Planet Neuroscience

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Ten Simple Rules for avoiding and resolving conflicts with your colleagues

by Fran Lewitter, Philip E. Bourne, Teresa K. Attwood

in PLOS Computational Biology: New Articles on January 18, 2019 10:00 PM.
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OpenCASA: A new open-source and scalable tool for sperm quality analysis

by Carlos Alquézar-Baeta, Silvia Gimeno-Martos, Sara Miguel-Jiménez, Pilar Santolaria, Jesús Yániz, Inmaculada Palacín, Adriana Casao, José Álvaro Cebrián-Pérez, Teresa Muiño-Blanco, Rosaura Pérez-Pé
In the field of assisted reproductive techniques (ART), computer-assisted sperm analysis (CASA) systems have proved their utility and potential for assessing sperm quality, improving the prediction of the fertility potential of a seminal dose. Although most laboratories and scientific centers use commercial systems, in the recent years certain free and open-source alternatives have emerged that can reduce the costs that research groups have to face. However, these open-source alternatives cannot analyze sperm kinetic responses to different stimuli, such as chemotaxis, thermotaxis or rheotaxis. In addition, the programs released to date have not usually been designed to encourage the scalability and the continuity of software development. We have developed an open-source CASA software, called OpenCASA, which allows users to study three classical sperm quality parameters: motility, morphodmetry and membrane integrity (viability) and offers the possibility of analyzing the guided movement response of spermatozoa to different stimuli (useful for chemotaxis, thermotaxis or rheotaxis studies) or different motile cells such as bacteria, using a single software. This software has been released in a Version Control System at Github. This platform will allow researchers not only to download the software but also to be involved in and contribute to further developments. Additionally, a Google group has been created to allow the research community to interact and discuss OpenCASA. For validation of the OpenCASA software, we analysed different simulated sperm populations (for chemotaxis module) and evaluated 36 ejaculates obtained from 12 fertile rams using other sperm analysis systems (for motility, membrane integrity and morphology modules). The results were compared with those obtained by Open-CASA using the Pearson’s correlation and Bland-Altman tests, obtaining a high level of correlation in all parameters and a good agreement between the different used methods and the OpenCASA. With this work, we propose an open-source project oriented to the development of a new software application for sperm quality analysis. This proposed software will use a minimally centralized infrastructure to allow the continued development of its modules by the research community.
in PLOS Computational Biology: New Articles on January 18, 2019 10:00 PM.
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Brain Vital Signs: Expanding From the Auditory to Visual Modality
Gabriela M. Pawlowski, Sujoy Ghosh-Hajra, Shaun D. Fickling, Careesa C. Liu, Xiaowei Song, Stephen Robinovitch, Sam M. Doesburg, Ryan C. N. D'Arcy
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 18, 2019 06:00 PM.
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Dynamic Computational Model of the Human Spinal Cord Connectome
Neural Computation, Volume 31, Issue 2, Page 388-416, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Functional Diversity in the Retina Improves the Population Code
Neural Computation, Volume 31, Issue 2, Page 270-311, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Accelerating Nonnegative Matrix Factorization Algorithms Using Extrapolation
Neural Computation, Volume 31, Issue 2, Page 417-439, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Learning Invariant Features in Modulatory Networks through Conflict and Ambiguity
Neural Computation, Volume 31, Issue 2, Page 344-387, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Calculating the Mutual Information between Two Spike Trains
Neural Computation, Volume 31, Issue 2, Page 330-343, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Modeling the Correlated Activity of Neural Populations: A Review
Neural Computation, Volume 31, Issue 2, Page 233-269, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Systems of Bounded Rational Agents with Information-Theoretic Constraints
Neural Computation, Volume 31, Issue 2, Page 440-476, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Equivalence of Equilibrium Propagation and Recurrent Backpropagation
Neural Computation, Volume 31, Issue 2, Page 312-329, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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The Effects of Family Socioeconomic Status on Psychological and Neural Mechanisms as Well as Their Sex Differences
Hikaru Takeuchi, Yasuyuki Taki, Rui Nouchi, Ryoishi Yokoyama, Yuka Kotozaki, Seishu Nakagawa, Atsushi Sekiguchi, Kunio Iizuka, Yuki Yamamoto, Sugiko Hanawa, Tsuyoshi Araki, Carlos Makoto Miyauchi, Kohei Sakaki, Takayuki Nozawa, Shigeyuki Ikeda, Susumu Yokota, Daniele Magistro, Yuko Sassa, Ryuta Kawashima
in Frontiers in Human Neuroscience | New and Recent Articles on January 18, 2019 06:00 AM.
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Identification of Altered Developmental Pathways in Human Juvenile HD iPSC With 71Q and 109Q Using Transcriptome Profiling
Karolina Świtońska, Wojciech J. Szlachcic, Luiza Handschuh, Paweł Wojciechowski, Łukasz Marczak, Michał Stelmaszczuk, Marek Figlerowicz, Maciej Figiel
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 18, 2019 06:00 AM.
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Predicting Illusory Contours Without Extracting Special Image Features
Albert Yankelovich, Hedva Spitzer
in Frontiers in Computational Neuroscience | New and Recent Articles on January 18, 2019 06:00 AM.
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Age Related Decline in Cortical Multifocal Flash VEP: Latency Increases Shown to Be Predominately Magnocellular
Alyse Brown, Molly Corner, David Crewther, Sheila Crewther
in Frontiers in Aging Neuroscience | New and Recent Articles on January 18, 2019 06:00 AM.
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A Manifold Regularized Multi-Task Learning Model for IQ Prediction from Multiple fMRI Paradigms. (arXiv:1901.05913v1 [q-bio.QM])

