison with experiments, the simulations should be multimodal in the sense that they should not only predict action potentials, but also electric, magnetic, and optical signals measured at the population and system levels.

in q-bio.NC updates on arXiv.org on June 17, 2019 01:30 AM.
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Imperfect fifths pack into musical scales. (arXiv:1906.06171v1 [cs.SD])

Musical scales are used in cultures throughout the world, but the question as to how they evolved remains open. Some suggest that scales based on the harmonic series are inherently pleasant, while others propose that scales are chosen that are easy to sing, hear and reproduce accurately. However, testing these theories has been hindered by the sparseness of empirical evidence. Here, to enable such examination, we assimilate data from diverse ethnomusicological sources into a cross-cultural database of scales. We generate populations of scales based on proposed and alternative theories and assess their similarity to empirical distributions from the database. Most scales can be explained as tending to include intervals roughly corresponding to perfect fifths ("imperfect fifths"), and packing arguments explain the salient features of the distributions. Scales are also preferred if their intervals are compressible, which could facilitate efficient communication and memory of melodies. While no single theory can explain all scales, which appear to evolve according to different selection pressures, the simplest harmonicity-based, imperfect-fifths packing model best fits the empirical data.

in q-bio.NC updates on arXiv.org on June 17, 2019 01:30 AM.
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Periodic Codes and Sound Localization. (arXiv:1906.06006v1 [q-bio.NC])

Inspired by the sound localization system of the barn owl, we define a new class of neural codes, called periodic codes, and study their basic properties. Periodic codes are binary codes with a special patterned form that reflects the periodicity of the stimulus. Because these codes can be used by the owl to localize sounds within a convex set of angles, we investigate whether they are examples of convex codes, which have previously been studied for hippocampal place cells. We find that periodic codes are typically not convex, but can be completed to convex codes in the presence of noise. We introduce the convex closure and Hamming distance completion as ways of adding codewords to make a code convex, and describe the convex closure of a periodic code. We also find that the probability of the convex closure arising stochastically is greater for sparser codes. Finally, we provide an algebraic method using the neural ideal to detect if a code is periodic. We find that properties of periodic codes help to explain several aspects of the behavior observed in the sound localization system of the barn owl, including common errors in localizing pure tones.

in q-bio.NC updates on arXiv.org on June 17, 2019 01:30 AM.
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Hot topic in optogenetics: new implications of in vivo tissue heating

Nature Neuroscience, Published online: 17 June 2019; doi:10.1038/s41593-019-0426-z
A new study by Owen et al. shows that widely used optogenetic light delivery can heat brain tissue and produce changes in neural activity and behavior in the absence of opsins. How will this finding influence experimental design in the optical age of neuroscience?
in Nature Neuroscience - Issue - nature.com science feeds on June 17, 2019 12:00 AM.
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Thermal constraints on in vivo optogenetic manipulations

Nature Neuroscience, Published online: 17 June 2019; doi:10.1038/s41593-019-0422-3
Optogenetics has revolutionized neuroscience, but intracranial illumination can cause off-target effects. Owen et al. identify a temperature-sensitive potassium current that modulates neuronal activity and behavior independent of opsin expression.
in Nature Neuroscience - Issue - nature.com science feeds on June 17, 2019 12:00 AM.
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Morphine withdrawal recruits lateral habenula cytokine signaling to reduce synaptic excitation and sociability

Nature Neuroscience, Published online: 17 June 2019; doi:10.1038/s41593-019-0421-4
The authors show that decreased synaptic efficacy onto raphe-projecting lateral habenula neurons supports opiate withdrawal-induced sociability deficits, and they demonstrate a role for TNF-α signaling in this process.
in Nature Neuroscience - Issue - nature.com science feeds on June 17, 2019 12:00 AM.
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Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

Nature Neuroscience, Published online: 17 June 2019; doi:10.1038/s41593-019-0419-y
Microglia are resident immune cells of the CNS. Here the authors show that neurons communicate to microglia via activity-dependent fractalkine and ADAM10 signaling to induce removal of synapses in the brain after sensory loss.
in Nature Neuroscience - Issue - nature.com science feeds on June 17, 2019 12:00 AM.
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Classification of electrophysiological and morphological neuron types in the mouse visual cortex

Nature Neuroscience, Published online: 17 June 2019; doi:10.1038/s41593-019-0417-0
Gouwens et al. established a morpho-electrical taxonomy of cell types for the mouse visual cortex via unsupervised clustering analysis of multiple quantitative features from 1,938 neurons available online at the Allen Cell Types Database.
in Nature Neuroscience - Issue - nature.com science feeds on June 17, 2019 12:00 AM.
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Genome-wide association study implicates CHRNA2 in cannabis use disorder

Nature Neuroscience, Published online: 17 June 2019; doi:10.1038/s41593-019-0416-1
The study reports a genome-wide significant locus for cannabis use disorder, replicating in an independent cohort, and implicates CHRNA2, which encodes an acetylcholine receptor subunit, in the disorder by analyses of genetically regulated gene expression.
in Nature Neuroscience - Issue - nature.com science feeds on June 17, 2019 12:00 AM.
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Acetic acid activates distinct taste pathways in Drosophila to elicit opposing, state-dependent feeding responses
Taste circuits are genetically determined to elicit an innate appetitive or aversive response, ensuring that animals consume nutritious foods and avoid the ingestion of toxins. We have examined the response of Drosophila melanogaster to acetic acid, a tastant that can be a metabolic resource but can also be toxic to the fly. Our data reveal that flies accommodate these conflicting attributes of acetic acid by virtue of a hunger-dependent switch in their behavioral response to this stimulus. Fed flies show taste aversion to acetic acid, whereas starved flies show a robust appetitive response. These opposing responses are mediated by two different classes of taste neurons, the sugar- and bitter-sensing neurons. Hunger shifts the behavioral response from aversion to attraction by enhancing the appetitive sugar pathway as well as suppressing the aversive bitter pathway. Thus a single tastant can drive opposing behaviors by activating distinct taste pathways modulated by internal state.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Pregnancy-associated plasma protein-aa supports hair cell survival by regulating mitochondrial function
To support cell survival, mitochondria must balance energy production with oxidative stress. Inner ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. We identified a novel molecular regulator of the hair cells' mitochondria and survival: Pregnancy-associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants' enhanced hair cell loss can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator of hair cell survival and essential mitochondrial function.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Cystic fibrosis drug ivacaftor stimulates CFTR channels at picomolar concentrations
The devastating inherited disease cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel. The recent approval of the CFTR potentiator drug ivacaftor (Vx-770) for the treatment of CF patients has marked the advent of causative CF therapy. Currently, thousands of patients are being treated with the drug, and its molecular mechanism of action is under intensive investigation. Here we determine the solubility profile and true stimulatory potency of Vx-770 towards wild-type (WT) and mutant human CFTR channels in cell-free patches of membrane. We find that its aqueous solubility is ~200-fold lower (~60 nanomolar), whereas the potency of its stimulatory effect is >100-fold higher, than reported, and is unexpectedly fully reversible. Strong, but greatly delayed, channel activation by picomolar Vx-770 identifies multiple sequential slow steps in the activation pathway. These findings provide solid guidelines for the design of in vitro studies using Vx-770.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Absolute quantification of cohesin, CTCF and their regulators in human cells
The organisation of mammalian genomes into loops and topologically associating domains (TADs) contributes to chromatin structure, gene expression and recombination. TADs and many loops are formed by cohesin and positioned by CTCF. In proliferating cells, cohesin also mediates sister chromatid cohesion, which is essential for chromosome segregation. Current models of chromatin folding and cohesion are based on assumptions of how many cohesin and CTCF molecules organise the genome. Here we have measured absolute copy numbers and dynamics of cohesin, CTCF, NIPBL, WAPL and sororin by mass spectrometry, fluorescence-correlation spectroscopy and fluorescence recovery after photobleaching in HeLa cells. In G1-phase there are ~250,000 nuclear cohesin complexes, of which ~160,000 are chromatin-bound. Comparison with chromatin immunoprecipitation-sequencing data implies that some genomic cohesin and CTCF enrichment sites are unoccupied in single cells at any one time. We discuss the implications of these findings for how cohesin can contribute to genome organisation and cohesion.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Cas9⁺ conditionally-immortalized macrophages as a tool for bacterial pathogenesis and beyond
Macrophages play critical roles in immunity, development, tissue repair, and cancer, but studies of their function have been hampered by poorly-differentiated tumor cell lines and genetically-intractable primary cells. Here we report a facile system for genome editing in non-transformed macrophages by differentiating ER-Hoxb8 myeloid progenitors from Cas9-expressing transgenic mice. These conditionally immortalized macrophages (CIMs) retain characteristics of primary macrophages derived from the bone marrow yet allow for easy genetic manipulation and a virtually unlimited supply of cells. We demonstrate the utility of this system for dissection of host genetics during intracellular bacterial infection using two important human pathogens: Listeria monocytogenes and Mycobacterium tuberculosis.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Rapid and iterative genome editing in the malaria parasite Plasmodium knowlesi provides new tools for P. vivax research
Tackling relapsing Plasmodium vivax and zoonotic Plasmodium knowlesi infections is critical to reducing malaria incidence and mortality worldwide. Understanding the biology of these important and related parasites was previously constrained by the lack of robust molecular and genetic approaches. Here, we establish CRISPR-Cas9 genome editing in a culture-adapted P. knowlesi strain and define parameters for optimal homology-driven repair. We establish a scalable protocol for the production of repair templates by PCR and demonstrate the flexibility of the system by tagging proteins with distinct cellular localisations. Using iterative rounds of genome-editing we generate a transgenic line expressing P. vivax Duffy binding protein (PvDBP), a lead vaccine candidate. We demonstrate that PvDBP plays no role in reticulocyte restriction but can alter the macaque/human host cell tropism of P. knowlesi. Critically, antibodies raised against the P. vivax antigen potently inhibit proliferation of this strain, providing an invaluable tool to support vaccine development.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Conformational switches control early maturation of the eukaryotic small ribosomal subunit
Eukaryotic ribosome biogenesis is initiated with the transcription of pre-ribosomal RNA at the 5’ external transcribed spacer, which directs the early association of assembly factors but is absent from the mature ribosome. The subsequent co-transcriptional association of ribosome assembly factors with pre-ribosomal RNA results in the formation of the small subunit processome. Here we show that stable rRNA domains of the small ribosomal subunit can independently recruit their own biogenesis factors in vivo. The final assembly and compaction of the small subunit processome requires the presence of the 5’ external transcribed spacer RNA and all ribosomal RNA domains. Additionally, our cryo-electron microscopy structure of the earliest nucleolar pre-ribosomal assembly - the 5’ external transcribed spacer ribonucleoprotein – provides a mechanism for how conformational changes in multi-protein complexes can be employed to regulate the accessibility of binding sites and therefore define the chronology of maturation events during early stages of ribosome assembly.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Liquid-crystal organization of liver tissue
Functional tissue architecture originates by self-assembly of distinct cell types, following tissue-specific rules of cell-cell interactions. In the liver, a structural model of the lobule was pioneered by Elias in 1949. This model, however, is in contrast with the apparent random 3D arrangement of hepatocytes. Since then, no significant progress has been made to derive the organizing principles of liver tissue. To solve this outstanding problem, we computationally reconstructed 3D tissue geometry from microscopy images of mouse liver tissue and analyzed it applying soft-condensed-matter-physics concepts. Surprisingly, analysis of the spatial organization of cell polarity revealed that hepatocytes are not randomly oriented but follow a long-range liquid-crystal order. This does not depend exclusively on hepatocytes receiving instructive signals by endothelial cells, since silencing Integrin-β1 disrupted both liquid-crystal order and organization of the sinusoidal network. Our results suggest that bi-directional communication between hepatocytes and sinusoids underlies the self-organization of liver tissue.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Anatomical and physiological foundations of cerebello-hippocampal interaction
Multiple lines of evidence suggest that functionally intact cerebello-hippocampal interactions are required for appropriate spatial processing. However, how the cerebellum anatomically and physiologically engages with the hippocampus to sustain such communication remains unknown. Using rabies virus as a retrograde transneuronal tracer in mice, we reveal that the dorsal hippocampus receives input from topographically restricted and disparate regions of the cerebellum. By simultaneously recording local field potential from both the dorsal hippocampus and anatomically connected cerebellar regions, we additionally suggest that the two structures interact, in a behaviorally dynamic manner, through subregion-specific synchronization of neuronal oscillations in the 6–12 Hz frequency range. Together, these results reveal a novel neural network macro-architecture through which we can understand how a brain region classically associated with motor control, the cerebellum, may influence hippocampal neuronal activity and related functions, such as spatial navigation.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Determining cellular CTCF and cohesin abundances to constrain 3D genome models
Achieving a quantitative and predictive understanding of 3D genome architecture remains a major challenge, as it requires quantitative measurements of the key proteins involved. Here, we report the quantification of CTCF and cohesin, two causal regulators of topologically associating domains (TADs) in mammalian cells. Extending our previous imaging studies (Hansen et al., 2017), we estimate bounds on the density of putatively DNA loop-extruding cohesin complexes and CTCF binding site occupancy. Furthermore, co-immunoprecipitation studies of an endogenously tagged subunit (Rad21) suggest the presence of cohesin dimers and/or oligomers. Finally, based on our cell lines with accurately measured protein abundances, we report a method to conveniently determine the number of molecules of any Halo-tagged protein in the cell. We anticipate that our results and the established tool for measuring cellular protein abundances will advance a more quantitative understanding of 3D genome organization, and facilitate protein quantification, key to comprehend diverse biological processes.
in eLife: latest articles on June 17, 2019 12:00 AM.
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Extracellular Pax6 Regulates Tangential Cajal–Retzius Cell Migration in the Developing Mouse Neocortex

Abstract
The embryonic mouse cortex displays a striking low caudo-medial and high rostro-lateral graded expression of the homeoprotein transcription factor Pax6, which presents both cell autonomous and direct noncell autonomous activities. Through the genetic induction of anti-Pax6 single-chain antibody secretion, we have analyzed Pax6 noncell autonomous activity on the migration of cortical hem- and septum-derived Cajal–Retzius (CR) neurons by live imaging of flat mount developing cerebral cortices. Blocking extracellular Pax6 disrupts tangential CR cell migration patterns by decreasing the distance traveled and changing both directionality and depth at which CR cells migrate. Tracking of single CR cells in mutant cortices revealed that extracellular Pax6 neutralization enhances contact repulsion in medial regions yet reduces it in lateral regions. This study demonstrates that secreted Pax6 controls neuronal migration and distribution and suggests that it acts as a bona fide morphogen at an early stage of cerebral cortex development.
in Cerebral Cortex Advance Access on June 17, 2019 12:00 AM.
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Brain State-dependent Gain Modulation of Corticospinal Output in the Active Motor System

Abstract
The communication through coherence hypothesis suggests that only coherently oscillating neuronal groups can interact effectively and predicts an intrinsic response modulation along the oscillatory rhythm. For the motor cortex (MC) at rest, the oscillatory cycle has been shown to determine the brain’s responsiveness to external stimuli. For the active MC, however, the demonstration of such a phase-specific modulation of corticospinal excitability (CSE) along the rhythm cycle is still missing. Motor evoked potentials in response to transcranial magnetic stimulation (TMS) over the MC were used to probe the effect of cortical oscillations on CSE during several motor conditions. A brain–machine interface (BMI) with a robotic hand orthosis allowed investigating effects of cortical activity on CSE without the confounding effects of voluntary muscle activation. Only this BMI approach (and not active or passive hand opening alone) revealed a frequency- and phase-specific cortical modulation of CSE by sensorimotor beta-band activity that peaked once per oscillatory cycle and was independent of muscle activity. The active MC follows an intrinsic response modulation in accordance with the communication through coherence hypothesis. Furthermore, the BMI approach may facilitate and strengthen effective corticospinal communication in a therapeutic context, for example, when voluntary hand opening is no longer possible after stroke.
in Cerebral Cortex Advance Access on June 17, 2019 12:00 AM.
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High-Frequency Activation of Nucleus Accumbens D1-MSNs Drives Excitatory Potentiation on D2-MSNs
Reward outcomes depend on the stimulation protocol used to activate nucleus accumbens medium spiny neuron (MSN) subtypes. In this issue of Neuron, Francis et al. demonstrate rebalanced MSN subtype excitation driven by high-frequency stimulation and substance P release.
in Neuron on June 17, 2019 12:00 AM.
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Neuronally Enriched RUFY3 Is Required for Caspase-Mediated Axon Degeneration
Hertz et al. identify the neuronally enriched protein RUFY3 as a key regulator downstream of (or in parallel to) caspase-3 in axon degeneration. RUFY3 is dephosphorylated and cleaved during degeneration. RUFY3 may provide a neuron-specific control point for neurons to locally control axon degeneration.
in Neuron on June 17, 2019 12:00 AM.
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The involvement of spinal annexin A10/NF-κB/MMP-9 pathway in the development of neuropathic pain in rats
Neuropathic pain (NP) is a prevalent disease, which badly impairs the life quality of patients. The underlying mechanism of NP is still not fully understood. It has been reported that spinal Annexin A10 (ANXA1...
in Most Recent Articles: BMC Neuroscience on June 17, 2019 12:00 AM.
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Gastrodin protects dopaminergic neurons via insulin-like pathway in a Parkinson’s disease model
Recently, the use of traditional Chinese medicine (TCM) has become more generally accepted, including by the Food and Drug Administration. To expand the use of TCM worldwide, it is important to study the molec...
in Most Recent Articles: BMC Neuroscience on June 17, 2019 12:00 AM.
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Live calcium imaging of Aedes aegypti neuronal tissues reveals differential importance of chemosensory systems for life-history-specific foraging strategies
The mosquito Aedes aegypti has a wide variety of sensory pathways that have supported its success as a species as well as a highly competent vector of numerous debilitating infectious pathogens. Investigations in...
in Most Recent Articles: BMC Neuroscience on June 17, 2019 12:00 AM.
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Evaluation of IL-1β levels in epilepsy and traumatic brain injury in dogs
Epilepsy is a common neurological disease in dogs affecting approximately 0.6–0.75% of the canine population. There is much evidence of neuroinflammation presence in epilepsy, creating new possibilities for th...
in Most Recent Articles: BMC Neuroscience on June 17, 2019 12:00 AM.
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Abnormal resting-state cerebral-limbic functional connectivity in bipolar depression and unipolar depression
Distinctive patterns of functional connectivity (FC) abnormalities in neural circuitry has been reported in patients with bipolar depression (BD) and unipolar depression (UD). However, it is unclear that wheth...
in Most Recent Articles: BMC Neuroscience on June 17, 2019 12:00 AM.
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Regulation of perineuronal nets in the adult cortex by the electrical activity of parvalbumin interneurons
Perineuronal net (PNN) accumulation around parvalbumin-expressing (PV) inhibitory interneurons marks the closure of critical periods of high plasticity, whereas PNN removal reinstates juvenile plasticity in the adult cortex. Using targeted chemogenetic in vivo approaches in the adult mouse visual cortex, we found that transient electrical silencing of PV interneurons, directly or through inhibition of local excitatory neurons, induced PNN regression. Conversely, excitation of either neuron types did not reduce the PNN. We also observed that chemogenetically inhibited PV interneurons exhibited reduced PNN compared to their untransduced neighbors, and confirmed that single PV interneurons express multiple genes enabling cell-autonomous control of their own PNN density. Our results indicate that PNNs are dynamically regulated in the adult by PV neurons acting as sensors of their local microcircuit activities. PNN regulation provides individual PV neurons with an activity-dependent mechanism to control the local remodeling of adult cortical circuits.
in bioRxiv Subject Collection: Neuroscience on June 17, 2019 12:00 AM.
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Neuron-Glial Antigen 2 (NG2)-based Glial Induction ofHuman BMSCs: A fast & safe glial progenitor cell-based therapy for congenital myelin disorders of the central nervous system
Oligodendrocytes (OLs) are the only myelinating glia in the central nervous system (CNS). In congenital myelin disorders, OL dysfunction or death results in loss of myelin. This causes progressive and irreversible impairment to motor and cognitive functions, and is amongst the most disabling neurological disorder. Neonatal engraftment by glial progenitor cells (GPCs) allows the robust myelination of congenitally dysmyelinated brain, thereby preserving brain function and quality of life of patients. However, endogenous sources of glial progenitors are hard to obtain without causing secondary injury, while use of exogenous sources such as embryonic stem cells and induced-pluripotent stem cells face considerable ethical and safety issues. To circumvent such hurdles, we asked whether NG2+ cells in the bone marrow could be a potential cell source for GPCs. We successfully generated glial progenitor cells (GPCs) from human bone marrow stromal cells (hBMSCs) from 3 donors using a 14-day induction protocol. The generated hBMSC-GPCs were highly enriched in OPC marker expression, including OLIG2, PDGFR, NG2, SOX10 and O4, and showed efficient differentiation into myelinogenic oligodendrocytes when transplanted into postnatal day 7 (P7) myelin-deficient shiverer mice. Remyelination of the shiverer mouse brain significantly extended lifespan and improved motor function. The novel induction protocol described here provides a method for fast, simple and effective glial therapy for myelin disorders, overcoming existent hurdles of cell source restriction and time frame requirement.
in bioRxiv Subject Collection: Neuroscience on June 17, 2019 12:00 AM.
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A Review of Recurrent Neural Networks: LSTM Cells and Network Architectures
Neural Computation, Volume 31, Issue 7, Page 1235-1270, July 2019.

in MIT Press: Neural Computation: Table of Contents on June 15, 2019 04:22 AM.
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A Reservoir Computing Model of Reward-Modulated Motor Learning and Automaticity
Neural Computation, Volume 31, Issue 7, Page 1430-1461, July 2019.

in MIT Press: Neural Computation: Table of Contents on June 15, 2019 04:21 AM.
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A Computational Perspective of the Role of the Thalamus in Cognition
Neural Computation, Volume 31, Issue 7, Page 1380-1418, July 2019.

in MIT Press: Neural Computation: Table of Contents on June 15, 2019 04:21 AM.
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Effect of Depth and Width on Local Minima in Deep Learning
Neural Computation, Volume 31, Issue 7, Page 1462-1498, July 2019.

in MIT Press: Neural Computation: Table of Contents on June 15, 2019 04:21 AM.
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Characterizing Brain Connectivity From Human Electrocorticography Recordings With Unobserved Inputs During Epileptic Seizures
Neural Computation, Volume 31, Issue 7, Page 1271-1326, July 2019.

in MIT Press: Neural Computation: Table of Contents on June 15, 2019 04:21 AM.
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Multi-Input, Multi-Output Neuronal Mode Network Approach to Modeling the Encoding Dynamics and Functional Connectivity of Neural Systems
Neural Computation, Volume 31, Issue 7, Page 1327-1355, July 2019.

in MIT Press: Neural Computation: Table of Contents on June 15, 2019 04:21 AM.
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Effective Dimensionality Reduction for Visualizing Neural Dynamics by Laplacian Eigenmaps
Neural Computation, Volume 31, Issue 7, Page 1356-1379, July 2019.

in MIT Press: Neural Computation: Table of Contents on June 15, 2019 04:21 AM.
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Matrix Product State–Based Quantum Classifier
Neural Computation, Volume 31, Issue 7, Page 1499-1517, July 2019.

in MIT Press: Neural Computation: Table of Contents on June 15, 2019 04:21 AM.
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A Case of Near-Optimal Sensory Integration Based on Kohonen Self-Organizing Maps
Neural Computation, Volume 31, Issue 7, Page 1419-1429, July 2019.

in MIT Press: Neural Computation: Table of Contents on June 15, 2019 04:20 AM.
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Neuronal Regulation of Immunity in the Skin and Lungs
The nervous and immune systems are classically studied as two separate entities. However, their interactions are crucial for maintaining barrier functions at tissues constantly exposed to the external environment. We focus here on the role of neuronal signaling in regulating the immune system at two major barriers: the skin and respiratory tract. Barrier tissues are heavily innervated by sensory and autonomic nerves, and are densely populated by resident immune cells, allowing rapid, coordinated responses to noxious stimuli, as well as to bacterial and fungal pathogens.
in Trends in Neurosciences on June 15, 2019 12:00 AM.
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Correction: Geospatial characteristics of measles transmission in China during 2005−2014

by Wan Yang, Liang Wen, Shen-Long Li, Kai Chen, Wen-Yi Zhang, Jeffrey Shaman

in PLOS Computational Biology: New Articles on June 14, 2019 09:00 PM.
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Correction: Most Undirected Random Graphs Are Amplifiers of Selection for Birth-Death Dynamics, but Suppressors of Selection for Death-Birth Dynamics

by The PLOS Computational Biology Staff

in PLOS Computational Biology: New Articles on June 14, 2019 09:00 PM.
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Correction: Ten Simple Rules for Taking Advantage of Git and GitHub

by The PLOS Computational Biology Staff

in PLOS Computational Biology: New Articles on June 14, 2019 09:00 PM.
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Correction: Deciphering Signaling Pathway Networks to Understand the Molecular Mechanisms of Metformin Action

by The PLOS Computational Biology Staff

in PLOS Computational Biology: New Articles on June 14, 2019 09:00 PM.
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Correction: The Equivalence of Information-Theoretic and Likelihood-Based Methods for Neural Dimensionality Reduction

by The PLOS Computational Biology Staff

in PLOS Computational Biology: New Articles on June 14, 2019 09:00 PM.
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Correction: Effects of Darwinian Selection and Mutability on Rate of Broadly Neutralizing Antibody Evolution during HIV-1 Infection

by The PLOS Computational Biology Staff

in PLOS Computational Biology: New Articles on June 14, 2019 09:00 PM.
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Correction: Reconstructible Phylogenetic Networks: Do Not Distinguish the Indistinguishable

by The PLOS Computational Biology Staff

in PLOS Computational Biology: New Articles on June 14, 2019 09:00 PM.
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DeepConv-DTI: Prediction of drug-target interactions via deep learning with convolution on protein sequences

by Ingoo Lee, Jongsoo Keum, Hojung Nam
Identification of drug-target interactions (DTIs) plays a key role in drug discovery. The high cost and labor-intensive nature of in vitro and in vivo experiments have highlighted the importance of in silico-based DTI prediction approaches. In several computational models, conventional protein descriptors have been shown to not be sufficiently informative to predict accurate DTIs. Thus, in this study, we propose a deep learning based DTI prediction model capturing local residue patterns of proteins participating in DTIs. When we employ a convolutional neural network (CNN) on raw protein sequences, we perform convolution on various lengths of amino acids subsequences to capture local residue patterns of generalized protein classes. We train our model with large-scale DTI information and demonstrate the performance of the proposed model using an independent dataset that is not seen during the training phase. As a result, our model performs better than previous protein descriptor-based models. Also, our model performs better than the recently developed deep learning models for massive prediction of DTIs. By examining pooled convolution results, we confirmed that our model can detect binding sites of proteins for DTIs. In conclusion, our prediction model for detecting local residue patterns of target proteins successfully enriches the protein features of a raw protein sequence, yielding better prediction results than previous approaches. Our code is available at https://github.com/GIST-CSBL/DeepConv-DTI.
in PLOS Computational Biology: New Articles on June 14, 2019 09:00 PM.
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Pathogenicity and functional impact of non-frameshifting insertion/deletion variation in the human genome

by Kymberleigh A. Pagel, Danny Antaki, AoJie Lian, Matthew Mort, David N. Cooper, Jonathan Sebat, Lilia M. Iakoucheva, Sean D. Mooney, Predrag Radivojac
Differentiation between phenotypically neutral and disease-causing genetic variation remains an open and relevant problem. Among different types of variation, non-frameshifting insertions and deletions (indels) represent an understudied group with widespread phenotypic consequences. To address this challenge, we present a machine learning method, MutPred-Indel, that predicts pathogenicity and identifies types of functional residues impacted by non-frameshifting insertion/deletion variation. The model shows good predictive performance as well as the ability to identify impacted structural and functional residues including secondary structure, intrinsic disorder, metal and macromolecular binding, post-translational modifications, allosteric sites, and catalytic residues. We identify structural and functional mechanisms impacted preferentially by germline variation from the Human Gene Mutation Database, recurrent somatic variation from COSMIC in the context of different cancers, as well as de novo variants from families with autism spectrum disorder. Further, the distributions of pathogenicity prediction scores generated by MutPred-Indel are shown to differentiate highly recurrent from non-recurrent somatic variation. Collectively, we present a framework to facilitate the interrogation of both pathogenicity and the functional effects of non-frameshifting insertion/deletion variants. The MutPred-Indel webserver is available at http://mutpred.mutdb.org/.
in PLOS Computational Biology: New Articles on June 14, 2019 09:00 PM.
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Different microvascular alterations underlie microbleeds and microinfarcts

Objective

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β (Aβ) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood.

Methods

We scanned intact formalin‐fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions.

Results

In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole‐brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of Aβ‐positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both Aβ (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but Aβ was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular Aβ was almost always observed at the core of the lesion (91%, p < 0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%).

Interpretation

These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 14, 2019 07:35 PM.
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Targeting microglia using Cx3cr1-cre lines: revisiting the specificity
Abstract
Microglia play a pivotal role in maintaining homeostasis of the CNS. There is growing interest in understanding how microglia influence normal brain function and disease progression. Several microglia-specific Cx3cr1-Cre lines have been developed and have become indispensable tools in many investigations of microglial function. However, some recent studies have reported that these lines may have significant leakage into neurons. Other studies have reported that Cx3cr1 is expressed in non-microglial cells, including neurons and astrocytes, in vitro or in vivo either during brain development or upon neurological insult. All these reports raise serious concerns about the trustworthiness of these Cre-lines and whether the conclusions drawn from previous studies are valid. Here, we found that a floxed fluorescent reporter mouse line which has been frequently used to verify Cre lines displayed spontaneous expression of the GFP reporter, independent of Cre recombinase, thus revealing a potential caveat in assessing cre lines. We further confirmed that two Cx3cr1-Cre mouse lines can drive fluorescent reporter expression largely restrictively in microglia. Finally, we clarified that these two mouse lines maintain microglia-specific expression even following excitatory injury. Together, our findings confirm that two previously created Cx3cr1-Cre lines remain as invaluable tools for studying microglia. Moreover, to ensure the quality of data generated and the soundness of conclusions drawn from such data, it should be compulsory to thoroughly examine reporter lines for spontaneous leakiness when labeling cells to study CNS function and diseases.
Significance Statement Microglia-specific Cre-lines are essential for studying the role of microglia in the CNS. Several Cx3cr1-Cre lines have been developed and used in a number of landmark studies. However, there is growing concern in the microglia research community regarding potential leakiness of Cre-lines into neurons. The conclusions drawn from previous studies are also being questioned and key ongoing studies have been stalled. We found that a GFP-reporter mouse lines used in a previous study displays spontaneous leakiness into neurons, independent of Cre recombinase. Furthermore, we confirmed that two Cre-lines are microglia-specific and thus can be redeployed without hesitation. Our study also suggests that testing for potential leakiness of GFP-reporter lines should be included as a control in cell-tracing experiments.

in RSS PAP on June 14, 2019 04:30 PM.
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Genetic risk for Alzheimer's disease is distinct from genetic risk for amyloid deposition

Abstract

Objectives

Alzheimer's disease (AD) is the most common form of dementia and is responsible for a huge and growing health care burden in the developed and developing world. The Polygenic Risk Score (PRS) approach has shown 75%‐84% prediction accuracy of identifying individuals with AD risk.

Methods

In this study we tested the prediction accuracy of AD, MCI and amyloid deposition risks with PRS, including and excluding APOE genotypes in a large publicly available data set with extensive phenotypic data: the Alzheimer's Disease Neuroimaging Initiative cohort. Among MCI individuals with amyloid positive status we examined PRS prediction accuracy in those who converted to AD. In addition, we divided polygenic risk score by biological pathways and tested them independently for distinguishing between AD, MCI and amyloid deposition.

Results

We found that AD and MCI are predicted by both APOE genotype and PRS (AUC=0.82% and 68%, respectively). Amyloid deposition is predicted by APOE only (AUC=79%). Further progression to AD of individuals with MCI and amyloid positive status is predicted by PRS over and above APOE (AUC=67%).

In pathway‐specific PRSs analyses the protein‐lipid complex has the strongest association with AD and amyloid deposition even when genes in APOE region were removed (p=0.0055 and p=0.0079, respectively).

Interpretation

The results showed different pattern of APOE contribution in PRS risk predictions of AD/MCI and amyloid deposition. Our study suggests that APOE mostly contributes to amyloid accumulation and the PRS affects risk of further conversion to AD.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on June 14, 2019 02:35 PM.
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Genetic risk for Alzheimer's disease is distinct from genetic risk for amyloid deposition

Abstract

Objectives

Alzheimer's disease (AD) is the most common form of dementia and is responsible for a huge and growing health care burden in the developed and developing world. The Polygenic Risk Score (PRS) approach has shown 75%‐84% prediction accuracy of identifying individuals with AD risk.

Methods

In this study we tested the prediction accuracy of AD, MCI and amyloid deposition risks with PRS, including and excluding APOE genotypes in a large publicly available data set with extensive phenotypic data: the Alzheimer's Disease Neuroimaging Initiative cohort. Among MCI individuals with amyloid positive status we examined PRS prediction accuracy in those who converted to AD. In addition, we divided polygenic risk score by biological pathways and tested them independently for distinguishing between AD, MCI and amyloid deposition.

Results

We found that AD and MCI are predicted by both APOE genotype and PRS (AUC=0.82% and 68%, respectively). Amyloid deposition is predicted by APOE only (AUC=79%). Further progression to AD of individuals with MCI and amyloid positive status is predicted by PRS over and above APOE (AUC=67%).

In pathway‐specific PRSs analyses the protein‐lipid complex has the strongest association with AD and amyloid deposition even when genes in APOE region were removed (p=0.0055 and p=0.0079, respectively).

Interpretation

The results showed different pattern of APOE contribution in PRS risk predictions of AD/MCI and amyloid deposition. Our study suggests that APOE mostly contributes to amyloid accumulation and the PRS affects risk of further conversion to AD.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on June 14, 2019 02:35 PM.
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Modeling and Interpreting Real-world Human Risk Decision Making with Inverse Reinforcement Learning. (arXiv:1906.05803v1 [cs.LG])

We model human decision-making behaviors in a risk-taking task using inverse reinforcement learning (IRL) for the purposes of understanding real human decision making under risk. To the best of our knowledge, this is the first work applying IRL to reveal the implicit reward function in human risk-taking decision making and to interpret risk-prone and risk-averse decision-making policies. We hypothesize that the state history (e.g. rewards and decisions in previous trials) are related to the human reward function, which leads to risk-averse and risk-prone decisions. We design features that reflect these factors in the reward function of IRL and learn the corresponding weight that is interpretable as the importance of features. The results confirm the sub-optimal risk-related decisions of human-driven by the personalized reward function. In particular, the risk-prone person tends to decide based on the current pump number, while the risk-averse person relies on burst information from the previous trial and the average end status. Our results demonstrate that IRL is an effective tool to model human decision-making behavior, as well as to help interpret the human psychological process in risk decision-making.

in q-bio.NC updates on arXiv.org on June 14, 2019 01:30 AM.
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Self-organized critical balanced networks: a unified framework. (arXiv:1906.05624v1 [nlin.AO])

Asynchronous irregular (AI) and critical states are two competing frameworks proposed to explain spontaneous neuronal activity. Here, we propose a mean-field model with simple stochastic neurons that generalizes the integrate-and-fire network of Brunel (2000). We show that the point with balanced inhibitory/excitatory synaptic weight ratio $g_c \approx 4$ corresponds to a second order absorbing phase transition usual in self-organized critical (SOC) models. At the synaptic balance point $g_c$, the network exhibits power-law neuronal avalanches with the usual exponents, whereas for nonzero external field the system displays the four usual synchronicity states of balanced networks. We add homeostatic inhibition and firing rate adaption and obtain a self-organized quasi-critical balanced state with avalanches and AI-like activity. Our model might explain why different inhibition levels are obtained in different experimental conditions and for different regions of the brain, since at least two dynamical mechanisms are necessary to obtain a truly balanced state, without which the network may hover in different regions of the presented theoretical phase diagram.

in q-bio.NC updates on arXiv.org on June 14, 2019 01:30 AM.
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Information capacity of a network of spiking neurons. (arXiv:1906.05584v1 [q-bio.NC])

We study a model of spiking neurons, with recurrent connections that result from learning a set of spatio-temporal patterns with a spike-timing dependent plasticity rule and a global inhibition. We investigate the ability of the network to store and selectively replay multiple patterns of spikes, with a combination of spatial population and phase-of-spike code. Each neuron in a pattern is characterized by a binary variable determining if the neuron is active in the pattern, and a phase-lag variable representing the spike-timing order among the active units. After the learning stage, we study the dynamics of the network induced by a brief cue stimulation, and verify that the network is able to selectively replay the pattern correctly and persistently. We calculate the information capacity of the network, defined as the maximum number of patterns that can be encoded in the network times the number of bits carried by each pattern, normalized by the number of synapses, and find that it can reach a value $\alpha_\text{max}\simeq 0.27$, similar to the one of sequence processing neural networks, and almost double of the capacity of the static Hopfield model. We study the dependence of the capacity on the global inhibition, connection strength (or neuron threshold) and fraction of neurons participating to the patterns. The results show that a dual population and temporal coding can be optimal for the capacity of an associative memory.

in q-bio.NC updates on arXiv.org on June 14, 2019 01:30 AM.
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Modeling functional resting-state brain networks through neural message passing on the human connectome. (arXiv:1906.05369v1 [q-bio.NC])

Understanding the relationship between the structure and function of the human brain is one of the most important open questions in Neurosciences. In particular, Resting State Networks (RSN) and more specifically the Default Mode Network (DMN) of the brain, which are defined from the analysis of functional data lack a definitive justification consistent with the anatomical structure of the brain. In this work, we show that a possible connection may naturally rest on the idea that information flows in the brain through a neural message-passing dynamics between macroscopic structures, like those defined by the human connectome (HC). In our model, each brain region in the HC is assumed to have a binary behavior (active or not), the strength of interactions among them is encoded in the anatomical connectivity matrix defined by the HC, and the dynamics of the system is defined by a neural message-passing algorithm, Belief Propagation (BP), working near the critical point of the human connectome. We show that in the absence of direct external stimuli the BP algorithm converges to a spatial map of activations that is similar to the DMN. Moreover, we computed, using Susceptibility Propagation (SP), the matrix of correlations between the different regions and show that the modules defined by a clustering of this matrix resemble several Resting States Networks determined experimentally. Both results suggest that the functional DMN and RSNs can be seen as simple consequences of the anatomical structure of the brain and a neural message-passing dynamics between macroscopic regions. We then show preliminary results indicating our predictions on how functional DMN maps change when the anatomical brain network suffers structural anomalies, like in Alzheimers Disease and in lesions of the Corpus Callosum.

in q-bio.NC updates on arXiv.org on June 14, 2019 01:30 AM.
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Mice keep their cool

Nature Reviews Neuroscience, Published online: 14 June 2019; doi:10.1038/s41583-019-0198-1
Ptgds-expressing neurons in the preoptic area of anterior hypothalamus detect increases in brain temperature and reduce core body temperature via increased production of prostaglandin D2.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on June 14, 2019 12:00 AM.
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Interspecies Differences in the Connectivity of Ventral Striatal Components Between Humans and Macaques
Although the evolutionarily conserved functions of the ventral striatal components have been used as a priori knowledge for further studies, whether these functions are conserved between species remains unclear. In particular, whether macroscopic connectivity supports this given the disproportionate volumetric differences between species in the brain regions that project to the ventral striatum, including the prefrontal and limbic areas, has not been established. The evolutionarily conserved functions of the ventral striatal components have been suggested and used as a priori knowledge for further studies. However, whether this hypothesis is supported by macroscopic connectivity remains unclear, especially when considering the disproportionate volumetric differences between species in the brain regions known to project to the ventral striatum, including the prefrontal and limbic areas. In this study, the human and macaque striatum was first tractographically parcellated to define the ventral striatum and its two subregions, the nucleus accumbens (Acb)-like and the neurochemically unique domains of the Acb and putamen (NUDAPs)-like divisions. Our results revealed a similar topographical distribution of the connectivity-based ventral striatal components in the two primate brains. Successively, a set of targets was extracted to construct a connectivity fingerprint to characterize these parcellation results, enabling cross-species comparisons. Our results indicated that the connectivity fingerprints of the ventral striatum-like divisions were dissimilar in the two species. We localized this difference to specific targets to analyze possible interspecies functional modifications. Our results also revealed interspecies-convergent connectivity ratio fingerprints of the target group to these two ventral striatum-like subregions. This convergence may suggest synchronous connectional changes of these ventral striatal components during primate evolution.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 14, 2019 12:00 AM.
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The Age-Related Central Auditory Processing Disorder: Silent Impairment of the Cognitive Ear
Age-related hearing loss (ARHL), also called presbycusis, is a progressive disorder affecting hearing functions and among the elderly has been recognized as the third most frequent condition. Among ARHL components, the age-related central auditory processing disorder (CAPD) refers to changes in the auditory network, negatively impacting auditory perception and/or the speech communication performance. The relationship between auditory-perception and speech communication difficulties in age-related CAPD is difficult to establish, mainly because many older subjects have concomitant peripheral ARHL and age-related cognitive changes. In the last two decades, the association between cognitive impairment and ARHL has received great attention. Peripheral ARHL has recently been defined as the modifiable risk factor with the greatest impact on the development of dementia. Even if very few studies have analyzed the relationship between cognitive decline and age-related CAPD, a strong association was highlighted. Therefore, age-related CAPD could be a specific process related to neurodegeneration. Since these two disorders can be concomitant, drawing causal inferences is difficult. The assumption that ARHL, particularly age-related CAPD, may increase the risk of cognitive impairment in the elderly remains unchallenged. This review aims to summarize the evidence of associations between age-related CAPD and cognitive disorders and to define the diagnostic procedure of CAPD in the elderly. Finally, we highlight the importance of tailoring the rehabilitation strategy to this relationship. Future longitudinal studies with larger sample sizes and the use of adequate assessment tools that can disentangle cognitive dysfunction from sensory impairments are warranted.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 14, 2019 12:00 AM.
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Brain Molecular Connectivity in Neurodegenerative Diseases: Recent Advances and New Perspectives Using Positron Emission Tomography
Positron Emission Tomography (PET) represents a unique molecular tool to get in vivo access to a wide spectrum of biological and neuropathological processes, of crucial relevance for neurodegenerative conditions. Although most PET findings are based on massive univariate approaches, in the last decade the increasing interest in multivariate methods has paved the way to the assessment of unexplored cerebral features, spanning from resting state brain networks to whole-brain connectome properties. Currently, the combination of molecular neuroimaging techniques with multivariate connectivity methods represents one of the most powerful, yet still emerging, approach to achieve novel insights into the pathophysiology of neurodegenerative diseases. In this Review, we will summarize the available evidence in the field of PET molecular connectivity, with the aim to provide an overview of how these studies may increase the understanding of the pathogenesis of neurodegenerative diseases, over and above “traditional” structural/functional connectivity studies. Considering the available evidence, a major focus will be represented by molecular connectivity studies using [18F]FDG-PET, today applied in the major neuropathological spectra, from amyloidopathies and tauopathies to synucleinopathies and beyond. Pioneering studies using PET tracers targeting brain neuropathology and neurotransmission systems for connectivity studies will be discussed, and their strengths and limitations highlighted with reference to both applied methodology and results interpretation. The most common methods for molecular connectivity assessment will be reviewed, with particular emphasis on the available strategies to investigate molecular connectivity at the single-subject level, of potential relevance for not only research but also diagnostic purposes. Finally, we will highlight possible future perspectives in the field, with reference in particular to newly available PET tracers, which will expand the application of molecular connectivity to new, exciting, unforeseen possibilities.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 14, 2019 12:00 AM.
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L-Dopa Modulation of Brain Connectivity in Parkinson’s Disease Patients: A Pilot EEG-fMRI Study
Studies of functional neurosurgery and electroencephalography in Parkinson’s disease have demonstrated abnormally synchronous activity between basal ganglia and motor cortex. Functional neuroimaging studies investigated brain dysfunction during motor task or resting state and primarily have shown altered patterns of activation and connectivity for motor areas. L-dopa administration relatively normalized these functional alterations. The aim of this pilot study was to examine the effects of L-dopa administration on functional connectivity in early-stage PD, as revealed by simultaneous recording of functional magnetic resonance imaging (fMRI) and electroencephalographic (EEG) data. Six patients with diagnosis of probable PD underwent EEG-fMRI acquisitions (1.5 T MR scanner and 64-channel cap) before and immediately after the intake of L-dopa. Regions of interest in the primary motor and sensorimotor regions were used for resting state fMRI analysis. From the EEG data, weighted partial directed coherence was computed in the inverse space after the removal of gradient and cardioballistic artifacts. FMRI results showed that the intake of L-dopa increased functional connectivity within the sensorimotor network, and between motor areas and both attention and default mode networks. EEG connectivity among regions of the motor network did not change significantly, while regions of the default mode network showed a strong tendency to increase their outflow toward the rest of the brain. This pilot study provided a first insight into the potentiality of simultaneous EEG-fMRI acquisitions in PD patients, showing for both techniques the analogous direction of increased connectivity after L-dopa intake, mainly involving motor, dorsal attention and default mode networks.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 14, 2019 12:00 AM.
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Hybrid Functional Brain Network With First-Order and Second-Order Information for Computer-Aided Diagnosis of Schizophrenia
Brain functional connectivity network (BFCN) analysis has been widely used in diagnosis of mental disorder, such as schizophrenia. In BFCN methods, the brain network construction is one of the core tasks due to its great influence on the diagnosis result. Most of the existing BFCN construction methods only consider the first-order relationship existing in each pair of brain regions and ignore the useful high-order information, including multi-regions correlation in the whole brain. Some of the early schizophrenia patients have subtle changes in brain function networks, which cannot be detected in conventional BFCN construction methods. It is well known that the high-order method is usually more sensitive to the subtle changes in signal than the low-order method. For exploiting the high-order information among brain regions, we define the triplet correlation among three brain regions, and derive the second-order brain network based on the connectivity difference and ordinal information in each triplet. For making full use of the complementary information in different brain networks, we proposed a hybrid approach to fuse the first-order and second-order brain networks. The proposed method is applied to identifying the biomarkers of schizophrenia. The experimental results on six schizophrenia datasets (totally including 439 patients and 426 controls) show that the proposed method outperforms the existing brain network methods in diagnosis of schizophrenia.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 14, 2019 12:00 AM.
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Mechanics of Brain Tissues Studied by Atomic Force Microscopy: A Perspective
Tissue morphology and mechanics are crucial to the regulation of organ function. Investigating the exceptionally complex tissue of the brain at the sub-micron scale turns out to be challenging due to the complex structure and softness of this tissue despite the large interest of biologist, medical engineers, biophysicists and other sin this topic. Atomic Force Microscopy (AFM) both as an imaging and as a mechanical tool provides an excellent opportunity to study soft biological samples such as live brain tissues. Here we review the principles of AFM, the performance of AFM in tissue imaging and me-chanical mapping of cells and tissues, and finally opening the prospects and challenges of probing the biophysical properties of brain tissue using AFM.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on June 14, 2019 12:00 AM.
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Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein
Parkinson’s disease (PD) and related disorders are characterized by filamentous or fibrous structures consisting of abnormal α-synuclein in the brains of patients, and the distributions and spread of these pathologies are closely correlated with disease progression. L-DOPA (a dopamine precursor) is the most effective therapy for PD, but it remains unclear whether the drug has any effect on the formation and propagation of pathogenic abnormal α-synuclein in vivo. Here, we tested whether or not L-DOPA influences the prion-like spread of α-synuclein pathologies in a wild-type mouse model of α-synuclein propagation. To quantitate the pathological α-synuclein in mice, we prepared brain sections stained with an anti-phosphoSer129 (PS129) antibody after pretreatments with autoclaving and formic acid, and carefully analyzed positive aggregates on multiple sections covering the areas of interest using a microscope. Notably, a significant reduction in the accumulation of phosphorylated α-synuclein was detected in substantia nigra of L-DOPA/benserazide (a dopamine decarboxylase inhibitor)-treated mice, compared with control mice. These results suggest that L-DOPA may slow the progression of PD in vivo by suppressing the aggregation of α-synuclein in dopaminergic neurons and the cell-to-cell propagation of abnormal α-synuclein. This is the first report describing the suppressing effect of L-DOPA/benserazide on the propagation of pathological α-synuclein. The experimental protocols and detection methods in this study are expected to be useful for evaluation of drug candidates or new therapies targeting the propagation of α-synuclein.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 14, 2019 12:00 AM.
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The Dual Role of AQP4 in Cytotoxic and Vasogenic Edema Following Spinal Cord Contusion and Its Possible Association With Energy Metabolism via COX5A
Spinal cord edema,mainly including vasogenic and cytotoxic edema,influence neurological outcome after spinal cord contusion (SCC).Aquaporin 4 (AQP4) is the most ubiquitous water channel in central nervous system (CNS),which is a rate-limiting factor in vasogenic edema expressing in brain injury,and it contributes to the formation of cytotoxic edema locating in astrocytes.However,little is known the regulatory mechanism of AQP4 within vasogenic and cytotoxic edema in SCC,and whether regulation mechanism of AQP4 is related to Cytochrome coxidase (COX5A) affecting energy metabolism.Therefore,SCC model is established by Allen’s method,and the degree of edema and neuronal area is measured.Motor function of rats is evaluated by the Basso,Beattie,and Bresnahan (BBB) scoring system.Meanwhile,AQP4 and COX5A are detected by real-time quantitative PCR (qRT-PCR) and western blot (WB).localization of targeted protein is exhibited by immunohistochemical staining (IHC) and immunofluoresce (IF).Besides,the methodology of AQP4 lentivirus-mediated RNA interference (AQP4-RNAi) is used to reveal the effect on edema of SCC and the regulating molecular mechanism. Firstly,we observe that tissue water content increase after SCC,and decrease after the peak value of tissue water content at 3 days (P<0.05) with abundant expression of AQP4 protein locating around vascular endothelial cells,which suggests that the increasing AQP4 promotes water reabsorption and improves vasogenic edema in the early stage of SCC.However,neuronal area is larger than sham group in the 7 days(P<0.05) with the total water content of spinal cord decrease.Meanwhile AQP4 migrate from vascular endothelial cells to neuronal cytomembrane,which indicates that AQP4 play a crucial role in aggravating the formation and development of cytotoxic edema in the middle stages of SCC. Secondly,AQP4-RNAi is used to elucidate the mechanism of AQP4 to edema of SCC.The neuronal area shrinks and the area of cytotoxic edema reduces after AQP4 downregulation.BBB scores is significantly higher than vector group after AQP4-RNAi at 5d,7d and 14d(P < 0.05).There is a relationship between AQP4 and COX5A shown by bioinformatics analysis.After AQP4 inhibition,expression of COX5A significantly up-regulated in the swelling astrocytes.Therefore,inhibition of AQP4 expression reduces cytotoxic edema in SCC and improves motor function,which may associate with upregulation of COX5A via affecting energy metabolism.Moreover,it isn’t clear how the inhibition of AQP4 directly causes the upregulation of COX5A.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 14, 2019 12:00 AM.
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Semantic Processing in Bilingual Aphasia: Evidence of Language Dependency
Individuals with aphasia frequently show lexical retrieval deficits due to increased interference of semantically related competitors, a phenomenon that can be observed in tasks such as naming pictures grouped by semantic category. These deficits are explained in terms of impaired semantic control, a set of abilities that are to some extent dependent upon executive control (EC). However, the extent to which semantic control abilities can be affected in a second and non-dominant language has not been extensively explored. Additionally, findings in healthy individuals are inconclusive regarding the degree to which semantic processing is shared between languages. In this study, we explored the effect of brain damage on semantic processing by comparing the performance of bilingual individuals with aphasia on tasks involving semantic control during word production and comprehension. Furthermore, we explored whether semantic deficits are related to domain-general (EC) deficits. First, we investigated the naming performance of Catalan-Spanish bilinguals with fluent aphasia and age-matched healthy controls on a semantically blocked cyclic naming task in each of their two languages. This task measured semantic interference in terms of the difference in naming latencies between pictures grouped by the same semantic category or different categories. Second, we explored whether lexical deficits extend to comprehension by testing participants in a word-picture matching task during a mixed language condition. Third, we used a conflict monitoring task to explore the presence of EC deficits in patients. We found two main results. First, in both language tasks, bilingual patients’ performances were more affected than those of healthy controls when they performed the task in their non-dominant language. Second, there was a significant correlation between the speed of processing on the EC task and the magnitude of the semantic interference effect exclusively in the non-dominant language. Taken together, these results suggest that lexical retrieval may be selectively impaired in bilinguals within those conditions where semantic competition is higher and this could be explained by an excessive amount of language inhibition. Moreover, lexico-semantic impairments seem to be at least somewhat related to conflict monitoring deficits, suggesting a certain degree of overlap between EC and semantic control.
in Frontiers in Human Neuroscience | New and Recent Articles on June 14, 2019 12:00 AM.
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Characterizing and Predicting Autism Spectrum Disorder by Performing Resting-State Functional Network Community Pattern Analysis
Growing evidence indicates that autism spectrum disorder (ASD) is a neuropsychological disconnection syndrome that can be analysed using various complex network metrics used as pathology biomarkers. Recently, community detection and analysis rooted in the complex network and graph theories have been introduced to investigate the changes in resting-state functional network community structure under neurological pathologies. However, the potential of hidden patterns in the modular organisation of networks derived from resting-state functional magnetic resonance imaging to predict brain pathology has never been investigated. In this study, we present a novel analysis technique to identify alterations in community patterns in functional networks under ASD. In addition, we design machine learning classifiers to predict the clinical class of patients with ASD and controls by using only community pattern quality metrics as features. Analyses conducted on six publicly available datasets from 235 subjects, including patients with ASD and age-matched controls revealed that the modular structure is significantly disturbed in patients with ASD. Machine learning algorithms showed that the predictive power of our five metrics is relatively high (~85.16 peak accuracy for in-site data and ~75.00% peak accuracy for multisite data). These results lend further credence to the dysconnectivity theory of this pathology.
in Frontiers in Human Neuroscience | New and Recent Articles on June 14, 2019 12:00 AM.
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Decoding P300 Variability Using Convolutional Neural Networks
Deep convolutional neural networks (CNN) have previously been shown to be useful tools for signal decoding and analysis in a variety of complex domains, such as image processing and speech recognition. By learning from large amounts of data, the representations encoded by these deep networks are often invariant to moderate changes in the underlying feature spaces. Recently, we proposed a CNN architecture that could be applied to electroencephalogram (EEG) decoding and analysis. In this article, we train our CNN model using data from prior experiments in order to later decode the P300 evoked response from an unseen, hold-out experiment. We analyze the CNN output as a function of the underlying variability in the P300 response and demonstrate that the CNN output is sensitive to the experiment-induced changes in the neural response. We then assess the utility of our approach as a means of improving the overall signal-to-noise ratio in the EEG record. Finally, we show an example of how CNN-based decoding can be applied to the analysis of complex data.
in Frontiers in Human Neuroscience | New and Recent Articles on June 14, 2019 12:00 AM.
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Are we there yet?
Traveling to conferences with children presents a number of logistical and financial challenges.
in eLife: latest articles on June 14, 2019 12:00 AM.
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Integrative modeling of the HIV-1 ribonucleoprotein complex

by David S. Goodsell, Andrew Jewett, Arthur J. Olson, Stefano Forli
A coarse-grain computational method integrates biophysical and structural data to generate models of HIV-1 genomic RNA, nucleocapsid and integrase condensed into a mature ribonucleoprotein complex. Several hypotheses for the initial structure of the genomic RNA and oligomeric state of integrase are tested. In these models, integrase interaction captures features of the relative distribution of gRNA in the immature virion and increases the size of the RNP globule, and exclusion of nucleocapsid from regions with RNA secondary structure drives an asymmetric placement of the dimerized 5’UTR at the surface of the RNP globule.
in PLOS Computational Biology: New Articles on June 13, 2019 09:00 PM.
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Correction: Atrial arrhythmogenicity of <i>KCNJ2</i> mutations in short QT syndrome: Insights from virtual human atria

by The PLOS Computational Biology Staff

in PLOS Computational Biology: New Articles on June 13, 2019 09:00 PM.
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Development of a physiologically-based pharmacokinetic pediatric brain model for prediction of cerebrospinal fluid drug concentrations and the influence of meningitis

by Laurens F. M. Verscheijden, Jan B. Koenderink, Saskia N. de Wildt, Frans G. M. Russel
Different pediatric physiologically-based pharmacokinetic (PBPK) models have been described incorporating developmental changes that influence plasma drug concentrations. Drug disposition into cerebrospinal fluid (CSF) is also subject to age-related variation and can be further influenced by brain diseases affecting blood-brain barrier integrity, like meningitis. Here, we developed a generic pediatric brain PBPK model to predict CSF concentrations of drugs that undergo passive transfer, including age-appropriate parameters. The model was validated for the analgesics paracetamol, ibuprofen, flurbiprofen and naproxen, and for a pediatric meningitis population by empirical optimization of the blood-brain barrier penetration of the antibiotic meropenem. Plasma and CSF drug concentrations derived from the literature were used to perform visual predictive checks and to calculate ratios between simulated and observed area under the concentration curves (AUCs) in order to evaluate model performance. Model-simulated concentrations were comparable to observed data over a broad age range (3 months– 15 years postnatal age) for all drugs investigated. The ratios between observed and simulated AUCs (AUCo/AUCp) were within 2-fold difference both in plasma (range 0.92–1.09) and in CSF (range 0.64–1.23) indicating acceptable model performance. The model was also able to describe disease-mediated changes in neonates and young children (<3m postnatal age) related to meningitis and sepsis (range AUCo/AUCp plasma: 1.64–1.66, range AUCo/AUCp CSF: 1.43–1.73). Our model provides a new computational tool to predict CSF drug concentrations in children with and without meningitis and can be used as a template model for other compounds that passively enter the CNS.
in PLOS Computational Biology: New Articles on June 13, 2019 09:00 PM.
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Disentangling juxtacrine from paracrine signalling in dynamic tissue

by Hiroshi Momiji, Kirsty L. Hassall, Karen Featherstone, Anne V. McNamara, Amanda L. Patist, David G. Spiller, Helen C. Christian, Michael R. H. White, Julian R. E. Davis, Bärbel F. Finkenstädt, David A. Rand
Prolactin is a major hormone product of the pituitary gland, the central endocrine regulator. Despite its physiological importance, the cell-level mechanisms of prolactin production are not well understood. Having significantly improved the resolution of real-time-single-cell-GFP-imaging, the authors recently revealed that prolactin gene transcription is highly dynamic and stochastic yet shows space-time coordination in an intact tissue slice. However, it still remains an open question as to what kind of cellular communication mediates the observed space-time organization. To determine the type of interaction between cells we developed a statistical model. The degree of similarity between two expression time series was studied in terms of two distance measures, Euclidean and geodesic, the latter being a network-theoretic distance defined to be the minimal number of edges between nodes, and this was used to discriminate between juxtacrine from paracrine signalling. The analysis presented here suggests that juxtacrine signalling dominates. To further determine whether the coupling is coordinating transcription or post-transcriptional activities we used stochastic switch modelling to infer the transcriptional profiles of cells and estimated their similarity measures to deduce that their spatial cellular coordination involves coupling of transcription via juxtacrine signalling. We developed a computational model that involves an inter-cell juxtacrine coupling, yielding simulation results that show space-time coordination in the transcription level that is in agreement with the above analysis. The developed model is expected to serve as the prototype for the further study of tissue-level organised gene expression for epigenetically regulated genes, such as prolactin.
in PLOS Computational Biology: New Articles on June 13, 2019 09:00 PM.
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Fostering bioinformatics education through skill development of professors: <i>Big Genomic Data Skills Training for Professors</i>

by Yingqian Ada Zhan, Charles Gregory Wray, Sandeep Namburi, Spencer T. Glantz, Reinhard Laubenbacher, Jeffrey H. Chuang
Bioinformatics has become an indispensable part of life science over the past 2 decades. However, bioinformatics education is not well integrated at the undergraduate level, especially in liberal arts colleges and regional universities in the United States. One significant obstacle pointed out by the Network for Integrating Bioinformatics into Life Sciences Education is the lack of faculty in the bioinformatics area. Most current life science professors did not acquire bioinformatics analysis skills during their own training. Consequently, a great number of undergraduate and graduate students do not get the chance to learn bioinformatics or computational biology skills within a structured curriculum during their education. To address this gap, we developed a module-based, week-long short course to train small college and regional university professors with essential bioinformatics skills. The bioinformatics modules were built to be adapted by the professor-trainees afterward and used in their own classes. All the course materials can be accessed at https://github.com/TheJacksonLaboratory/JAXBD2K-ShortCourse.
in PLOS Computational Biology: New Articles on June 13, 2019 09:00 PM.
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Dynamic brain interactions during picture naming
Abstract
Brain computations involve multiple processes by which sensory information is encoded and transformed to drive behavior. These computations are thought to be mediated by dynamic interactions between populations of neurons. Here we demonstrate that human brains exhibit a reliable sequence of neural interactions during speech production. We use an autoregressive hidden Markov model to identify dynamical network states exhibited by electrocorticographic signals recorded from human neurosurgical patients. Our method resolves dynamic latent network states on a trial-by-trial basis. We characterize individual network states according to the patterns of directional information flow between cortical regions of interest. These network states occur consistently and in a specific, interpretable sequence across trials and subjects: the data support the hypothesis of a fixed-length visual processing state, followed by a variable-length language state, and then by a terminal articulation state. This empirical evidence validates classical psycho-linguistic theories that have posited such intermediate states during speaking. It further reveals these state dynamics are not localized to one brain area or one sequence of areas, but are instead a network phenomenon.
Significance Cued speech production engages a distributed set of brain regions that must interact with each other to perform this behavior rapidly and precisely. To characterize the spatio-temporal properties of the networks engaged in picture naming, we recorded from electrodes placed directly on the brain surfaces of patients with epilepsy being evaluated for surgical resection. We used a flexible statistical model applied to broadband gamma to characterize changing brain interactions. Unlike conventional models, ours can identify changes on individual trials that correlate with behavior. Our results reveal that interactions between brain regions are consistent across trials. This flexible statistical model provides a useful platform for quantifying brain dynamics during cognitive processes.

in RSS PAP on June 13, 2019 04:30 PM.
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Issue Information

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Annals of Neurology: Volume 86, Number 1, July 2019

A fluorescence photomicrograph showing the localization of JBTS17, a protein that organizes microtubules during cell division and which is mutated in Joubert syndrome. The nucleus of the cell is stained blue, the microtubules red and JBTS17 green. Note the localization of JBTS17 along the nuclear envelope and in the cytoplasm along microtubules. See Hong et al., pp. 99–115 for details.

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Electroencephalographic reactivity as predictor of neurological outcome in postanoxic coma: A multicenter prospective cohort study

Objective

Outcome prediction in patients after cardiac arrest (CA) is challenging. Electroencephalographic reactivity (EEG‐R) might be a reliable predictor. We aimed to determine the prognostic value of EEG‐R using a standardized assessment.

Methods

In a prospective cohort study, a strictly defined EEG‐R assessment protocol was executed twice per day in adult patients after CA. EEG‐R was classified as present or absent by 3 EEG readers, blinded to patient characteristics. Uncertain reactivity was classified as present. Primary outcome was best Cerebral Performance Category score (CPC) in 6 months after CA, dichotomized as good (CPC = 1–2) or poor (CPC = 3–5). EEG‐R was considered reliable for predicting poor outcome if specificity was ≥95%. For good outcome prediction, a specificity of ≥80% was used. Added value of EEG‐R was the increase in specificity when combined with EEG background, neurological examination, and somatosensory evoked potentials (SSEPs).

Results

Of 160 patients enrolled, 149 were available for analyses. Absence of EEG‐R for poor outcome prediction had a specificity of 82% and a sensitivity of 73%. For good outcome prediction, specificity was 73% and sensitivity 82%. Specificity for poor outcome prediction increased from 98% to 99% when EEG‐R was added to a multimodal model. For good outcome prediction, specificity increased from 70% to 89%.

Interpretation

EEG‐R testing in itself is not sufficiently reliable for outcome prediction in patients after CA. For poor outcome prediction, it has no substantial added value to EEG background, neurological examination, and SSEPs. For prediction of good outcome, EEG‐R seems to have added value. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Residual descending motor pathways influence spasticity after spinal cord injury

Objective

Spasticity is one of the most common symptoms manifested in humans with spinal cord injury (SCI). The neural mechanisms contributing to its development are not yet understood. Using neurophysiological and imaging techniques, we examined the influence of residual descending motor pathways on spasticity in humans with SCI.

Methods

We measured spasticity in 33 individuals with motor complete SCI (determined by clinical examination) without preservation of voluntary motor output in the quadriceps femoris muscle. To examine residual descending motor pathways, we used magnetic and electrical stimulation over the leg motor cortex to elicit motor evoked potentials (MEPs) in the quadriceps femoris muscle and structural magnetic resonance imaging to measure spinal cord atrophy.

Results

We found that 60% of participants showed symptoms of spasticity, whereas the other 40% showed no spasticity, demonstrating the presence of 2 clear subgroups of humans with motor complete SCI. MEPs were only present in individuals who had spasticity, and MEP size correlated with the severity of spasticity. Spinal cord atrophy was greater in nonspastic compared with spastic subjects. Notably, the degree of spared tissue in the lateral regions of the spinal cord was positively correlated with the severity of spasticity, indicating preservation of white matter related to motor tracts when spasticity was present.

Interpretation

These results support the hypothesis that preservation of descending motor pathways influences spasticity in humans with motor complete SCI; this knowledge might help the rehabilitation and assessment of people with SCI. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

Objective

To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell‐associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)‐T cell therapy in children and young adults.

Methods

We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19‐directed CAR/T cells for acute lymphoblastic leukemia (ALL).

Results

Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity‐related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR‐T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calcium‐binding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon‐γ (IFNγ), interleukin (IL)‐6, IL‐10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL‐10, GzB, granulocyte macrophage colony‐stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL‐6. We did not find direct evidence of endothelial activation.

Interpretation

Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Genetic risk of dementia mitigated by cognitive reserve: A cohort study

Objective

We investigated whether cognitive reserve modifies the risk of dementia attributable to apolipoprotein ε4 (APOE‐ε4), a well‐known genetic risk factor for dementia.

Methods

We followed 2,556 cognitively intact participants aged ≥60 years from the ongoing prospective community‐based Swedish National Study on Aging and Care in Kungsholmen (SNAC‐K). Dementia was ascertained through clinical and neuropsychological assessments and diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria. Structural equation modeling was used to generate a cognitive reserve indicator from 4 previously validated contributors: early life education, midlife substantive work complexity, late life leisure activities, and late life social networks. Cox proportional hazard models estimated dementia risk in relation to cognitive reserve indicator. The interaction between the cognitive reserve indicator and APOE‐ε4 was assessed on multiplicative and additive scales.

Results

After an average of 6.3 years (range = 2.1–10.7) of follow‐up, 232 dementia cases were ascertained. Relative to individuals in the lowest tertile of cognitive reserve indicator, those with moderate and high reserve were at a reduced risk of dementia. There was no multiplicative interaction between APOE‐ε4 status and cognitive reserve indicator (p = 0.113). Additive interaction was statistically significant. Relative to APOE‐ε4 carriers with low cognitive reserve, ε4 carriers with high reserve had a reduced risk of dementia (hazard ratio [HR] = 0.28, 95% confidence interval [CI] = 0.13–0.59). The magnitude of risk reduction was similar in ε4 noncarriers with a high cognitive reserve indicator (HR = 0.24, 95% CI = 0.15–0.40).

Interpretation

Lifelong engagement in reserve‐enhancing activities attenuates the risk of dementia attributable to APOE‐ε4. Promoting cognitive reserve might be especially effective in subpopulations with high genetic risk of dementia. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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A multicenter retrospective study of charcot‐marie‐tooth disease type 4B (CMT4B) associated with mutations in myotubularin‐related proteins (MTMRs)

Objective

Charcot‐Marie‐Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin‐related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B.

Methods

We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score.

Results

There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more‐severe disease than CMT4B2, with earlier onset, more‐frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations.

Interpretation

This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Epilepsy in families: Age at onset is a familial trait, independent of syndrome

Objective

We tested 2 hypotheses regarding age at onset within familial epilepsies: (1) family members with epilepsy tend to have similar ages at onset, independent of epilepsy syndrome; and (2) age at onset is younger in successive generations after controlling for sampling bias.

Methods

We analyzed clinical data collected by the Epi4K Consortium (303 multiplex families, 1,120 individuals). To test hypothesis 1, we used both linear mixed models commonly used for heritability analysis and Cox regression models with frailty terms to assess clustering of onset within families after controlling for other predictors. To test hypothesis 2, we used mixed effects models, pairwise analyses, and survival analysis to address sampling‐related bias that may mimic anticipation.

Results

Regarding hypothesis 1, age at seizure onset was significantly heritable (intraclass correlation coefficient = 0.17, p < 0.001) after adjusting for epilepsy type, sex, site, history of febrile seizure, and age at last observation. This finding remained significant after adjusting for epilepsy syndromes, and was robust across statistical methods in all families and in generalized families. Regarding hypothesis 2, the mean age at onset decreased in successive generations (p < 0.001). After adjusting for age at last observation, this effect was not significant in mixed effects models (p = 0.14), but remained significant in pairwise (p = 0.0003) and survival analyses (p = 0.02).

Interpretation

Age at seizure onset is an independent familial trait, and may have genetic determinants distinct from the determinants of particular epilepsy syndromes. Younger onsets in successive generations can be explained in part by sampling bias, but the presence of genetic anticipation cannot be excluded. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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The Effect of Intrathecal Baclofen in Dyskinetic Cerebral Palsy: The IDYS Trial

Objective

Intrathecal baclofen treatment is used for the treatment of dystonia in patients with severe dyskinetic cerebral palsy; however, the current level of evidence for the effect is low. The primary aim of this study was to provide evidence for the effect of intrathecal baclofen treatment on individual goals in patients with severe dyskinetic cerebral palsy.

Methods

This multicenter, randomized, double‐blind, placebo‐controlled trial was performed at 2 university medical centers in the Netherlands. Patients with severe dyskinetic cerebral palsy (Gross Motor Functioning Classification System level IV–V) aged 4 to 24 years who were eligible for intrathecal baclofen were included. Patients were assigned by block randomization (2:2) for treatment with intrathecal baclofen or placebo for 3 months via an implanted microinfusion pump. The primary outcome was goal attainment scaling of individual treatment goals (GAS T score). A linear regression model was used for statistical analysis with study site as a covariate. Safety analyses were done for number and type of (serious) adverse events.

Results

Thirty‐six patients were recruited from January 1, 2013, to March 31, 2018. Data for final analysis were available for 17 patients in the intrathecal baclofen group and 16 in the placebo group. Mean (standard deviation) GAS T score at 3 months was 38.9 (13.2) for intrathecal baclofen and 21.0 (4.6) for placebo (regression coefficient = 17.8, 95% confidence interval = 10.4‐25.0, p < 0.001). Number and types of (serious) adverse events were similar between groups.

Interpretation

Intrathecal baclofen treatment is superior to placebo in achieving treatment goals in patients with severe dyskinetic cerebral palsy. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Reply to “Grading the severity of autoimmune encephalitis: Advances and pitfalls”

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Grading the severity of autoimmune encephalitis: Advances and pitfalls

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Histological features of intracranial thrombi in stroke patients with cancer

The histological features of thrombus in stroke patients with cancer are not well known. Using immunohistochemical staining of thrombi retrieved during mechanical thrombectomy in stroke patients, thrombus compositions were compared between 16 patients with active cancer, 16 patients with inactive cancer, and 16 patients without any history of cancer. The active cancer group showed higher platelet and lower erythrocyte fractions than the inactive cancer or the control group. Four patients with vegetation showed very high platelet and low erythrocyte fractions. Patients with cryptogenic etiology in the active cancer group showed a similar pattern to those with vegetation. These findings may aid the determination of treatment strategies in cancer‐associated stroke. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy

Objective

To define a distinct, dominantly inherited, mild skeletal myopathy associated with prominent and consistent tremor in two unrelated, three‐generation families.

Methods

Clinical evaluations as well as exome and panel sequencing analyses were performed in affected and nonaffected members of two families to identify genetic variants segregating with the phenotype. Histological assessment of a muscle biopsy specimen was performed in 1 patient, and quantitative tremor analysis was carried out in 2 patients. Molecular modeling studies and biochemical assays were performed for both mutations.

Results

Two novel missense mutations in MYBPC1 (p.E248K in family 1 and p.Y247H in family 2) were identified and shown to segregate perfectly with the myopathy/tremor phenotype in the respective families. MYBPC1 encodes slow myosin binding protein‐C (sMyBP‐C), a modular sarcomeric protein playing structural and regulatory roles through its dynamic interaction with actin and myosin filaments. The Y247H and E248K mutations are located in the NH₂‐terminal M‐motif of sMyBP‐C. Both mutations result in markedly increased binding of the NH₂ terminus to myosin, possibly interfering with normal cross‐bridge cycling as the first muscle‐based step in tremor genesis. The clinical tremor features observed in all mutation carriers, together with the tremor physiology studies performed in family 2, suggest amplification by an additional central loop modulating the clinical tremor phenomenology.

Interpretation

Here, we link two novel missense mutations in MYBPC1 with a dominant, mild skeletal myopathy invariably associated with a distinctive tremor. The molecular, genetic, and clinical studies are consistent with a unique sarcomeric origin of the tremor, which we classify as “myogenic tremor.” ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Cell therapy for ischemic stroke: Are differences in preclinical and clinical study design responsible for the translational loss of efficacy?

in Wiley: Annals of Neurology: Table of Contents on June 13, 2019 10:45 AM.
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Hysteresis, neural avalanches and critical behaviour near a first-order transition of a spiking neural network. (arXiv:1906.05166v1 [q-bio.NC])

Many experimental results, both in-vivo and in-vitro, support the idea that the brain cortex operates near a critical point, and at the same time works as a reservoir of precise spatio-temporal patterns. However the mechanism at the basis of these observations is still not clear. In this paper we introduce a model which combines both these features, showing that scale-free avalanches are the signature of a system posed near the spinodal line of a first order transition, with many spatio-temporal patterns stored as dynamical metastable attractors. Specifically, we studied a network of leaky integrate and fire neurons, whose connections are the result of the learning of multiple spatio-temporal dynamical patterns, each with a randomly chosen ordering of the neurons. We found that the network shows a first order transition between a low spiking rate disordered state (down), and a high rate state characterized by the emergence of collective activity and the replay of one of the stored patterns (up). The transition is characterized by hysteresis, or alternation of up and down states, depending on the lifetime of the metastable states. In both cases, critical features and neural avalanches are observed. Notably, critical phenomena occur at the edge of a discontinuous phase transition, as recently observed in a network of glow lamps.

in q-bio.NC updates on arXiv.org on June 13, 2019 01:30 AM.
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Author Correction: Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39

Nature Neuroscience, Published online: 13 June 2019; doi:10.1038/s41593-019-0446-8
Author Correction: Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39
in Nature Neuroscience - Issue - nature.com science feeds on June 13, 2019 12:00 AM.
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Metabolism of Stem and Progenitor Cells: Proper Methods to Answer Specific Questions
Stem cells can stay quiescent for long period of time or proliferate and differentiate into multiple lineages. The activity of stage-specific metabolic programs allows stem cells to best adapt their functions in different microenvironments. Specific cellular phenotypes can be, therefore, defined by precise metabolic signatures. Notably, not only cellular metabolism describes a defined cellular phenotype, but experimental evidences now clearly indicate that also rewiring cells towards a particular cellular metabolism can drive their cellular phenotype and function accordingly. Cellular metabolism can be studied by both targeted and untargeted approaches. Targeted analyses focus on a subset of identified metabolites and on their metabolic fluxes. In addition, the overall assessment of the oxygen consumption rate gives a measure of the overall cellular oxidative metabolism and mitochondrial function. Untargeted approach provides a large-scale identification and quantification of the whole metabolome with the aim to describe a metabolic fingerprinting. In this review, we overview the methodologies currently available for the study of in vitro stem cell metabolism, including metabolic fluxes, fingerprint analyses, and single cell metabolomics. Moreover, we summarize available approaches for the study of in vivo stem cell metabolism. For all of the described methods, we highlight their specificities and limitations. In addition, we discuss practical concerns about the most threatening steps, including metabolic quenching, sample preparation and extraction. A better knowledge of the precise metabolic signature defining specific cell population is instrumental to the design of novel therapeutic strategies able to drive undifferentiated stem cells towards a selective and valuable cellular phenotype.
in Frontiers in Molecular Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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Lack of Fractalkine Receptor on Macrophages Impairs Spontaneous Recovery of Ribbon Synapses After Moderate Noise Trauma in C57BL/6 Mice
Noise trauma causes loss of synaptic connections between cochlear inner hair cells (IHCs) and the spiral ganglion neurons (SGNs). Such synaptic loss can trigger slow and progressive degeneration of SGNs. Macrophage fractalkine signaling is critical for neuron survival in the injured cochlea, but its role in cochlear synaptopathy is unknown. Fractalkine, a chemokine, is constitutively expressed by SGNs and signals via its receptor CX3CR1 that is expressed on macrophages. The present study characterized the immune response and examined the function of fractalkine signaling in degeneration and repair of cochlear synapses following noise trauma. Adult mice wild type, heterozygous and knockout for CX3CR1 on a C57BL/6 background were exposed for 2 hours to an octave band noise at 90 dB SPL. Noise exposure caused temporary shifts in hearing thresholds without any evident loss of hair cells in CX3CR1 heterozygous mice that have intact fractalkine signaling. Enhanced macrophage migration towards the inner hair cell-synaptic region was observed immediately after exposure in all genotypes. Synaptic immunolabeling revealed a rapid loss of synapses throughout the basal turn of the cochlea of all genotypes. The damaged synapses spontaneously recovered in mice with intact CX3CR1. However, CX3CR1 knockout (KO) animals displayed enhanced synaptic degeneration that correlated with attenuated suprathreshold neural responses at higher frequencies. Exposed CX3CR1 KO mice also exhibited increased loss of IHCs and SGN cell bodies compared to exposed heterozygous mice. These results indicate that macrophages can promote repair of damaged synapses after moderate noise trauma and that repair requires fractalkine signaling.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 13, 2019 12:00 AM.
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Editorial: Spatial Navigation: Memory Mechanisms and Executive Function Interactions