Multi-modal brain functional connectivity (FC) data have shown great potential for providing insights into individual variations in behavioral and cognitive traits. The joint learning of multi-modal imaging data can utilize the intrinsic association, and thus can boost the learning performance. Although several multi-task based learning models have already been proposed by viewing the feature learning on each modality as one task, most of them ignore the geometric structure information inherent in the modalities, which may play an important role in extracting discriminative features. In this paper, we propose a new manifold regularized multi-task learning model by simultaneously considering between-subject and between-modality relationships. Besides employing a group-sparsity regularizer to jointly select a few common features across multiple tasks (modalities), we design a novel manifold regularizer to preserve the structure information both within and between modalities in our model. This will make our model more adaptive for realistic data analysis. Our model is then validated on the Philadelphia Neurodevelopmental Cohort dataset, where we regard our modalities as functional MRI (fMRI) data collected under two paradigms. Specifically, we conduct experimental studies on fMRI based FC network data in two task conditions for intelligence quotient (IQ) prediction. The results demonstrate that our proposed model can not only achieve improved prediction performance, but also yield a set of IQ-relevant biomarkers.

in q-bio.NC updates on arXiv.org on January 18, 2019 01:30 AM.
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Early Salient Region Selection Does Not Drive Rapid Visual Categorization. (arXiv:1901.04908v1 [cs.CV] CROSS LISTED)

The current dominant visual processing paradigm in both human and machine research is the feedforward, layered hierarchy of neural-like processing elements. Within this paradigm, visual saliency is seen by many to have a specific role, namely that of early selection. Early selection is thought to enable very fast visual performance by limiting processing to only the most relevant candidate portions of an image. Though this strategy has indeed led to improved processing time efficiency in machine algorithms, at least one set of critical tests of this idea has never been performed with respect to the role of early selection in human vision. How would the best of the current saliency models perform on the stimuli used by experimentalists who first provided evidence for this visual processing paradigm? Would the algorithms really provide correct candidate sub-images to enable fast categorization on those same images? Here, we report on a new series of tests of these questions whose results suggest that it is quite unlikely that such an early selection process has any role in human rapid visual categorization.