in Frontiers in Human Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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Functional Spectroscopy Mapping of Pain Processing Cortical Areas During Non-painful Peripheral Electrical Stimulation of the Accessory Spinal Nerve
Peripheral electrical stimulation (PES), which encompasses several techniques with heterogeneous physiological responses, has shown in some cases remarkable outcomes for pain treatment and clinical rehabilitation. However, results are still mixed, mainly because there is a lack of understanding regarding its neural mechanisms of action. In this study, we aimed to assess its effects by measuring cortical activation as indexed by functional near infrared spectroscopy (fNIRS). fNIRS is a functional optical imaging method to evaluate hemodynamic changes in oxygenated (HbO) and de-oxygenated (HbR) blood hemoglobin concentrations in cortical capillary networks that can be related to cortical activity. We hypothesized that non-painful PES of accessory spinal nerve (ASN) can promote cortical activation of sensorimotor cortex (SMC) and dorsolateral prefrontal cortex (DLPFC) pain processing cortical areas. Fifteen healthy volunteers received both active and sham ASN electrical stimulation in a randomized crossover study. The hemodynamic cortical response to unilateral right ASN burst electrical stimulation with 10 Hz was measured by a 40-channel fNIRS system. The effect of ASN electrical stimulation over HbO concentration in cortical areas of interest was observed through the activation of right-DLPFC (p=0.025) and left-SMC (p=0.042) in the active group but not in sham group. Regarding left-DLPFC (p=0.610) and right-SMC (p=0.174) there was no statistical difference between groups. As in non-invasive brain stimulation (NIBS) top-down modulation, bottom-up electrical stimulation to the accessory spinal nerve seems to activate the same critical cortical areas on pain pathways related to sensory-discriminative and affective-motivational pain dimensions. These results provide additional mechanistic evidence to develop and optimize the effects of peripheral neural electrical stimulation. (NCT 03295370 - clinicaltrials.gov).
in Frontiers in Human Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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Links Between the Amplitude Modulation of Low-Frequency Spontaneous Fluctuation Across Resting State Conditions and Thalamic Functional Connectivity
A comparison of the different types of resting state reveals some interesting characteristics of spontaneous brain activity that cannot be found in a single condition. Differences in the amplitude of low-frequency fluctuation (ALFF) between the eyes open (EO) and the eyes closed (EC) almost have a spatially distinct pattern with traditional EO-EC activation within sensory systems, suggesting the divergent functional roles of ALFF and activation. However, the underlying mechanism is far from clear. Since the thalamus plays an essential role in sensory processing, one critical step towards understanding the divergences is to depict the relationships between the thalamus and the ALFF modulation in sensory regions. In this preliminary study, we examined the association between the changes of ALFF and the changes of thalamic functional connectivity (FC) between EO and EC. We focused on two visual thalamic nuclei, the lateral geniculate nucleus (LGN) and the pulvinar (Pu). FC results showed that LGN had stronger synchronization with regions in lateral but not in medial visual networks, while Pu had a weaker synchronization with auditory and sensorimotor areas during EO compared with EC. Moreover, the patterns of FC modulation exhibited considerable overlaps with the ALFF modulation, and there were significant correlations between them across subjects. Our findings support the crucial role of the thalamus in amplitude modulation of low-frequency spontaneous activity in sensory systems, and may pave the way to elucidate the mechanisms governing distinction between evoked activation and modulation of low-frequency spontaneous brain activity.
in Frontiers in Human Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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Modulation of Fronto-Striatal Functional Connectivity Using Transcranial Magnetic Stimulation
Background The fronto-striatal network is involved in various motor, cognitive and emotional processes, such as spatial attention, working memory, decision-making and emotion regulation. Intermittent theta burst transcranial magnetic stimulation (iTBS) has been shown to modulate functional connectivity of brain networks. Long stimulation intervals, as well as high stimulation intensities are typically applied in transcranial magnetic stimulation therapy for mood disorders. The role of stimulation intensity on network function and homeostasis has not been explored systematically yet. Objective We aimed to modulate fronto-striatal connectivity by applying iTBS at different intensities to the left dorso-lateral prefrontal cortex (DLPFC). We measured individual and group changes by comparing resting state functional magnetic resonance imaging (rsfMRI) pre-iTBS und post iTBS. Differential effects of individual sub- versus supra-resting motor-threshold stimulation intensities were assessed. Methods Sixteen healthy subjects underwent excitatory iTBS at two intensities (90 % and 120 % of individual resting motor threshold) on separate days. 600 pulses (2 s trains, 8 s pauses, duration of 3 minutes, 20 seconds) were applied over the left DLPFC. Directly before and 7 min after stimulation, task-free rsfMRI sessions, lasting 10 min each, were conducted. Individual seed-to-seed functional connectivity changes were calculated for ten fronto-striatal and amygdala regions of interest with the SPM toolbox DPABI. Results Sub-threshold-iTBS increased functional connectivity directly between the left DLPFC and the left and right caudate, respectively, as well as between the right DLPFC and the left caudate. Indirectly, functional connectivity between the right putamen and the left nucleus accumbens and the left amygdala, respectively, was increased. Supra-threshold stimulation did not change fronto-striatal functional connectivity, but only increased functional connectivity between the left amygdala and the caudate nuclei, as well as the left putamen, respectively. Conclusion A short iTBS protocol applied at sub-threshold intensities was not only sufficient, but favourable in order to increase bilateral fronto-striatal functional connectivity, while minimising side effects. Decreased functional connectivity after supra-threshold stimulation was possibly caused by network homeostatic effects.
in Frontiers in Human Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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Intrinsic Spine Dynamics Are Critical for Recurrent Network Learning in Models With and Without Autism Spectrum Disorder
It is often assumed that Hebbian synaptic plasticity forms a cell assembly, a mutually interacting group of neurons that encodes memory. However, in recurrently connected networks with pure Hebbian plasticity, cell assemblies typically diverge or fade under ongoing changes of synaptic strength. Previously assumed mechanisms that stabilize cell assemblies do not robustly reproduce the experimentally reported unimodal and long-tailed distribution of synaptic strengths. Here, we show that augmenting Hebbian plasticity with experimentally observed intrinsic spine dynamics can stabilize cell assemblies and reproduce the distribution of synaptic strengths. Moreover, we posit that strong intrinsic spine dynamics impair learning performance. Our theory explains how excessively strong spine dynamics, experimentally observed in several animal models of autism spectrum disorder, impair learning associations in the brain.
in Frontiers in Computational Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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Transient Potassium Channels: Therapeutic Targets for Brain Disorders
Transient potassium current channels (IA channels), which are expressed in most brain areas, have a central role in modulating feedforward and feedback inhibition along the dendroaxonic axis. Loss of the modulatory channels is tightly associated with a number of brain diseases such as Alzheimer's disease, epilepsy, fragile X syndrome, Parkinson’s disease, chronic pain, tinnitus, and ataxia. However, the functional significance of IA channels in these diseases has so far been underestimated. In this review, we discuss the distribution and function of IA channels. Particularly, we posit that downregulation of IA channels results in neuronal (mostly dendritic) hyperexcitability accompanied by imbalanced excitation and inhibition ratio in the brain's networks, eventually causing the brain diseases. Finally, we propose a potential therapeutic target: the enhanced action of IA channels to counteract Ca2+-permeable channels including NMDA receptors could be harnessed to restore dendritic excitability, leading to a balanced neuronal state.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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Neuroinflammation and Glial Phenotypic Changes in Alpha-Synucleinopathies
The role of neuroinflammation has been increasingly recognized in the field of neurodegenerative diseases. Many studies focusing on the glial cells involved in the inflammatory responses of the brain, namely microglia and astroglia, have over the years pointed out the dynamic and changing behavior of these cells, accompanied by different morphologies and activation forms. This is particularly evident in diseased conditions, where glia react to any shift from homeostasis, acquiring different phenotypes. Particularly for microglia, it has soon become clear that such phenotypes are multiple, as multiple are the functions related to them. Several approaches have over time revealed different facets of microglial phenotypic diversity, and advanced genetic analyses, in recent years, have added new insights into microglial heterogeneity, opening novel scenarios that researchers have just started to explore. Among neurodegenerative diseases, an important section is represented by alpha-synucleinopathies. Here alpha-synuclein accumulates abnormally in the brain and, depending on its pattern of distribution, leads to the development of different clinical conditions. Also for these proteinopathies, neuroinflammation and glial activation have been identified as constant and crucial factors during disease development. In the present review we will address the current literature about glial phenotypic changes with respect to alpha-synucleinopathies, as well as consider the pathophysiological and therapeutic implications of such a dynamic cellular behavior.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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17β-Estradiol Treatment Attenuates Neurogenesis Damage and Improves Behavior Performance After Ketamine Exposure in Neonatal Rats
Ketamine exposure in the developing brain disturbed normal neurogenesis and resulted in subsequent neurocognitive deficits. 17β-estradiol provides robust neuroprotection in a variety of brain injury models in animals of both sexes and attenuates neurodegeneration induced by anesthesia agents. In the present study, we investigated whether 17β-estradiol could attenuate disturbed neurogenesis and behavioural deficits induced by ketamine exposure in neonatal rats. Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either normal saline, ketamine, or 17β-estradiol prior/after ketamine exposure, respectively. The rats were decapitated at PND14 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, neuronal differentiation, and apoptosis were assessed by immunohistochemistry and TUNEL, respectively. The protein expressions of caspase-3 in vivo and GSK-3β, p-GSK-3β in vitro were assessed by western blotting. Spatial learning and memory abilities were measured by the Morris water maze test at PND 42-47. Ketamine exposure decreased cell proliferation in the SVZ and SGZ, inhibited NSC proliferation and neuronal differentiation, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, ketamine increased caspase-3 expression in vivo and decreased protein expressions of p-GSK-3β in vitro. Treatment with 17β-estradiol attenuated ketamine-elicited changes both in vivo and in vitro. We for the first time showed that 17β-estradiol alleviated ketamine-induced neurogenesis damage and neurocognitive deficits in developing rat brain. Moreover, the protection of17β-estradiol is associated with the GSK-3β.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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Hippocampal Sequences During Exploration: Mechanisms and Functions
Although the hippocampus plays a critical role in spatial and episodic memories, the mechanisms underlying memory formation, stabilization, and recall for adaptive behavior remain relatively unknown. During exploration, within single cycles of the ongoing theta rhythm that dominates hippocampal local field potentials, place cells form precisely ordered sequences of activity. These neural sequences result from the integration of both external inputs conveying sensory-motor information, and intrinsic network dynamics possibly related to memory processes. Their endogenous replay during subsequent sleep is critical for memory consolidation. The present review discusses possible mechanisms and functions of hippocampal theta sequences during exploration. We present several lines of evidence suggesting that these neural sequences play a key role in information processing and support the formation of initial memory traces, and discuss potential functional distinctions between neural sequences emerging during theta versus awake sharp-wave ripples.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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Involvement of microRNA-34a in Age-Related Susceptibility to Oxidative Stress in ARPE-19 Cells by Targeting the Silent Mating Type Information Regulation 2 Homolog 1/p66shc Pathway: Implications for Age-Related Macular Degeneration
The aging retinal pigment epithelium and oxidative stress, mediated by reactive oxygen species accumulation, have been implicated in the mechanisms of age-related macular degeneration (AMD). The expression level of the adapter protein p66shc, a key protein that regulates cellular oxidative stress, is relatively low under normal conditions because of the effects of silent mating type information regulation 2 homolog 1 (SIRT1) on the binding of fully deacetylated histone H3’ to the p66shc promoter region, thus inhibiting p66shc transcription and expression. The equilibrium between SIRT1 and p66shc is disrupted in the presence of various stresses, including AMD. As a major target gene, SIRT1 is regulated by microRNA-34a (miR-34a), and overexpression of miR-34a results in significant inhibition of post-transcriptional expression of SIRT1. Furthermore, our recent studies demonstrated that miR-34a is significantly upregulated, accompanied by reduced tolerance to oxidative stress in hydrogen peroxide-induced prematurely senescent ARPE-19 cells. Moreover, the expression of SIRT1 is decreased, whereas that of p66shc is increased in these cells. Accordingly, miR-34a may play a key role in age-related susceptibility to oxidative stress in ARPE-19 cells by targeting the SIRT1/p66shc pathway, leading to AMD. In this review, we discuss the functions of miR-34a in modulating the SIRT1/p66shc pathway in age-related conditions, including AMD.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 13, 2019 12:00 AM.
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A Discrete Dorsal Raphe to Basal Amygdala 5-HT Circuit Calibrates Aversive Memory
Sengupta and Holmes use in vivo imaging, optogenetic, electrophysiological, and histological approaches to investigate the circuit-specific role of the DRN→BA 5-HT pathway in fear learning. They show this pathway is uniquely positioned, functionally and anatomically, to shape fear memory.
in Neuron on June 13, 2019 12:00 AM.
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A Specialized Neural Circuit Gates Social Vocalizations in the Mouse
Tschida et al. use an intersectional method to identify specialized midbrain neurons whose activity is necessary and sufficient for the production of social vocalizations in the mouse, affording an entry point for genetically dissecting the brain-wide circuits for vocal communication.
in Neuron on June 13, 2019 12:00 AM.
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A roadmap for understanding memory: Decomposing cognitive processes into operations and representations
Abstract
Thanks to patients Phineas Gage and Henry Molaison, we have long known that behavioral control depends on the frontal lobes, whereas declarative memory depends on the medial temporal lobes (MTL). For decades, cognitive functions – behavioral control, declarative memory – have served as labels for characterizing the division of labor in cortex. This approach has made enormous contributions to understanding how the brain enables the mind, providing a systems-level explanation of brain function that constrains lower-level investigations of neural mechanism. Today, the approach has evolved such that functional labels are often applied to brain networks rather than focal brain regions. Furthermore, the labels have diversified to include both broadly-defined cognitive functions (declarative memory, visual perception) and more circumscribed mental processes (recollection, familiarity, priming). We ask whether a process – a high-level mental phenomenon corresponding to an introspectively-identifiable cognitive event – is the most productive label for dissecting memory. For example, recollection conflates a neurocomputational operation (pattern completion-based retrieval) with a class of representational content (associative, high-dimensional memories). Because a full theory of memory must identify operations and representations separately, and specify how they interact, we argue that processes like recollection constitute inadequate labels for characterizing neural mechanisms. Instead, we advocate considering the component operations and representations of processes like recollection in isolation. For the organization of memory, the evidence suggests that pattern completion is recapitulated widely across the ventral visual stream and MTL, but the division of labor between sites within this pathway can be explained by representational content.
Significance Statement Accounts of cognition often assume that the brain is organized along lines of cognitive process, for example, with recollection mediated by one neural structure and familiarity by another. We argue that cognitive processes – introspectively-identifiable mental events like recollection – are inadequate labels for characterizing neural mechanisms, because they conflate lower-level components of the mechanisms we seek to identify. Recollection involves both a neurocomputational operation (pattern completion) and a neural representation (high-dimensional, associative content). To uncover memory's mechanisms, we must decompose memory processes into their operations and representations, asking how each contributes to mnemonic phenomena. Decomposing recollection suggests that, within the ventral visual pathway and MTL, different brain regions contribute to memory retrieval according to their representational content.

in RSS PAP on June 12, 2019 05:42 PM.
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Spontaneous Recurrent Absence Seizure-like Events in Wild-Caught Rats

Absence epilepsy is a heritable human neurological disorder characterized by brief nonconvulsive seizures with behavioral arrest, moderate-to-severe loss of consciousness (absence), and distinct spike-wave discharges (SWDs) in the EEG and electrocorticogram (ECoG). Genetic models of this disorder have been created by selectively inbreeding rats for absence seizure-like events with similar electrical and behavioral characteristics. However, these events are also common in outbred laboratory rats, raising concerns about whether SWD/immobility accurately reflects absence epilepsy as opposed to "normal" rodent behavior. We hypothesized that, if SWD/immobility models absence seizures, it would not exist in wild-caught rats due to the pressures of natural selection. To test this hypothesis, we compared chronic video/electrocorticogram recordings from male and female wild-caught (Brown-Norway [BN]) rats to recordings from laboratory outbred BN, outbred Long–Evans, and inbred WAG/Rij rats (i.e., a model of absence epilepsy). Wild-caught BN rats displayed absence-like SWD/immobility events that were highly similar to outbred BN rats in terms of spike-wave morphology, frequency, diurnal rhythmicity, associated immobility, and sensitivity to the anti-absence drug, ethosuximide; however, SWD bursts were less frequent and of shorter duration in wild-caught and outbred BN rats than the outbred Long–Evans and inbred WAG/Rij strains. We conclude that SWD/immobility in rats does not represent absence seizures, although they appear to have many similarities. In wild rats, SWD/immobility appears to represent normal brain activity that does not reduce survival in natural environments, a conclusion that logically extends to outbred laboratory rats and possibly to those that have been inbred to model absence epilepsy.

SIGNIFICANCE STATEMENT Spike-wave discharges (SWDs), behavioral arrest, and diminished consciousness are cardinal signs of seizures in human absence epilepsy and are used to model this disorder in inbred rats. These characteristics, however, are routinely found in outbred laboratory rats, leading to debate on whether SWD/immobility is a valid model of absence seizures. The SWD/immobility events in wild-caught rats appear equivalent to those found in outbred and inbred rat strains, except for lower incidence and shorter durations. Our results indicate that the electrophysiological and behavioral characteristics of events underlying hypothetical absence epilepsy in rodent models are found in wild rats captured in their natural environment. Other criteria beyond observation of SWDs and associated immobility are required to objectively establish absence epilepsy in rat models.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder

Pathogenic mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD), a rare disease marked by early-life seizures, autistic behaviors, and intellectual disability. Although mouse models of CDD exhibit dendritic instability and alterations in synaptic scaffolding proteins, studies of glutamate receptor levels and function are limited. Here we used a novel mouse model of CDD, the Cdkl5^R59X knock-in mouse (R59X), to investigate changes in synaptic glutamate receptor subunits and functional consequences. Male mice were used for all experiments to avoid the confounding effects of X-inactivation that would be present in female heterozygous mice. We showed that adult male R59X mice recapitulated the behavioral outcomes observed in other mouse models of CDD, including social deficits and memory and learning impairments, and exhibited decreased latency to seizure upon pentylenetetrazol administration. Furthermore, we observed a specific increase in GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (AMPARs) in the adult R59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR EPSCs and elevated early-phase long term potentiation (LTP). Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.

SIGNIFICANCE STATEMENT CDKL5 deficiency disorder (CDD) is a rare disease marked by autistic-like behaviors, intellectual disability, and seizures. While synaptic dysfunction has been observed in mouse models of CDD, there is limited information on how synaptic alterations contribute to behavioral and functional changes in CDD. Here we reveal elevated hippocampal GluA2-lacking AMPAR expression in a novel mouse model of CDD that is accompanied by changes in synaptic AMPAR function and plasticity. We also show, for the first time, that acutely targeting GluA2-lacking AMPAR dysregulation rescues core synaptic and neurobehavioral deficits in CDD.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice

Fragile X syndrome (FXS) is characterized by hypersensitivity to sensory stimuli, including environmental sounds. We compared the auditory brainstem response (ABR) recorded in vivo in mice lacking the gene (Fmr1^–/y) for fragile X mental retardation protein (FMRP) with that in wild-type animals. We found that ABR wave I, which represents input from the auditory nerve, is reduced in Fmr1^–/y animals, but only at high sound levels. In contrast, wave IV, which represents the activity of auditory brainstem nuclei is enhanced at all sound levels, suggesting that loss of FMRP alters the central processing of auditory signals. Current-clamp recordings of neurons in the medial nucleus of the trapezoid body in the auditory brainstem revealed that, in contrast to neurons from wild-type animals, sustained depolarization triggers repetitive firing rather than a single action potential. In voltage-clamp recordings, K⁺ currents that activate at positive potentials ("high-threshold" K⁺ currents), which are required for high-frequency firing and are carried primarily by Kv3.1 channels, are elevated in Fmr1^–/y mice, while K⁺ currents that activate near the resting potential and inhibit repetitive firing are reduced. We therefore tested the effects of AUT2 [((4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl) benzonitrile], a compound that modulates Kv3.1 channels. AUT2 reduced the high-threshold K⁺ current and increased the low-threshold K⁺ currents in neurons from Fmr1^–/y animals by shifting the activation of the high-threshold current to more negative potentials. This reduced the firing rate and, in vivo, restored wave IV of the ABR. Our results from animals of both sexes suggest that the modulation of the Kv3.1 channel may have potential for the treatment of sensory hypersensitivity in patients with FXS.

SIGNIFICANCE STATEMENT mRNA encoding the Kv3.1 potassium channel was one of the first described targets of the fragile X mental retardation protein (FMRP). Fragile X syndrome is caused by loss of FMRP and, in humans and mice, causes hypersensitivity to auditory stimuli. We found that components of the auditory brain response (ABR) corresponding to auditory brainstem activity are enhanced in mice lacking FMRP. This is accompanied by hyperexcitability and altered potassium currents in auditory brainstem neurons. Treatment with a drug that alters the voltage dependence of Kv3.1 channels normalizes the imbalance of potassium currents, as well as ABR responses in vivo, suggesting that such compounds may be effective in treating some symptoms of fragile X syndrome.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Synaptic Depotentiation and mGluR5 Activity in the Nucleus Accumbens Drive Cocaine-Primed Reinstatement of Place Preference

Understanding the neurobiological processes that incite drug craving and drive relapse has the potential to help target efforts to treat addiction. The NAc serves as a critical substrate for reward and motivated behavior, in part due to alterations in excitatory synaptic strength within cortical-accumbens pathways. The present studies investigated a causal link between cocaine-induced reinstatement of conditioned place preference and rapid reductions of cocaine-dependent increases in NAc shell synaptic strength in male mice. Cocaine-conditioned place preference behavior and ex vivo whole-cell electrophysiology showed that cocaine-primed reinstatement and synaptic depotentiation were disrupted by inhibiting AMPAR internalization via intra-NAc shell infusion of a Tat-GluA2_3Y peptide. Furthermore, reinstatement was driven by an mGluR5-dependent reduction in AMPAR signaling. Intra-NAc shell infusion of the mGluR5 antagonist MTEP blocked cocaine-primed reinstatement and corresponding depotentiation, whereas infusion of the mGluR5 agonist CHPG itself promoted reinstatement and depotentiated synaptic strength in the NAc shell. Optogenetic examination of circuit-specific plasticity showed that inhibition of infralimbic cortical input to the NAc shell blocked cocaine-primed reinstatement, whereas low-frequency stimulation (10 Hz) of this pathway in the absence of cocaine triggered a reduction in synaptic strength akin to that observed with cocaine, and was sufficient to promote reinstatement in the absence of a cocaine challenge. These data support a model in which mGluR5-mediated reduction in GluA2-containing AMPARs at NAc shell synapses receiving input from the infralimbic cortex is a critical factor in triggering reinstatement of cocaine-primed conditioned approach behavior.

SIGNIFICANCE STATEMENT These studies identified a sequence of neural events whereby reexposure to cocaine activates a signaling cascade that alters synaptic strength in the NAc shell and triggers a behavioral response driven by a drug-associated memory.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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EEG Frontal Alpha Asymmetry and Dream Affect: Alpha Oscillations over the Right Frontal Cortex during REM Sleep and Presleep Wakefulness Predict Anger in REM Sleep Dreams

Affective experiences are central not only to our waking life but also to rapid eye movement (REM) sleep dreams. Despite our increasing understanding of the neural correlates of dreaming, we know little about the neural correlates of dream affect. Frontal alpha asymmetry (FAA) is considered a marker of affective states and traits as well as affect regulation in the waking state. Here, we explored whether FAA during REM sleep and during evening resting wakefulness is related to affective experiences in REM sleep dreams. EEG recordings were obtained from 17 human participants (7 men) who spent 2 nights in the sleep laboratory. Participants were awakened 5 min after the onset of every REM stage after which they provided a dream report and rated their dream affect. Two-minute preawakening EEG segments were analyzed. Additionally, 8 min of evening presleep and morning postsleep EEG were recorded during resting wakefulness. Mean spectral power in the alpha band (8–13 Hz) and corresponding FAA were calculated over the frontal (F4-F3) sites. Results showed that FAA during REM sleep, and during evening resting wakefulness, predicted ratings of dream anger. This suggests that individuals with greater alpha power in the right frontal hemisphere may be less able to regulate (i.e., inhibit) strong affective states, such as anger, in dreams. Additionally, FAA was positively correlated across wakefulness and REM sleep. Together, these findings imply that FAA may serve as a neural correlate of affect regulation not only in the waking but also in the dreaming state.

SIGNIFICANCE STATEMENT We experience emotions not only during wakefulness but also during dreaming. Despite our increasing understanding of the neural correlates of dreaming, we know little about the neural correlates of dream emotions. Here we used electroencephalography to explore how frontal alpha asymmetry (FAA)—the relative difference in alpha power between the right and left frontal cortical areas that is associated with emotional processing and emotion regulation in wakefulness—is related to dream emotions. We show that individuals with greater FAA (i.e., greater right-sided alpha power) during rapid eye movement sleep, and during evening wakefulness, experience more anger in dreams. FAA may thus reflect the ability to regulate emotions not only in the waking but also in the dreaming state.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Neural Coding for Shape and Texture in Macaque Area V4

The distinct visual sensations of shape and texture have been studied separately in cortex; therefore, it remains unknown whether separate neuronal populations encode each of these properties or one population carries a joint encoding. We directly compared shape and texture selectivity of individual V4 neurons in awake macaques (1 male, 1 female) and found that V4 neurons lie along a continuum from strong tuning for boundary curvature of shapes to strong tuning for perceptual dimensions of texture. Among neurons tuned to both attributes, tuning for shape and texture were largely separable, with the latter delayed by ~30 ms. We also found that shape stimuli typically evoked stronger, more selective responses than did texture patches, regardless of whether the latter were contained within or extended beyond the receptive field. These results suggest that there are separate specializations in mid-level cortical processing for visual attributes of shape and texture.

SIGNIFICANCE STATEMENT Object recognition depends on our ability to see both the shape of the boundaries of objects and properties of their surfaces. However, neuroscientists have never before examined how shape and texture are linked together in mid-level visual cortex. In this study, we used systematically designed sets of simple shapes and texture patches to probe the responses of individual neurons in the primate visual cortex. Our results provide the first evidence that some cortical neurons specialize in processing shape whereas others specialize in processing textures. Most neurons lie between the ends of this continuum, and in these neurons we find that shape and texture encoding are largely independent.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Single-Cell Membrane Potential Fluctuations Evince Network Scale-Freeness and Quasicriticality

What information single neurons receive about general neural circuit activity is a fundamental question for neuroscience. Somatic membrane potential (V_m) fluctuations are driven by the convergence of synaptic inputs from a diverse cross-section of upstream neurons. Furthermore, neural activity is often scale-free, implying that some measurements should be the same, whether taken at large or small scales. Together, convergence and scale-freeness support the hypothesis that single V_m recordings carry useful information about high-dimensional cortical activity. Conveniently, the theory of "critical branching networks" (one purported explanation for scale-freeness) provides testable predictions about scale-free measurements that are readily applied to V_m fluctuations. To investigate, we obtained whole-cell current-clamp recordings of pyramidal neurons in visual cortex of turtles with unknown genders. We isolated fluctuations in V_m below the firing threshold and analyzed them by adapting the definition of "neuronal avalanches" (i.e., spurts of population spiking). The V_m fluctuations which we analyzed were scale-free and consistent with critical branching. These findings recapitulated results from large-scale cortical population data obtained separately in complementary experiments using microelectrode arrays described previously (Shew et al., 2015). Simultaneously recorded single-unit local field potential did not provide a good match, demonstrating the specific utility of V_m. Modeling shows that estimation of dynamical network properties from neuronal inputs is most accurate when networks are structured as critical branching networks. In conclusion, these findings extend evidence of critical phenomena while also establishing subthreshold pyramidal neuron V_m fluctuations as an informative gauge of high-dimensional cortical population activity.

SIGNIFICANCE STATEMENT The relationship between membrane potential (V_m) dynamics of single neurons and population dynamics is indispensable to understanding cortical circuits. Just as important to the biophysics of computation are emergent properties such as scale-freeness, where critical branching networks offer insight. This report makes progress on both fronts by comparing statistics from single-neuron whole-cell recordings with population statistics obtained with microelectrode arrays. Not only are fluctuations of somatic V_m scale-free, they match fluctuations of population activity. Thus, our results demonstrate appropriation of the brain's own subsampling method (convergence of synaptic inputs) while extending the range of fundamental evidence for critical phenomena in neural systems from the previously observed mesoscale (fMRI, LFP, population spiking) to the microscale, namely, V_m fluctuations.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Pedunculopontine Glutamatergic Neurons Provide a Novel Source of Feedforward Inhibition in the Striatum by Selectively Targeting Interneurons

The main excitatory inputs to the striatum arising from the cortex and the thalamus innervate both striatal spiny projection neurons and interneurons. These glutamatergic inputs to striatal GABAergic interneurons have been suggested to regulate the spike timing of striatal projection neurons via feedforward inhibition. Understanding how different excitatory inputs are integrated within the striatal circuitry and how they regulate striatal output is crucial for understanding basal ganglia function and related behaviors. Here, using VGLUT2 mice from both sexes, we report the existence of a glutamatergic projection from the mesencephalic locomotor region to the striatum that avoids the spiny neurons and selectively innervates interneurons. Specifically, optogenetic activation of glutamatergic axons from the pedunculopontine nucleus induced monosynaptic excitation in most recorded striatal cholinergic interneurons and GABAergic fast-spiking interneurons. Optogenetic stimulation in awake head-fixed mice consistently induced an increase in the firing rate of putative cholinergic interneurons and fast-spiking interneurons. In contrast, this stimulation did not induce excitatory responses in spiny neurons but rather disynaptic inhibitory responses ex vivo and a decrease in their firing rate in vivo, suggesting a feedforward mechanism mediating the inhibition of spiny projection neurons through the selective activation of striatal interneurons. Furthermore, unilateral stimulation of pedunculopontine nucleus glutamatergic axons in the striatum induced ipsilateral head rotations consistent with the inhibition of striatal output neurons. Our results demonstrate the existence of a unique interneuron-specific midbrain glutamatergic input to the striatum that exclusively recruits feedforward inhibition mechanisms.

SIGNIFICANCE STATEMENT Glutamatergic inputs to the striatum have been shown to target both striatal projection neurons and interneurons and have been proposed to regulate spike timing of the projection neurons in part through feedforward inhibition. Here, we reveal the existence of a midbrain source of glutamatergic innervation to the striatum, originating in the pedunculopontine nucleus. Remarkably, this novel input selectively targets striatal interneurons, avoiding the projection neurons. Furthermore, we show that this selective innervation of interneurons can regulate the firing of the spiny projection neurons and inhibit the striatal output via feedforward inhibition. Together, our results describe a unique source of excitatory innervation to the striatum which selectively recruits feedforward inhibition of spiny neurons without any accompanying excitation.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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The Spinal Transcriptome after Cortical Stroke: In Search of Molecular Factors Regulating Spontaneous Recovery in the Spinal Cord

In response to cortical stroke and unilateral corticospinal tract degeneration, compensatory sprouting of spared corticospinal fibers is associated with recovery of skilled movement in rodents. To date, little is known about the molecular mechanisms orchestrating this spontaneous rewiring. In this study, we provide insights into the molecular changes in the spinal cord tissue after large ischemic cortical injury in adult female mice, with a focus on factors that might influence the reinnervation process by contralesional corticospinal neurons. We mapped the area of cervical gray matter reinnervation by sprouting contralesional corticospinal axons after unilateral photothrombotic stroke of the motor cortex in mice using anterograde tracing. The mRNA profile of this reinnervation area was analyzed using whole-genome sequencing to identify differentially expressed genes at selected time points during the recovery process. Bioinformatic analysis revealed two phases of processes: early after stroke (4–7 d post-injury), the spinal transcriptome is characterized by inflammatory processes, including phagocytic processes as well as complement cascade activation. Microglia are specifically activated in the denervated corticospinal projection fields in this early phase. In a later phase (28–42 d post-injury), biological processes include tissue repair pathways with upregulated genes related to neurite outgrowth. Thus, the stroke-denervated spinal gray matter, in particular its intermediate laminae, represents a growth-promoting environment for sprouting corticospinal fibers originating from the contralesional motor cortex. This dataset provides a solid starting point for future studies addressing key elements of the post-stroke recovery process, with the goal to improve neuroregenerative treatment options for stroke patients.

SIGNIFICANCE STATEMENT We show that the molecular changes in the spinal cord target tissue of the stroke-affected corticospinal tract are mainly defined by two phases: an early inflammatory phase during which microglia are specifically activated in the target area of reinnervating corticospinal motor neurons; and a late phase during which growth-promoting factors are upregulated which can influence the sprouting response, arborization, and synapse formation. By defining for the first time the endogenous molecular machinery in the stroke-denervated cervical spinal gray matter with a focus on promotors of axon growth through the growth-inhibitory adult CNS, this study will serve as a basis to address novel neuroregenerative treatment options for chronic stroke patients.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Regeneration of Dopaminergic Neurons in Adult Zebrafish Depends on Immune System Activation and Differs for Distinct Populations

Adult zebrafish, in contrast to mammals, regenerate neurons in their brain, but the extent and variability of this capacity is unclear. Here we ask whether the loss of various dopaminergic neuron populations is sufficient to trigger their functional regeneration. Both sexes of zebrafish were analyzed. Genetic lineage tracing shows that specific diencephalic ependymo-radial glial (ERG) progenitor cells give rise to new dopaminergic [tyrosine hydroxylase-positive (TH⁺)] neurons. Ablation elicits an immune response, increased proliferation of ERG progenitor cells, and increased addition of new TH⁺ neurons in populations that constitutively add new neurons (e.g., diencephalic population 5/6). Inhibiting the immune response attenuates neurogenesis to control levels. Boosting the immune response enhances ERG proliferation, but not addition of TH⁺ neurons. In contrast, in populations in which constitutive neurogenesis is undetectable (e.g., the posterior tuberculum and locus ceruleus), cell replacement and tissue integration are incomplete and transient. This is associated with a loss of spinal TH⁺ axons, as well as permanent deficits in shoaling and reproductive behavior. Hence, dopaminergic neuron populations in the adult zebrafish brain show vast differences in regenerative capacity that correlate with constitutive addition of neurons and depend on immune system activation.

SIGNIFICANCE STATEMENT Despite the fact that zebrafish show a high propensity to regenerate neurons in the brain, this study reveals that not all types of dopaminergic neurons are functionally regenerated after specific ablation. Hence, in the same adult vertebrate brain, mechanisms of successful and incomplete regeneration can be studied. We identify progenitor cells for dopaminergic neurons and show that activating the immune system promotes the proliferation of these cells. However, in some areas of the brain this only leads to insufficient replacement of functionally important dopaminergic neurons that later disappear. Understanding the mechanisms of regeneration in zebrafish may inform interventions targeting the regeneration of functionally important neurons, such as dopaminergic neurons, from endogenous progenitor cells in nonregenerating mammals.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Reorganization of Recurrent Layer 5 Corticospinal Networks Following Adult Motor Training

Recurrent synaptic connections between neighboring neurons are a key feature of mammalian cortex, accounting for the vast majority of cortical inputs. Although computational models indicate that reorganization of recurrent connectivity is a primary driver of experience-dependent cortical tuning, the true biological features of recurrent network plasticity are not well identified. Indeed, whether rewiring of connections between cortical neurons occurs during behavioral training, as is widely predicted, remains unknown. Here, we probe M1 recurrent circuits following motor training in adult male rats and find robust synaptic reorganization among functionally related layer 5 neurons, resulting in a 2.5-fold increase in recurrent connection probability. This reorganization is specific to the neuronal subpopulation most relevant for executing the trained motor skill, and behavioral performance was impaired following targeted molecular inhibition of this subpopulation. In contrast, recurrent connectivity is unaffected among neighboring layer 5 neurons largely unrelated to the trained behavior. Training-related corticospinal cells also express increased excitability following training. These findings establish the presence of selective modifications in recurrent cortical networks in adulthood following training.

SIGNIFICANCE STATEMENT Recurrent synaptic connections between neighboring neurons are characteristic of cortical architecture, and modifications to these circuits are thought to underlie in part learning in the adult brain. We now show that there are robust changes in recurrent connections in the rat motor cortex upon training on a novel motor task. Motor training results in a 2.5-fold increase in recurrent connectivity, but only within the neuronal subpopulation most relevant for executing the new motor behavior; recurrent connectivity is unaffected among adjoining neurons that do not execute the trained behavior. These findings demonstrate selective reorganization of recurrent synaptic connections in the adult neocortex following novel motor experience, and illuminate fundamental properties of cortical function and plasticity.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Sexually Dimorphic Regulation of Behavioral States by Dopamine in Caenorhabditis elegans

Sex differences in behavior allow animals to effectively mate and reproduce. However, the mechanism by which biological sex regulates behavioral states, which underlie the regulation of sex-shared behaviors, such as locomotion, is largely unknown. In this study, we studied sex differences in the behavioral states of Caenorhabditis elegans and found that males spend less time in a low locomotor activity state than hermaphrodites and that dopamine generates this sex difference. In males, dopamine reduces the low activity state by acting in the same pathway as polycystic kidney disease-related genes that function in male-specific neurons. In hermaphrodites, dopamine increases the low activity state by suppression of octopamine signaling in the sex-shared SIA neurons, which have reduced responsiveness to octopamine in males. Furthermore, dopamine promotes exploration both inside and outside of bacterial lawn (the food source) in males and suppresses it in hermaphrodites. These results demonstrate that sexually dimorphic signaling allows the same neuromodulator to promote adaptive behavior for each sex.

SIGNIFICANCE STATEMENT The mechanisms that generate sex differences in sex-shared behaviors, including locomotion, are not well understood. We show that there are sex differences in the regulation of behavioral states in the model animal Caenorhabditis elegans. Dopamine promotes the high locomotor activity state in males, which must search for mates to reproduce, and suppresses it in self-fertilizing hermaphrodites through distinct molecular mechanisms. This study demonstrates that sex-specific signaling generates sex differences in the regulation of behavioral states, which in turn modulates the locomotor activity to suit reproduction for each sex.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Cell-Type-Specific Regulation of Nucleus Accumbens Synaptic Plasticity and Cocaine Reward Sensitivity by the Circadian Protein, NPAS2

The circadian transcription factor neuronal PAS domain 2 (NPAS2) is linked to psychiatric disorders associated with altered reward sensitivity. The expression of Npas2 is preferentially enriched in the mammalian forebrain, including the nucleus accumbens (NAc), a major neural substrate of motivated and reward behavior. Previously, we demonstrated that downregulation of NPAS2 in the NAc reduces the conditioned behavioral response to cocaine in mice. We also showed that Npas2 is preferentially enriched in dopamine receptor 1 containing medium spiny neurons (D1R-MSNs) of the striatum. To extend these studies, we investigated the impact of NPAS2 disruption on accumbal excitatory synaptic transmission and strength, along with the behavioral sensitivity to cocaine reward in a cell-type-specific manner. Viral-mediated knockdown of Npas2 in the NAc of male and female C57BL/6J mice increased the excitatory drive onto MSNs. Using Drd1a-tdTomato mice in combination with viral knockdown, we determined these synaptic adaptations were specific to D1R-MSNs relative to non-D1R-MSNs. Interestingly, NAc-specific knockdown of Npas2 blocked cocaine-induced enhancement of synaptic strength and glutamatergic transmission specifically onto D1R-MSNs. Last, we designed, validated, and used a novel Cre-inducible short-hairpin RNA virus for MSN-subtype-specific knockdown of Npas2. Cell-type-specific Npas2 knockdown in D1R-MSNs, but not D2R-MSNs, in the NAc reduced cocaine conditioned place preference. Together, our results demonstrate that NPAS2 regulates excitatory synapses of D1R-MSNs in the NAc and cocaine reward-related behavior.

SIGNIFICANCE STATEMENT Drug addiction is a widespread public health concern often comorbid with other psychiatric disorders. Disruptions of the circadian clock can predispose or exacerbate substance abuse in vulnerable individuals. We demonstrate a role for the core circadian protein, NPAS2, in mediating glutamatergic neurotransmission at medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a region critical for reward processing. We find that NPAS2 negatively regulates functional excitatory synaptic plasticity in the NAc and is necessary for cocaine-induced plastic changes in MSNs expressing the dopamine 1 receptor (D1R). We further demonstrate disruption of NPAS2 in D1R-MSNs produces augmented cocaine preference. These findings highlight the significance of cell-type-specificity in mechanisms underlying reward regulation by NPAS2 and extend our knowledge of its function.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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PTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease

In addition to amyloid-β plaques and tau tangles, mitochondrial dysfunction is implicated in the pathology of Alzheimer's disease (AD). Neurons heavily rely on mitochondrial function, and deficits in brain energy metabolism are detected early in AD; however, direct human genetic evidence for mitochondrial involvement in AD pathogenesis is limited. We analyzed whole-exome sequencing data of 4549 AD cases and 3332 age-matched controls and discovered that rare protein altering variants in the gene pentatricopeptide repeat-containing protein 1 (PTCD1) show a trend for enrichment in cases compared with controls. We show here that PTCD1 is required for normal mitochondrial rRNA levels, proper assembly of the mitochondrial ribosome and hence for mitochondrial translation and assembly of the electron transport chain. Loss of PTCD1 function impairs oxidative phosphorylation and forces cells to rely on glycolysis for energy production. Cells expressing the AD-linked variant of PTCD1 fail to sustain energy production under increased metabolic stress. In neurons, reduced PTCD1 expression leads to lower ATP levels and impacts spontaneous synaptic activity. Thus, our study uncovers a possible link between a protein required for mitochondrial function and energy metabolism and AD risk.

SIGNIFICANCE STATEMENT Mitochondria are the main source of cellular energy and mitochondrial dysfunction is implicated in the pathology of Alzheimer's disease (AD) and other neurodegenerative disorders. Here, we identify a variant in the gene PTCD1 that is enriched in AD patients and demonstrate that PTCD1 is required for ATP generation through oxidative phosphorylation. PTCD1 regulates the level of 16S rRNA, the backbone of the mitoribosome, and is essential for mitochondrial translation and assembly of the electron transport chain. Cells expressing the AD-associated variant fail to maintain adequate ATP production during metabolic stress, and reduced PTCD1 activity disrupts neuronal energy homeostasis and dampens spontaneous transmission. Our work provides a mechanistic link between a protein required for mitochondrial function and genetic AD risk.

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Interferon-{gamma} as a Potential Link between Diabetes Mellitus and Dementia

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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This Week in The Journal

in Journal of Neuroscience current issue on June 12, 2019 04:30 PM.
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Dopamine Depletion Affects Vocal Acoustics and Disrupts Sensorimotor Adaptation in Songbirds
Abstract
Dopamine is hypothesized to convey error information in reinforcement learning tasks with explicit appetitive or aversive cues. However, during motor skill learning feedback signals arise from an animal’s evaluation of sensory feedback resulting from its own behavior, rather than any external reward or punishment. It has previously been shown that intact dopaminergic signaling from the ventral tegmental area/substantia nigra pars compacta (VTA/SNc) complex is necessary for vocal learning when songbirds modify their vocalizations to avoid hearing distorted auditory feedback (playbacks of white noise). However, it remains unclear whether dopaminergic signaling underlies vocal learning in response to more naturalistic errors (pitch-shifted feedback delivered via headphones). We used male Bengalese finches (Lonchura striata var. domestica) to test the hypothesis that the necessity of dopamine signaling is shared between the two types of learning. We combined 6-hydroxydopamine (6-OHDA) lesions of dopaminergic terminals within Area X, a basal ganglia nucleus critical for song learning, with a headphones learning paradigm that shifted the pitch of auditory feedback and compared their learning to that of unlesioned controls. We found that 6-OHDA lesions affected song behavior in two ways. First, over a period of days lesioned birds systematically lowered their pitch regardless of the presence or absence of auditory errors. Second, 6-OHDA lesioned birds also displayed severe deficits in sensorimotor learning in response to pitch-shifted feedback. Our results suggest roles for dopamine in both motor production and auditory error processing, and a shared mechanism underlying vocal learning in response to both distorted and pitch-shifted auditory feedback.

in eNeuro current issue on June 12, 2019 04:30 PM.
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Lovastatin, not Simvastatin, Corrects Core Phenotypes in the Fragile X Mouse Model

The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability (ID). The therapeutic efficacy of lovastatin is being tested in clinical trials for FX; however, the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in Fmr1^-/y mice versus WT littermates: excessive hippocampal protein synthesis and susceptibility to audiogenic seizures (AGSs). We find that simvastatin does not correct excessive hippocampal protein synthesis in the Fmr1^-/y hippocampus at any dose tested. In fact, simvastatin significantly increases protein synthesis in both Fmr1^-/y and WT. Moreover, injection of simvastatin does not reduce AGS in the Fmr1^-/y mouse, while lovastatin significantly reduces AGS incidence and severity versus vehicle-treated animals. These results show that unlike lovastatin, simvastatin does not correct core phenotypes in the Fmr1^-/y mouse model.

in eNeuro current issue on June 12, 2019 04:30 PM.
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The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
Abstract
Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2^{lox/lox;NEX-Cre} conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.

in eNeuro current issue on June 12, 2019 04:30 PM.
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Reciprocal Inhibitory Glomerular Circuits Contribute to Excitation-Inhibition Balance in the Mouse Olfactory Bulb
Abstract
The major inhibitory interneurons in olfactory bulb (OB) glomeruli are periglomerular cells (PGCs) and short axon cells (SACs). PGCs and SACs provide feedforward inhibition to all classes of projection neurons, but inhibition between PGCs and SACs is not well understood. We crossed Cre and GFP transgenic mice and used virally-delivered optogenetic constructs to selectively activate either SACs or GAD65cre-ChR2-positive PGCs while recording from identified GAD65cre-ChR2-positive PGCs or SACs, respectively, to investigate inhibitory interactions between these two interneuron types. We show that GAD65cre-ChR2-positive PGCs robustly inhibit SACs and SACs strongly inhibit PGCs. SACs form the interglomerular circuit, which inhibits PGCs in distant glomeruli. Activation of GAD65cre-ChR2-positive PGCs monosynaptically inhibit mitral cells (MCs), which complements recent findings that SACs directly inhibit MCs. Thus, both classes of glomerular inhibitory neurons inhibit each other, as well as OB output neurons. We further show that olfactory nerve input to one glomerulus engages the interglomerular circuit and inhibits PGCs in distant glomeruli. Sensory activation of the interglomerular circuit directly inhibits output neurons in other glomeruli and by inhibiting intraglomerular PGCs, may potentially disinhibit output neurons in other glomeruli. The nature and context of odorant stimuli may determine whether inhibition or excitation prevails so that odors are represented in part by patterns of active and inactive glomeruli.

in eNeuro current issue on June 12, 2019 04:30 PM.
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Critical Analysis of Particle Detection Artifacts in Synaptosome Flow Cytometry
Abstract
Flow cytometry and fluorescence-activated sorting are powerful techniques that hold great promise for studying heterogeneous populations of submicron particles such as synaptosomes, but many technical challenges arise in these experiments. To date, most flow cytometry studies of synaptosomes have relied on particle detection using forward scatter (FSC) measurements and size estimation with polystyrene (PS) bead standards. However, these practices have serious limitations, and special care must be taken to overcome the poor sensitivity of conventional flow cytometers in the analysis of submicron particles. Technical artifacts can confound these experiments, especially the detection of multiple particles as a single event. Here, we compared analysis of P2 crude synaptosomal preparations from murine forebrain on multiple flow cytometers using both FSC-triggered and fluorescence-triggered detection. We implemented multicolor fluorescent dye-based assays to quantify coincident particle detection and aggregation, and we assessed the false colocalization of antigens in immunostaining analyses. Our results demonstrate that fluorescence triggering and proper dilution can control for coincident particle detection, but not particle aggregation. We confirmed previous studies showing that FSC-based size estimation with PS beads underestimates biological particle size, and we identified pervasive aggregation in the FSC range analyzed in most synaptosome flow cytometry studies. We found that analyzing P2 samples in sucrose/EDTA/tris (SET) buffer reduces aggregation compared to PBS, but does not completely eliminate the presence of aggregates, especially in immunostaining experiments. Our study highlights challenges and pitfalls in synaptosome flow cytometry and provides a methodological framework for future studies.

in eNeuro current issue on June 12, 2019 04:30 PM.
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Corrigendum: Gap Junctions in A8 Amacrine Cells Are Made of Connexin36 but Are Differently Regulated Than Gap Junctions in AII Amacrine Cells

in Frontiers in Molecular Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Accelerated Age-Related Degradation of the Tectorial Membrane in the Ceacam16βgal/βgal Null Mutant Mouse, a Model for Late-Onset Human Hereditary Deafness DFNB113
CEACAM16 is a non-collagenous protein of the tectorial membrane, an extracellular structure of the cochlea essential for normal hearing. Dominant and recessive mutations in CEACAM16 have been reported to cause postlingual and progressive forms of deafness in humans. In a previous study of young Ceacam16 βgal/βgal null mutant mice on a C57Bl/6J background, the incidence of spontaneous otoacoustic emissions (SOAEs) was greatly increased relative to Ceacam16+/+ and Ceacam16+/βgal mice, but auditory brain-stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were near normal, indicating auditory thresholds were not significantly affected. To determine if the loss of CEACAM16 leads to hearing loss at later ages in this mouse line, cochlear structure and auditory function were examined in Ceacam16+/+, Ceacam16+/βgal and Ceacam16βgal/βgal mice at 6 and 12 months of age and compared to that previously described at 1 month. Analysis of older Ceacam16βgal/βgal mice reveals a progressive loss of matrix from the core of the tectorial membrane that is more extensive in the apical, low-frequency regions of the cochlea. In Ceacam16βgal/βgal mice at 6-7 months, the DPOAE magnitude at 2f1-f2 and the incidence of SOAEs both decrease relative to young animals. By ~12 months, SOAEs and DPOAEs are not detected in Ceacam16βgal/βgal mice and ABR thresholds are increased by up to ~40 dB across frequency, despite a complement of hair cells similar to that present in Ceacam16+/+ mice. Although SOAE incidence decreases with age in Ceacam16βgal/βgal mice, it increases in ageing heterozygous Ceacam16+/βgal mice and is accompanied by a reduction in the accumulation of CEACAM16 in the tectorial membrane relative to controls. An apically-biased loss of matrix from the core of the tectorial membrane, similar to that observed in young Ceacam16βgal/βgal mice, is also seen in Ceacam16+/+ and Ceacam16+/βgal mice, and other strains of wild-type mice, but at much later ages. The loss of Ceacam16 therefore accelerates age-related degeneration of the tectorial membrane leading, as in humans with mutations in CEACAM16, to a late-onset progressive form of hearing loss.
in Frontiers in Molecular Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Elevated Serum SIRT 2 May Differentiate Parkinson’s Disease From Atypical Parkinsonian Syndromes
Atypical Parkinson Syndromes (APSs) often have symptoms that overlap with those of Parkinson's disease (PD), especially in early in disease, making these disorders difficult to diagnose. Previous studies have demonstrated association of oligomeric α-synuclein (α-Syn), a key element in the pathogenesis of PD, with Sirtuin (SIRT)2 proteins for modulating PD. We aimed to evaluate SIRT proteins expression in serum of PD patients and compare it with APSs and normal elderly control (GC); and correlate with α-Syn. SIRT proteins expression was evaluated in sera of 68 PD; 34 APS and 68 GC without any neuro-psychiatric illness as controls by Surface Plasmon Resonance. SIRT2 expression was correlated with α-Syn in PD and GC. Significant (p<0.0001) differences were observed between serum SIRT2 concentration in PD and APS and GC; and between APS and GC. ROC analysis revealed the strong cut off value to differentiate PD from APS and GC and also APS from GC. Significant correlation was observed among SIRT2 levels in early PD patients with UPDRS, H and Y and increase duration of disease. In addition, a strong positive correlation of SIRT2 with α-Syn (p<0.0001) was observed. However, no such difference was detected for serum SIRT1 in cases of PD and APS; and GC. The present study is the first to report elevated serum SIRT2 in PD. The study also provided a simple test to distinguish PD from APS and may have translational utility for diagnosis.
in Frontiers in Molecular Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Intracortical Inhibition and Surround Inhibition in the Motor Cortex: A TMS-EEG Study
Background: Short-latency intracortical inhibition (SICI) and motor surround inhibition (mSI) are cortical phenomena that have been investigated with Transcranial Magnetic Stimulation (TMS). mSI is believed to be necessary for the execution of fine finger movements, and SICI may participate in mSI genesis, however, the mechanisms underlying both mSI and SICI are not entirely clear. Objective: We explored the cortical physiology of SICI and mSI in healthy subjects by TMS-evoked cortical potentials (TEPs). Methods: Single (sp) and paired-pulse (pp) TMS were delivered on the ADM muscle cortical hotspot while recording EEG and EMG. Three conditions were tested: spTMS and ppTMS at rest, and spTMS at the onset of an index finger movement. SICI and mSI were calculated on the ADM motor evoked potential (MEP) and two groups were defined based on the presence of mSI. Average TEPs were calculated for each condition and for five regions of interest. Results: At movement onset we observed a widespread reduction of the inhibitory late component N100 suggesting cortical facilitation associated with motor performance. At motor cortex level, SICI and mSI are associated with similar modulation of TEPs consisting in a reduction of P30 and an increase of N45 amplitude. Conclusions: Our findings suggest that SICI and mSI modulate cortical excitability with shared inhibitory mechanisms.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on June 12, 2019 12:00 AM.
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Canine Cognitive Dysfunction and Alzheimer’s Disease – Two Facets of the Same Disease?
Neurodegenerative diseases present a major and increasing burden in the societies worldwide. With aging populations, the prevalence of neurodegenerative diseases is increasing, yet there are no effective cures and very few treatment options are available. Alzheimer’s disease is one of the most prevalent neurodegenerative conditions and although the pathology is well studied, the pathogenesis of this debilitating illness is still poorly understood. This is, among other reasons, also due to the lack of good animal models as laboratory rodents do not develop spontaneous neurodegenerative diseases and human Alzheimer’s disease is only partially mimicked by transgenic rodent models. On the other hand, older dogs commonly develop canine cognitive dysfunction, a disease that is similar to Alzheimer’s disease in many aspects. Dogs show cognitive deficits that could be paralleled to human symptoms such as disorientation, memory loss, changes in behavior, and in their brains, beta amyloid plaques are commonly detected both in extracellular space as senile plaques and around the blood vessels. Dogs could be therefore potentially a very good model for studying pathological process and novel treatment options for Alzheimer’s disease. In the present article, we will review the current knowledge about the pathogenesis of canine cognitive dysfunction, its similarities and dissimilarities with Alzheimer’s disease, and developments of novel treatments for these two diseases with a focus on canine cognitive dysfunction.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 12, 2019 12:00 AM.
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Classification of Multiple Sclerosis Clinical Profiles via Graph Convolutional Neural Networks
Recent advances in image acquisition and processing techniques, along with the success of novel deep learning architectures, have given the opportunity to develop innovative algorithms capable to provide a better characterization of neurological related diseases. In this work, we introduce a neural network based approach to classify Multiple Sclerosis (MS) patients into four clinical profiles. Starting from their structural connectivity information, obtained by diffusion tensor imaging and represented as a graph, we evaluate the classification performances using unweighted and weighted connectivity matrices. Furthermore, we investigate the role of graph- based features for a better characterization and classification of the pathology. 90 MS patients (12 clinically isolated syndrome, 30 relapsing-remitting, 28 secondary-progressive, and 20 primary- progressive) along with 24 healthy controls, were considered in this study. This work shows the great performances achieved by neural networks methods in the classification of the clinical profiles. Furthermore, it shows local graph metrics do not improve the classification results suggesting that the latent features created by the neural network in its layers have a much important informative content. Finally, we observe that graph weights representation of brain connections preserve important information to discriminate between clinical forms.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 12, 2019 12:00 AM.
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Using the Wild Bootstrap to Quantify Uncertainty in Mean Apparent Propagator MRI
Purpose: Estimation of uncertainty of MAP-MRI metrics is an important topic, for several reasons. Bootstrap derived uncertainty, such as the standard deviation, provides valuable information, and can be incorporated in MAP-MRI studies to provide more extensive insight. Methods: In this paper, the uncertainty of different MAPMRI metrics was quantified by estimating the empirical distributions using the wild bootstrap. We applied the wild bootstrap to both phantom data and human brain data, and obtain empirical distributions for theMAP-MRImetrics returnto- origin probability (RTOP), non-Gaussianity (NG) and propagator anisotropy (PA). Results: We demonstrated the impact of diffusion acquisition scheme (number of shells and number of measurements per shell) on the uncertainty of MAP-MRI metrics. We demonstrated how the uncertainty of these metrics can be used to improve group analyses, and to compare different preprocessing pipelines. We demonstrated that with uncertainty considered, the results for a group analysis can be different. Conclusion: Bootstrap derived uncertain measures provide additional information to the MAP-MRI derived metrics, and should be incorporated in ongoing and future MAP-MRI studies to provide more extensive insight.
in Frontiers in Neuroinformatics | New and Recent Articles on June 12, 2019 12:00 AM.
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Disparities in Diffuse Cortical White Matter Integrity Between Socioeconomic Groups
There is a growing literature demonstrating a link between lower socioeconomic status (SES) and poorer neuroanatomical health, such as smaller total and regional gray and white matter volumes, as well as greater white matter lesion volumes. Little is known, however, about the relation between SES and white matter integrity. Here we examined the relation between SES and white matter integrity of the brain’s primary cortical regions, and evaluated potential moderating influences of age and self-identified race. Participants were 192 neurologically intact, community-dwelling African American and White adults (mean age = 52 years; 44% male, 60% White, low SES = 52%) from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) SCAN study. Participants underwent 3.0-T cranial magnetic resonance imaging. Diffusion tensor imaging was used to estimate regional fractional anisotropy (FA) to quantify the brain’s white matter integrity and trace to capture diffusivity. Multiple regression analyses examined independent and interactive associations of SES, age, and race with FA of the frontal, temporal, parietal, and occipital lobes bilaterally. Sensitivity analyses assessed the influence of several biopsychosocial risk factors on these associations. Exploratory analyses examined these relations with trace and using additional SES indicators. Results indicated there were no significant interactions of SES, age, and race for any region. Individuals with low SES had lower FA in all regions, and higher trace in the right and left frontal, right and left temporal, and left occipital lobes. Findings remained largely unchanged after inclusion of sensitivity variables. Older age was associated with lower FA and greater trace for all regions, except for the right temporal lobe with FA. No main effects were found for race in FA, and Whites had higher trace values in the parietal lobes. Novel findings of this study indicate that relative to the high SES group, low SES was associated with poorer white matter integrity and greater diffusivity. These results may, in part, reflect exposures to various biopsychosocial risk factors experienced by those of lower SES across the lifespan, and may help explain the preponderance of cognitive and functional disparities between socioeconomic groups.
in Frontiers in Human Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Corrigendum: The Binocular Balance at High Spatial Frequencies as Revealed by the Binocular Orientation Combination Task

in Frontiers in Human Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Neural Correlates of Verbal Working Memory: An fMRI Meta-Analysis
Verbal Working memory (vWM) capacity measures the ability to maintain and manipulate verbal information for a short period of time. The specific neural correlates of this construct are still a matter of debate. The aim of this study was to conduct a coordinate-based meta-analysis of 42 fMRI studies on visual vWM in healthy subjects (n=795, males=459, females=325, unknown=11; age range: 18-75). The studies were obtained after an exhaustive literature search on PubMed, Scopus, Web of Science, and Brainmap database. We analyzed regional activation differences during fMRI tasks with the anisotropic effect-size version of seed-based d mapping software (ES-SDM). The results were further validated by performing jackknife sensitivity analyses and heterogeneity analyses. We investigated the effect of numerous relevant influencing factors by fitting corresponding linear regression models. We isolated consistent activation in a network containing fronto-parietal areas, right cerebellum, and basal ganglia structures. Regarding lateralization, the results pointed towards a bilateral frontal activation, a left-lateralization of parietal regions and a right-lateralization of the cerebellum, indicating that the left-hemisphere concept of vWM should be reconsidered. We also isolated activation in regions important for response inhibition, emphasizing the role of attentional control in vWM. Moreover, we found a significant influence of mean reaction time, load and age on activation associated with vWM. Activation in left medial frontal gyrus, left precentral gyrus and left precentral gyrus turned out to be positively associated with mean reaction time whereas load was associated with activation across the PFC, fusiform gyrus, parietal cortex and parts of the cerebellum. In the latter case activation was mainly detectable in both hemispheres whereas the influence of age became manifest predominantly in the left hemisphere. This led us to conclude that future vWM studies should take these factors into consideration.
in Frontiers in Human Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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The Human Default Consciousness and Its Disruption: Insights From an EEG Study of Buddhist Jhāna Meditation
The “neural correlates of consciousness” (NCC) is a familiar topic in neuroscience, overlapping with research on the brain’s “default mode network”. Task-based studies of NCC by their nature recruit one part of the cortical network to study another, and are therefore both limited and compromised in what they can reveal about consciousness itself. The form of consciousness explored in such research, we term the human default consciousness (DCs), our everyday waking consciousness. In contrast, studies of anaesthesia, coma, deep sleep, or some extreme pathological states such as epilepsy, reveal very different cortical activity; all of which states are essentially involuntary, and generally regarded as “unconscious”. An exception to involuntary disruption of consciousness is Buddhist jhāna meditation, whose implicit aim is to intentionally withdraw from the default consciousness, to an inward-directed state of stillness referred to as jhāna consciousness, as a basis to develop insight. The default consciousness is sensorily-based, where information about, and our experience of, the outer world is evaluated against personal and organic needs and forms the basis of our ongoing self-experience. This view conforms both to Buddhist models, and to the emerging work on active inference and minimisation of free energy in determining the network balance of the human default consciousness. This paper is a preliminary report on the first detailed EEG study of jhāna meditation, with findings radically different to studies of more familiar, less focused forms of meditation. While remaining highly alert and “present” in their subjective experience, a high proportion of subjects display “spindle” activity in their EEG, superficially similar to sleep spindles of stage 2 nREM sleep, while more-experienced subjects display high voltage slow-waves reminiscent, but significantly different, to the slow waves of deeper stage 4 nREM sleep, or even high-voltage delta coma. Some others show brief posterior spike-wave bursts, again similar, but with significant differences, to absence epilepsy. Some subjects also develop the ability to consciously evoke clonic seizure-like activity at will, under full control. We suggest that the remarkable nature of these observations reflects a profound disruption of the human DCs when the personal element is progressively withdrawn.
in Frontiers in Human Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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EEG Microstates Analysis in Young Adults With Autism Spectrum Disorder During Resting-State
Electroencephalography (EEG) is a useful tool to inspect the brain activity in resting-state and allows to characterize spontaneous brain activity that is not detected when a subject is cognitively engaged. Moreover, taking advantage of the high time resolution in EEG, it is possible to perform fast topographical reference-free analysis, since different scalp potential fields correspond to changes in the underlying sources within the brain. In this study, the spontaneous EEG resting-state (eyes closed) was compared between ten young adults ages 18-30 years with Autism Spectrum Disorder (ASD) and thirteen neurotypical controls. A microstate analysis was applied, focusing on four temporal parameters: mean duration, the frequency of occurrence, the ratio of time coverage, and the Global Explained Variance (GEV). Using data that were acquired from a 65 channel EEG system, six resting-state topographies that best describe the dataset across all subjects were identified by running a two-step cluster analysis, labeled as microstate classes A-F. The results indicated that microstates B and E displayed a statistically significant differences between both groups among the temporal parameters evaluated. Classes B, D, E, and F were consistently more present in ASD, and class C in controls. The combination of these findings with the putative functional significance of the different classes suggests that during resting-state, the ASD group was more focused on visual scene-reconstruction, while the control group was more engaged with self-memory retrieval. Furthermore, from a connectivity perspective, the resting-state networks that have been previously associated with each microstate class overlap the brain regions implicated in impaired social communication and repetitive behaviors that characterize ASD.
in Frontiers in Human Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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DC Shifts-fMRI: A Supplement to Event-Related fMRI
Event-related fMRI have been widely used in locating brain regions that respond to specific tasks. However, activities of brain regions which modulate or indirectly participate in the response to a specific task are not event-related. Event-related fMRI can’t locate these regulatory regions, detrimental to the integrity of the result that event-related fMRI revealed. Direct-current EEG shifts (DC shifts) have been found linked to the inner brain activity, a fusion DC shifts-fMRI method may have the ability to reveal a more complete response of the brain. In this study, we used DC shifts-fMRI to verify that even when responding to a very simple task, 1). The response of the brain is complicated than event-related fMRI generally revealed; 2). DC shifts-fMRI have the ability of revealing brain regions whose responses are not in event-related way. We used a classical and simple paradigm which is often used in auditory cortex tonotopic mapping. Data were recorded from 50 subjects (25 male, 25 female) who were presented with randomly presented pure tone sequences with six different frequencies (200, 400, 800, 1600, 3200, 6400 Hz). Our traditional fMRI results are consistent with previous findings that the activations are concentrate on the auditory cortex. Our DC shifts-fMRI results showed that the cingulate-caudate-thalamus network which underpins sustained attention is positively activated while the dorsal attention network and the right middle frontal gyrus which underpin attention orientation are negatively activated. The regional-specific correlations between DC shifts and brain networks indicate the complexity of the response of the brain even to a simple task and that the DC shifts can effectively reflect these non-event-related inner brain activities.
in Frontiers in Computational Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Dynamic Factors for Transmitter Release at Small Presynaptic Boutons Revealed by Direct Patch-Clamp Recordings
Small size of an axon and presynaptic structures have hindered direct functional analysis of axonal signaling and transmitter release at presynaptic boutons in the central nervous system. However, recent technical advances in subcellular patch-clamp recordings and in fluorescent imagings are shedding light on the dynamic nature of axonal and presynaptic mechanisms. Here I summarize the functional design of an axon and presynaptic boutons, such as diversity and activity-dependent changes of action potential waveforms, Ca2+ influx, and kinetics of transmitter release, revealed by the technical tour de force of direct patch-clamp recordings and the leading-edge fluorescent imagings. I highlight the critical factors for dynamic modulation of transmitter release and presynaptic short-term plasticity.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Acetylcholine Release Inhibits Distinct Excitatory Inputs Onto Hippocampal CA1 Pyramidal Neurons via Different Cellular and Network Mechanisms
In hippocampal CA1, muscarinic acetylcholine (ACh) receptor (mAChR) activation via exogenous application of cholinergic agonists has been shown to presynaptically inhibit Schaffer collateral (SC) glutamatergic inputs in stratum radiatum (SR), and temporoammonic (TA) and thalamic nucleus reuniens (RE) glutamatergic inputs in stratum lacunosum-moleculare (SLM). However, steady-state uniform mAChR activation may not mimic the effect of ACh release in an intact hippocampal network. To more accurately examine the effect of ACh release on glutamatergic synaptic efficacy, we measured electrically evoked synaptic responses in CA1 pyramidal cells (PCs) following the optogenetic release of ACh in genetically modified mouse brain slices. The ratio of synaptic amplitudes in response to paired-pulse SR stimulation (stimulus 2/stimulus 1) was significantly reduced by the optogenetic release of ACh, consistent with a postsynaptic decrease in synaptic efficacy. The effect of ACh release was blocked by the M3 receptor antagonist 4-DAMP, the GABAB receptor antagonist CGP 52432, inclusion of GDP-β-S, cesium, QX314 in the intracellular patch clamp solution, or extracellular barium. These observations suggest that ACh release decreased SC synaptic transmission through an M3 muscarinic receptor-mediated increase in inhibitory interneuron excitability, which activate GABAB receptors and inwardly rectifying potassium channels on CA1 pyramidal cells. In contrast, the ratio of synaptic amplitudes in response to paired-pulse stimulation in the SLM was increased by ACh release, consistent with presynaptic inhibition. ACh-mediated effects in SLM were blocked by the M2 receptor antagonist AF-DX 116, presumably located on presynaptic terminals. Therefore, our data indicate that ACh release differentially modulates excitatory inputs in SR and SLM of CA1 through different cellular and network mechanisms.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Hedgehog Pathway Activation Alters Ciliary Signaling in Primary Hypothalamic Cultures
Primary cilia dysfunction has been associated with hyperphagia and obesity in both ciliopathy patients and mouse models of cilia perturbation. Neurons throughout the brain possess these solitary cellular appendages, including in the feeding centers of the hypothalamus. Several cell biology questions associated with primary neuronal cilia signaling are challenging to address in vivo. Here we utilize primary hypothalamic neuronal cultures to study ciliary signaling in relevant cell types. Importantly, these cultures contain neuronal populations critical for appetite and satiety such as pro-opiomelanocortin (POMC) and agouti related peptide (AgRP) expressing neurons and are thus useful for studying signaling involved in feeding behavior. Correspondingly, these cultured neurons also display electrophysiological activity and respond to both local and peripheral signals that act on the hypothalamus to influence feeding behaviors, such as leptin and melanin concentrating hormone (MCH). Interestingly, we found that cilia mediated hedgehog signaling, generally associated with developmental processes, can influence ciliary GPCR signaling (Mchr1) in terminally differentiated neurons. Specifically, pharmacological activation of the hedgehog-signaling pathway using the smoothened agonist, SAG, attenuated the ability of neurons to respond to ligands (MCH) of ciliary GPCRs. Understanding how the hedgehog pathway influences cilia GPCR signaling in terminally differentiated neurons could reveal the molecular mechanisms associated with clinical features of ciliopathies, such as hyperphagia-associated obesity.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Synaptic FUS Localization During Motoneuron Development and Its Accumulation in Human ALS Synapses
Mutations in the Fused in Sarcoma (FUS) gene induce cytoplasmic FUS aggregations, contributing to the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in certain cases. While FUS is mainly a nuclear protein involved in transcriptional processes with limited cytoplasmatic functions, it shows an additional somatodendritic localization in neurons. In this study we analyzed the localization of FUS in motoneuron synapses, these being the most affected neurons in ALS, using super-resolution microscopy to distinguish between the pre- and postsynaptic compartments. We report a maturation based variation of FUS localization in rodent synapses where a predominantly postsynaptic FUS was observed in the early stages of synaptic development, while in mature synapses the protein was entirely localized in the axonal terminal. Likewise, we also show that at the synapse of human motoneurons derived from induced pluripotent stem cells of a healthy control, FUS is mainly postsynaptic in the early developmental stages. In motoneurons derived from ALS patients harboring a very aggressive juvenile FUS mutation, increased synaptic accumulation of mutated FUS was observed. Moreover increased aggregation of other synaptic proteins Bassoon and Homer1 was also detected in these abnormal synapses. Having demonstrated changes in the FUS localization during synaptogenesis, a role of synaptic FUS in both dendritic and axonal cellular compartments is probable, and we propose a gain-of-toxic-function due to the synaptic aggregation of mutant FUS in ALS.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Co-transplantation of Epidermal Neural Crest Stem Cells and Olfactory Ensheathing Cells Repairs Sciatic Nerve Defects in Rats
Cell-based therapy is an alternative strategy to improve outcomes of peripheral nerve injury (PNI). Epidermal neural crest stem cell (EPI-NCSC) is obtained from autologous tissue without immunological rejection, which could expand quickly in vitro and is suitable candidate for cell-based therapy. Olfactory ensheathing cell (OEC) could secrete multiple neurotrophic factors, which is often used to repair PNI individually. However, whether the combination of EPI-NCSC and OEC have better effects on PNI repair remains unclear. Here we use EPI-NCSC and OEC co-transplantation in a rat sciatic nerve defect model to ascertain the effects and potential mechanisms of cells co-transplantation on PNI. The effect of EPI-NCSC and OEC co-transplantation on PNI is assessed by using a combination of immunohistochemistry (IHC), electrophysiological recording and neural function test. Co-transplantation of EPI-NCSC and OEC exerts a beneficial effect upon PNI such as better organized structure, nerve function recovery, and lower motoneuron apoptosis. IHC and ELISA further demonstrate that cells co-transplantation may improve PNI via the expression of BDNF and NGF up-regulated by EPI-NCSC and OEC synergistically. Eventually, the results from this study reveal that EPI-NCSC and OEC co-transplantation effectively repairs PNI through enhancing the level of BDNF and NGF, indicating that cells co-transplantation may serve as a fruitful avenue for PNI in clinic treatment.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Activated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Missorting and Synaptotoxicity
Type 2 diabetes increases the risk for dementia, including Alzheimer’s disease (AD). Pioglitazone (Pio), a pharmacological agonist of the peroxisome proliferator-activated receptor γ (PPARγ), improves insulin sensitivity and has been suggested to have potential in the management of AD symptoms, albeit through mostly unknown mechanisms. We here investigated the potential of Pio to counter synaptic malfunction and loss, a characteristic of AD pathology and its accompanying cognitive deficits. Results from experiments on primary mouse neuronal cultures and a human neural cell line (SH-SY5Y) show that Pio treatment attenuates amyloid β (Aβ)-triggered the pathological (mis-)processing of amyloid precursor protein (APP) and inhibits Aβ-induced accumulation and hyperphosphorylation of Tau. These events are accompanied by increased glutamatergic receptor 2B subunit (GluN2B) levels that are causally linked with neuronal death. Further, Pio treatment blocks Aβ-triggered missorting of hyperphosphorylated Tau to synapses and the subsequent loss of PSD95-positive synapses. These latter effects of Pio are PPARγ-mediated since they are blocked in the presence of GW9662, a selective PPARγ inhibitor. Collectively, these data show that activated PPARγ buffer neurons against APP misprocessing, Tau hyperphosphorylation and its missorting to synapses and subsequently, synaptic loss. These first insights into the mechanisms through which PPARγ influences synaptic loss make a case for further exploration of the potential usefulness of PPARγ agonists in the prevention and treatment of synaptic pathology in AD.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Mental Flexibility Influences the Association Between Poor Balance and Falls in Older People – A Secondary Analysis
Impairments of balance predispose older people to falls. Some cognitive functions, especially executive functioning have been shown to affect balance and discriminate fallers from non-fallers. Mental flexibility is a component of the executive function and comprises multiple cognitive processes that work together to adjust the course of thoughts or actions according to the changing demands of a situation without the use of explicit instructions. However, the role of mental flexibility in balance in older people remains unclear. Mental flexibility comprises complementary cognitive functions required for dealing with unpredictable environmental demands. The study aim was to examine the relationship between mental flexibility and falls in a cohort of 212 older people (80.6 ±4.9 years; 62% female). We hypothesized that: (i) participants with impaired balance would have worse mental flexibility compared to those with good balance; and (ii) poor mental flexibility would predict falls in the sub-group with impaired balance. Balance performance was assessed by measuring postural sway while standing on a medium density foam mat with eyes open for 30 seconds. Mental flexibility was assessed using a computerized short-form of the Wisconsin Card Sorting Test (WCST; 64 cards) with its sub-components comprising general performance, perseveration, failure-to-maintain set and conceptual ability. Falls were measured prospectively for 12-months using monthly calendars. MANCOVA revealed that WCST performance was associated with balance (Wilks’ Lambda = 0.883, F=2.168; p=0.013, partial eta squared (η2p) =.061) due primarily to reduced concept formation ability (F2,207=5.787, p=0.004, η2p =.053). Negative binomial regression analysis adjusting for age, education, contrast sensitivity, proprioception, inhibition and inhibitory choice stepping reaction time revealed that lower concept formation ability was predictive for falls (Incidence Rate Ratio 1.0648 (95% confidence interval 1.0316-1.08199)). Further, lower concept formation ability partly explained the association between balance and falls: i.e. fallers in the upper balance tertile had reduced concept formation performance whereas non-fallers had similar concept formation performance across the three balance tertiles. These findings suggest that poor mental flexibility affects the ability to maintain steady balance contributing to increased risk of falls in older people.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Erratum: Cingulate Cortex Atrophy Is Associated With Hearing Loss in Presbycusis With Cochlear Amplifier Dysfunction

in Frontiers in Aging Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Insulin Resistance Is a Risk Factor for Overall Cerebral Small Vessel Disease Burden in Old Nondiabetic Healthy Adult Population
Background and Purpose：This study aimed to investigate whether insulin resistance (IR) was associated with overall cerebral small vessel disease (CSVD) burden, independent of other clinical risk factors in old nondiabetic healthy subjects. Methods: We recruited old nondiabetic healthy subjects with no taking any medications prospectively. The overall effect of CSVD on the brain was described by validated CSVD score. The homeostasis model assessment–estimated insulin resistance index(HOMA-IR) was used for IR estimation, and HOMA-IR ≥2.80 was defined as IR. We evaluated the association between IR and increasing severity of CSVD score by ordinal regression models, adjusted for demographics and cardiovascular risk factors. Results: Our study included 156 healthy participants. 34 showed IR, 122 showed non-IR. The mean age of the IR group was older than non-IR group(70.03± 7.30 versus 67.45 ±5.92, p=0.04), and the ratio of hypertension in IR was higher than non-IR.( 53.28% versus 82.35%, p<0.01). The distribution of lacunar, CMB, EPVS and CSVD score was different between 2 groups, but the WMH. In ordinal regression analysis, IR was positively associated with increasing severity of the total CSVD score (adjusted odds ratio 3.74, 95%CI was 1.63-5.08, and p<0.01 ) after adjusting for traditional risk factors. Furthermore, HOMA-IR levels revealed a positive dose-dependent correlation with the total CSVD score(p <0.01, p for trend <0.01). Conclusions: IR was independently associated with increasing severity of overall CSVD burden, independent of other clinical risk factors in nondiabetic healthy adult population. Furthermore, HOMA-IR level is correlated with CSVD burden in a dose-dependent manner.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 12, 2019 12:00 AM.
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Apamin Improves Prefrontal Nicotinic Impairment in Mouse Model of Alzheimer’s Disease

Abstract
Disruption of attention is an early and disabling symptom of Alzheimer’s disease (AD). The underlying cellular mechanisms are poorly understood and treatment options for patients are limited. These early attention deficits are evident in the TgCRND8 mouse, a well-established murine model of AD that recapitulates several features of the disease. Here, we report severe impairment of the nicotinic receptor–mediated excitation of prefrontal attentional circuitry in TgCRND8 mice relative to wild-type littermate controls. We demonstrate that this impairment can be remedied by apamin, a bee venom neurotoxin peptide that acts as a selective antagonist to the SK family of calcium-sensitive potassium channels. We probe this seeming upregulation of calcium-sensitive inhibition and find that the attenuated nicotinic firing rates in TgCRND8 attention circuits are mediated neither by greater cellular calcium signals nor by elevated SK channel expression. Instead, we find that TgCRND8 mice show enhanced functional coupling of nicotinic calcium signals to inhibition. This SK-mediated inhibition exerts a powerful negative feedback on nicotinic excitation, dampening attention-relevant signaling in the TgCRND8 brain. These mechanistic findings identify a new cellular target involved in the modulation of attention and a novel therapeutic target for early attention deficits in AD.
in Cerebral Cortex Advance Access on June 12, 2019 12:00 AM.
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A VTA GABAergic Neural Circuit Mediates Visually Evoked Innate Defensive Responses
Zhou et al. identified a neural circuit related to VTAGABA+ neurons that mediates visually evoked innate defensive responses, involving the SCGlut+- VTAGABA+-CeA pathway.
in Neuron on June 12, 2019 12:00 AM.
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Prefrontal Cortex Regulates Sensory Filtering through a Basal Ganglia-to-Thalamus Pathway
Making sense of a noisy world depends on active filtering of behaviorally relevant sensory information. Nakajima et al. illuminates a pathway that implements this function, demonstrating how control circuits regulate early sensory processing to suppress distractors and improve behaviorally relevant signals.
in Neuron on June 12, 2019 12:00 AM.
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Parallel scalable simulations of biological neural networks using TensorFlow: A beginner's guide. (arXiv:1906.03958v1 [q-bio.NC])

Neuronal networks are often modeled as systems of coupled, nonlinear, ordinary or partial differential equations. The number of differential equations used to model a network increases with the size of the network and the level of detail used to model individual neurons and synapses. As one scales up the size of the simulation it becomes important to use powerful computing platforms. Many tools exist that solve these equations numerically. However, these tools are often platform specific. There is a high barrier of entry to developing flexible general purpose code that is platform independent and supports hardware acceleration on modern computing architectures such as GPUs/TPUs and Distributed Platforms. TensorFlow is a Python-based open-source package initially designed for machine learning algorithms, but it presents a scalable environment for a variety of computations including solving differential equations using iterative algorithms such as Runge Kutta methods. In this article, organized as a series of tutorials, we present a simple exposition of numerical methods to solve ordinary differential equations using Python and TensorFlow. It consists of a series of Python notebooks that, over the course of five sessions, will lead novice programmers from writing programs to integrate simple 1-dimensional differential equations using Python, to solving a large system (1000's of differential equations) of conductance-based neurons using a highly parallel and scalable framework. Embedded within the tutorial is a physiologically realistic implementation of a network in the insect olfactory system. This system, consisting of multiple neuron and synapse types, can serve as a template to simulate other networks.

in q-bio.NC updates on arXiv.org on June 11, 2019 01:30 AM.
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Secrets of the Brain: An Introduction to the Brain Anatomical Structure and Biological Function. (arXiv:1906.03314v1 [q-bio.NC])

In this paper, we will provide an introduction to the brain structure and function. Brain is an astonishing living organ inside our heads, weighing about 1.5kg, consisting of billions of tiny cells. The brain enables us to sense the world around us (to touch, to smell, to see and to hear, etc.), to think and to respond to the world as well. The main obstacles that prevent us from creating a machine which can behavior like real-world creatures are due to our limited knowledge about the brain in both its structure and its function. In this paper, we will focus introducing the brain anatomical structure and biological function, as well as its surrounding sensory systems. Many of the materials used in this paper are from wikipedia and several other neuroscience introductory articles, which will be properly cited in this article. This is the first of the three tutorial articles about the brain (the other two are [26] and [27]). In the follow-up two articles, we will further introduce the low-level composition basis structures (e.g., neuron, synapse and action potential) and the high-level cognitive functions (e.g., consciousness, attention, learning and memory) of the brain, respectively.