in q-bio.NC updates on arXiv.org on January 18, 2019 01:30 AM.
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Identification of a bilirubin receptor may mediate a component of cholestatic itch
Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite this association, the pruritogenic capacity of bilirubin itself has not been explored, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either Mrgpra1 or Blvra, the gene that encodes the bilirubin-producing enzyme, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1^-/- animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch.
in eLife: latest articles on January 18, 2019 12:00 AM.
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HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4⁺CD8⁺ thymocytes for CD4-lineage commitment
CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Neuronal morphologies built for reliable physiology in a rhythmic motor circuit
It is often assumed that highly-branched neuronal structures perform compartmentalized computations. Instead, the Gastric Mill (GM) neuron in the crustacean stomatogastric ganglion (STG) operates like a single electrotonic compartment, despite having thousands of branch points and total cable length >10 mm (Otopalik et al., 2017a, b). We now show: 1) that compact electrotonic architecture is generalizable to other STG neuron types, 2) these neurons present direction-insensitive, linear voltage integration, suggesting they pool synaptic inputs across their neuronal structures. 3) Simulations of 720 cable models spanning a broad range of geometries and passive properties show that compact electrotonus, linear integration, and directional insensitivity in STG neurons arise from their neurite geometries (diameters tapering from 10-20 µm to < 2 µm at their terminal tips). A broad parameter search reveals multiple morphological and biophysical solutions for achieving different degrees of passive electrotonic decrement and computational strategies in the absence of active properties.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Cellular cartography of the organ of Corti based on optical tissue clearing and machine learning
The highly organized spatial arrangement of sensory hair cells in the organ of Corti is essential for inner ear function. Here, we report a new analytical pipeline, based on optical clearing of tissue, for the construction of a single-cell resolution map of the organ of Corti. A sorbitol-based optical clearing method enabled imaging of the entire cochlea at subcellular resolution. High-fidelity detection and analysis of all hair cell positions along the entire longitudinal axis of the organ of Corti were performed automatically by machine learning–based pattern recognition. Application of this method to samples from young, adult, and noise-exposed mice extracted essential information regarding cellular pathology, including longitudinal and radial spatial characteristics of cell loss, implying that multiple mechanisms underlie clustered cell loss. Our method of cellular mapping is effective for system-level phenotyping of the organ of Corti under both physiological and pathological conditions.
in eLife: latest articles on January 18, 2019 12:00 AM.
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A conserved filamentous assembly underlies the structure of the meiotic chromosome axis
The meiotic chromosome axis plays key roles in meiotic chromosome organization and recombination, yet the underlying protein components of this structure are highly diverged. Here, we show that 'axis core proteins' from budding yeast (Red1), mammals (SYCP2/SYCP3), and plants (ASY3/ASY4) are evolutionarily related and play equivalent roles in chromosome axis assembly. We first identify 'closure motifs' in each complex that recruit meiotic HORMADs, the master regulators of meiotic recombination. We next find that axis core proteins form homotetrameric (Red1) or heterotetrameric (SYCP2:SYCP3 and ASY3:ASY4) coiled-coil assemblies that further oligomerize into micron-length filaments. Thus, the meiotic chromosome axis core in fungi, mammals, and plants shares a common molecular architecture, and likely also plays conserved roles in meiotic chromosome axis assembly and recombination control.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Multiple factors maintain assembled trans-SNARE complexes in the presence of NSF and aSNAP
Neurotransmitter release requires formation of trans-SNARE complexes between the synaptic vesicle and plasma membranes, which likely underlies synaptic vesicle priming to a release-ready state. It is unknown whether Munc18-1, Munc13-1, complexin-1 and synaptotagmin-1 are important for priming because they mediate trans-SNARE complex assembly and/or because they prevent trans-SNARE complex disassembly by NSF-aSNAP, which can lead to de-priming. Here we show that trans-SNARE complex formation in the presence of NSF-aSNAP requires both Munc18-1 and Munc13-1, as proposed previously, and is facilitated by synaptotagmin-1. Our data also show that Munc18-1, Munc13-1, complexin-1 and likely synaptotagmin-1 contribute to maintaining assembled trans-SNARE complexes in the presence of NSF-aSNAP. We propose a model whereby Munc18-1 and Munc13-1 are critical not only for mediating vesicle priming but also for precluding de-priming by preventing trans-SNARE complex disassembly; in this model, complexin-1 also impairs de-priming, while synaptotagmin-1 may assist in priming and hinder de-priming.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Essential metabolism for a minimal cell
JCVI-syn3A, a robust minimal cell with a 543 kbp genome and 493 genes, provides a versatile platform to study the basics of life. Using the vast amount of experimental information available on its precursor, Mycoplasma mycoides capri, we assembled a near-complete metabolic network with 98% of enzymatic reactions supported by annotation or experiment. The model agrees well with genome-scale in vivo transposon mutagenesis experiments, showing a Matthews correlation coefficient of 0.59. The genes in the reconstruction have a high in vivo essentiality or quasi-essentiality of 92% (68% essential), compared to 79% in silico essentiality. This coherent model of the minimal metabolism in JCVI-syn3A at the same time also points toward specific open questions regarding the minimal genome of JCVI-syn3A, which still contains many genes of generic or completely unclear function. In particular, the model, its comparison to in vivo essentiality and proteomics data yield specific hypotheses on gene functions and metabolic capabilities; and provide suggestions for several further gene removals. In this way, the model and its accompanying data guide future investigations of the minimal cell. Finally, the identification of 30 essential genes with unclear function will motivate the search for new biological mechanisms beyond metabolism.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Domain-specific working memory, but not dopamine-related genetic variability, shapes reward-based motor learning