in q-bio.NC updates on arXiv.org on June 11, 2019 01:30 AM.
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Corrigendum: Patch-Seq Protocol to Analyze the Electrophysiology, Morphology and Transcriptome of Whole Single Neurons Derived From Human Pluripotent Stem Cells

in Frontiers in Molecular Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Effects of the LPA1 Receptor Deficiency and Stress on the Hippocampal LPA Species in Mice
Lysophosphatidic acid (LPA) is an important bioactive lipid species that functions in intracellular signaling through six characterized G protein-coupled receptors (LPA1–6). Among these receptors, LPA1 is a strong candidate to mediate the central effects of LPA on emotion and may be involved in promoting normal emotional behaviors. Alterations in this receptor may induce vulnerability to stress and predispose an individual to a psychopathological disease. In fact, mice lacking the LPA1 receptor exhibit emotional dysregulation and cognitive alterations in hippocampus-dependent tasks. Moreover, the loss of this receptor results in a phenotype of low resilience with dysfunctional coping in response to stress and induces anxiety and several behavioral and neurobiological changes that are strongly correlated with mood disorders. In fact, our group proposes that maLPA1-null mice represent an animal model of anxious depression. However, despite the key role of the LPA-LPA1-pathway in emotion and stress coping behaviors, the available information describing the mechanisms by which the LPA-LPA1-pathway regulates emotion is currently insufficient. Because activation of LPA1 requires LPA, here, we used a Matrix-Assisted Laser Desorption/ Ionization mass spectrometry-based approach to evaluate the effects of an LPA1 receptor deficiency on the hippocampal levels of LPA species. Additionally, the impact of stress on the LPA profile was also examined in both wild-type (WT) and the Malaga variant of LPA1-null mice (maLPA1-null-mice). Mice lacking LPA1 did not exhibit gross perturbations in the hippocampal LPA species, but the LPA profile was modified, showing an altered relative abundance of 18:0 LPA. Regardless of the genotype, restraint stress produced profound changes in all LPA species examined, revealing that hippocampal LPA species are a key target of stress. Finally, the relationship between the hippocampal levels of LPA species and performance in the elevated plus maze was established. To our knowledge, this study is the first to detect, identify and profile LPA species in the hippocampus of both LPA1-receptor null mice and WT mice at baseline and after acute stress, as well as to link these LPA species with anxiety-like behaviors. In conclusion, the hippocampal LPA species are a key target of stress and may be involved in psychopathological conditions.
in Frontiers in Molecular Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Neuroprotection by Therapeutic Hypothermia
Hypothermia therapy is an old and important method of neuroprotection. Until now, many neurological diseases such as stroke, traumatic brain injury, intracranial pressure elevation, subarachnoid hemorrhage, spinal cord injury, hepatic encephalopathy, and neonatal peripartum encephalopathy have proven to be suppressed by therapeutic hypothermia. Beneficial effects of therapeutic hypothermia have also been discovered, and progress has been made towards improving the benefits of therapeutic hypothermia further through combinations with other neuroprotective treatments and by probing the mechanism of hypothermia neuroprotection. In this review, we compare different hypothermia induction methods and provide a summarized account of the synergistic effect of hypothermia therapy with other neuroprotective treatments along with an overview of hypothermia neuroprotection mechanisms and cold/hypothermia-induced proteins.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 11, 2019 12:00 AM.
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Spatial Resolution and Imaging Encoding fMRI Settings for Optimal Cortical and Subcortical Motor Somatotopy in the Human Brain
There is much controversy about the optimal trade-off between blood-oxygen-level-dependent (BOLD) sensitivity and spatial precision in experiments on brain’s topology properties using functional magnetic resonance imaging (fMRI). The sparse empirical evidence and regional specificity of these interactions pose a practical burden for the choice of imaging protocol parameters. Here, we test in a motor somatotopy experiment the impact of fMRI spatial resolution on differentiation between body part representations in cortex and subcortical structures. Motor somatotopy patterns were obtained in a block-design paradigm and visually cued movements of face, upper and lower limbs at 1.5, 2 and 3 mm3 spatial resolution. The degree of segregation of the body parts’ spatial representations was estimated using a pattern component model. In cortical areas, we observed the same level of segregation between somatotopy maps across all three resolutions. In subcortical areas the degree of effective similarity between spatial representations was significantly impacted by the image resolution. The 1.5 mm 3D EPI and 3 mm 2D EPI protocols led to higher segregation between motor representations compared to the 2 mm 3D EPI protocol. This finding could not be attributed to differential BOLD sensitivity or delineation of functional areas alone and suggests a crucial role of the image encoding scheme (2D vs 3D EPI). Our study contributes to the field by providing empirical evidence about the impact of acquisition protocols for the delineation of somatotopic areas in cortical and sub-cortical brain regions.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 11, 2019 12:00 AM.
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Microstates as Disease and Progression Markers in Patients With Mild Cognitive Impairment
Network dysfunction is well established in patients with Alzheimer’s disease (AD) and has been shown to be present early in the disease. This is especially interesting in patients with mild cognitive impairment (MCI) since the majority later develop AD. In EEG, one type of network analysis is microstates where the EEG is divided into quasi-stable states and these microstates have been linked to networks found with resting state functional MRI. In the current exploratory study, we therefore wanted to explore the changes in microstates in MCI, and AD compared to healthy controls (HC) and whether microstates were able to separate patients with MCI who progressed (pMCI) and those who remained stable (sMCI). EEGs were recorded at baseline for 17 patients with AD, 27 patients with MCI, and 38 older HC and the patients were followed for three years. To investigate whole-brain dynamics we extracted different microstate parameters. We found that patients with MCI, and AD had significantly higher occurrence (p-value = 0.028), and coverage (p-value = 0.010) for microstate A compared to HC. However, we did not find any significant systematic deviation of the transition probabilities from randomness for any of the groups. No significant differences were found between pMCI and sMCI but the largest difference in duration was found for microstate C. Microstate A has been linked to the temporal lobes in studies combining EEG and fMRI and the temporal lobes are the most affected by AD pathology in the early stages of the disease. This supports our idea that microstate A may be the first affected microstate in early AD. Even though not significant between pMCI and sMCI, Microstate C has previously been shown to be associated with the cingulate gyri in fMRI and studies have found that posterior cingulate cortex is associated with progression from MCI to AD. However, larger studies are needed to confirm these findings.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 11, 2019 12:00 AM.
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Proteomics Approaches for Biomarker and Drug Target Discovery in ALS and FTD
Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasing in prevalence but lack targeted therapeutics. Although the pathological mechanisms behind these diseases remain unclear, both ALS and FTD are characterized pathologically by aberrant protein aggregation and inclusion formation within neurons, which correlates with neurodegeneration. Notably, aggregation of several key proteins, including TAR DNA binding protein of 43 kDa (TDP-43), superoxide dismutase 1 (SOD1), and tau, have been implicated in these diseases. Proteomics methods are being increasingly applied to better understand disease-related mechanisms and to identify biomarkers of disease, using model systems as well as human samples. Proteomics-based approaches offer unbiased, high-throughput, and quantitative results with numerous applications for investigating proteins of interest. Here, we review recent advances in the understanding of ALS and FTD pathophysiology obtained using proteomics approaches, and we assess technical and experimental limitations. We compare findings from various mass spectrometry approaches including quantitative proteomics methods such as stable isotope labelling by amino acids in cell culture (SILAC) and tandem mass tagging (TMT) to approaches such as label-free quantitation (LFQ) and sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) in studies of ALS and FTD. Similarly, we describe disease-related protein-protein interaction (PPI) studies using approaches including immunoprecipitation mass spectrometry (IP-MS) and proximity dependent biotin identification (BioID) and discuss future application of new techniques including proximity-dependent ascorbic acid peroxidase labelling (APEX) and biotinylation by antibody recognition (BAR). Furthermore, we explore the use of mass spectrometry to detect post-translational modifications, such as ubiquitination and phosphorylation, of disease-relevant proteins in ALS and FTD. We also discuss upstream technologies that enable enrichment of proteins of interest, highlighting the contributions of new techniques to isolate disease-relevant protein inclusions including flow cytometric analysis of inclusions and trafficking (FloIT). These recently developed approaches, as well as related advances yet to be applied to studies of these neurodegenerative diseases, offer numerous opportunities for discovery of potential therapeutic targets and biomarkers for ALS and FTD.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 11, 2019 12:00 AM.
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Modeling the Switching Behavior of Functional Connectivity Microstates (FCμstates) as a Novel Biomarker for Mild Cognitive Impairment
It is evident the need for designing and validating novel biomarkers for the detection of mild cognitive impairment (MCI). MCI patients have a high risk of developing Alzheimer’s disease (AD), and for that reason the introduction of novel and reliable biomarkers is of significant clinical importance. Motivated by recent findings about the rich information of dynamic functional connectivity graphs (DFCGs) about brain (dys)function, we introduced a novel approach of identifying MCI based on magnetoencephalographic (MEG) resting state recordings. The activity of different brain rhythms {δ, θ, α1, α2, β1, β2, γ1, γ2} was first beamformed with linear constrained minimum norm variance in the MEG data to determine ninety anatomical regions of interest (ROIs). A dynamic functional connectivity graph (DFCG) was then estimated using the imaginary part of phase lag value (iPLV) for both intra-frequency coupling (8) and also cross-frequency coupling pairs (28). We analysed DFCG profiles of neuromagnetic resting state recordings of 18 Mild Cognitive Impairment (MCI) patients and 20 healthy controls. We followed our model of identifying the dominant intrinsic coupling mode (DICM) across MEG sources and temporal segments that further leads to the construction of an integrated DFCG (iDFCG). We then filtered statistically and topologically every snapshot of the iDFCG with data-driven approaches. Estimation of the normalized Laplacian transformation for every temporal segment of the iDFCG and the related eigenvalues created a 2D map based on the network metric time series of the eigenvalues (NMTSeigs). NMTSeigs preserves the non-stationarity of the fluctuated synchronizability of iDCFG for each subject. Employing the initial set of 20 healthy elders and 20 MCI patients, as training set, we built an overcomplete dictionary set of network microstates (nμstates). Afterward, we tested the whole procedure in an extra blind set of 20 subjects for external validation. We succeeded a high classification accuracy on the blind dataset (85 %) which further supports the proposed Markovian modelling of the evolution of brain states. The adaptation of appropriate neuroinformatic tools that combine advanced signal processing and network neuroscience tools could manipulate properly the non-stationarity of time-resolved FC patterns revealing a robust biomarker for MCI.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 11, 2019 12:00 AM.
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Short Version Dental Anxiety Inventory Score May Predict the Response in the Insular Cortex to Stimuli Mimicking Dental Treatment
Background Dental anxiety is a common reason for avoiding dental visits and is associated with poor dental status. The short version of Dental Anxiety Inventory is an easy-to-use, multi-faceted questionnaire for assessing the level of trait dental anxiety. However, there was no neurophysiological data indicating if its score associates with the state anxiety when an individual is under real / mock dental environment. We hypothesized that there exists such an association. Materials and methods Twenty systemic healthy adults with dental attendance experience and self-claimed free of dental phobia were recruited in this cross-sectional study, with their dental anxiety level assessed by short version of Dental Anxiety Inventory. Functional magnetic resonance imaging recorded their brain signals in response to audiovisual footages resembling dental scaler or turbine in action. After the brain imaging, they gave fear ratings to the footages in visual analog scale. Results Participants’ short version of Dental Anxiety Inventory scores positively correlated with their responses in the insular cortex (r2 = 0.388–0.445, P < 0.005). Their short version of Dental Anxiety Inventory scores also positively correlated with their fear ratings of the footages (r2 = 0.415–0.555, P < 0.005). Discussion Our findings indicated a possible neurobiological relevance of short version of Dental Anxiety Inventory, and reinforced its neurobiological validity in assessing dental anxiety level of dental attenders.
in Frontiers in Human Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Exploring the Neural Correlates in Adopting a Realistic View: A Neural Structural and Functional Connectivity Study With Female Nurses
Empathizing leads to positive and negative consequences. To avoid empathy-induced distress, adopting a realistic view (dealing with a situation practically and efficiently independent of one’s emotional state) is important. We hypothesized that empathy-demanding professions (e.g., nursing) may require individuals to adopt a realistic view, which may demonstrate modulated neural structure and functional connectivity. We confirmed that female nurses showed a higher tendency, compared to controls, to adopt a realistic view, using the Fantasy subscale of the Interpersonal Reactivity Index (inverse scale of the realistic view). We then employed voxel-based morphometry and resting-state functional magnetic resonance imaging to explore the neural underpinnings related to realistic view adoption. Nurses exhibited significantly lower gray-matter volume (GMV) in the right striatum. In multiple regression analysis, only the Fantasy subscale score showed a significant positive correlation with GMV within the striatum cluster. Moreover, nurses exhibited lower functional connectivity between the right striatum and the right lateral prefrontal cortex (PFC), representing emotional regulation. These findings show that structural differences in the striatum correlated with the realistic view. Furthermore, lower functional connectivity between the striatum and lateral PFC suggests that nurses may use efficient coping strategies that may lessen the recruitment of effortful emotional regulation.
in Frontiers in Human Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Motor Imagery of Speech: The Involvement of Primary Motor Cortex in Manual and Articulatory Motor Imagery
Motor imagery refers to the phenomenon of imagining performing an action without action execution. Motor imagery and motor execution are assumed to share a similar underlying neural system that involves primary motor cortex (M1). Previous studies have focused on motor imagery of manual actions, but articulatory motor imagery has not been investigated. In this study, transcranial magnetic stimulation (TMS) was used to elicit motor-evoked potentials (MEPs) from the articulatory muscles (orbicularis oris) as well as from hand muscles (first dorsal interosseous). Twenty participants were asked to execute or imagine performing a simple squeezing task involving a pair of tweezers, which was comparable across both effectors. MEPs were elicited at six timepoints (50, 150, 250, 350, 450, 550ms post-stimulus) to track the time-course of M1 involvement in both lip and hand tasks. The results showed increased MEP amplitudes for action execution compared to rest for both effectors at time points 350, 450 and 550ms, but we found no evidence of increased cortical activation for motor imagery. The results indicate that motor imagery does not involve M1 for simple tasks for manual or articulatory muscles. The results have implications for models of mental imagery of simple articulatory gestures, in that no evidence is found for somatotopic activation of lip muscles in sub-phonemic contexts during motor imagery of such tasks, suggesting that motor simulation of relatively simple actions does not involve M1.
in Frontiers in Human Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Low Prefrontal GABA Levels Are Associated With Poor Cognitive Functions in Professional Boxers
Cognitive dysfunction has long been recognized as a frequently observed symptom in individuals with repetitive mild traumatic brain injury (rmTBI) such as professional boxers. The exact neurobiological mechanisms underlying this cognitive deficit have not yet been identified, but it is agreed upon that the prefrontal cortex (PFC) is one of the most commonly affected brain regions in professional boxers. Noting the pivotal role of the two major brain metabolites in human cognitive functions, γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx), we hypothesized that alterations in levels of GABA and Glx in the PFC would be prominent and may correlate with cognitive deficits in professional boxers. Twenty male professional boxers (Boxers) and 14 age-matched healthy males who had never experienced any traumatic brain injury (CON) were recruited. Using a 3T MRI scanner, single-voxel proton magnetic resonance spectroscopy with Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence was performed to evaluate the levels of GABA and Glx in the PFC. Cognitive function was assessed using the memory and attention domains from the Cambridge Neuropsychological Test Automated Battery. The Boxers showed lower GABA level in the PFC compared to the CON, while also showing lower performance in the attention and memory domains. There were no significant between-group differences in Glx levels. Furthermore, the GABA level correlated with memory performance in the Boxers, but not in attention performance. The current findings may suggest that alterations in GABA levels in the PFC may be a potential neurochemical correlate underlying memory dysfunction related to rmTBI.
in Frontiers in Human Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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EEG-Based Prediction of Cognitive Load in Intelligence Tests
Measuring and assessing the cognitive load associated with different tasks is crucial for many applications, from the design of instructional materials to monitoring the mental well-being of aircraft pilots. The goal of this paper is to utilize EEG to infer the cognitive workload of subjects during intelligence tests. We chose the well established advanced progressive matrices test, an ideal work-frame because it presents problems at increasing levels of difficulty, and has been rigorously validated in past experiments. We train classic machine learning models using basic EEG measures as well as measures of network connectivity and signal complexity. Our findings demonstrate that cognitive load can be well predicted using these features, even for a low number of channels. We show that by creating an individually tuned neural network for each subject, we can improve prediction compared to a general model and that such models are robust to decreasing the number of available channels as well.
in Frontiers in Human Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Touching! An Augmented Reality System for Unveiling Face Topography in Very Young Children
Developmental body topography, particularly of the face, is a fundamental research topic in the current decade. However, empirical investigation of this topic for very young children faces a number of difficulties related to the task requirements and technical procedures. In this study, we developed a new task to study the spatially-sensed position of facial parts in a self-face recognition task for 2.5- and 3.5-year-old children. Using the technique of augmented reality (AR) and 3D face tracking technology, we presented participants with their projected self-image on a screen, accompanied by a digital mark located on parts of their face. We prepared a cheerful visual and auditory reward on the screen when participants showed correct localization of the mark. We then tested whether they could indicate the position of the mark on their own faces and remain motivated for task repetition. To assess the efficacy of this task, thirty-one 2.5- and eleven 3.5-year-old children participated in this study. About half of the 2.5-year-olds and 80% of the 3.5-year-olds could perform more than 30 trials. Our new task, then, was to maintain young children’s motivation for task repetition using the cheerful visual and auditory reward. The analysis of localization errors suggested the uniqueness of spatial knowledge of self-face in young children. The efficacy of this new task for studying the development of body image has been confirmed.
in Frontiers in Human Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Ability-Based Emotional Intelligence Is Associated With Greater Cardiac Vagal Control and Reactivity
Several distinct models of Emotional Intelligence (EI) have been developed over the past two decades. The ability model conceptualizes EI as a narrow set of interconnected, objectively measured, cognitive-emotional abilities, including the ability to perceive, manage, facilitate, and understand the emotions of the self and others. By contrast, trait or mixed models focus on subjective ratings of emotional/social competencies. Theoretically, EI is associated with neurobiological processes involved in emotional regulation and reactivity. The neurovisceral integration (NVI) model proposes a positive relationship between cardiac vagal control (CVC) and cognitive-emotional abilities similar to those encompassed by EI. The current study examined the association between CVC and EI. Because ability EI is directly tied to actual performance on emotional tasks, we hypothesized that individuals with higher ability-based EI scores would show greater levels of CVC at rest, and in response to a stressful task. Because mixed-models of EI are not linked directly to observable emotional behavior, we predicted no association with CVC. Consistent with expectations, individuals with higher levels of ability EI, but not mixed EI, had higher levels of CVC. We also found that individuals with greater levels of CVC who demonstrated reactivity to a stress induction had significantly higher EI compared to individuals that did not respond to the stress induction. Our findings support the theoretically-expected overlap between constructs within the NVI model and ability EI model, however, the observed effect size was small, and the associations between EI and CVC should not be taken to indicate a causal connection. Results suggest that variance in the ability to understand emotional processes in oneself and to reason about one’s visceral experience may facilitate better CVC. Future work manipulating either CVC or EI may prove informative in teasing apart the causal role driving their observed relationship.
in Frontiers in Human Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Inner Ear Therapeutics: An Overview of Middle Ear Delivery
There are a variety of methods to access the inner ear and many of these methods depend on utilizing the middle ear as a portal. In this approach the middle ear can be used as a passive receptacle, as part of an active drug delivery system, or simply as the most convenient way to access the inner ear directly in human subjects. The purpose of this volume is to examine some of the more cutting-edge approaches to treating the middle ear. Before considering these therapies, this manuscript provides an overview of some therapies that have been delivered through the middle ear both in the past and at the current time. This manuscript also serves as a review of many of the methods for accessing the inner ear that directly utilize or pass though the middle ear. This manuscript provides the reader a basis for understanding middle ear delivery, the basis of delivery of medicines via cochlear implants, and examines the novel approach of using hypothermia as a method of altering the responses of the inner ear to damage.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Alzheimer’s Disease Associated Genes Ankyrin and Tau Cause Shortened Lifespan and Memory Loss in Drosophila
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by intracellular neurofibrillary tangles of hyperphosphorylated Tau, including the 0N4R isoform and accumulation of extracellular amyloid beta (ABeta) plaques. However less than 5% of AD cases are familial, with many addition risk factors contributing to AD including ageing, lifestyle, the environment and epigenetics. Recent epigenome-wide association studies (EWAS) of AD have identified a number of loci that are differentially methylated in the AD cortex. Indeed, hypermethylation and reduced expression of the Ankyrin 1 (ANK1) gene in AD has been reported in the cortex in numerous different post-mortem brain cohorts. Little is known about the normal function of ANK1 in the healthy brain, nor the role it may play in AD. We have generated Drosophila models to allow us to functionally characterize Drosophila Ank2, the ortholog of human ANK1 and to determine its interaction with human Tau and ABeta. We show expression of human Tau 0N4R or the oligomerizing ABeta 42 amino acid peptide caused shortened lifespan, degeneration, disrupted movement, memory loss and decreased excitability of memory neurons with co-expression tending to make the pathology worse. We find that Drosophila with reduced neuronal Ank2 expression have shortened lifespan, reduced locomotion, reduced memory and reduced neuronal excitability similar to flies overexpressing either human Tau 0N4R or ABeta42. Therefore, we show that the mis-expression of Ank2 can drive disease relevant processes and phenocopy some features of AD. Therefore, we propose targeting human ANK1 may have therapeutic potential. This represents the first study to characterize a gene implicated in AD, which was nominated from EWAS.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Merkel Cells Release Glutamate Following Mechanical Stimulation: Implication of Glutamate in the Merkel Cell-Neurite Complex
Merkel cells (MCs) have been proposed to form a part of the MC-neurite complex with sensory neurons. Although recent evidence has indicated that mechano-sensitive ion channels, such as transient receptor potential channels and Piezo channels, contribute to the mechanosensory transduction in MCs, the detailed mechanism for intercellular communication between MCs and neurons have yet to be clarified. The present study examined the increases in intracellular free Ca2+ concentration ([Ca2+]i) induced by direct mechanical stimulation of MCs. We also measured [Ca2+]i in the trigeminal ganglion neurons (TGs) following direct mechanical stimulation to the MCs in an MC-TGs coculture. The MCs were isolated from hamster buccal mucosa, while TGs were isolated from neonatal Wistar rats. Both cell populations showed depolarization-induced [Ca2+]i. Direct mechanical stimulation to MCs increased [Ca2+]i, showing stimulation strength dependence. In the MC-TGs coculture, the application of direct mechanical stimulation to MCs resulted in increased [Ca2+]i in the TGs. These changes were significantly suppressed by antagonists of glutamate-permeable anion channels (4,4'-diisothiocyanato-2,2'-stilbenedisulfonic acid; DIDS), and non-competitive antagonist of the N-Methyl-D-aspartate (NMDA) receptors (MK801). Apyrase, an ATP-degrading enzyme, and suramin, a non-selective P2 purinergic receptor antagonist, did not exert inhibitory effects on these [Ca2+]i increases in the TGs following MC stimulation. These results indicated that MCs are capable of releasing glutamate, but not ATP, in response to cellular deformation by direct mechanical stimulation. The released glutamate activates the NMDA receptors on TGs. We suggest that MCs act as mechanoelectrical transducers and establish synaptic transmission with neurons, through the MC-neurite complex, to mediate mechanosensory transduction.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking
Meningioma expressed antigen 6 (MEA6), also called cutaneous T cell lymphoma-associated antigen 5 (cTAGE5), was initially found in tumor tissues. MEA6 is located in endoplasmic reticulum (ER) exit sites and regulates the transport of collagen, very low density lipoprotein, and insulin. It is also reported that MEA6 might be related to Fahr’s syndrome, which comprises neurological, movement, and neuropsychiatric disorders. Here, we show that MEA6 is critical to cerebellar development and motor performance. Mice with conditional knockout of MEA6 (Nestin-Cre;MEA6F/F) display smaller sizes of body and brain compared to control animals, and survive maximal 28 days after birth. Immunohistochemical and behavioral studies demonstrate that these mutant mice have defects in cerebellar development and motor performance. In contrast, PC deletion of MEA6 (pCP2-Cre;MEA6F/F) causes milder phenotypes in cerebellar morphology and motor behaviors. While pCP2-Cre;MEA6F/F mice have normal lobular formation and gait, they present the extensive self-crossing of PC dendrites and damaged motor learning. Interestingly, the expression of key molecules that participates in cerebellar development, including Slit2 and brain derived neurotrophic factor (BDNF), is significantly increased in ER, suggesting that MEA6 ablation impairs ER function and thus these proteins are arrested in ER. Our study provides insight into the roles of MEA6 in the brain and the pathogenesis of Fahr’s syndrome.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Sphingolipids as Emerging Mediators in Retina Degeneration
The sphingolipids ceramide (Cer), sphingosine-1-phosphate (S1P), sphingosine (Sph) and ceramide-1-phosphate (C1P) are key signaling molecules that regulate major cellular functions. Their roles in the retina have gained increasing attention during the last decade since they emerge as mediators of proliferation, survival, migration, neovascularization, inflammation and death in retina cells. As exacerbation of these processes is central to retina degenerative diseases, they appear as crucial players in their progression. This review analyzes the functions of these sphingolipids in retina cell types and their possible pathological roles. Cer appears as a key arbitrator in diverse retinal pathologies; it promotes inflammation in endothelial and retina pigment epithelium (RPE) cells and its increase is a common feature in photoreceptor death in vitro and in animal models of retina degeneration; noteworthy, inhibiting Cer synthesis preserves photoreceptor viability and functionality. In turn, S1P acts as a double edge sword in the retina. It is essential for retina development, promoting the survival of photoreceptors and ganglion cells and regulating proliferation and differentiation of photoreceptor progenitors. However, S1P has also deleterious effects, stimulating migration of Müller glial cells, angiogenesis and fibrosis, contributing to the inflammatory scenario of proliferative retinopathies and age related macular degeneration (AMD). C1P, as S1P, promotes photoreceptor survival and differentiation. Collectively, the expanding role for these sphingolipids in the regulation of critical processes in retina cell types and in their dysregulation in retina degenerations makes them attractive targets for treating these diseases.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Ketamine Within Clinically Effective Range Inhibits Glutamate Transmission From Astrocytes to Neurons and Disrupts Synchronization of Astrocytic SICs
Background: Astrocytes are now considered as crucial modulators of neuronal synaptic transmission. General anesthetics have been found to inhibit astrocytic activities, but it is not clear whether general anesthetics within the clinical concentration range affects the astrocyte-mediated synaptic regulation. Methods: The effects of propofol, dexmedetomidine, and ketamine within clinically effective ranges on the slow inward currents (SICs) were tested by using the whole-cell recording in acute prefrontal cortex (PFC) slice preparations of rats. Astrocytes culture and HPLC were used to measure the effects of different anesthetics on the glutamate release of astrocytes. Results: Propofol and dexmedetomidine showed no significant effect on the amplitude or frequency of SICs. Ketamine was found to inhibit the frequency of SICs in a concentration-dependent manner. The SICs synchronization rate of paired neurons was inhibited by 30 μM ketamine (from 42.5 ± 1.4% to 9.6 ± 0.8%) and was abolished by 300 μM ketamine. The astrocytic glutamate release induced by DHPG, an agonist of astrocytic type I metabotropic glutamate receptors, was not affected by ketamine, and ifenprodil, a selective antagonist of GluN1/GluN2B receptor, blocked all SICs and enhanced the inhibitory effect of 30 μM ketamine on the frequency of SICs. Ketamine at low concentration (3 μM) could inhibit the frequency of SICs, not the miniature excitatory postsynaptic currents (mEPSCs), and the inhibition rate of SICs was significantly higher than mEPSCs with 30 μM ketamine (44.5 ± 3% inhibition vs. 28.3 ± 6% inhibition). Conclusions: Our data indicated that ketamine, not propofol and dexmedetomidine, within clinical concentration range inhibits glutamatergic transmission from astrocytes to neurons, which is likely mediated by the extrasynaptic GluN1/GluN2B receptor activation.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Commentary: The Nomenclature of Human White Matter Association Pathways: Proposal for a Systematic Taxonomic Anatomical Classification

in Frontiers in Neuroanatomy | New and Recent Articles on June 11, 2019 12:00 AM.
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Early-Onset Molecular Derangements in the Olfactory Bulb of Tg2576 Mice: Novel Insights Into the Stress-Responsive Olfactory Kinase Dynamics in Alzheimer’s Disease
The olfactory bulb (OB) is the first processing station in the olfactory pathway. Despite smell impairment is considered an early event in Alzheimer´s disease (AD), little is known about the initial molecular disturbances that accompany the AD development at olfactory level. We have interrogated the time-dependent OB molecular landscape in Tg2576 AD mice prior to the appearance of neuropathological amyloid plaques (2-, and 6-month-old), using combinatorial omics analysis. The metabolic modulation induced by human mutated amyloid precursor protein (APP) overproduction clearly differs between both time points. Besides the progressive perturbation of the APP interactome, functional network analysis unveiled an inverse regulation of downstream extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) routes in 2-month-old Tg2576 mice respect to wild-type (WT) mice. In contrast, Akt and mitogen-activated protein kinase Kinase 4 (SEK1)/ stress-activated protein kinase (SAPK) axis were parallel activated in the OB of 6-months-old-Tg2576 mice. Furthermore, a survival kinome profiling performed during the aging process (2-, 6-, and 18-month-old) revealed that olfactory APP overexpression leads to changes in the activation dynamics of protein kinase A (PKA), and SEK1/MKK4-SAPK/JNK between 6 and 18 months of age, when memory deficits appear and AD pathology is well established in transgenic mice. Interestingly, both olfactory pathways were differentially activated in a stage-dependent manner in human sporadic AD subjects with different neuropathological grading. Taken together, our data reflect the early impact of mutated APP on the OB molecular homeostasis, highlighting the progressive modulation of specific signaling pathways during the olfactory amyloidogenic pathology.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Sleep, Aging, and Cellular Health: Aged-Related Changes in Sleep and Protein Homeostasis Converge in Neurodegenerative Diseases
Many neurodegenerative diseases manifest in an overall aged population, the pathology of which is hallmarked by abnormal protein aggregation. It is known that across aging, sleep quality becomes less efficient and protein homeostatic regulatory mechanisms deteriorate. There is a known relationship between extended wakefulness and poorly consolidated sleep and an increase in cellular stress. In an aged population, when sleep is chronically poor, and proteostatic regulatory mechanisms are less efficient, the cell is inundated with misfolded proteins and suffers a collapse in homeostasis. In this review, we explore the interplay between aging, sleep quality, and proteostasis and how these processes are implicated in the development and progression of neurodegenerative diseases like Alzheimer’s disease. We also present data suggesting that reducing cellular stress and improving proteostasis and sleep quality could serve as potential therapeutic solutions for the prevention or delay in the progression of these diseases.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Lifespan Changes in Network Structure and Network Topology Dynamics During Rest and Auditory Oddball Performance
Behavioral and physiological evidence suggests that developmental changes lead to enhanced cortical differentiation and integration through maturation and learning, and that senescent changes during aging result in dedifferentiation and reduced cortical specialization of neural cell assemblies. We used electroencephalographic (EEG) recordings to evaluate network structure and network topology dynamics during rest with eyes closed and open, and during auditory oddball task across the lifespan. For this evaluation, we constructed a hyper-frequency network (HFN) based on within- and cross-frequency coupling (WFC and CFC, respectively) at 10 oscillation frequencies ranging between 2 and 20 Hz. We found that WFC increased monotonously across the lifespan, whereas CFC showed a U-shaped relationship. These changes in WFC and CFC strengths coevolve with changes in network structure and network topology dynamics, namely the magnitude of graph-theoretical topology measures increased linearly with age (except for characteristic path length, which is going shorter), while their standard deviation showed an inverse U-shaped relationship with a peak in young adults. Temporal as well as structural or nodal similarity of network topology (with some exceptions) seems to coincide with variability changes, i.e., stronger variability is related to higher similarity between consecutive time windows or nodes. Furthermore, network complexity measures showed different lifespan-related patterns, which depended on the balance of WFC and CFC strengths. Both variability and complexity of HFNs were strongly related to the perceptual speed scores. Finally, investigation of the modular organization of the networks revealed higher number of modules and stronger similarity of community structures across time in young adults as compared with children and older adults. We conclude that network variability and complexity measures reflect temporal and structural topology changes in the functional organization and reorganization of neuronal cell assemblies across the lifespan.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 11, 2019 12:00 AM.
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Evidence for Similar Prefrontal Structural and Functional Alterations in Male and Female Rats Following Chronic Stress or Glucocorticoid Exposure

Abstract
Previous work of ours and others has documented regressive changes in neuronal architecture and function in the medial prefrontal cortex (mPFC) of male rats following chronic stress. As recent focus has shifted toward understanding whether chronic stress effects on mPFC are sexually dimorphic, here we undertake a comprehensive analysis to address this issue. First, we show that chronic variable stress (14-day daily exposure to different challenges) resulted in a comparable degree of adrenocortical hyperactivity, working memory impairment, and dendritic spine loss in mPFC pyramidal neurons in both sexes. Next, exposure of female rats to 21-day regimen of corticosterone resulted in a similar pattern of mPFC dendritic spine attrition and increase in spine volume. Finally, we examined the effects of another widely used regimen, chronic restraint stress (CRS, 21-day of daily 6-h restraint), on dendritic spine changes in mPFC in both sexes. CRS resulted in response decrements in adrenocortical output (habituation), and induced a pattern of consistent, but less widespread, dendritic spine loss similar to the foregoing challenges. Our data suggest that chronic stress or glucocorticoid exposure induces a relatively undifferentiated pattern of structural and functional alterations in mPFC in both males and females.
in Cerebral Cortex Advance Access on June 11, 2019 12:00 AM.
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Cerebellar Contribution to Preparatory Activity in Motor Neocortex
Chabrol et al. show that the cerebellum is directly involved in maintaining preparatory activity in the premotor neocortex during learned, goal-directed behavior. Their results suggest the cerebellum provides a learned timing signal required for motor preparation in the neocortex.
in Neuron on June 11, 2019 12:00 AM.
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Open Source Brain: A Collaborative Resource for Visualizing, Analyzing, Simulating, and Developing Standardized Models of Neurons and Circuits
Open Source Brain is an online resource of neuronal and circuit models that enables browser-based visualization, analysis, and simulation. Gleeson et al. describe how the resource and tools for collaborative model development provide accessible, up-to-date models from different brain regions.
in Neuron on June 11, 2019 12:00 AM.
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Nociceptor deletion of Tsc2 enhances axon regeneration by inducing a conditioning injury response in dorsal root ganglia
Abstract
Neurons of the peripheral nervous system are able to regenerate injured axons, a process requiring significant cellular resources to establish and maintain long-distance growth. Genetic activation of mTORC1, a potent regulator of cellular metabolism and protein translation, improves axon regeneration of peripheral neurons by an unresolved mechanism. To gain insight into this process, we activated mTORC1 signaling in mouse nociceptors via genetic deletion of its negative regulator Tsc2. Perinatal deletion of Tsc2 in nociceptors enhanced initial axon growth after sciatic nerve crush, however by three days post-injury axon elongation rate became similar to controls. mTORC1 inhibition prior to nerve injury was required to suppress the enhanced axon growth. Gene expression analysis in purified nociceptors revealed that Tsc2-deficient nociceptors had increased activity of regeneration-associated transcription factors (RATFs), including cJun and Atf3, in the absence of injury. Additionally, nociceptor deletion of Tsc2 activated satellite glial cells and macrophages in the dorsal root ganglia (DRG) in a similar manner to nerve injury. Surprisingly, these changes improved axon length but not percentage of initiating axons in dissociated cultures. The pro-regenerative environment in naïve DRG was recapitulated by AAV8-mediated deletion of Tsc2 in adult mice, suggesting that this phenotype does not result from a developmental effect. Consistently, AAV8-mediated Tsc2 deletion did not improve behavioral recovery after a sciatic nerve crush injury despite initially enhanced axon growth. Together, these data show that neuronal mTORC1 activation induces an incomplete pro-regenerative environment in the DRG that improves initial but not later axon growth after nerve injury.
Significance Statement Long distance axon regeneration poses a significant hurdle to recovery following nervous system injury. Increased mTORC1 signaling improves axon regeneration, however the underlying mechanisms are incompletely understood. We activated neuronal mTORC1 signaling by genetically deleting Tsc2 in Nav1.8-positive neurons perinatally or by AAV8-mediated viral infection in adult mice and observed improved short- but not long-term axon regeneration after sciatic nerve injury. We suggest that Tsc2 deletion promotes initial but not later peripheral axon regeneration by upregulating expression of neuronal pro-regenerative genes and activating non-neuronal responses in the surrounding environment. Activating mTORC1 signaling in peripheral neurons may provide therapeutic benefit in circumstances with poor initial growth such as after spinal cord injury to the dorsal column or peripheral nerve repair.

in RSS PAP on June 10, 2019 04:30 PM.
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Ryanodine Receptor 2 Contributes to Impaired Protein Localization in Cyclic Nucleotide-gated Channel Deficiency
Abstract
The photoreceptor cyclic nucleotide-gated (CNG) channel plays a pivotal role in phototransduction and cellular calcium homeostasis. Mutations in the cone photoreceptor CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. CNG channel deficiency leads to endoplasmic reticulum (ER) stress-associated cone apoptosis, protein mislocalization, and ER calcium dysregulation. This work investigated the potential mechanisms of protein mislocalization associated with ER calcium dysregulation using Cnga3-/- mice lacking ER Ca2+ channel ryanodine receptor 2 (RyR2) specifically in cones. Deletion of Ryr2 improved outer segment (OS) localization of the cone proteins M-opsin, S-opsin, and cone phosphodiesterase subunit α’ (PDE6C) and decreased inner segment localization. One-month-old Cnga3-/- mice showed approximately 30% of M-opsin, 55% of S-opsin, and 50% of PDE6C localized to the OS. Cnga3-/- mice with Ryr2 deletion at the same age showed almost 60% of M- opsin, 70% of S-opsin, and 70% of PDE6C localized to the OS. Deletion of Ryr2 nearly completely reversed elevations of the ER stress markers phospho-IRE1α and phospho-eIF2α and suppressed cone apoptosis. Consistent with the improved cone protein localization and reduced ER stress/cone apoptosis, cone survival was improved by deletion of Ryr2. The number of cones was increased by about 28% in 2-4 month-old Cnga3-/- mice with Ryr2 deletion, compared with age-matched Cnga3-/- mice. This work demonstrates a role of RyR2/ER calcium dysregulation in protein mislocalization, ER stress and cone death. The findings provide novel insights into the mechanisms of photoreceptor degeneration and support strategies targeting ER calcium regulation to manage retinal degeneration.
Significance Statement The cyclic nucleotide-gated (CNG) channel plays a pivotal role in phototransduction and photoreceptor calcium homeostasis. Mutations in the cone CNG channel subunits are associated with achromatopsia and cone dystrophies. CNG channel deficiency leads to endoplasmic reticulum (ER) stress-associated cone apoptosis, protein mislocalization, and ER calcium dysregulation. This work demonstrates a role of ER Ca2+ channel ryanodine receptor 2 and ER calcium dysregulation in protein mislocalization and subsequent ER stress and cone cell death. The findings provide novel insights into the mechanisms of photoreceptor degeneration. Altered calcium signaling and ER stress-associated cell death are common throughout retinal degenerative diseases. Thus, strategies targeting ER calcium regulation may help treat or slow photoreceptor degeneration.

in RSS PAP on June 10, 2019 04:30 PM.
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Vocal Motor Performance in Birdsong Requires Brain-Body Interaction

Significance statement Motor skill learning typically occurs in a period when the brain needs to navigate a body that is still growing and developing. How the changing body, neural circuit formation and motor coding influence each other remains unknown. Songbirds provide excellent model systems to study motor skill learning. It has recently been shown that songbird vocal muscles double in speed during sensorimotor learning. Here we argue that these contractile as well as morphological changes stem predominantly from use and only secondarily from hormones or genetic programs. This implies that muscle training constrains skill learning trajectories. As contractile muscle property changes must require altered motor codes for achieving the same acoustic targets, the final performance results from interactions between brain and body.

in RSS PAP on June 10, 2019 04:30 PM.
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Central nervous system regeneration is driven by microglia necroptosis and repopulation

Nature Neuroscience, Published online: 10 June 2019; doi:10.1038/s41593-019-0418-z
Lloyd et al. find that regeneration of CNS myelin requires death of proinflammatory microglia followed by repopulation to a pro-regenerative state, revealing new therapeutic targets for neurodegenerative disease.
in Nature Neuroscience - Issue - nature.com science feeds on June 10, 2019 12:00 AM.
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Circuit mechanisms for the maintenance and manipulation of information in working memory

Nature Neuroscience, Published online: 10 June 2019; doi:10.1038/s41593-019-0414-3
The role of persistent spiking activity in working memory has recently come under debate. Here the authors use biologically realistic recurrent neural networks to explain why the strength of persistent activity can vary markedly between tasks.
in Nature Neuroscience - Issue - nature.com science feeds on June 10, 2019 12:00 AM.
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State-dependent decoupling of sensory and motor circuits underlies behavioral flexibility in Drosophila

Nature Neuroscience, Published online: 10 June 2019; doi:10.1038/s41593-019-0413-4
Ache et al. show that neurons controlling landing in flies are permissively gated by flight, indicating that brain sensory networks are flexibly coupled to or decoupled from motor networks in the nerve cord to promote contextually appropriate actions.
in Nature Neuroscience - Issue - nature.com science feeds on June 10, 2019 12:00 AM.
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Divergence in the functional organization of human and macaque auditory cortex revealed by fMRI responses to harmonic tones

Nature Neuroscience, Published online: 10 June 2019; doi:10.1038/s41593-019-0410-7
Norman-Haignere et al. report that humans but not macaque monkeys possess cortical regions with a strong preference for harmonic tones compared to noise. This species difference may be driven by the demands of speech and music perception in humans.
in Nature Neuroscience - Issue - nature.com science feeds on June 10, 2019 12:00 AM.
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Paraventricular Thalamus Projection Neurons Integrate Cortical and Hypothalamic Signals for Cue-Reward Processing
The paraventricular nucleus of the thalamus is a substrate underlying reward seeking. Otis, Zhu, et al. demonstrate that projection-defined thalamic neurons are controlled by dissociable response features in cortical and hypothalamic inputs during reward processing.
in Neuron on June 10, 2019 12:00 AM.
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Subcortical Substrates of Explore-Exploit Decisions in Primates
How do we decide whether to explore a new opportunity or stick with what we know? Costa et al. reveal that neurons in amygdala and ventral striatum, motivational centers of the brain, help to solve this complex reinforcement learning problem.
in Neuron on June 10, 2019 12:00 AM.
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Neuro-genetic plasticity of Caenorhabditis elegans behavioral thermal tolerance
Animal responses to thermal stimuli involve intricate contributions of genetics, neurobiology and physiology, with temperature variation providing a pervasive environmental factor for natural selection. Therma...
in Most Recent Articles: BMC Neuroscience on June 10, 2019 12:00 AM.
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Contribution of FEF to attentional periodicity during visual search: a TMS study
Abstract
Visual search, looking for a target embedded among distractors, has long been used to study attention. Current theories postulate a two-stage process in which early visual areas perform feature extraction, while higher-order regions perform attentional selection. Such a model implies iterative communication between low- and high-level regions to sequentially select candidate targets in the array, focus attention on these elements, and eventually permit target recognition. This leads to two independent predictions: (1) high-level, attentional regions and (2) early visual regions should both be involved periodically during the search. Here, we used Transcranial Magnetic Stimulation (TMS) applied over the Frontal-Eye Field (FEF) in humans, known to be involved in attentional selection, at various delays while observers performed a difficult, attentional search task. We observed a periodic pattern of interference at ~6 Hz (theta) suggesting that the FEF is periodically involved during this difficult search task. We further compared this result with two previous studies (Dugué et al., 2011; 2015a) in which a similar TMS procedure was applied over the early visual cortex (V1) while observers performed the same task. This analysis revealed the same pattern of interference, i.e. V1 is periodically involved during this difficult search task, at the theta frequency. Past V1 evidence reappraised for this paper, together with our current FEF results, confirm both of our independent predictions, and suggest that difficult search is supported by low- and high-level regions, each involved periodically at the theta frequency.
Significant statement Attention models postulate a two-stage process during visual search in which early visual regions perform feature extraction, while higher-order regions perform attentional selection, these two levels iteratively (periodically) communicating until target recognition. Using TMS, we tested whether there is a causal link between these brain regions and attentional search performance. Similar to past V1 evidence reappraised in this study, we showed that difficult attention search is supported in the FEF by periodic processing at the theta frequency (~6 Hz). Taken together, these two findings support the idea that difficult search tasks are processed by a hierarchical system involving low- and high-level regions, each involved periodically, and allowing successful attentional exploration. Nonetheless, their potential interactions remain to be demonstrated.

in RSS PAP on June 07, 2019 04:30 PM.
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Quantification of Phase-Amplitude Coupling in Neuronal Oscillations: Comparison of Phase-Locking Value, Mean Vector Length, Modulation Index, and Generalized-Linear-Modeling-Cross-Frequency-Coupling
Phase-amplitude coupling is a promising construct to study cognitive processes in electroencephalography (EEG) and magnetencephalography (MEG). Due to the novelty of the concept, various measures are used in the literature to calculate phase-amplitude coupling. Here, performance of the three most widely used phase-amplitude coupling measures – phase-locking value (PLV), mean vector length (MVL), and modulation index (MI) – and of the generalized linear modeling cross-frequency coupling (GLM-CFC) method is thoroughly compared with the help of simulated data. We combine advantages of previous reviews and use a realistic data simulation, examine moderators and provide inferential statistics for the comparison of all four indices of phase-amplitude coupling. Our analyses show that all four indices successfully differentiate coupling strength and coupling width when monophasic coupling is present. While the mean vector length was most sensitive to modulations in coupling strengths and width, only the modulation index and GLM-CFC can detect biphasic coupling. Coupling values of all four indices were influenced by moderators including data length, signal-to-noise-ratio, and sampling rate when approaching Nyquist frequencies. The modulation index was most robust against confounding influences of these moderators. Based on our analyses, we recommend the modulation index for noisy and short data epochs with unknown forms of coupling. For high quality and long data epochs with monophasic coupling and a high signal-to-noise ratio, the use of the mean vector length is recommended. Ideally, both indices are reported simultaneously for one data set.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 07, 2019 12:00 AM.
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Diffusion MRI: Assessment of the Impact of Acquisition and Preprocessing Methods Using the BrainVISA-Diffuse Toolbox
Diffusion MR images are prone to severe geometric distortions induced by head movement, eddy-current and inhomogeneity of magnetic susceptibility. Various correction methods have been proposed that depend on the choice of the acquisition settings and potentially provide highly different data quality. However, the impact of this choice has not been evaluated in terms of the ratio between scan time and preprocessed data quality. This study aims at investigating the impact of six well-known preprocessing methods, each associated to specific acquisition settings, on the outcome of diffusion analyses. For this purpose, we developed a comprehensive toolbox called Diffuse which automatically guides the user to the best preprocessing pipeline according to the input data. Using MR images of 20 subjects from the HCP dataset, we compared the six pre-processing pipelines regarding the following criteria: the ability to recover brain’s true geometry, the tensor model estimation and derived indices in the white matter, and finally the spatial dispersion of six well known connectivity pathways. As expected, the pipeline associated to the longer acquisition fully repeated with reversed phase-encoding (RPE) yielded the higher data quality and was used as a reference to evaluate the other pipelines. In this way, we highlighted several significant aspects of other pre-processing pipelines. Our results first established that eddy-current correction improves the tensor-fitting performance with a localized impact especially in the corpus callosum. Concerning susceptibility distortions, we showed that the use of a field map is not sufficient and involves additional smoothing, yielding to an artificial decrease of tensor-fitting error. Of most importance, our findings demonstrate that, for an equivalent scan time, the acquisition of a b0 volume with RPE ensures a better brain’s geometry reconstruction and local improvement of tensor quality, without any smoothing of the image. This was found to be the best scan time / data quality compromise. To conclude, this study highlights and attempts to quantify the strong dependence of diffusion metrics on acquisition settings and preprocessing methods.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 07, 2019 12:00 AM.
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The Effects of NMDA Receptor Blockade on Sensory-Evoked Responses in Superficial Layers of the Rat Barrel Cortex
Transmission of excitation from L4 to L2/3 is a part of the canonical circuit of cortical sensory signal processing. While synapses from L4 to L2/3 are mediated by both AMPA and NMDA glutamate receptors, previous studies have suggested that sensory-evoked excitation of neurons in the supragranular layers is almost entirely mediated by NMDA receptors. Here, we readdressed this question using extracellular recordings of sensory-evoked potentials (SEPs) and multiple unit activity (MUA) in the rat barrel cortex. We found that blockade of NMDA receptors using the selective antagonist dAPV profoundly inhibited the late part of L2/3 SEP and MUA response but did not affect its initial part. Our results indicate that both non-NMDA and NMDA receptors are involved in the sensory signal transmission from L4 to L2/3. While non-NMDA receptors mediate fast transmission of sensory signals, NMDA receptors are involved in the generation of the late phase of the sensory-evoked response in supragranular layers.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 07, 2019 12:00 AM.
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Brain Aging and Electrophysiological Signaling: Revisiting the Spreading Depression Model
As a consequence of worldwide improvement in health care, the aging portion of the human population has increased, now representing a higher proportion of the total population. This fact raises great concern regarding how to age while maintaining good brain function. Very often, alterations in brain electrophysiological signaling are associated with age-dependent functional disorders of the brain. Therefore, animal models suitable for the study of age-related changes in electrical activity of the brain can be very useful. Herein, we review changes in brain electrophysiological features as a function of age by analyzing studies in the rat brain on the phenomenon known as cortical spreading depression (CSD). Alterations in the brain’s capability to generate and propagate CSD may be related to differences in the propensity to develop certain neurological diseases, such as epilepsy, stroke, and migraine, which can biunivocally interact with the aging process. In this review, we revisit ours and others’ previous studies on electrophysiological features of the CSD phenomenon, such as its velocity of propagation and amplitude and duration of its slow negative DC shift, as a function of the animal age, as well as the interaction between age and other factors, such as ethanol consumption, physical exercise, and nutritional status. In addition, we discuss one relatively new feature through which CSD modulates brain signaling: the ability to potentiate the brain’s spontaneous electrical activity. We conclude that the CSD model might importantly contribute to a better understanding of the aging/brain signaling relationship.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 07, 2019 12:00 AM.
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Resting-State Functional Connectivity Is Associated With Cerebrospinal Fluid Levels of the Synaptic Protein NPTX2 in Non-demented Older Adults
Intrinsic functional connectivity of large-scale brain networks has been shown to change with aging and Alzheimer’s disease (AD). These alterations are thought to reflect changes in synaptic function, but the underlying biological mechanisms are poorly understood. This study examined whether Neuronal Pentraxin 2 (NPTX2), a synaptic protein that mediates homeostatic strengthening of inhibitory circuits to control cortical excitability, is associated with functional connectivity as measured by resting-state functional magnetic resonance imaging (rsfMRI) in five large-scale cognitive brain networks. In this cross-sectional study, rsfMRI scans were obtained from 130 older individuals (mean age=69 years) with normal cognition (N=113) and Mild Cognitive Impairment (N=17); NPTX2 was measured in the same individuals in cerebrospinal fluid (CSF). Higher levels of NPTX2 in CSF were associated with greater functional connectivity in the salience/ventral attention network, based on linear regression analysis. Moreover, this association was stronger among individuals with lower levels of cognitive reserve, as measured by a composite score (comprised of years of education, reading, and vocabulary measures). Additionally, higher connectivity in the salience/ventral attention network was related to better performance on a composite measure of executive function. Levels of NPTX2 were not associated with connectivity in other networks (executive control, limbic, dorsal attention, and default-mode). Findings also confirmed prior reports that individuals with MCI have lower levels of NPTX2 compared to those with normal cognition. Taken together, the results suggest that NPTX2 mechanisms may play a central role among older individuals in connectivity within the salience/ventral attention network and for cognitive tasks that require modulation of attention and response selection.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 07, 2019 12:00 AM.
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Precision Aging: Applying Precision Medicine to the Field of Cognitive Aging
The current ‘one size fits all’ approach to our cognitive aging population is not adequate to close the gap between cognitive health span and lifespan. In this review paper, we present a a novel model for understanding, preventing, and treating age-related cognitive impairment (ARCI) based on the concepts precision medicine. We will discuss how multiple risk factors can be classified into risk categories because of their interrelatedness in real life, the brain drivers or common mechanisms mediating brain aging, and the genetic variants that increase sensitivity to, or ameliorate, risk for ARCI. Rather than providing a definitive model of risk for ARCI and cognitive decline, the Precision Aging model is meant as a starting point to guide future research. To that end, after briefly discussing key risk categories, brain drivers, and genetic risks, we conclude with a discussion of steps that can be taken to move the field forward.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 07, 2019 12:00 AM.
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Corrigendum to: Histological and MRI Study of the Development of the Human Indusium Griseum
The article 10.1093/cercor/bhz004, “Histological and MRI Study of the Development of the Human Indusium Griseum” contained an error in the funding section.
in Cerebral Cortex Advance Access on June 07, 2019 12:00 AM.
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Corrigendum to: Sensitive Period for Cognitive Repurposing of Human Visual Cortex
In Table 1, cause of blindness for some congenitally blind participants was incorrectly labeled as Retinitis Pigmentosa (RP) rather than Retinopathy of Prematurity (ROP). Table 1 has been corrected and the authors apologize for this error.
in Cerebral Cortex Advance Access on June 07, 2019 12:00 AM.
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Accelerating Structural Degeneration in Temporal Regions and Their Effects on Cognition in Aging of MCI Patients

Abstract
Age is the major risk factor for Alzheimer’s disease (AD) and for mild cognitive impairment (MCI). However, there is limited evidence about MCI-specific aging-related simultaneous changes of the brain structure and their impact on cognition. We analyzed the brain imaging data from 269 subjects (97 MCI patients and 172 cognitively normal [CN] elderly) using voxel-based morphometry and tract-based spatial statistics procedures to explore the special structural pattern during aging. We found that the patients with MCI showed accelerated age-related reductions in gray matter volume in the left planum temporale, thalamus, and posterior cingulate gyrus. The similar age×group interaction effect was found in the fractional anisotropy of the bilateral parahippocampal cingulum white matter tract, which connects the temporal regions. Importantly, the age-related temporal gray matter and white matter alterations were more significantly related to performance in memory and attention tasks in MCI patients. The accelerated degeneration patterns in the brain structure provide evidence for different neural mechanisms underlying aging in MCI patients. Temporal structural degeneration may serve as a potential imaging marker for distinguishing the progression of the preclinical AD stage from normal aging.
in Cerebral Cortex Advance Access on June 07, 2019 12:00 AM.
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Pannexin 1 Regulates Network Ensembles and Dendritic Spine Development in Cortical Neurons

Dendritic spines are the postsynaptic targets of excitatory synaptic inputs that undergo extensive proliferation and maturation during the first postnatal month in mice. However, our understanding of the molecular mechanisms that regulate spines during this critical period is limited. Previous work has shown that pannexin 1 (Panx1) regulates neurite growth and synaptic plasticity. We therefore investigated the impact of global Panx1 KO on spontaneous cortical neuron activity using Ca²⁺ imaging and in silico network analysis. Panx1 KO increased both the number and size of spontaneous co-active cortical neuron network ensembles. To understand the basis for these findings, we investigated Panx1 expression in postnatal synaptosome preparations from early postnatal mouse cortex. Between 2 and 4 postnatal weeks, we observed a precipitous drop in cortical synaptosome protein levels of Panx1, suggesting it regulates synapse proliferation and/or maturation. At the same time points, we observed significant enrichment of the excitatory postsynaptic density proteins PSD-95, GluA1, and GluN2a in cortical synaptosomes from global Panx1 knock-out mice. Ex vivo analysis of pyramidal neuron structure in somatosensory cortex revealed a consistent increase in dendritic spine densities in both male and female Panx1 KO mice. Similar findings were observed in an excitatory neuron-specific Panx1 KO line (Emx1-Cre driven; Panx1 cKO^E) and in primary Panx1 KO cortical neurons cultured in vitro. Altogether, our study suggests that Panx1 negatively regulates cortical dendritic spine development.

in eNeuro current issue on June 06, 2019 04:31 PM.
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Handedness Matters for Motor Control But Not for Prediction

Skilled motor behavior relies on the ability to control the body and to predict the sensory consequences of this control. Although there is ample evidence that manual dexterity depends on handedness, it remains unclear whether control and prediction are similarly impacted. To address this issue, right-handed human participants performed two tasks with either the right or the left hand. In the first task, participants had to move a cursor with their hand so as to track a target that followed a quasi-random trajectory. This hand-tracking task allowed testing the ability to control the hand along an imposed trajectory. In the second task, participants had to track with their eyes a target that was self-moved through voluntary hand motion. This eye-tracking task allowed testing the ability to predict the visual consequences of hand movements. As expected, results showed that hand tracking was more accurate with the right hand than with the left hand. In contrast, eye tracking was similar in terms of spatial and temporal gaze attributes whether the target was moved by the right or the left hand. Although these results extend previous evidence for different levels of control by the two hands, they show that the ability to predict the visual consequences of self-generated actions does not depend on handedness. We propose that the greater dexterity exhibited by the dominant hand in many motor tasks stems from advantages in control, not in prediction. Finally, these findings support the notion that prediction and control are distinct processes.

in eNeuro current issue on June 06, 2019 04:31 PM.
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Reward Expectation Modulates Local Field Potentials, Spiking Activity and Spike-Field Coherence in the Primary Motor Cortex
ABSTRACT
Reward modulation of the primary motor cortex (M1) could be exploited in developing an autonomously updating brain-computer interface (BCI) based on a reinforcement learning (RL) architecture. For an autonomously updating RL based BCI system, we would need a reward prediction error, or a state-value representation from the user’s neural activity, which the RL-BCI agent could use to update its BCI-decoder. In order to understand the multifaceted effects of reward on M1 activity, we investigated how neural spiking, oscillatory activities and their functional interactions are modulated by conditioned stimuli related reward expectation. To do so, local field potentials (LFPs) and single-unit/multiunit activities were recorded simultaneously and bilaterally from M1 cortices while four non-human primates performed cued center-out reaching or grip force tasks either manually using their right arm/hand or observed passively. We found that reward expectation influenced the strength of alpha (8-14 Hz) power, alpha-gamma comodulation, alpha spike-field coherence, and firing rates in general in M1. Furthermore, we found that an increase in alpha-band power was correlated with a decrease in neural spiking activity, that firing rates were highest at the trough of the alpha-band cycle and lowest at the peak of its cycle. These findings imply that alpha oscillations modulated by reward expectation have an influence on spike firing rate and spike timing during both reaching and grasping tasks in M1. These LFP, spike, and spike-field interactions could be used to follow the M1 neural state in order to enhance BCI decoding (An et al., 2018; Zhao et al., 2018).
Significance Statement Knowing the subjective value of performed or observed actions is valuable feedback that could be used to improve the performance of an autonomously updating brain-computer interface (BCI). Reward-related information in the primary motor cortex (M1) may be crucial for more stable and robust BCI decoding (Zhao et al., 2018). Here, we present how expectation of reward during motor tasks, or simple observation, is represented by increased spike firing rates in conjunction with decreased alpha (8-14 Hz) oscillatory power, alpha-gamma comodulation, and alpha spike-field coherence, as compared to nonrewarding trials. Moreover, a phasic relation between alpha oscillations and firing rates was observed where firing rates were found to be lowest and highest at the peak and trough of alpha oscillations, respectively.

in RSS PAP on June 06, 2019 04:30 PM.
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Striatal circuits for reward learning and decision-making

Nature Reviews Neuroscience, Published online: 06 June 2019; doi:10.1038/s41583-019-0189-2
The striatum is crucial for learning and decision-making. Cox and Witten provide an updated overview of the roles of different parts of the striatal circuit in learning and decision-making, showing how recent experiments support and contradict previous models.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on June 06, 2019 12:00 AM.
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Axon Guidance and Collective Cell Migration by Substrate-Derived Attractants
Neurons have evolved specialized growth structures to reach and innervate their target cells. These growth cones express specific receptor molecules that sense environmental cues and transform them into steering decisions. Historically, various concepts of axon guidance have been developed to better understand how axons reach and identify their targets. The essence of these efforts seems to be that growth cones require solid substrates, and that major guidance decisions are initiated by extracellular cues. These sometimes highly conserved ligands and receptors have been extensively characterized and mediate four major guidance forces: chemoattraction, chemorepulsion, contact attraction and contact repulsion. However, during development, cells, too, do migrate in order to reach molecularly-defined niches at target locations. In fact, axonal growth could be regarded as a special case of cellular migration, where only a highly polarized portion of the cell is elongating. Here, I combine several examples from genetically tractable model organisms, such as Drosophila or zebrafish, in which cells and axons are guided by attractive cues. Regardless, if these cues are secreted into the extracellular space or exposed on cellular surfaces, migrating cells and axons seem to keep close contact to these attractants and seem to detect them right at their source. Migration towards and along such substrate-derived attractants seem to be particularly robust, as genetic deletion induces obvious searching behaviors and permanent guidance errors. In addition, forced expression of these factors in ectopic tissues is highly distractive too, regardless of the pattern of other endogenous cues. Thus, guidance and migration towards and along attractive tissues is a powerful steering mechanism that exploits affinity differences to the surroundings and, in some instances, determines growth trajectories from source to target region.
in Frontiers in Molecular Neuroscience | New and Recent Articles on June 06, 2019 12:00 AM.
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Application of Graph Theory for Identifying Connectivity Patterns in Human Brain Networks: A Systematic Review
Background: Analysis of the human connectome using functional magnetic resonance imaging (fMRI) started in the mid-1990s and attracted increasing attention in attempts to discover the neural underpinnings of human cognition and neurological disorders. In general, brain connectivity patterns from fMRI data are classified as statistical dependencies (functional connectivity) or causal interactions (effective connectivity) among various neural units. Computational methods, especially graph theory-based methods, have recently played a significant role in understanding brain connectivity architecture. Objectives: Thanks to the emergence of graph theoretical analysis, the main purpose of the current paper is to systematically review how brain properties can emerge through the interactions of distinct neuronal units in various cognitive and neurological applications using fMRI. Moreover, this article provides an overview of the existing functional and effective connectivity methods used to construct the brain network, along with their advantages and pitfalls. Methods: In this systematic review, the databases Science Direct, Scopus, arXiv, Google Scholar, IEEE Xplore, PsycINFO, PubMed, and SpringerLink are employed for exploring the evolution of computational methods in human brain connectivity from 1990 to the present, focusing on graph theory. The Cochrane Collaboration's tool was used to assess the risk of bias in individual studies. Results: Our results show that graph theory and its implications in cognitive neuroscience have attracted the attention of researchers since 2009 (as the Human Connectome Project launched), because of their prominent capability in characterizing the behavior of complex brain systems. Although graph theoretical approach can be generally applied to either functional or effective connectivity patterns during rest or task performance, to date, most articles have focused on the resting-state functional connectivity. Conclusions: This review provides an insight into how to utilize graph theoretical measures to make neurobiological inferences regarding the mechanisms underlying human cognition and behavior as well as different brain disorders.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on June 06, 2019 12:00 AM.
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Complex Electroresponsive Dynamics in Olivocerebellar Neurons Represented With Extended-Generalized Leaky Integrate and Fire Models
The neurons of the olivocerebellar circuit exhibit complex electroresponsive dynamics, which are thought to play a fundamental role for network entraining, plasticity induction, signal processing and noise filtering. In order to reproduce these properties in single-point neuron models, we have optimized the Extended-Generalized Leaky Integrate and Fire (E-GLIF) neuron through a multi-objective gradient-based algorithm targeting the desired input-output relationships. In this way, E-GLIF was tuned toward the unique input-output properties of Golgi cells, granule cells, Purkinje cells, molecular layer interneurons, deep cerebellar nuclei cells and inferior olivary cells. E-GLIF proved able to simulate the complex cell-specific electroresponsive dynamics of the main olivocerebellar neurons including pacemaking, adaptation, bursting, post-inhibitory rebound excitation, subthreshold oscillations, resonance and phase reset. The integration of these E-GLIF point-neuron models into olivocerebellar Spiking Neural Networks will allow to evaluate the impact of complex electroresponsive dynamics at the higher scales, up to motor behaviour, in closed-loop simulations of sensorimotor tasks.
in Frontiers in Computational Neuroscience | New and Recent Articles on June 06, 2019 12:00 AM.
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Deletion of CD38 Suppresses Glial Activation and Neuroinflammation in a Mouse Model of Demyelination
CD38 is an enzyme that catalyzes the synthesis of cyclic adenosine diphosphate-ribose from nicotinamide adenine dinucleotide (NAD+). We recently reported that this molecule regulates the maturation and differentiation of glial cells such as astrocytes and oligodendrocytes in the developing brain. To analyze its role in the demyelinating situation, we employed cuprizone (CPZ)-induced demyelination model in mice, which is characterized by oligodendrocyte-specific apoptosis, followed by the strong glial activation, demyelination and repopulation of oligodendrocytes. By using this model, we found that CD38 was upregulated in both astrocytes and microglia after CPZ administration. Experiments using wild-type and CD38 knockout (KO) mice, together with those using cultured glial cells, revealed that CD38 deficiency did not affect the initial decrease of the number of oligodendrocytes, while it attenuated CPZ-induced demyelination and neurodegeneration. Importantly, the clearance of the degraded myelin and oligodendrocyte repopulation were also reduced in CD38 KO mice. Further experiments revealed that these observations were associated with reduced levels of glial activation and inflammatory responses including phagocytosis, most likely through the enhanced level of NAD+ in CD38-deleted condition. Our results suggest that CD38 and NAD+ in the glial cells play a critical role in the demyelination and subsequent oligodendrocyte remodeling through the modulation of glial activity and neuroinflammation.
in Frontiers in Cellular Neuroscience | New and Recent Articles on June 06, 2019 12:00 AM.
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Anatomical and Surgical Evaluation of the Common Marmoset as an Animal Model in Hearing Research
Recent studies have indicated that direct administration of viral vectors or small compounds to the inner ear may aid in the treatment of sensorineural hearing loss. However, due to species differences between humans and rodents, translating experimental results into clinical applications remains challenging. The common marmoset (Callithrix jacchus), a New World monkey, is considered a pre-clinical animal model. In the present study, we describe morphometric data acquired from the temporal bone of the common marmoset in order to define the routes of topical drug administration to the inner ear. Dissection and diffusion tensor tractography (DTT) were performed on the fixed cadaverous heads of thirteen common marmosets. To investigate potential routes for drug administration to the inner ear, we explored the anatomy of the round window, oval window, semicircular canal, and endolymphatic sac. Among these, the approach via the round window with posterior tympanotomy appeared feasible for delivering drugs to the inner ear without manipulating the tympanic membrane, minimizing the chances of conductive hearing loss. The courses of four critical nerves (including the facial nerve) were visualized using three-dimensional DTT, which may help to avoid nerve damage during surgery. Finally, to investigate the feasibility of actual drug administration, we measured the volume of the round window niche, which was approximately 0.9 µL. The present findings may help to establish experimental standards for evaluating new therapies in this primate model.
in Frontiers in Neuroanatomy | New and Recent Articles on June 06, 2019 12:00 AM.
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The Pre-synaptic Landscape of Mitral/Tufted Cells of the Main Olfactory Bulb
In olfaction, all volatile odor information is tunneled through the main olfactory bulb (OB). Odor information is then processed before it is transferred to higher brain centers. Odor processing in the OB is carried out by numerous local inhibitory circuits and modulated by top-down input. Top-down modulation of OB function has been shown to act via interneurons but evidence also exists for its direct impact onto the principle mitral and tufted cells (M/Ts). Here, we used monosynaptic rabies trans-synaptic tracing from the OB to map and quantify the local and top-down presynaptic landscape of M/Ts and local inhibitory interneurons. We found that M/Ts receive a significant amount of top-down inputs from various brain regions that matches qualitatively but not quantitatively those that synapse onto local inhibitory inter-neurons. These results show that M/Ts are direct targets of top-down inputs.
in Frontiers in Neuroanatomy | New and Recent Articles on June 06, 2019 12:00 AM.
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Phosphorylation and Dephosphorylation of Tau Protein During Synthetic Torpor
Tau protein is of primary importance for many physiological processes in neurons, where it affects the dynamics of the microtubule system. When hyperphosphorylated (PP-Tau), Tau monomers detach from microtubules and tend to aggregate firstly in oligomers, and then in neurofibrillary tangles, as it occurs in a group of neurodegenerative disorders named thauopathies. A hypothermia-related accumulation of PP-Tau, which is quickly reversed after the return to normothermia, has been shown to occur in the brain of hibernators during torpor. Since, recently, in our lab, a hypothermic torpor-like condition (synthetic torpor, ST) was pharmacologically induced in the rat, a non-hibernator, the aim of the present work was to assess whether ST can lead to a reversible PP-Tau accumulation in the rat brain. PP-Tau was immunohistochemically assessed by staining for AT8 (phosphorylated Tau) and Tau-1 (non-phosphorylated Tau) in 19 brain structures, which were chosen mostly due to their involvement in the regulation of autonomic and cognitive functions in relation to behavioral states. During ST, AT8 staining was strongly expressed throughout the brain, while Tau-1 staining was reduced compared to control conditions. During the following recovery period, AT8 staining progressively reduced close to zero after 6h from ST. However, Tau-1 staining remained low even after 38h from ST. Thus, overall, these results show that ST induced an accumulation of PP Tau that was, apparently, only partially reversed to normal during the recovery period. While the accumulation of PP-Tau may only depend on the physicochemical characteristics of the enzymes regulating Tau phosphorylation, the reverse process of dephosphorylation should be actively regulated, also in non-hibernators. In conclusion, in this work a reversible and widespread PP-Tau accumulation has been induced through a procedure that leads a non-hibernator to a degree of reversible hypothermia, which is comparable to that observed in hibernators. Therefore, the physiological mechanism involved in this process can sustain an adaptive neuronal response to extreme conditions, which may however lead to neurodegeneration when particular intensities and durations are exceeded.
in Frontiers in Neuroanatomy | New and Recent Articles on June 06, 2019 12:00 AM.
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A Hyperkinetic Redox Sensor Drives Flies to Sleep
Several different potassium channels modulate the activity of sleep-promoting neurons in the Drosophila brain, but the regulation of these channels is not completely understood. A recent study (Kempf et al., Nature, 2019) found that one of the potassium channel subunits, Hyperkinetic, alters the firing properties of sleep-promoting neurons in response to NADPH oxidation. These findings are the first to link cellular redox state and mitochondrial metabolism directly to sleep.
in Trends in Neurosciences on June 06, 2019 12:00 AM.
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Modulating Human Memory via Entrainment of Brain Oscillations
In the human brain, oscillations occur during neural processes that are relevant for memory. This has been demonstrated by a plethora of studies relating memory processes to specific oscillatory signatures. Several recent studies have gone beyond such correlative approaches and provided evidence supporting the idea that modulating oscillations via frequency-specific entrainment can alter memory functions. Such causal evidence is important because it allows distinguishing mechanisms directly related to memory from mere epiphenomenal oscillatory signatures of memory.
in Trends in Neurosciences on June 06, 2019 12:00 AM.
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Sleep Regulation by Neurotensinergic Neurons in a Thalamo-Amygdala Circuit
Using a three-step approach for systematic screening, Ma et al. identified GABAergic neurons in CeA and glutamatergic neurons in the posterior thalamus that promote NREM sleep. Each population uses both the NTS peptide and a classical neurotransmitter to promote sleep.
in Neuron on June 06, 2019 12:00 AM.
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Widespread and Highly Correlated Somato-dendritic Activity in Cortical Layer 5 Neurons
Beaulieu-Laroche et al. perform near-simultaneous calcium imaging of somatic and dendritic activity to reveal that active dendritic integration is an integral feature of information processing in cortical pyramidal neurons.
in Neuron on June 06, 2019 12:00 AM.
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The chromatin landscape of neuronal plasticity

Publication date: December 2019
Source: Current Opinion in Neurobiology, Volume 59
Author(s): Margaret Herre, Erica Korb
Examining the links between neuronal activity, transcriptional output, and synaptic function offers unique insights into how neurons adapt to changing environments and form memories. Epigenetic markers, such as DNA methylation and histone modifications, have been implicated in the formation of not only cellular memories such as cell fate, but also memories of experience at the organismal level. Here, we review recent advances in chromatin regulation that contribute to synaptic plasticity and drive adaptive behaviors through dynamic and precise regulation of transcription output in neurons. We discuss chromatin-associated proteins, histone variant proteins, the contribution of cis-regulatory elements and their interaction with histone modifications, and how these mechanisms are integrated into distinct behavior and environmental response paradigms.

in ScienceDirect Publication: Current Opinion in Neurobiology on June 05, 2019 05:00 PM.
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TrkB-Shc Signaling Protects against Hippocampal Injury Following Status Epilepticus

Temporal lobe epilepsy (TLE) is a common and commonly devastating form of human epilepsy for which only symptomatic therapy is available. One cause of TLE is an episode of de novo prolonged seizures [status epilepticus (SE)]. Understanding the molecular signaling mechanisms by which SE transforms a brain from normal to epileptic may reveal novel targets for preventive and disease-modifying therapies. SE-induced activation of the BDNF receptor tyrosine kinase, TrkB, is one signaling pathway by which SE induces TLE. Although activation of TrkB signaling promotes development of epilepsy in this context, it also reduces SE-induced neuronal death. This led us to hypothesize that distinct signaling pathways downstream of TrkB mediate the desirable (neuroprotective) and undesirable (epileptogenesis) consequences. We subsequently demonstrated that TrkB-mediated activation of phospholipase C1 is required for epileptogenesis. Here we tested the hypothesis that the TrkB-Shc-Akt signaling pathway mediates the neuroprotective consequences of TrkB activation following SE. We studied measures of molecular signaling and cell death in a model of SE in mice of both sexes, including wild-type and TrkB^Shc/Shc mutant mice in which a point mutation (Y515F) of TrkB prevents the binding of Shc to activated TrkB kinase. Genetic disruption of TrkB-Shc signaling had no effect on severity of SE yet partially inhibited activation of the prosurvival adaptor protein Akt. Importantly, genetic disruption of TrkB-Shc signaling exacerbated hippocampal neuronal death induced by SE. We conclude that therapies targeting TrkB signaling for preventing epilepsy should spare TrkB-Shc-Akt signaling and thereby preserve the neuroprotective benefits.

SIGNIFICANCE STATEMENT Temporal lobe epilepsy (TLE) is a common and devastating form of human epilepsy that lacks preventive therapies. Understanding the molecular signaling mechanisms underlying the development of TLE may identify novel therapeutic targets. BDNF signaling thru TrkB receptor tyrosine kinase is one molecular mechanism promoting TLE. We previously discovered that TrkB-mediated activation of phospholipase C1 promotes epileptogenesis. Here we reveal that TrkB-mediated activation of Akt protects against hippocampal neuronal death in vivo following status epilepticus. These findings strengthen the evidence that desirable and undesirable consequences of status epilepticus-induced TrkB activation are mediated by distinct signaling pathways downstream of this receptor. These results provide a strong rationale for a novel therapeutic strategy selectively targeting individual signaling pathways downstream of TrkB for preventing epilepsy.

in Journal of Neuroscience current issue on June 05, 2019 04:30 PM.
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Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors

Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of Ephx2 (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release in vitro and in vivo. Moreover, astrocytic ATP release was required for the antidepressant-like effect of Ephx2 deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress.

SIGNIFICANCE STATEMENT Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports.

in Journal of Neuroscience current issue on June 05, 2019 04:30 PM.
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Reward-Related Expectations Trigger Dendritic Spine Plasticity in the Mouse Ventrolateral Orbitofrontal Cortex

An essential aspect of goal-directed decision-making is selecting actions based on anticipated consequences, a process that involves the orbitofrontal cortex (OFC) and potentially, the plasticity of dendritic spines in this region. To investigate this possibility, we trained male and female mice to nose poke for food reinforcers, or we delivered the same number of food reinforcers non-contingently to separate mice. We then decreased the likelihood of reinforcement for trained mice, requiring them to modify action–outcome expectations. In a separate experiment, we blocked action–outcome updating via chemogenetic inactivation of the OFC. In both cases, successfully selecting actions based on their likely consequences was associated with fewer immature, thin-shaped dendritic spines and a greater proportion of mature, mushroom-shaped spines in the ventrolateral OFC. This pattern was distinct from spine loss associated with aging, and we identified no effects on hippocampal CA1 neurons. Given that the OFC is involved in prospective calculations of likely outcomes, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for solidifying durable expectations. To investigate causal relationships, we inhibited the RNA-binding protein fragile X mental retardation protein (encoded by Fmr1), which constrains dendritic spine turnover. Ventrolateral OFC-selective Fmr1 knockdown recapitulated the behavioral effects of inducible OFC inactivation (and lesions; also shown here), impairing action–outcome conditioning, and caused dendritic spine excess. Our findings suggest that a proper balance of dendritic spine plasticity within the OFC is necessary for one's ability to select actions based on anticipated consequences.

SIGNIFICANCE STATEMENT Navigating a changing environment requires associating actions with their likely outcomes and updating these associations when they change. Dendritic spine plasticity is likely involved, yet relationships are unconfirmed. Using behavioral, chemogenetic, and viral-mediated gene silencing strategies and high-resolution microscopy, we find that modifying action–outcome expectations is associated with fewer immature spines and a greater proportion of mature spines in the ventrolateral orbitofrontal cortex (OFC). Given that the OFC is involved in prospectively calculating the likely outcomes of one's behavior, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for maintaining durable expectations.

in Journal of Neuroscience current issue on June 05, 2019 04:30 PM.
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Circuits That Mediate Expression of Signaled Active Avoidance Converge in the Pedunculopontine Tegmentum

An innocuous sensory stimulus that reliably signals an upcoming aversive event can be conditioned to elicit locomotion to a safe location before the aversive outcome ensues. The neural circuits that mediate the expression of this signaled locomotor action, known as signaled active avoidance, have not been identified. While exploring sensorimotor midbrain circuits in mice of either sex, we found that excitation of GABAergic cells in the substantia nigra pars reticulata blocks signaled active avoidance by inhibiting cells in the pedunculopontine tegmental nucleus (PPT), not by inhibiting cells in the superior colliculus or thalamus. Direct inhibition of putative-glutamatergic PPT cells, excitation of GABAergic PPT cells, or excitation of GABAergic afferents in PPT, abolish signaled active avoidance. Conversely, excitation of putative-glutamatergic PPT cells, or inhibition of GABAergic PPT cells, can be tuned to drive avoidance responses. The PPT is an essential junction for the expression of signaled active avoidance gated by nigral and other synaptic afferents.

SIGNIFICANCE STATEMENT When a harmful situation is signaled by a sensory stimulus (e.g., street light), subjects typically learn to respond with active or passive avoidance responses that circumvent the threat. During signaled active avoidance behavior, subjects move away to avoid a threat signaled by a preceding innocuous stimulus. We identified a part of the midbrain essential to process the signal and avoid the threat. Inhibition of neurons in this area eliminates avoidance responses to the signal but preserves escape responses caused by presentation of the threat. The results highlight an essential part of the neural circuits that mediate signaled active avoidance behavior.

in Journal of Neuroscience current issue on June 05, 2019 04:30 PM.
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Publisher Correction: Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug

Nature Neuroscience, Published online: 05 June 2019; doi:10.1038/s41593-019-0441-0
Publisher Correction: Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug
in Nature Neuroscience - Issue - nature.com science feeds on June 05, 2019 12:00 AM.
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Author Correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability

Nature Neuroscience, Published online: 05 June 2019; doi:10.1038/s41593-019-0402-7
Author Correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability
in Nature Neuroscience - Issue - nature.com science feeds on June 05, 2019 12:00 AM.
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Aberrant adaptive myelination in ‘chemobrain’

Nature Reviews Neuroscience, Published online: 05 June 2019; doi:10.1038/s41583-019-0194-5
Dysregulation of adaptive myelination might contribute to methotrexate chemotherapy-related cognitive impairment in mice.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on June 05, 2019 12:00 AM.
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases
Neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are chronic, progressive and age-associated neurological disorders characterized by neuronal deterioration in specific brain regions. Although the specific pathological mechanisms underlying these disorders have remained elusive, ion channel dysfunction has become increasingly accepted as a potential mechanism for neurodegenerative diseases. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by the HCN1-4 gene family and conduct the hyperpolarization-activated current (Ih). These channels play important roles in modulating cellular excitability, rhythmic activity, dendritic integration and synaptic transmission. In the present review we first provide a comprehensive picture of the role of HCN channels in PD by summarizing their role in the regulation of neuronal activity in PD-related brain regions. Dysfunction of Ih may participate in 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity and represent a pathogenic mechanism in PD. Given current reports that the critical role of HCN channels in neuroinflammation and depression, we also discussed the putative contribution of HCN channels in inflammatory processes and non-motor symptoms in PD. In the second section, we summarize how HCN channels regulate the formation of β-amyloid peptide in AD and the role of these channels in learning and memory. Finally, we briefly discuss the effects of HCN channels in ALS and SMA based on existing discoveries.
in Frontiers in Molecular Neuroscience | New and Recent Articles on June 05, 2019 12:00 AM.
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Astrocyte, a Promising Target for Mood Disorder Interventions
Mood disorders have multiple phenotypes and complex underlying biological mechanisms, and as such, there are no effective therapeutic strategies. A review of recent work on the role of astrocytes in mood disorders is thus warranted and we argue that there is tremendous potential for novel strategies for therapeutic interventions based on the role of astrocytes. Astrocytes are traditionally considered to have supporting roles within the brain, yet emerging evidence has shown that astrocytes have more direct roles in influencing brain function. Notably, evidence from postmortem human brain tissues has highlighted changes in glial cell morphology, density and astrocyte-related biomarkers and genes following mood disorders, indicating astrocyte involvement in mood disorders. Findings from animal models imply strongly that astrocytes not only change astrocyte morphology and physiological characteristics but also influence neural circuits via synapse structure and formation. This review pays particular attention to interactions between astrocytes and neurons and argues that astrocyte dysfunction affects the monoaminergic system, excitatory-inhibitory balance and neurotrophic states of local networks. Together, these studies provide a foundation of knowledge about the exact role of astrocytes in mood disorders. Changing focus from neurons to glial cells and their interactions is important so that we can understand newly proposed mechanisms underlying mood disorders, and to identify more diagnostic indicators or effective targets for treatment of these diseases.
in Frontiers in Molecular Neuroscience | New and Recent Articles on June 05, 2019 12:00 AM.
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DMT1 Expression and Iron Levels at the Crossroads Between Aging and Neurodegeneration
Iron homeostasis is an essential prerequisite for metabolic and neurological functions throughout the healthy human life, with a dynamic interplay between intracellular and systemic iron metabolism. The development of different neurodegenerative diseases is associated with alterations of the intracellular transport of iron and heavy metals, principally mediated by Divalent Metal Transporter1 (DMT1), responsible for Non Transferrin Bound Iron transport (NTBI). In addition, DMT1 regulation and its compartmentalization in specific brain regions play important roles during aging. This review highlights the contribution of DMT1 to the physiological exchange and distribution of body iron and heavy metals during aging and neurodegenerative diseases. DMT1 also mediates the crosstalk between central nervous system and peripheral tissues, by systemic diffusion through the Blood Brain Barrier (BBB), with the involvement of peripheral iron homeostasis in association with inflammation. In conclusion, a survey about the role of DMT1 and iron will illustrate the complex panel of interrelationship with aging, neurodegeneration and neuroinflammation.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 05, 2019 12:00 AM.
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Increased Interleukin-6 Levels in the Astrocyte-Derived Exosomes of Sporadic Amyotrophic Lateral Sclerosis Patients
Neuroinflammation plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. However, it is difficult to evaluate inflammation of the central nervous system (CNS) or the relationship between neuroinflammation and disease progression in ALS patients. Recent advances in the field of exosomes and CNS-derived exosomes extraction technology provide the possibility of measuring the inflammatory status in the CNS without brain biopsy. In this pilot study, we extracted astrocyte-derived exosomes from the plasma of sporadic ALS patients and age-, sex-matched healthy controls and determined Interleukin-6 (IL-6) levels by enzyme-linked immunosorbent assay (ELISA). The IL-6 levels in astrocyte-derived exosomes were increased in sALS patients and positively associated with the rate of disease progression. However, the association between IL-6 levels and disease progression rate was limited to patients whose disease duration were less than 12 months. These data suggest an increased inflammatory cascade in the CNS of sALS patients. Our pilot study demonstrates that CNS-derived exosomes could be useful to reveal neuroinflammation of the CNS in ALS patients.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 05, 2019 12:00 AM.
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Continuous Theta Burst Stimulation Over the Right Orbitofrontal Cortex Impairs Conscious Olfactory Perception
The right orbitofrontal cortex (rOFC) has been proposed as the region where conscious olfactory perception arises; however, evidence supporting this hypothesis has all been collected from neuroimaging and lesion studies in which only correlation and not a temporal pattern can be established. Continuous theta burst stimulation (cTBS) causes a reversible disruption of cortical activity and has been used successfully to disrupt orbitofrontal activity. To overcome intrinsic limitations of current experimental research, a crossover, double-blind, prospective and longitudinal study was carried out in which cTBS was applied over the rOFC to evaluate its effect on odorant stimuli detection. All subjects received real and sham cTBS. Experimental procedures were done in two different sessions with a separation of at least one week between them to avoid carryover and learning effects. A total of 15 subjects completed the experiment, and their data were included in the final analysis (10 women, 5 men, mean age 22.40 ± 3.41). Every session consisted of two different measures of the conscious olfactory perception task: A baseline measure and one 5 minutes after cTBS/sham. Compared to baseline, marks in the olfactory task during the sham cTBS session increased (p =0.010), while marks during the real cTBS session decreased (p =0.017). Our results support the hypothesis that rOFC is an important node of a complex network required for conscious olfactory perception to arise. However, the exact mechanism that explains our results is unclear and could be explained by the disruption of other cognitive functions related to the rOFC.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on June 05, 2019 12:00 AM.
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Alcohol Dehydrogenase 1B Suppresses β-Amyloid-Induced Neuron Apoptosis
Amyloid-β (Aβ) deposition, neurofibrillary tangles induced by phosphorylation of tau protein and neuronal apoptosis are pathological hallmarks of Alzheimer’s disease (AD).The dementia rate in the alcoholic abusers were found to be higher than the control people. The present study explored potential roles of alcohol dehydrogenase 1B (ADH1B) in AD pathological process.The results showed that ADH1B level decreased significantly both in the serum of AD patients and in the hippocampus of APP/PS-1 AD model mice.The apoptotic rate was reduced and the viability was elevated significantly for the AD model cell transfected with ADH1B over-expressed vector. Moreover,the level of p75 neurotrophin receptor (p75NTR), a receptor of Aβ1-42,was down-regulated in the ADH1B over-expressed AD model cell and up-regulated in the cells transfected with shRNA vector of ADH1B. Furthermore, the protein levels of cleaved caspase-3 and Bax decreased significantly, and Bcl-2 level increased in the cells when overexpressing ADH1B.The opposite trend of cleaved caspase-3,Bax and Bcl-2 were observed in the cells transfected with shRNA vector of ADH1B. The level of reactive oxidative species (ROS) was found to be reduced in the ADH1B over-expressed cells and be enhanced when transfected with shRNA vector of ADH1B. These results indicated that ADH1B might be significant in the prevention of AD, especially for the abusers of alcohol, and a new potential target of AD treatment.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 05, 2019 12:00 AM.
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Shaking Paws Is Not the Same as Shaking Hands
A recent Nature paper shows that activity in rodent forelimb somatosensory cortex is related to the animal’s behavioral report of vibration intensity and identifies candidate mechanoreceptors responsible for the cortical response. Results highlight striking anatomical and neural differences from primates.
in Neuron on June 05, 2019 12:00 AM.
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Mitochondria Re-set Epilepsy
Neuronal networks maintain stable activity around a given set point, an enigmatic variable in homeostatic systems. In this issue of Neuron, Styr et al. (2019) now show that set points are regulated by mitochondria and propose a potential strategy to treat refractory forms of epilepsy.
in Neuron on June 05, 2019 12:00 AM.
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A Chronic Pain in the ACC
In this issue of Neuron, Meda et al. (2019) provide novel insights into how chronic pain alters connectivity and excitatory-inhibitory balance in a mediodorsal thalamus to anterior cingulate cortex circuit to promote aversive learning.
in Neuron on June 05, 2019 12:00 AM.
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Leaving the Lights on Using Gamma Entrainment to Protect against Neurodegeneration
The brain generates natural oscillations from coordinated neuronal activity. Recent work exploring gamma oscillation entrainment raised the possibility that the phenomenon can be exploited to preserve neural function. In this issue of Neuron, Adaikkan et al. (2019) now show that chronic gamma entrainment using visual stimuli protects against several neurodegenerative phenotypes.
in Neuron on June 05, 2019 12:00 AM.
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Interneurons: Learning on the Job
In this issue, Wester et al. (2019) examine the obligate relationship between cortical interneurons and pyramidal neurons. By genetically converting superficial IT pyramidal cells into PT-like deep-layer pyramidal cells, they alter the position, connectivity, and gene expression within CGE-derived interneurons.
in Neuron on June 05, 2019 12:00 AM.
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Central Amygdala Prepronociceptin-Expressing Neurons Mediate Palatable Food Consumption and Reward
(Neuron 102, 1037–1052; June 5, 2019)
in Neuron on June 05, 2019 12:00 AM.
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Publisher Correction: L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control

Nature Neuroscience, Published online: 04 June 2019; doi:10.1038/s41593-019-0438-8
Publisher Correction: L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control
in Nature Neuroscience - Issue - nature.com science feeds on June 04, 2019 12:00 AM.
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Scn2a Haploinsufficiency in Mice Suppresses Hippocampal Neuronal Excitability, Excitatory Synaptic Drive, and Long-Term Potentiation, and Spatial Learning and Memory
Nav1.2, a voltage-gated sodium channel subunit encoded by the Scn2a gene, has been implicated in various brain disorders, including epilepsy, autism spectrum disorder, intellectual disability, and schizophrenia. Nav1.2 is known to regulate the generation of action potentials in the axon initial segment and their propagation along axonal pathways. Nav1.2 also regulates synaptic integration and plasticity by promoting back-propagation of action potentials to dendrites, but whether Nav1.2 deletion in mice affects neuronal excitability, synaptic transmission, synaptic plasticity, and/or disease-related animal behaviors remains largely unclear. Here we report that mice heterozygous for the Scn2a gene (Scn2a+/– mice) show decreased neuronal excitability and suppressed excitatory synaptic transmission in the presence of network activity in the hippocampus. In addition, Scn2a+/– mice show suppressed hippocampal long-term potentiation in association with impaired spatial learning and memory, but show largely normal locomotor activity, anxiety-like behavior, social interaction, repetitive behavior, and whole-brain excitation. These results suggest that Nav1.2 regulates hippocampal neuronal excitability, excitatory synaptic drive, long-term potentiation, and spatial learning and memory in mice.
in Frontiers in Molecular Neuroscience | New and Recent Articles on June 04, 2019 12:00 AM.
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Neurogenesis in Neurodegenerative Diseases: Role of MFG-E8
Neurodegenerative diseases are devastating medical conditions with no effective treatments. Restoration of impaired neurogenesis represents a promising therapeutic strategy for neurodegenerative diseases. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein that plays a wide range of cellular functions including phagocytosis of apoptotic cells, anti-inflammation, tissue regeneration and homeostasis. The beneficial role of MFG-E8 has been shown in cerebral ischemia (stroke), neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, and traumatic brain injury (TBI). In stroke, MFG-E8 promotes neural stem cell proliferation and their migration towards the ischemic brain tissues. These novel functions of MFG-E8 are primarily mediated through its receptor αvβ3-integrin. Here we focus on the pivotal role of MFG-E8 in protecting against neuronal diseases by promoting neurogenesis. We also discuss the mechanisms of MFG-E8-mediated neural stem/progenitor cell (NSPC) proliferation and migration, and the potential of MFG-E8 for neural stem cell niche maintenance via angiogenesis. We propose further investigation of the molecular pathways for MFG-E8 signaling in NSPC and effective strategies for MFG-E8 delivery across the blood-brain barrier, which will help develop MFG-E8 as a future drug candidate for the bedside management of neurodegenerative diseases.
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on June 04, 2019 12:00 AM.
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Cortical Excitability Dynamics During Fear Processing
Background: Little is known about the modulation of cortical excitability in the prefrontal cortex during fear processing in humans. Here, we aimed to transiently modulate and test the cortical excitability during fear processing using transcranial magnetic stimulation (TMS) and brain oscillations in theta and alpha frequency bands with electroencephalography (EEG). Methods: We conducted two separate experiments (no-TMS and TMS). In the no-TMS experiment, EEG recordings were performed during the instructed fear paradigm in which a visual cue (CS+) was paired with an aversive unconditioned stimulus (electric shock), while the other visual cue was unpaired (CS-). In the TMS experiment, in addition the TMS was applied on the right dorsomedial prefrontal cortex (dmPFC). The participants also underwent structural MRI (magnetic resonance imaging) scanning and were assigned pseudo-randomly to both experiments, such that age and gender were matched. The cortical excitability was evaluated by time-frequency analysis and functional connectivity with weighted phase lag index (WPLI). We further linked the excitability patterns with markers of stress coping capability. Results: After visual cue onset, we found increased theta power in the frontal lobe and decreased alpha power in the occipital lobe during CS+ relative to CS- trials. TMS of dmPFC increased theta power in the frontal lobe and reduced alpha power in the occipital lobe during CS+. The TMS pulse increased the information flow from the sensorimotor region to the prefrontal and occipital regions in the theta and alpha bands respectively during CS+ compared to CS-. Pre-stimulation frontal theta power (0.75-1 s) predicted the magnitude of frontal theta power changes after stimulation (1-1.25 s). Finally, the increased frontal theta power during CS+ compared to CS- was positively correlated with stress coping behavior. Conclusion: Our results show that TMS over dmPFC transiently modulated the regional cortical excitability and the fronto-occipital information flows during fear processing, while the pre-stimulation frontal theta power determined the strength of achieved effects. The frontal theta power may serve as a biomarker for fear processing and stress-coping responses in individuals and could be clinically tested in mental disorders.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on June 04, 2019 12:00 AM.
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Heterogeneous Nuclear Ribonucleoprotein E2 (hnRNP E2) Is a Component of TDP-43 Aggregates Specifically in the A and C Pathological Subtypes of Frontotemporal Lobar Degeneration
TAR DNA-binding protein 43 (TDP-43) is the major component of the ubiquitin-positive protein aggregates seen in the majority of frontotemporal lobar degeneration and amyotrophic lateral sclerosis cases. TDP-43 belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family that is involved in the regulation of RNA transcription, splicing, transport and translation. There are a great many hnRNPs, which often have overlapping functions and act cooperatively in RNA processing. Here we demonstrate that another hnRNP family member, hnRNP E2, shows a striking accumulation within dystrophic neurites and cytoplasmic inclusions in the frontal cortex and hippocampus of a subset of FTLD-TDP cases belonging to pathological subtypes A and C, where hnRNP E2 was found to co-localize with 85% of TDP-43 immunopositive inclusions. hnRNP E2-positive inclusions were not seen in FTLD-TDP cases with the C9orf72 expansion or in any other neurodegenerative disorders examined. This interaction with TDP-43 in specific FTLD subtypes suggests different underlying neurodegenerative pathways.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 04, 2019 12:00 AM.
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Influence of Head Tissue Conductivity Uncertainties on EEG Dipole Reconstruction
Reliable EEG source analysis depends on sufficiently detailed and accurate head models. In this study, we investigate how uncertainties inherent to the experimentally determined conductivity values of the different conductive compartments influence the results of EEG source analysis. In a single source scenario, the superficial and focal somatosensory P20/N20 component, we analyze the influence of varying conductivities on dipole reconstructions using a generalized polynomial chaos (gPC) approach. We find that in particular the conductivity uncertainties for skin and skull have a significant influence on the EEG inverse solution, leading to variations in source localization by several centimeters. The conductivity uncertainties for gray and white matter were found to have little influence on the source localization, but a strong influence on the strength and orientation of the reconstructed source, respectively. As the CSF conductivity is most accurately determined of all conductivities in a realistic head model, CSF conductivity uncertainties had a negligible influence on the source reconstruction. This small uncertainty is a further benefit of distinguishing the CSF in realistic volume conductor models.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on June 04, 2019 12:00 AM.
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Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance
The blood-brain barrier (BBB) mediates the communication between the periphery and the central nervous system (CNS). Recently, CNS insulin resistance has been elucidated to play a role in neurodegenerative disease. This has stimulated a wealth of information on the molecular impact of insulin in the brain, particularly in the improvement of cognition. Since the BBB regulates the transport of insulin into the brain and thus, helps to regulate CNS levels, alterations in the BBB response to insulin could impact CNS insulin resistance. In this review, we summarize the effect of insulin on some of the cell types that make up the BBB, including endothelial cells, neurons, astrocytes, and pericytes. We broadly discuss how these changes in specific cell types could ultimately impact the BBB. We also summarize how insulin can regulate levels of the pathological hallmarks of Alzheimer’s disease, including amyloid beta (Aβ) and tau within each cell type. Finally, we suggest interventional approaches to overcome detrimental effects on the BBB in regards to changes in insulin transport.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on June 04, 2019 12:00 AM.
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Design and Development of Microscale Thickness Shear Mode (TSM) Resonators for Sensing Neuronal Adhesion
The overall goal of this study is to develop thickness shear mode (TSM) resonators for real-time, label-free, non-destructive sensing of biological adhesion events in small populations (hundreds) of neurons in a cell culture medium and subsequently in vivo in the future. Such measurements will enable discoveries of the role of biomechanical events in neuronal function and dysfunction. Conventional TSM resonators have been used for chemical sensing and biosensing applications in media with hundreds of thousands of cells in culture. However, the sensitivity and spatial resolution of conventional TSM devices need to be further enhanced for sensing smaller cell populations or molecules of interest. In this report, we focus on key challenges such as eliminating inharmonics in solution and maximizing Q-factor while simultaneously miniaturizing the active sensing (electrode) area to make them suitable for small populations of cells. We use theoretical expressions for sensitivity and electrode area of TSM sensors operating in liquid. As a validation of the above design effort, we fabricated prototype TSM sensors with resonant frequencies of 42, 47, 75 and 90 MHz and characterized their performance in liquid using electrode diameters of 150, 200, 400, 800 and 1200 μm and electrode thicknesses of 33 and 230 nm. We validated a candidate TSM resonator with the highest sensitivity and Q-factor for real-time monitoring of adhesion of cortical neurons. We reduced the size of the sensing area to 150-400 μm for TSM devices improving the spatial resolution by monitoring few 100s to 1000s of neurons. Finally, we modified the electrode surface with single-walled carbon nanotubes (SWCNT) to further enhance adhesion and sensitivity of the TSM sensor to adhering neurons (Marx, 2003).
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on June 04, 2019 12:00 AM.
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Processing Pipeline for Atlas-Based Imaging Data Analysis of Structural and Functional Mouse Brain MRI (AIDAmri)
Magnetic resonance imaging (MRI) is a key technology in multimodal animal studies of brain connectivity and disease pathology. In vivo MRI provides non-invasive, whole brain macroscopic images containing structural and functional information, thereby complementing invasive in vivo high-resolution microscopy and ex vivo molecular techniques. Brain mapping, the correlation of corresponding regions between multiple brains in a standard brain atlas system, is widely used in human MRI. For small animal MRI, however, there is no scientific consensus on pre-processing strategies and atlas-based neuroinformatics. Thus, it remains difficult to compare and validate results from different pre-clinical studies which were processed using custom-made code or individual adjustments of clinical MRI software and without a standard brain reference atlas. Here, we describe AIDAmri, a novel Atlas-based Imaging Data Analysis pipeline to process structural and functional mouse brain data including anatomical MRI, fiber tracking using diffusion tensor imaging (DTI) and functional connectivity analysis using resting-state functional MRI (rs-fMRI). The AIDAmri pipeline includes automated pre-processing steps, such as raw data conversion, skull-stripping and bias-field correction as well as image registration with the Allen Brain Reference Atlas (ARA). Following a modular structure developed in Python scripting language, the pipeline integrates established and newly developed algorithms. Each processing step was optimized for efficient data processing requiring minimal user-input and user programming skills. The raw data is analyzed and results transferred to the ARA coordinate system in order to allow an efficient and highly-accurate region-based analysis. AIDAmri is intended to fill the gap of a missing open-access and cross-platform toolbox for the most relevant mouse brain MRI sequences thereby facilitating data processing in large cohorts and multi-center studies.
in Frontiers in Neuroinformatics | New and Recent Articles on June 04, 2019 12:00 AM.
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Exploiting Multi-Level Parallelism for Stitching Very Large Microscopy Images
Due to the limited field of view of the microscopes, acquisitions of macroscopic specimens require many parallel image stacks to cover the whole volume of interest. Overlapping regions are introduced among stacks in order to make it possible automatic alignment by means of a 3D stitching tool. Since state-of-the-art microscopes coupled with chemical clearing procedures can generate 3D images whose size exceeds the Terabyte, parallelization is required to keep stitching time within acceptable limits. In the present paper we discuss how multi-level parallelization reduces the execution times of TeraStitcher, a tool designed to deal with very large images. %Parallelization has been carried out in such a way that its impact on user interface and software maintenance is negligible. Two algorithms performing dataset partition for efficient parallelization in a transparent way are presented together with experimental results proving the effectiveness of the approach that achieves a speedup close to 300$\times$, when both coarse- and fine-grained parallelism are exploited. Multi-level parallelization of TeraStitcher led to a significant reduction of processing times with no changes in the user interface, and with no additional effort required for the maintenance of code.
in Frontiers in Neuroinformatics | New and Recent Articles on June 04, 2019 12:00 AM.
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Multi-Lag Analysis of Symbolic Entropies on EEG Recordings for Distress Recognition
Distress is a critical problem in developed societies given its long-term negative effects on physical and mental health. The interest in studying this emotion has notably increased during last years, being electroencephalography (EEG) signals preferred over other physiological variables in this research field. In addition, the non-stationary nature of brain dynamics has impulsed the use of non-linear metrics such as symbolic entropies in brain signal analysis. However, only consecutive samples in a time series have been considered in the scientific literature for entropy computation applied to distress identification. Thus, the influence of time-lag on brain patterns assessment has not been tested. Hence, in the present study two permutation entropies denominated Delayed Permutation Entropy and Permutation Min-Entropy have been computed for the first time at different time-lags to discern between calmness and distress emotional states in EEG signals. Moreover, a number of curve-related features were also calculated to assess the signal dynamics across different temporal intervals.Complementary information among these variables was studied through stepwise regression and ten-fold cross-validation approaches. According to the results obtained, the multi-lag analysis has been able to reveal new significant insights so far undiscovered, thus notably improving the process of distress recognition from EEG recordings.
in Frontiers in Neuroinformatics | New and Recent Articles on June 04, 2019 12:00 AM.
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Differences in Sodium Channel Densities in the Apical Dendrites of Pyramidal Cells of the Electrosensory Lateral Line Lobe
Heterogeneity of neural properties within a given neural class is ubiquitous in the nervous system and permits different sub-classes of neurons to specialize for specific purposes. This principle has been thoroughly investigated in the hindbrain of the weakly electric fish A. leptorhynchus in the primary electrosensory area, the Electrosensory Lateral Line lobe (ELL). The pyramidal cells that receive inputs from tuberous electroreceptors are organized in three maps in distinct segments of the ELL. The properties of these cells vary greatly across maps due to differences in connectivity, receptor expression, and ion channel composition. These cells are a seminal example of bursting neurons and their bursting dynamic relies on the presence of voltage-gated Na+ channels in the extensive apical dendrites of the superficial pyramidal cells. Other ion channels can affect burst generation and their expression varies across ELL neurons and segments. For example, SK channels cause hyperpolarizing after-potentials decreasing the likelihood of bursting, yet bursting propensity is similar across segments. We question whether the depolarizing mechanism that generates the bursts presents quantitative differences across segments that could counterbalance other differences having the opposite effect. Although their presence and role are established, the distribution and density of the apical dendrites’ Na+ channels have not been quantified and compared across ELL maps. Therefore, we test the hypothesis that Na+ channel density varies across segment by quantifying their distribution in the apical dendrites of immunolabeled ELL sections. We found the Na+ channels to be two-fold denser in the lateral segment than in the centro-medial segment, the centro-lateral segment being intermediate. Our results imply that this differential expression of voltage-gated Na+ channels could counterbalance or interact with other aspects of neuronal physiology that vary across segments (e.g. SK channels). We argue that burst coding of sensory signals, and the way the network regulates bursting, should be influenced by these variations in Na+ channel density.
in Frontiers in Neural Circuits | New and Recent Articles on June 04, 2019 12:00 AM.
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Combined Assessment of Diffusion Parameters and Cerebral Blood Flow Within Basal Ganglia in Early Parkinson’s Disease
Diffusion tensor imaging (DTI) is a sensitive tool for detecting brain tissue microstructural alterations in Parkinson’s disease (PD). Abnormal cerebral perfusion patterns have also been reported in PD patients using arterial spin labeling (ASL) MRI. In this study we aimed to perform a combined DTI and ASL assessment in PD patients within the basal ganglia, in order to test the relationship between microstructural and perfusion alterations. Fifty-two subjects participated in this study. Specifically, twenty-six PD patients (mean age [SD]=66.7[8.9] years, 21 males, median [IQR] Modified Hoehn and Yahr = 1.5 [1-1.6]) and twenty-six healthy controls (HC, mean age [SD]=65.2[7.5], 15 males) were scanned with 1.5T MRI. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) maps were derived from diffusion-weighted images, while cerebral blood flow (CBF) maps were computed from ASL data. After registration to Montreal Neurological Institute standard space, FA, MD, AD, RD and CBF median values were extracted within specific regions of interest: substantia nigra, caudate, putamen, globus pallidum, thalamus, red nucleus and subthalamic nucleus. DTI measures and CBF were compared between the two groups. The relationship between diffusion parameters and CBF was tested with Spearman’s correlations. False discovery rate (FDR)-corrected p-values lower than 0.05 were considered significant, while uncorrected p-values < 0.05 were considered a trend. No significant FA differences were observed. AD was significantly increased in PD patients compared with HC in the putamen (p=0.039, pFDR=0.035). No significant CBF differences were found between PD patients and HC. Diffusion parameters were not significantly correlated with CBF in the HC group, while a significant correlation emerged for PD patients in the caudate nucleus, for all DTI measures (with FA: r=0.543, pFDR=0.028; with MD: r=-0.661, pFDR=0.002; with AD: r=-0.628, pFDR=0.007; with RD: r=-0.635, pFDR=0.003). This study showed that DTI is a more sensitive technique than ASL to detect alterations in the basal ganglia in the early phase of PD. Our results suggest that, although DTI and ASL convey different information, a relationship between microstructural integrity and perfusion changes in the caudate may be present.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 04, 2019 12:00 AM.
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Neurocompensatory Effects of the Default Network in Older Adults
The hemispheric asymmetry reduction in older adults (HAROLD) is a neurocompensatory process that has been observed across several cognitive functions but has not yet been examined in relation to task-induced relative deactivations of the default mode network. The present study investigated the presence of HAROLD effects specific to neural activations and deactivations using a functional magnetic resonance imaging (fMRI) n-back paradigm. It was hypothesized that HAROLD effects would be identified in relative activations and deactivations during the paradigm, and that they would be associated with better 2-back performance. Forty-five older adults (M age=63.8; range=53-83) were administered a verbal n-back paradigm during fMRI. For each participant, the volume of brain response was summarized by left and right frontal regions of interest, and laterality indices (LI; i.e., left/right) were calculated to assess HAROLD effects. Group level results indicated that age was significantly and negatively correlated with LI (i.e., reduced left lateralization) for deactivations, but positively correlated with LI (i.e., increased left lateralization) for activations. The relationship between age and LI for deactivation was significantly moderated by performance level, revealing a stronger relationship between age and LI at higher levels of 2-back performance. Findings suggest that older adults may employ neurocompensatory processes specific to deactivations, and task-independent processes may be particularly sensitive to age-related neurocompensation.
in Frontiers in Aging Neuroscience | New and Recent Articles on June 04, 2019 12:00 AM.
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Brain–Heart Interactions Underlying Traditional Tibetan Buddhist Meditation

Abstract
Despite accumulating evidence suggesting improvement in one’s well-being as a result of meditation, little is known about if or how the brain and the periphery interact to produce these behavioral and mental changes. We hypothesize that meditation reflects changes in the neural representations of visceral activity, such as cardiac behavior, and investigated the integration of neural and visceral systems and the spontaneous whole brain spatiotemporal dynamics underlying traditional Tibetan Buddhist meditation. In a large cohort of long-term Tibetan Buddhist monk meditation practitioners, we found distinct transient modulations of the neural response to heartbeats in the default mode network (DMN), along with large-scale network reconfigurations in the gamma and theta bands of electroencephalography (EEG) activity induced by meditation. Additionally, temporal-frontal network connectivity in the EEG theta band was negatively correlated with the duration of meditation experience, and gamma oscillations were uniquely, directionally coupled to theta oscillations during meditation. Overall, these data suggest that the neural representation of cardiac activity in the DMN and large-scale spatiotemporal network integrations underlie the fundamental neural mechanism of meditation and further imply that meditation may utilize cortical plasticity, inducing both immediate and long-lasting changes in the intrinsic organization and activity of brain networks.
in Cerebral Cortex Advance Access on June 04, 2019 12:00 AM.
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Perineuronal Nets: Plasticity, Protection, and Therapeutic Potential
The relationship between neurons and perineuronal nets (PNNs) is attracting attention as a central mechanism controlling brain plasticity. In the cortex, PNNs primarily surround inhibitory parvalbumin interneurons, playing roles as both a regulator of synaptic plasticity and a protective barrier. PNNs have a delayed developmental trajectory and are key components in the closure of critical periods of heightened neuroplasticity. In animal models, manipulating PNNs outside this critical window can enhance cognition, suggesting a potentially therapeutic approach for attenuating cognitive decline.
in Trends in Neurosciences on June 04, 2019 12:00 AM.
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Single-cell activity tracking reveals that orbitofrontal neurons acquire and maintain a long-term memory to guide behavioral adaptation

Nature Neuroscience, Published online: 03 June 2019; doi:10.1038/s41593-019-0408-1
Namboodiri, Otis et al. reveal that orbitofrontal cortex acquires and maintains a long-term memory of cue–reward associations to guide multiple aspects of behavioral learning, and that it routes select information to a downstream learning center.
in Nature Neuroscience - Issue - nature.com science feeds on June 03, 2019 12:00 AM.
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A supporting role

Nature Reviews Neuroscience, Published online: 03 June 2019; doi:10.1038/s41583-019-0193-6
Astrocytes internalize and metabolize toxic neuronal lipids in an activity-dependent manner to maintain brain homeostasis.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on June 03, 2019 12:00 AM.
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Reply to ‘Active and effective replay: systems consolidation reconsidered again’

Nature Reviews Neuroscience, Published online: 03 June 2019; doi:10.1038/s41583-019-0192-7
Reply to ‘Active and effective replay: systems consolidation reconsidered again’
in Nature Reviews Neuroscience - Issue - nature.com science feeds on June 03, 2019 12:00 AM.
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Active and effective replay: systems consolidation reconsidered again

Nature Reviews Neuroscience, Published online: 03 June 2019; doi:10.1038/s41583-019-0191-8
Active and effective replay: systems consolidation reconsidered again
in Nature Reviews Neuroscience - Issue - nature.com science feeds on June 03, 2019 12:00 AM.
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Editorial: The Superior Colliculus/Tectum: Cell Types, Circuits, Computations, Behaviors

in Frontiers in Neural Circuits | New and Recent Articles on June 03, 2019 12:00 AM.
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Endothelial Cells Filopodia in the Anastomosis of Central Nervous System Capillaries
In this Perspective we explore filopodia of endothelial cells in the developing central nervous system using the Golgi method and transmission electron microscopy. Filopodia of endothelial cells play a crucial role in the anastomosis of growing capillaries of the central nervous system. The leading endothelial cells filopodia from approaching capillaries interconnect forming complex conglomerates that precede the anastomotic event. The contacting filopodia form narrow spaces between them filled with proteinaceous basal lamina material. The original narrow spaces coalesce into larger ones leading to the formation of a single one that will interconnect (anastomose) the two approaching capillaries. The four leading endothelial cells (two for each approaching capillary) become the wall of the newly formed post-anastomotic CNS capillaries. These new CNS capillaries are very small with narrow and irregular lumina that might permit the passage of fluid but not yet of blood cells. Eventually, their lumen enlarges and permits the passage of blood cells.
in Frontiers in Neuroanatomy | New and Recent Articles on June 03, 2019 12:00 AM.
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Schizophrenia Exhibits Bi-directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits

Abstract
Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia (SCZ), yet a tension exists between studies pinpointing focal disruptions versus those implicating brain-wide disturbances. The cerebellum and the striatum communicate reciprocally with the thalamus and cortex through monosynaptic and polysynaptic connections, forming cortico-striatal-thalamic-cerebellar (CSTC) functional pathways that may be sensitive to brain-wide dysconnectivity in SCZ. It remains unknown if the same pattern of alterations persists across CSTC systems, or if specific alterations exist along key functional elements of these networks. We characterized connectivity along major functional CSTC subdivisions using resting-state functional magnetic resonance imaging in 159 chronic patients and 162 matched controls. Associative CSTC subdivisions revealed consistent brain-wide bi-directional alterations in patients, marked by hyper-connectivity with sensory-motor cortices and hypo-connectivity with association cortex. Focusing on the cerebellar and striatal components, we validate the effects using data-driven k-means clustering of voxel-wise dysconnectivity and support vector machine classifiers. We replicate these results in an independent sample of 202 controls and 145 patients, additionally demonstrating that these neural effects relate to cognitive performance across subjects. Taken together, these results from complementary approaches implicate a consistent motif of brain-wide alterations in CSTC systems in SCZ, calling into question accounts of exclusively focal functional disturbances.
in Cerebral Cortex Advance Access on June 03, 2019 12:00 AM.
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Studying Laboratory Mice – Into the Wild
Studies using rewilded laboratory mice have begun to provide important clues into the complex relationship between environment, immunity, and behavior. In a recent paper, Cope and colleagues (Hippocampus, 2019) showed that exposing laboratory mice to outdoor living, either with or without peripheral worm infection, increased adult neurogenesis and had major effects on microglia, but only outdoor living coupled with worm infection increased anxiety.
in Trends in Neurosciences on June 03, 2019 12:00 AM.
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MeCP2: an epigenetic regulator of critical periods

Publication date: December 2019
Source: Current Opinion in Neurobiology, Volume 59
Author(s): Nathalie Picard, Michela Fagiolini
Complex adult behaviors arise from the integration of sequential and often overlapping critical periods (CPs) early in life and adolescence. These processes rely on a subtle interplay between the set of genes inherited from the parents, the surrounding environment and epigenetic regulation. Methyl-CpG-binding protein 2 (MeCP2) has been shown to recognize epigenetic states and regulate gene expression by reading methylated DNA. Here, we will review the recent findings revealing the role of MeCP2 during postnatal CPs of development using mouse models of Rett (RTT) syndrome.

in ScienceDirect Publication: Current Opinion in Neurobiology on June 02, 2019 05:00 PM.
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The neuronal stimulation–transcription coupling map

Publication date: December 2019
Source: Current Opinion in Neurobiology, Volume 59
Author(s): Kelsey M Tyssowski, Jesse M Gray
Neurons transcribe different genes in response to different extracellular stimuli, and these genes regulate neuronal plasticity. Thus, understanding how different stimuli regulate different stimulus-dependent gene modules would deepen our understanding of plasticity. To systematically dissect the coupling between stimulation and transcription, we propose creating a ‘stimulation–transcription coupling map’ that describes the transcription response to each possible extracellular stimulus. While we are currently far from having a complete map, recent genomic experiments have begun to facilitate its creation. Here, we describe the current state of the stimulation–transcription coupling map as well as the transcriptional regulation that enables this coupling.

in ScienceDirect Publication: Current Opinion in Neurobiology on June 02, 2019 05:00 PM.
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Glial regulation of synaptic function in models of addiction

Publication date: August 2019
Source: Current Opinion in Neurobiology, Volume 57
Author(s): David Stellwagen, Gina M Kemp, Simone Valade, Julien Chambon
The glial regulation of synaptic function provides important modulation of the synaptic and behavioral changes induced by drugs of abuse. In some cases, this regulation is adaptive, reducing drug-induced change, and in other cases maladaptive, contributing to the induction or maintenance of these changes. Understanding the contribution of glia to addictive behaviors will be important to fully understand the development of addiction, and a critical entry into methods to potentially mitigate this affliction. This review will cover recent advances in elucidating the contribution of the major types of glia – microglia and astrocytes – to drug-induced synaptic plasticity.

in ScienceDirect Publication: Current Opinion in Neurobiology on June 02, 2019 05:00 PM.
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Subscription and Copyright Information

in Trends in Neurosciences on June 01, 2019 12:00 AM.
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Editorial Board and Contents

in Trends in Neurosciences on June 01, 2019 12:00 AM.
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Nanoscale Organization of Vesicle Release at Central Synapses
Presynaptic boutons support neurotransmitter release with nanoscale precision at sub-millisecond timescales. Studies over the past two decades have revealed a rich tapestry of molecular players governing synaptic vesicle fusion at highly specialized release sites in the active zone (AZ). However, the spatiotemporal organization of release at active synapses remains elusive, in part owing to the extremely small size of the AZ and the limited resolution of conventional approaches. Recent advances in fluorescence nanoscopy have revolutionized direct investigation of presynaptic release organization and dynamics.
in Trends in Neurosciences on June 01, 2019 12:00 AM.
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SUMOylating Two Distinct Sites on the A-type Potassium Channel, Kv4.2, Increases Surface Expression and Decreases Current Amplitude
Post-translational conjugation of Small Ubiquitin-like Modifier (SUMO) peptides to lysine (K) residues on target proteins alters their interactions. SUMOylation of a target protein can either promote its interaction with other proteins that possess SUMO binding domains, or it can prevent target protein interactions that normally occur in the absence of SUMOylation. One subclass of voltage-gated potassium channels that mediates an A-type current, IA, exists as a ternary complex comprising Kv4 pore forming subunits, Kv channel interacting proteins (KChIP) and transmembrane dipeptidyl peptidase like proteins (DPPL). SUMOylation could potentially regulate intra- and/or intermolecular interactions within the complex. This study began to test this hypothesis and showed that Kv4.2 channels were SUMOylated in the rat brain and in human embryonic kidney (HEK) cells expressing a GFP-tagged mouse Kv4.2 channel (Kv4.2g). Prediction software identified two putative SUMOylation sites in the Kv4.2 C-terminus at K437 and K579. These sites were conserved across mouse, rat, and human Kv4.2 channels and across mouse Kv4 isoforms. Increasing Kv4.2g SUMOylation at each site by ~30% produced a significant ~22-50% decrease in IA Gmax, and a ~70-95% increase in channel surface expression. Site-directed mutagenesis of Kv4.2g showed that K437 SUMOylation regulated channel surface expression, while K579 SUMOylation controlled IA Gmax. The K579R mutation mimicked and occluded the SUMOylation-mediated decrease in IA Gmax, suggesting that SUMOylation at K579 blocked an intra- or inter-protein interaction involving K579. The K437R mutation did not obviously alter channel surface expression or biophysical properties, but it did block the SUMOylation-mediated increase in channel surface expression. Interestingly, enhancing K437 SUMOylation in the K579R mutant roughly doubled channel surface expression, but produced no change in IA Gmax, suggesting that the newly inserted channels were electrically silent. This is the first report that Kv4.2 channels are SUMOylated and that SUMOylation can independently regulate Kv4.2 surface expression and IA Gmax in opposing directions. The next step will be to determine if/how SUMOylation affects Kv4 interactions within the ternary complex.
in Frontiers in Molecular Neuroscience | New and Recent Articles on May 31, 2019 12:00 AM.
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Elevated Levels of Arachidonic Acid-Derived Lipids Including Prostaglandins and Endocannabinoids Are Present Throughout ABHD12 Knockout Brains: Novel Insights Into the Neurodegenerative Phenotype
Derived from arachidonic acid (AA), the endogenous cannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) is a substrate for αβ-hydrolase domain 12 (ABHD12). Loss-of-function mutations of ABHD12 are associated with the neurodegenerative disorder polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC). ABHD12 knockout (KO) mice show PHARC-like behaviors in older adulthood. Here, we test the hypothesis that ABHD12 deletion age-dependently regulates bioactive lipids in the CNS. Lipidomics analysis of the brainstem, cerebellum, cortex, hippocampus, hypothalamus, midbrain, striatum and thalamus from male young (3-4 months) and older (7 months) adult ABHD12 KO and age-matched wild-type (WT) mice was performed on over 80 lipids via HPLC/MS/MS, including eCBs, lipoamines, 2-acyl glycerols, free fatty acids, and prostaglandins (PGs). Aging and ABHD12 deletion drove widespread changes in the CNS lipidome; however, the effects of ABHD12 deletion were similar between old and young mice, meaning that many alterations in the lipidome precede PHARC-like symptoms. AA-derived lipids were particularly sensitive to ABHD12 deletion. 2-AG increased in the striatum, hippocampus, cerebellum, thalamus, midbrain, and brainstem, whereas the eCB N-arachidonoyl ethanolamine increased in all 8 brain regions, along with at least 2 PGs. Aging also had a widespread effect on the lipidome and more age-related changes in bioactive lipids were found in ABHD12 KO mice than WT suggesting that ABHD12 deletion exacerbates the effects of age. The most robust effects of aging (independent of genotype) across the CNS were decreases in N-acyl GABAs and N-acyl glycines. In conclusion, levels of bioactive lipids are dynamic throughout adulthood and deleting ABHD12 disrupts the wider lipidome, modulating multiple AA-derived lipids with potential consequences for neuropathology.
in Frontiers in Molecular Neuroscience | New and Recent Articles on May 31, 2019 12:00 AM.
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Novel Strategies for the Generation of Neuronal Diversity: Lessons From the Fly Visual System
Among all organs of an adult animal, the central nervous system stands out because of its vast complexity and morphological diversity. During early development, the entire central nervous system develops from an apparently homogenous group of progenitors that differentiate into all neural cell types. Therefore, understanding the molecular and genetic mechanisms that give rise to the cellular and anatomical diversity of the brain is a key goal of the developmental neurobiology field. With this aim in mind, the development of the central nervous system of model organisms has been extensively studied. From more than a century, the mechanisms of neurogenesis have been studied in the fruit fly Drosophila melanogaster. The visual system comprises one of the major structures of the Drosophila brain. The visual information is collected by the eye-retina photoreceptors and then processed by the four optic lobe ganglia: the lamina, medulla, lobula and lobula plate. The molecular mechanisms that originate neuronal diversity in the optic lobe have been unveiled in the past decade. In this article, we describe the early development and differentiation of the lobula plate ganglion, from the formation of the optic placode and the inner proliferation centre to the specification of motion detection neurons. We focused specifically on how the precise combination of signalling pathways and cell-specific transcription factors patterns the pool of neural stem cells that generates the different neurons of the motion detection system.
in Frontiers in Molecular Neuroscience | New and Recent Articles on May 31, 2019 12:00 AM.
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Proestrus Differentially Regulates Expression of Ion Channel and Calcium Homeostasis Genes in GnRH Neurons of Mice
In proestrus, the changing gonadal hormone milieu alters the physiological properties of GnRH neurons and contributes to the development of the GnRH surge. We hypothesized that proestrus also influences the expression of different ion channel genes in mouse GnRH neurons. Therefore, we performed gene expression profiling of GnRH neurons collected from intact, proestrous and metestrous GnRH-GFP transgenic mice, respectively. Proestrus changed the expression of 37 ion channel and 8 calcium homeostasis-regulating genes. Voltage-gated sodium channels responded with upregulation of three alpha subunits (Scn2a1, Scn3a and Scn9a). Within the voltage-gated potassium channel class, Kcna1, Kcnd3, Kcnh3 and Kcnq2 were upregulated, while others (Kcna4, Kcnc3, Kcnd2 and Kcng1) underwent downregulation. Proestrus also had impact on inwardly rectifying potassium channel subunits manifested in enhanced expression of Kcnj9 and Kcnj10 genes, whereas Kcnj1, Kcnj11 and Kcnj12 subunit genes were downregulated. The two-pore domain potassium channels also showed differential expression with upregulation of Kcnk1 and reduced expression of three subunit genes (Kcnk7, Kcnk12 and Kcnk16). Changes in expression of chloride channels involved both the voltage-gated (Clcn3 and Clcn6) and the intracellular (Clic1) subtypes. Regarding the pore-forming alpha-1 subunits of voltage-gated calcium channels, two (Cacna1b and Cacna1h) were upregulated, while Cacna1g showed downregulation. The ancillary subunits were also differentially regulated (Cacna2d1, Cacna2d2, Cacnb1, Cacnb3, Cacnb4, Cacng5, Cacng6 and Cacng8). In addition, ryanodine receptor 1 (Ryr1) gene was downregulated, while a transient receptor potential cation channel (Trpm3) gene showed enhanced expression. Genes encoding proteins regulating the intracellular calcium homeostasis were also influenced (Calb1, Hpca, Hpcal1, Hpcal4, Cabp7, Cab 39l and Cib2). The differential expression of genes coding for ion channel proteins in GnRH neurons at late proestrus indicates that the altering hormone milieu contributes to remodeling of different kinds of ion channels of GnRH neurons, which might be a prerequisite of enhanced cellular activity of GnRH neurons and the subsequent surge release of the neurohormone.
in Frontiers in Molecular Neuroscience | New and Recent Articles on May 31, 2019 12:00 AM.
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Resting-State Brain Network Dysfunctions Associated With Visuomotor Impairments in Autism Spectrum Disorder
Background: Individuals with autism spectrum disorder (ASD) show elevated levels of motor variability that are associated with clinical outcomes. Cortical-cerebellar networks involved in visuomotor control have been implicated in postmortem and anatomical imaging studies of ASD. However, the extent to which these networks show intrinsic functional alterations in patients, and the relationship between intrinsic functional properties of cortical-cerebellar networks and visuomotor impairments in ASD have not yet been clarified. Methods: We examined the amplitude of low frequency fluctuation (ALFF) of cortical and cerebellar brain regions during resting-state functional MRI (rs-fMRI) in 23 individuals with ASD and 16 typically developing (TD) controls. Regions of interest (ROIs) with ALFF values significantly associated with motor variability were identified for patients and controls respectively, and their functional connectivity (FC) to each other and the rest of the brain were examined. Results: For TD controls, greater ALFF in bilateral cerebellar crus I, left superior temporal gyrus, left inferior frontal gyrus, right supramarginal gyrus and left angular gyrus each were associated with greater visuomotor variability. Greater ALFF in cerebellar lobule VIII was associated with less visuomotor variability. For individuals with ASD, greater ALFF in right calcarine cortex, right middle temporal gyrus (including MT/V5), left Heschl’s gyrus, left postcentral gyrus, right precentral gyrus, and left precuneus was related to greater visuomotor variability. Greater ALFF in cerebellar vermis VI was associated with less visuomotor variability. Individuals with ASD and TD controls did not show differences in ALFF for any of these ROIs. Individuals with ASD showed greater posterior cerebellar connectivity with occipital and parietal cortices relative to TD controls, and reduced FC within cerebellum and between lateral cerebellum and prefrontal and other regions of association cortex. Conclusion: Together, these findings suggest that increased resting oscillations within visuomotor networks in ASD are associated with more severe deficits in controlling variability during precision visuomotor behavior. Differences between individuals with ASD and TD controls in the topography of networks showing relationships to visuomotor behavior suggest atypical patterns of cerebellar-cortical specialization and connectivity in ASD that underlies previously documented visuomotor deficits.
in Frontiers in Integrative Neuroscience | New and Recent Articles on May 31, 2019 12:00 AM.
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Enhanced γ-Glutamyltranspeptidase Imaging That Unravels the Glioma Recurrence in Post-radio/Chemotherapy Mixtures for Precise Pathology via Enzyme-Triggered Fluorescent Probe
Accurate pathological diagnosis of gliomas recurrence is crucial for the optimal management and prognosis prediction. The study here unravels that γ-glutamyltranspeptidase (GGT) fluorescence probe imaging in twenty recurrent glioma tissues selectively recognize the most malignant portion from treatment responsive tissues induced by radio/chemo-therapy (Figure 1). The overexpression of GGT in recurrent gliomas and low level in radiation necrosis were validated by western blot analysis and immunohistochemistry. Furthermore, the ki-67 index evaluation demonstrated the significant increase of malignancy aided by GGT-responsive fluorescent probe to screen out the right specimen through fast enhanced imaging of enzyme activity. Importantly, our GGT-targeting probe can be used for accurate determination of pathologic evaluation of tumor malignancy, and eventually for guiding the following management in patients with recurrent.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on May 31, 2019 12:00 AM.
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A Crosstalk Between Brain Cholesterol Oxidation and Glucose Metabolism in Alzheimer’s Disease
In Alzheimer’s disease (AD), both cholesterol and glucose dysmetabolism precede the onset of memory deficit and contribute to the disease progression. It is indeed now believed that oxidized cholesterol in the form of oxysterols and altered glucose uptake are main triggers in AD affecting production and clearance of Aβ, and tau phosphorylation. However, only a few studies highlight the relationship between them, suggesting the importance of further extensive studies on this topic. Recently, a molecular link was demonstrated between cholesterol oxidative metabolism and glucose uptake in the brain. In particular, 27-hydroxycholesterol, a key linker between hypercholesterolemia and the increased AD risk, is considered a biomarker for reduced glucose metabolism. In fact, its excess increases the activity of the renin-angiotensin system in the brain, thus reducing insulin-mediated glucose uptake, which has a major impact on brain functioning. Despite this important evidence regarding the role of this oxysterol in regulating glucose uptake by neurons, the involvement of other cholesterol oxidation products that have been clearly demonstrated to be key players in AD, cannot be ruled out. This review highlights the current understanding of the potential role of cholesterol and glucose dysmetabolism in AD progression, and the bidirectional crosstalk between these two phenomena.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on May 31, 2019 12:00 AM.
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Inhomogeneities in Network Structure and Excitability Govern Initiation and Propagation of Spontaneous Burst Activity
The mesoscale architecture of neuronal networks strongly influences the initiation of spontaneous activity and its pathways of propagation. Spontaneous activity has been studied extensively in networks of cultured cortical neurons that generate complex yet reproducible patterns of synchronous bursting events that resemble the activity dynamics in developing neuronal networks in vivo. Synchronous bursts are mostly thought to be triggered at burst initiation sites due to build-up of noise or by highly active neurons, or to reflect reverberating activity that circulates within larger networks, although neither of these has been observed directly. Inferring such collective dynamics in neuronal populations from electrophysiological recordings crucially depends on the spatial resolution and sampling ratio relative to the size of the networks assessed. Using large-scale microelectrode arrays with 1024 electrodes at 0.3 mm pitch that covered the full extent of in vitro networks on about 1 cm2, we investigated where bursts of spontaneous activity arise and how their propagation patterns relate to the regions of origin, the network’s structure, and to the overall distribution of activity. A set of alternating burst initiation zones dominated the initiation of distinct bursting events and triggered specific propagation patterns. Moreover, burst initiation zones were typically located in areas with moderate activity levels, i.e. at transitions between hot and cold spots. The activity-dependent alternation between these zones suggests that the local networks forming the dominating burst initiation zones enter a transient depressed state after several cycles (similar to Eytan et al 2003), allowing other burst initiation zones to take over temporarily. We propose that inhomogeneities in the network structure define such burst initiation zones and that the depletion of local synaptic resources limit repetitive burst initiation.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on May 31, 2019 12:00 AM.
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Diagnosis of Alzheimer’s Disease via Multi-Modality 3D Convolutional Neural Network
Abstract Alzheimer’s Disease (AD) is one of the most concerned neurodegenerative diseases. In the last decade, studies on AD diagnosis attached great significance to artificial intelligence (AI)-based diagnostic algorithms. Among the diverse modality imaging data, T1-weighted MRI and 18F-FDG-PET are widely researched for this task. In this paper, we propose a novel convolutional neural network (CNN) to fuse the multi-modality information including T1-MRI and FDG-PDT images around the hippocampal area for the diagnosis of AD. Different from the traditional machine learning algorithms, this method does not require manually extracted features, and utilizes the state-of-art 3D image-processing CNNs to learn features for the diagnosis and prognosis of AD. To validate the performance of the proposed network, we trained the classifier with paired T1-MRI and FDG-PET images using the ADNI datasets, including 731 Normal (NL) subjects, 647 AD subjects, 441 stable MCI (sMCI) subjects and 326 progressive MCI (pMCI) subjects. We obtained the maximal accuracies of 90.10% for NL/AD task, 87.46% for NL/pMCI task, and 76.90% for sMCI/pMCI task. The proposed framework yields comparative results against state-of-the-art approaches. Moreover, the experimental results have demonstrated that (1) segmentation is not a prerequisite by using CNN, (2) the hippocampal area provides enough information to give a reference to AD diagnosis.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on May 31, 2019 12:00 AM.
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Metabolic and Stress Response Changes Precede Disease Onset in the Spinal Cord of Mutant SOD1 ALS Mice
Many Amyotrophic Lateral Sclerosis (ALS) patients experience hypermetabolism, or an increase in measured versus calculated metabolic rate. The cause of hypermetabolism and the effects on neuronal metabolism in ALS are currently unknown, but the efficacy of dietary interventions shows promise for metabolism as an ALS therapeutic target. The goal of this study is to measure changes in metabolic pathways as a function of disease progression in spinal cords of the SOD1G93A mouse model of ALS. We conducted a comprehensive assessment of protein expression for metabolic pathways, antioxidants, chaperones, and proteases in lumbar spinal cord from male SOD1G93A mice at pre-onset, onset, and end-stages of the disease using targeted proteomic analysis. These results reveal that protein content of metabolic proteins including proteins involved in glycolysis, β-oxidation, and mitochondrial metabolism is altered in SOD1G93A mouse spinal cord well before disease onset. The changes in mitochondrial metabolism proteins are associated with decreased maximal respiration and glycolytic flux in SOD1G93A dermal fibroblasts and increased hydrogen peroxide and lipid hydroperoxide production in mitochondria from sciatic nerve and gastrocnemius muscle fibers at end stage of disease. Consistent with redox dysregulation, expression of the glutathione antioxidant system is decreased, and peroxiredoxins and catalase expression are increased. In addition, stress response proteases and chaperones, including those involved in the mitochondrial unfolded protein response, are induced before disease onset. In summary, we report that metabolic and stress response changes occur in SOD1G93A lumbar spinal cord before motor symptom onset, and are primarily caused by SOD1G93A expression and do not vary greatly as a function of disease course.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on May 31, 2019 12:00 AM.
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Unsupervised Detection of Cell-Assembly Sequences by Similarity-Based Clustering
Neurons which fire in a fixed temporal pattern (i.e., ``cell assemblies'') are hypothesized to be a fundamental unit of neural information processing. Several methods are available for the detection of cell assemblies without time structure. However, the systematic detection of cell assemblies with time structure has been challenging, especially in large datasets, due to the lack of efficient methods for handling the time structure. Here, we show a method to detect a variety of cell-assembly activity patterns recurring in noisy neural population activity at multiple timescales. The key innovation is the use of a computer science method for comparing strings (``edit similarity'') to group spikes into assemblies. We validated the method by using artificial data and experimental data, which were previously recorded from the hippocampus of male Long-Evans rats and the prefrontal cortex of male Brown Norway/Fisher hybrid rats. From the hippocampus, we could simultaneously extract place-cell sequences occurring on different timescales during navigation and awake replay. From the prefrontal cortex, we could discover multiple spike sequences of neurons encoding different segments of a goal-directed task. Unlike conventional event-driven statistical approaches, our method detects cell assemblies without creating event-locked averages. Thus, the method offers a novel analytical tool for deciphering the neural code during arbitrary behavioral and mental processes.
in Frontiers in Neuroinformatics | New and Recent Articles on May 31, 2019 12:00 AM.
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ELFENN: A Generalized Platform for Modeling Ephaptic Coupling in Spiking Neuron Models
The transmembrane ionic currents that underlie changes in a cell’s membrane potential give rise to electric fields in the extracellular space. In the context of brain activity, these electric fields form the basis for extracellularly recorded signals such as multiunit activity, local field potentials and electroencephalograms. Understanding the underlying neuronal dynamics and localizing current sources using these signals is often challenging, and therefore effective computational modeling approaches are critical. Typically, the electric fields from neural activity are modeled in a post-hoc form, i.e. a traditional neuronal model is used to first generate the membrane currents, which in turn are then used to calculate the electric fields. When the conductivity of the extracellular space is high, the electric fields are weak, and therefore treating membrane currents and electric fields separately is justified. However, in brain regions of lower conductivity, extracellular fields can feed back and significantly influence the underlying transmembrane currents and dynamics of nearby neurons – this is often referred to as ephaptic coupling. The closed-loop nature of ephaptic coupling cannot be modeled using the post-hoc approaches implemented by existing software tools; instead, electric fields and neuronal dynamics must be solved simultaneously. To this end, we have developed a generalized modeling toolbox for studying ephaptic coupling in compartmental neuron models: ELFENN (ELectric Field Effects in Neural Networks). In open loop conditions, we validate the separate components of ELFENN for modeling membrane dynamics and associated field potentials against standard approaches (NEURON and LFPy). Unlike standard approaches however, ELFENN enables the closed-loop condition to be modeled as well, in that the field potentials can feed back and influence membrane dynamics. As an example closed-loop case, we use ELFENN to study phase-locking of action potentials generated by a population of axons running parallel in a bundle. Being able to efficiently explore ephaptic coupling from a computational perspective using tools such as ELFENN will allow us to better understand the physical basis of electric fields in the brain, as well as the conditions in which these fields may influence neuronal dynamics in general.
in Frontiers in Neuroinformatics | New and Recent Articles on May 31, 2019 12:00 AM.
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Distribution of GABAergic Neurons and VGluT1 and VGAT Immunoreactive Boutons in the Ferret (Mustela putorius) Piriform Cortex and Endopiriform Nucleus. Comparison With Visual Areas 17, 18 and 19
We studied the cellular organization of the piriform network (comprising the piriform cortex and endopiriform nucleus) of the ferret (Mustela putorius) -a highly excitable region prone to seizures- and, more specifically, the distribution and morphology of different types of GABAergic neurons, and the distribution and ratio of glutamatergic and GABAergic boutons, and we compared our findings to those in primary visual area 17, and secondary areas 18 and 19. We accomplished this by using cytochrome oxidase and immunohistochemistry for mature neuronal nuclei (NeuN), GABAergic neurons (glutamic acid decarboxylase-67, calretinin and parvalbumin), and for excitatory (vesicular glutamate transporter 1; VGluT1) and inhibitory (vesicular GABA transporter; VGAT) boutons. In the ferret, the cellular organization of the piriform network is similar to that described in other species such as cats, rats and opossums although some differences also exist. GABAergic immunolabeling showed similarities between cortical layers I-III of the piriform cortex and visual areas, such as the relative distribution of GABAergic neurons and the density and area of VGluT1- and VGAT-immunoreactive boutons. However, multiple differences between the piriform network and visual areas (layers I-VI) were found, such as the percentage of GABAergic neurons with respect to the total number of neurons and the ratio of VGluT1- and VGAT-immunoreactive boutons. These findings are relevant to better understand the high excitability of the piriform network.
in Frontiers in Neuroanatomy | New and Recent Articles on May 31, 2019 12:00 AM.
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The Anatomical Boundary of the Rat Claustrum
The claustrum is a subcortical nucleus that exhibits dense connectivity across the neocortex. Considerable recent progress has been made in establishing its genetic and anatomical characteristics, however a core, contentious issue that regularly presents in the literature pertains to the rostral extent of its anatomical boundary. The present study addressed this issue in the rat brain. Using a combination of immunohistochemistry and neuroanatomical tract tracing, we have examined the expression profiles of several genes that have previously been identified as exhibiting a differential expression profile in the claustrum relative to the surrounding cortex. The expression profiles of parvalbumin (PV), crystallin mu (Crym), and guanine nucleotide binding protein (G protein), gamma 2 (Gng2) were assessed immunohistochemically alongside, or in combination with cortical anterograde, or retrograde tracer injections. Retrograde tracer injections into various thalamic nuclei were used to further establish the rostral border of the claustrum. Expression of all three markers delineated a nuclear boundary that extended considerably (~500 µm) beyond the anterior horn of the neostriatum. Cortical retrograde and anterograde tracer injections, respectively, revealed distributions of cortically-projecting claustral neurons and cortical efferent inputs to the claustrum that overlapped with the gene marker-derived claustrum boundary. Finally, retrograde tracer injections into the thalamus revealed insular cortico-thalamic projections encapsulating a claustral area with strongly diminished cell label, that extended rostral to the striatum.
in Frontiers in Neuroanatomy | New and Recent Articles on May 31, 2019 12:00 AM.
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Lifespan Intellectual Factors, Genetic Susceptibility, and Cognitive Phenotypes in Aging: Implications for Interventions
Along with rapid global population aging, the age-related cognitive disorders such as mild cognitive impairment and dementia have posed a serious threat to public health, health care system, and sustainable economic and societal development of all countries. In this narrative review, we seek to summarize the major epidemiological studies from the life-course perspective that investigate the influence of genetic susceptibility (e.g., APOE ε4 allele and BDNF) and intellectual or psychosocial factors (e.g., educational attainments and leisure activities) as well as their interactions on cognitive phenotypes in aging. Numerous population-based studies have suggested that early-life educational attainments and socioeconomic status, midlife work complexity and social engagements, late-life leisure activities (social, physical, and mentally-stimulating activities), certain personality traits (e.g., high neuroticism and low conscientiousness), and depression significantly affect late-life cognitive phenotypes. Furthermore, certain intellectual or psychosocial factors (e.g., leisure activities and depression) may interact with genetic susceptibility (e.g., APOE ε4 allele) to affect the phenotypes of cognitive aging such that risk or beneficial effects of these factors on cognitive function may vary by carrying the susceptibility genes. The cognitive reserve hypothesis has been proposed to partly explain the beneficial effects of lifetime intellectual and psychosocial factors on late-life cognitive function. This implies that, from a life-course perspective, preventive intervention strategies targeting those modifiable intellectual or psychosocial factors could interfere with clinical expression of the cognitive phenotypes in aging and delay the onset of dementia syndrome, and thus, may help achieve healthy brain aging.
in Frontiers in Aging Neuroscience | New and Recent Articles on May 31, 2019 12:00 AM.
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Working Memory Capacity as a Predictor of Cognitive Training Efficacy in the Elderly Population
Aging is associated with a decline in a wide range of cognitive functions and working memory (WM) deterioration is considered a main factor contributing to this. Therefore, any attempt to counteract WM decline seems to have a potential benefit for older adults. However, determination of whether such methods like WM trainings are effective is a subject of a serious debate in the literature. Despite a substantial number of training studies and several meta-analyses, there is no agreement on the matter of their effectiveness. The other important and still not fully explored issue is the impact of the preexisting level of intellectual functioning on the training’s outcome. In our study we investigated the impact of WM training on variety of cognitive tasks performance among older adults and the impact of the initial WM capacity (WMC) on the training efficiency. 85 healthy older adults (55-81 years of age; 55 female, 30 males) received five weeks of training on adaptive dual N-back task (experimental group) or memory quiz (active controls). Cognitive performance was assessed before and after intervention with measures of WM, memory updating, inhibition, attention shifting, short-term memory (STM) and reasoning. We found post-intervention group independent improvements across all cognitive tests except for inhibition and STM. With multi-level analysis individual learning curves were modeled, which enabled examining of the intra-individual change in training and inter-individual differences in intra-individual changes. We observed a systematic and positive, but relatively small, learning trend with time. Moderator analyses with demographic characteristics as moderators showed no additional effects on learning curves. Only initial WMC level was a significant moderator of training effectiveness. Older adults with initially lower WMC improved less and reached lower levels of performance, compared to the group with higher WMC. Overall, our findings are in accordance with the research suggesting that post-training gains are within reach of older adults. Our data provide evidence supporting the presence of transfer after N-back training in older adults. More importantly, our findings suggest that it is more important to take into account an initial WMC level, rather than demographic characteristics when evaluating WM training in older adults.
in Frontiers in Aging Neuroscience | New and Recent Articles on May 31, 2019 12:00 AM.
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Addressing Disparities in Alzheimer's Disease and African-American Participation in Research: An Asset-Based Community Development Approach

in Frontiers in Aging Neuroscience | New and Recent Articles on May 31, 2019 12:00 AM.
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Humanin, a Mitochondrial-Derived Peptide Released by Astrocytes, Prevents Synapse Loss in Hippocampal Neurons
Astroglial cells are crucial for central nervous system homeostasis. They undergo complex morpho-functional changes during aging and in response to hormonal milieu. Ovarian hormones positively affect different astroglia parameters, including regulation of cell morphology and release of neurotrophic and neuroprotective factors. Thus, ovarian hormone loss during menopause has profound impact in astroglial pathophysilogy and has been widely associated to the process of brain aging. Humanin is a secreted mitochondrial-encoded peptide with neuroprotective effects. It has been localized in several tissues with high metabolic rate and its expression decreases with age. In the brain, humanin has been localized in glial cells in physiological conditions. We previously reported that surgical menopause induces hippocampal mitochondrial dysfunction that mimics an aging phenotype. However, the effect of ovarian hormone deprivation on humanin expression in this area has not been studied. Also, whether astrocytes express and release humanin and the regulation of such processes by ovarian hormones remain elusive. Although humanin has also proven to be beneficial in ameliorating cognitive impairment induced by different insults, its putative actions on structural synaptic plasticity have not been fully addressed. In a model of surgical menopause in rats, we studied hippocampal humanin expression and localization by RT-qPCR and double immunohistochemistry, respectively. Humanin production and release and ovarian hormone regulation of such processes were studied in cultured astrocytes by flow cytometry and ELISA, respectively. Humanin effects on glutamate-induced structural synaptic alterations were determined in primary cultures of hippocampal neurons by immunocytochemistry. Humanin expression was lower in the hippocampus of ovariectomized rats and its immunoreactivity colocalized with astroglial markers. Chronic ovariectomy also promoted the presence of less complex astrocytes in this area. Ovarian hormones increased humanin intracellular content and release by cultured astrocytes. Humanin prevented glutamateinduced dendritic atrophy and reduction in puncta number and total puncta area for presynaptic marker synaptophysin in cultured hippocampal neurons. In conclusion, astroglial functional and morphological alterations induced by chronic ovariectomy resemble an aging phenotype and could affect astroglial support to neuronal function by altering synaptic connectivity and functionality. Reduced astroglial-derived humanin may represent an underlying mechanism for synaptic dysfunction and cognitive decline after menopause.
in Frontiers in Aging Neuroscience | New and Recent Articles on May 31, 2019 12:00 AM.
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New subtypes of allele-specific epigenetic effects: implications for brain development, function and disease

Publication date: December 2019
Source: Current Opinion in Neurobiology, Volume 59
Author(s): Stephanie N Kravitz, Christopher Gregg
Typically, it is assumed that the maternal and paternal alleles for most genes are equally expressed. Known exceptions include canonical imprinted genes, random X-chromosome inactivation, olfactory receptors and clustered protocadherins. Here, we highlight recent studies showing that allele-specific expression is frequent in the genome and involves subtypes of epigenetic allelic effects that differ in terms of heritability, clonality and stability over time. Different forms of epigenetic allele regulation could have different roles in brain development, function, and disease. An emerging area involves understanding allelic effects in a cell-type and developmental stage-specific manner and determining how these effects influence the impact of genetic variants and mutations on the brain. A deeper understanding of epigenetics at the allele and cellular level in the brain could help clarify the mechanisms underlying phenotypic variance.

in ScienceDirect Publication: Current Opinion in Neurobiology on May 30, 2019 05:00 PM.
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Adaptive learning under expected and unexpected uncertainty

Nature Reviews Neuroscience, Published online: 30 May 2019; doi:10.1038/s41583-019-0180-y
Successful learning and decision-making require estimates of expected uncertainty and unexpected uncertainty. Soltani and Izquierdo define these concepts, describe proposed models of how they may be computed and discuss their neural substrates.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on May 30, 2019 12:00 AM.
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Monoamine Oxidases (MAOs) as Privileged Molecular Targets in Neuroscience: Research Literature Analysis
Background: Monoamine oxidases (MAOs) were discovered nearly a century ago. This article aims to analyze the research literature landscape associated with MAOs as privileged class of neuronal enzymes (neuroenzymes) with key functions in the processes of neurodegeneration, serving as important biological targets in neuroscience. With the accumulating publications on this topic, we aimed to evaluate the publication and citation performance of the contributors, reveal the popular research themes, and identify its historical roots. Methods: The electronic database of Web of Science (WoS) Core Collection was searched to identify publications related to MAOs, which were analyzed according to their publication year, authorship, institutions, countries/regions, journal title, WoS category, total citation count, and publication type. VOSviewer was utilized to visualize the citation patterns of the words appearing in the titles and abstracts, and author keywords. CRExplorer was utilized to identify seminal references cited by the MAO publications. Results: The literature analysis was based on 19,854 publications. Most of them were original articles (n = 15,148, 76.3%) and reviews (n = 2,039, 10.3%). The top five WoS categories of the analyzed MAO publications were Pharmacology/Pharmacy (n = 4,664, 23.5%), Neurosciences (n = 4,416, 22.2%), Psychiatry (n = 2,906, 14.6%), Biochemistry/Molecular Biology (n = 2,691, 13.6%), and Clinical Neurology (n = 1,754, 8.8%). The top ten institutions are scattered in the United States, UK, France, Sweden, Canada, Israel, and Russia, while the top ten countries/regions with the most intensive research on the field of MAOs are the United States, followed by European and Asian countries. More highly cited publications generally involved neurotransmitters, such as dopamine, serotonin, and norepinephrine, as well as the MAO-A inhibitors moclobemide and clorgyline, and the irreversible MAO-B inhibitors selegiline and rasagiline. Conclusion: Through decades of research, the literature has accumulated many publications investigating the therapeutic effects of MAO inhibitors (MAOIs) on various neurological conditions, such as Alzheimer’s disease, Parkinson’s disease, and depression. We envision that MAO literature will continue to grow steadily, with more new therapeutic candidates being tested for better management of neurological conditions, in particular, with the development of multi-target acting drugs against neurodegenerative diseases.
in Frontiers in Molecular Neuroscience | New and Recent Articles on May 29, 2019 12:00 AM.
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Editorial: Bayesian Estimation and Inference in Computational Anatomy and Neuroimaging: Methods and Applications

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on May 29, 2019 12:00 AM.
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Linking the Endoplasmic Reticulum to Parkinson’s Disease and Alpha-Synucleinopathy
Accumulation of misfolded proteins is a central paradigm in neurodegeneration. Because of the key role of the endoplasmic reticulum (ER) in regulating protein homeostasis, in the last decade multiple reports implicated this organelle in the progression of Parkinson’s Disease (PD) and other neurodegenerative illnesses. In PD, dopaminergic neuron loss or more broadly neurodegeneration has been improved by overexpression of genes involved in the ER stress response. In addition, toxic alpha-synuclein (αS), the main constituent of proteinacious aggregates found in tissue samples of PD patients, has been shown to cause ER stress by altering intracellular protein traffic, synaptic vesicles transport and Ca2+ homeostasis. In this review, we will be summarizing evidence correlating impaired ER functionality to PD pathogenesis, focusing our attention on how toxic, aggregated αS can promote ER stress and cell death.
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on May 29, 2019 12:00 AM.
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Impact of Sleep–Wake-Associated Neuromodulators and Repetitive Low-Frequency Stimulation on Human iPSC-Derived Neurons
The cross-regional neurons in the brainstem, hypothalamus, and thalamus regulate the central nervous system, including the cerebral cortex, in a sleep–wake cycle-dependent manner. A characteristic brain wave, called slow wave, of about 1 Hz is observed during non-REM sleep, and the sleep homeostasis hypothesis proposes that the synaptic connection of a neural network is weakened during sleep. In the present study, in in vitro human induced pluripotent stem cell (iPSC)-derived neurons, we investigated the responses to the neuromodulator known to be involved in sleep–wake regulation. We also determined whether long-term depression (LTD)-like phenomena could be induced by 1 Hz low-frequency stimulation (LFS), which is within the range of the non-REM sleep slow wave. A dose-dependent increase was observed in the number of synchronized burst firings (SBFs) when 0.1–1000 nM of serotonin, acetylcholine, histamine, orexin, or noradrenaline, all with increased extracellular levels during wakefulness, was administered to hiPSC-derived dopaminergic (DA) neurons. The number of SBFs repeatedly increased up to 5 hours after 100 nM serotonin administration, inducing a 24-h rhythm cycle. Next, in human iPSC-derived glutamate neurons, 1 Hz LFS was administered four times for 15 min every 90 min. A significant reduction in both the number of firings and SBFs was observed in the 15 minutes immediately after LFS. Decreased frequency of spontaneous activity and recovery over time were repeatedly observed. Furthermore, we found that LFS attenuates synaptic connections, and particularly attenuates the strong connections in the neuronal network, and does not cause uniform attenuation. These results suggest sleep–wake states can be mimicked by cyclic neuromodulator administration and show that LTD-like phenomena can be induced by LFS in in vitro human iPSC-derived neurons. These results could be applied in studies on the mechanism of slow waves during sleep or in an in vitro drug efficacy evaluation depending on sleep–wake state.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on May 29, 2019 12:00 AM.
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Antiepileptic Effects of a Novel Non-invasive Neuromodulation Treatment in a Subject With Early-Onset Epileptic Encephalopathy: Case Report With 20 Sessions of HD-tDCS Intervention
The current clinical investigation examined high-definition transcranial direct current stimulation (HD-tDCS) as a focal, non-invasive, anti-epileptic treatment in a child with early-onset epileptic encephalopathy. We investigated the clinical impact of repetitive (20 daily sessions) cathode-centered 4x1 HD-tDCS (1 mA, 20 minutes, 4 cm ring radius) over the dominant seizure-generating cortical zone in a 40-month old child suffering from a severe neonatal epileptic syndrome known as Ohtahara syndrome (OS). Seizures and epileptiform activity were monitored and quantified using video-EEG over multiple days of baseline, intervention, and post intervention periods. Primary outcome measures were changes in seizure frequency and duration on the last day of intervention versus the last baseline day, preceding the intervention. In particular, we examined changes in tonic spasms, tonic-myoclonic seizures, and myoclonic seizures from baseline to post-intervention. A trend in tonic-myoclonic seizure (TM-S) frequency was observed indicating a reduction of 73% in TM-S frequency, which was non-significant (t(4) = 2.05, p = 0.1), and denoted a clinically significant change. Myoclonic seizure (M-S) frequency was significantly reduced (t(4) = 3.83, p = 0.019) by 68.42%, compared to baseline, and indicated a significant clinical change as well. A 73% decrease in interictal epileptic discharges (IED) frequency was also observed immediately after the intervention period, compared to IED frequency at three days prior to intervention. Post-intervention seizure-related peak delta desynchronization was reduced by 57%. Our findings represent a case-specific significant clinical response, reduction in IED, and change in seizure-related delta activity following the application of HD-tDCS. The clinical outcomes, as noted in the current study, encourage the further investigation of this focal, non-invasive neuromodulation procedure in other severe electroclinical syndromes (e.g., West syndrome) and in larger pediatric populations diagnosed with early-onset epileptic encephalopathy.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on May 29, 2019 12:00 AM.
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How Do Price and Quantity Promotions Affect Hedonic Purchases? An ERPs Study
Due to consuming hedonic products unnecessary to basic well-being, consumers need justifications for pleasure. However, different justifications have differential influences in promotion of hedonic purchases, such as price and quantity promotions (PP and QP), the difference between which is that the latter requires purchasing additional units to get the same discount as the former. In the present study, even-related potentials (ERPs) was applied to revealing timing of brain activities for further understand of how promotion information consisted of promotion type (PP and QP) and discount depth, deep and shallow discounts (DD and SD) on hedonic products was processed. Behaviorally, consumers were more willing to purchase items in PP and DD conditions than QP and SD conditions respectively, and spent more time making final purchase decision in QP and DD condition or PP and SD condition compared to PP and DD condition. Neurophysiologically, DD recruited automatically attentional resources than SD and led a higher P2 amplitude. QP and DD condition or PP and SD condition evoked a larger N2 amplitude and enhanced perceptual conflict compared to PP and DD condition. During late stage, PP and DD elicited a more positive LPP amplitude in contrast to QP and SD respectively, indicating that people have stronger purchase intention and positive affect in PP and DD contexts. These findings provided evidence for the differential influences between PP and QP and what ultimately made consumers buy hedonic products or not.
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on May 29, 2019 12:00 AM.
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Editorial: Collaborative Efforts for Understanding the Human Brain

in Frontiers in Neuroinformatics | New and Recent Articles on May 29, 2019 12:00 AM.
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Evaluation of Enhanced Learning Techniques for Segmenting Ischaemic Stroke Lesions in Brain Magnetic Resonance Perfusion Images Using a Convolutional Neural Network Scheme
Magnetic resonance (MR) perfusion imaging non-invasively measures cerebral perfusion, which describes the blood's passage through the brain's vascular network. Therefore it is widely used to assess cerebral ischaemia. Convolutional Neural Networks (CNN) constitute the state-of-the-art method in automatic pattern recognition and hence, in segmentation tasks. But none of the CNN architectures developed to date have achieved high accuracy when segmenting ischaemic stroke lesions, being the main reasons their heterogeneity in location, shape, size, image intensity and texture, especially in this imaging modality. We use a freely available CNN framework, developed for MR imaging lesion segmentation, as core algorithm to evaluate the impact of enhanced machine learning techniques, namely data augmentation, transfer learning and post-processing, in the segmentation of stroke lesions using the ISLES 2017 dataset, which contains expert annotated diffusion-weighted perfusion and diffusion brain MRI of 43 stroke patients. Of all the techniques evaluated, data augmentation with binary closing achieved the best results, improving the mean Dice score in 17\% over the baseline model. Consistent with previous works, better performance was obtained in the presence of large lesions.
in Frontiers in Neuroinformatics | New and Recent Articles on May 29, 2019 12:00 AM.
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Editorial: The Functional Anatomy of the Reticular Formation

in Frontiers in Neuroanatomy | New and Recent Articles on May 29, 2019 12:00 AM.
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Iron concentrations in neurons and glial cells with estimates on ferritin concentrations
Brain iron is an essential as well as a toxic redox active element. Physiological levels are not uniform among the different cell types. Besides the availability of quantitative methods, the knowledge about th...
in Most Recent Articles: BMC Neuroscience on May 29, 2019 12:00 AM.
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Regulation of neuronal connectivity in the mammalian brain by chromatin remodeling

Publication date: December 2019
Source: Current Opinion in Neurobiology, Volume 59
Author(s): Jared V. Goodman, Azad Bonni
Precise temporal and spatial control of gene expression is essential for brain development. Besides DNA sequence-specific transcription factors, epigenetic factors play an integral role in the control of gene expression in neurons. Among epigenetic mechanisms, chromatin remodeling enzymes have emerged as essential to the control of neural circuit assembly and function in the brain. Here, we review recent studies on the roles and mechanisms of the chromodomain-helicase-DNA-binding (Chd) family of chromatin remodeling enzymes in the regulation of neuronal morphogenesis and connectivity in the mammalian brain. We explore the field through the lens of Chd3, Chd4, and Chd5 proteins, which incorporate into the nucleosome remodeling and deacetylase (NuRD) complex, and the related proteins Chd7 and Chd8, implicated in the pathogenesis of intellectual disability and autism spectrum disorders. These studies have advanced our understanding of the mechanisms that regulate neuronal connectivity in brain development and neurodevelopmental disorders of cognition.

in ScienceDirect Publication: Current Opinion in Neurobiology on May 28, 2019 11:00 AM.
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Relaying ageing signals

Nature Reviews Neuroscience, Published online: 28 May 2019; doi:10.1038/s41583-019-0190-9
Blood-borne pro-ageing signals are transmitted to the brain via VCAM1 and blocking its signalling can prevent cognitive decline in aged mice.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on May 28, 2019 12:00 AM.
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Comparing integration and contextual binding accounts of memory impairment

Nature Reviews Neuroscience, Published online: 28 May 2019; doi:10.1038/s41583-019-0188-3
Comparing integration and contextual binding accounts of memory impairment
in Nature Reviews Neuroscience - Issue - nature.com science feeds on May 28, 2019 12:00 AM.
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Using second-person neuroscience to elucidate the mechanisms of social interaction

Nature Reviews Neuroscience, Published online: 28 May 2019; doi:10.1038/s41583-019-0179-4
Studies that examine brain activity during real-time social interactions may advance our understanding of human social behaviour. Redcay and Schilbach describe progress in ‘second-person’ neuroscience and discuss the insights into the brain mechanisms of social behaviour that have been gained.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on May 28, 2019 12:00 AM.
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Unsupervised Temporal Contiguity Experience Does Not Break the Invariance of Orientation Selectivity Across Spatial Frequency
The images projected onto the retina can vary widely for a single object. Despite these transformations primates can quickly and reliably recognize objects. At the neural level, transformation tolerance in monkey inferotemporal cortex is affected by the temporal contiguity statistics of the visual input. Here we investigated whether temporal contiguity learning also influences the basic feature detectors in lower levels of the visual hierarchy, in particular the independent coding of orientation and spatial frequency (SF) in primary visual cortex. Eight male Long Evans rats were repeatedly exposed to a temporal transition between two gratings that changed in SF and had either the same (control SF) or a different (swap SF) orientation. Electrophysiological evidence showed that the responses of single neurons during this exposure were sensitive to the change in orientation. Nevertheless, the tolerance of orientation selectivity for changes in SF was unaffected by the temporal contiguity manipulation, as observed in 239 single neurons isolated pre-exposure and 234 post-exposure. Temporal contiguity learning did not affect orientation selectivity in V1. The basic filter mechanisms that characterize V1 processing seem unaffected by temporal contiguity manipulations.
in Frontiers in Systems Neuroscience | New and Recent Articles on May 28, 2019 12:00 AM.
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Lysophosphatidic Acid and Glutamatergic Transmission
Signaling through bioactive lipids regulates nervous system development and functions. Lysophosphatidic acid (LPA), a membrane-derived lipid mediator particularly enriched in brain, is able to induce many responses in neurons and glial cells by affecting key processes like synaptic plasticity, neurogenesis, differentiation and proliferation. Early studies noted sustained elevations of neuronal intracellular calcium, a primary response to LPA exposure, suggesting functional modifications of NMDA and AMPA glutamate receptors. However, the crosstalk between LPA signaling and glutamatergic transmission has only recently been shown. Stimulation of presynaptic LPA receptors in hippocampal neurons regulates glutamate release from the presynaptic terminal, while excess of LPA signaling results in overexcitation and hippocampal epilepsy. Further evidences indicating a role of LPA in the modulation of neuronal transmission has been inferred from animal models with deficits on LPA receptors, mainly LPA1 which is the most prevalent receptor in human and mouse brain tissue. LPA1 null-mice exhibit cognitive and attention deficits characteristic of schizophrenia which are related with altered glutamatergic transmission and reduced neuropathic pain. Furthermore, silencing of LPA1 receptor in mice induced a severe down-regulation of the main glutaminase isoform (GLS) in cerebral cortex and hippocampus, along with a parallel sharp decrease on active matrix-metalloproteinase 9. The downregulation of both enzymes correlated with an altered morphology of glutamatergic pyramidal cells dendritic spines towards a less mature phenotype, indicating important implications of LPA in synaptic excitatory plasticity which may contribute to the cognitive and memory deficits shown by LPA1-deficient mice. In this review, we present an updated account of current evidences pointing to important implications of LPA in the modulation of synaptic excitatory transmission.
in Frontiers in Molecular Neuroscience | New and Recent Articles on May 28, 2019 12:00 AM.
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Structural and Functional Abnormalities in the Olfactory System of Fragile X Syndrome Models
Fragile Syndrome X (FXS) is the most common inherited form of intellectual disability. It is produced by mutation of the Fmr1 gene that encodes for the Fragile Mental Retardation Protein (FMRP), an important RNA-binding protein that regulates the expression of multiple proteins located in neuronal synapses. Individuals with FXS exhibit abnormal sensory information processing frequently leading to hypersensitivity across sensory modalities and consequently a wide array of behavioral symptoms. Insects and mammals engage primarily their sense of smell to create proper representations of the external world and guide adequate decision-making processes. This feature in combination with the exquisitely organized neuronal circuits found throughout the olfactory system and the wide expression of FMRP in brain regions that process olfactory information makes it an ideal model to study sensory alterations in FXS models. In the last decade several groups have taken advantage of these features and have used the olfactory system of fruit fly and rodents to understand neuronal alteration giving rise to sensory perception issues. In this review we will discuss molecular, morphological and physiological aspects of the olfactory information processing in FXS models. We will highlight the decreased inhibitory/excitatory synaptic balance and the diminished synaptic plasticity found in this system resulting in behavioral alteration of individuals in the presence of odorant stimuli.
in Frontiers in Molecular Neuroscience | New and Recent Articles on May 28, 2019 12:00 AM.
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Resilience and Vulnerability to Trauma: Early Life Interventions Modulate Aversive Memory Reconsolidation in the Dorsal Hippocampus
Early life experiences program lifelong responses to stress. In agreement, resilience and vulnerability to psychopathologies, such as posttraumatic stress disorder (PTSD), have been suggested to depend on the early background. New therapies have targeted memory reconsolidation as a strategy to modify the emotional valence of traumatic memories. Here, we used animal models to study the molecular mechanism through which early experiences may later affect aversive memory reconsolidation. Handling (H) – separation of pups from dams for 10 minutes - or maternal separation (MS) – 3-hour separation - were performed from PDN1-10, using non-handled (NH) litters as controls. Adult males were trained in a contextual fear conditioning task; 24 hours later, a short reactivation session was conducted in the conditioned or in a novel context, followed by administration of midazolam 3 mg/kg i.p. (mdz), known to disturb reconsolidation, or vehicle; a test session was performed 24 hours after. The immunocontent of relevant proteins was studied 15 and 60 minutes after memory reactivation in the dorsal hippocampus (dHc) and basolateral amygdala complex (BLA). Mdz-treated controls (NH) showed decreased freezing to the conditioned context, consistent with reconsolidation impairment, but H and MS were resistant to labilization. Additionally, MS males showed increased freezing to the novel context, suggesting fear generalization; H rats showed lower freezing than the other groups, in accordance with previous suggestions of reduced emotionality facing adversities. Increased levels of Zif268, GluN2B, β-actin and polyubiquitination found in the BLA of all groups suggest that memory reconsolidation was triggered. In the dHc, only NH showed increased Zif268 levels after memory retrieval; also, a delay in ERK1/2 activation was found in H and MS animals. We showed here that reconsolidation of a contextual fear memory is insensitive to interference by a GABAergic drug in adult male rats exposed to different neonatal experiences; surprisingly, we found no differences in the reconsolidation process in the BLA, but the dHc appears to suffer temporal desynchronization in the engagement of reconsolidation. Our results support a hippocampal-dependent mechanism for reconsolidation resistance in models of early experiences, which aligns with current hypotheses for the etiology of PTSD.
in Frontiers in Molecular Neuroscience | New and Recent Articles on May 28, 2019 12:00 AM.
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Neuronal Cells Rearrangement During Aging and Neurodegenerative Disease: Metabolism, Oxidative Stress and Organelles Dynamic
Brain cells normally respond adaptively to the oxidative stress or bioenergetic challenges, resulting from ongoing activity in neuronal circuits. During aging and in neurodegenerative disorders, these mechanisms are compromised. In fact, neurons show unique age-related changes in function and metabolism, resulting in greater susceptibility to insults and diseases. Aging affects the cells in the nervous system much as do cells in other organ systems. More precisely, as the nervous system ages, neuron metabolism may change, inducing glucose hypometabolism, impaired transport of critical substrates underlying metabolism, alterations in calcium signalling, mitochondrial dysfunction and so on. Moreover, in neuronal aging an accumulation of dysfunctional and aggregated proteins and mitochondria is observed, as a result of an oxidative imbalance: reduced antioxidant defenses and/or increase of reactive oxygen species (ROS). These changes lead to greater vulnerability of neurons in various regions of the brain and increasing susceptibility to various diseases. In particular, in this review we will focus on neuronal cell rearrangement during aging, in response to changes in metabolism and oxidative stress.
in Frontiers in Molecular Neuroscience | New and Recent Articles on May 28, 2019 12:00 AM.
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Characterizing the Structural Pattern Predicting Medication Response in Herpes Zoster Patients Using Multivoxel Pattern Analysis
Herpes zoster (HZ) can cause a blistering skin rash with severe neuropathic pain. Pharmacotherapy is the most common treatment for HZ patients. However, most of these patients are the elderly and immunocompromised, thus often suffering from side effects and easily getting intractable post-herpetic neuralgia (PHN) if medication fails. It is challenging for clinicians to tailor treatment for patients, due to the lack of prognosis information regarding neurological pathogenesis underlying HZ. In the current study, we aimed at characterizing the brain structural pattern of HZ before medication treatment that could help predict medication responses. High-resolution structural magnetic resonance imaging (MRI) scans of 14 right-handed HZ patients (aged 61.0±7.0, 8 males) with poor response and 15 (aged 62.6±8.3, 5 males) age- (p = 0.58), gender-matched (p = 0.20) patients responding well were acquired and analyzed. Multivoxel pattern analysis (MVPA) with searchlight algorithm and support vector machine (SVM) was applied to identify the spatial pattern of gray matter (GM) volume with high predicting accuracy. The predictive regions with accuracy higher than 79% located within the cerebellum, posterior insular cortex (pIC), middle and orbital frontal lobes (mFC, OFC), anterior and middle cingulum (ACC, MCC), precuneus (PCu) and cuneus. Among these regions, mFC, pIC and MCC displayed significant increases of GM volumes in patients with poor response than those with good response. Combination of sMRI and MVPA might be a useful tool to explore the neuroanatomical imaging biomarkers of HZ-related pain associating with medication responses.
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on May 28, 2019 12:00 AM.

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