The addition of rewarding feedback to motor learning tasks has been shown to increase the retention of learning, spurring interest in the possible utility for rehabilitation. However, laboratory-based motor tasks employing rewarding feedback have repeatedly been shown to lead to great inter-individual variability in performance. Understanding the causes of such variability is vital for maximising the potential benefits of reward-based motor learning. Thus, in this pre-registered study, we assessed whether spatial (SWM), verbal (VWM) and mental rotation (RWM) working memory capacity as well as dopamine-related genetic profiles could predict performance in two reward-based motor tasks, using a large cohort of participants (N=241). The first task assessed participant's ability to follow a hidden and slowly shifting reward region based on hit/miss (binary) feedback. The second task investigated participant's capacity to preserve performance with binary feedback after adapting to the shift with full visual feedback. Our results demonstrate that SWM strongly predicts a participant's capacity to reliably reproduce a successful motor action, measured as change in reach angle following reward, while RWM predicted a participant's propensity to express an explicit strategy when required to make large adjustments in reach angle. Therefore, both SWM and RWM were reliable predictors of success during reward-based motor learning. Change in reach direction following failure was also a strong predictor of success rate, although we observed no consistent relationship with any type of working memory. Surprisingly, no dopamine-related genotypes predicted performance. Therefore, working memory capacity plays a pivotal in determining individual ability in reward-based motor learning.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Isogenic human iPSC pairs reveal a neuronal subtype-specific and genetic background-independent mechanism of SCN1A epilepsy
Over 1250 mutations in SCN1A, the voltage-gated sodium channel gene Nav1.1, are associated with seizure disorders including GEFS+ and Dravet Syndrome (DS). To evaluate how a specific mutation, independent of genetic background, causes seizure activity we generated two pairs of isogenic human iPSC lines by CRISPR/Cas9 gene editing. One pair is a control line from an unaffected sibling, and the mutated control carrying the GEFS+ K1270T SCN1A mutation. The second pair is a GEFS+ patient line with the K1270T mutation, and the corrected patient line. By comparing the electrophysiological properties in inhibitory and excitatory iPSC-derived neurons from these pairs, we found the K1270T mutation causes gene dosage-dependent and cell type-specific alterations in sodium current density and evoked firing, resulting in hyperactive neural networks. We also identified differences associated with genetic background and interaction between the mutation and genetic background. Dual isogenic iPSC-derived neuronal cultures provide a novel platform for developing patient-specific anti-seizure therapies.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Direct binding of the flexible C-terminal segment of periaxin to β4 integrin suggests a molecular basis for CMT4F
The process of myelination in the nervous system requires coordinated formation of both transient and stable supramolecular complexes. Myelin-specific proteins play key roles in these assemblies, which may link membranes to each other or connect the myelinating cell cytoskeleton to the extracellular matrix. The myelin protein periaxin is known to play an important role in linking the Schwann cell cytoskeleton to the basal lamina through membrane receptors, such as the dystroglycan complex. Mutation that truncate periaxin from the C terminus cause demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 4F, indicating a function for the periaxin C-terminal region in myelination. We identified the cytoplasmic domain of {beta}4 integrin as a specific high-affinity binding partner for periaxin. The C-terminal region of periaxin remains unfolded and flexible when bound to the third fibronectin type III domain of {beta}4 integrin. Our data suggest that periaxin is able to link the Schwann cell cytoplasm to the basal lamina through a two-pronged interaction via different membrane protein complexes, which bind close to the N and C terminus of this elongated, flexible molecule.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Global and regional white matter development in early childhood
White matter development continues throughout childhood and into early adulthood, but few studies have examined early childhood, and the specific trajectories and regional variation in this age range remain unclear. The aim of this study was to characterize developmental trajectories and sex differences of white matter in typically developing young children. Three hundred and ninety-six diffusion tensor imaging datasets from 120 children (57 male) aged 2-8 years were analyzed using tractography. Fractional anisotropy (FA) increased and mean diffusivity (MD) decreased in all white matter tracts by 5-15% over the 6-year period, likely reflecting increases in myelination and axonal packing. Males showed steeper slopes in a number of brain areas. Overall, early childhood is associated with substantial development of all white matter and appears to be an important period for the development of occipital and limbic connections, which showed the largest changes. This study provides a detailed characterization of age-related white matter changes in early childhood, offering baseline data that can be used to understand cognitive and behavioural development, as well as to identify deviations from normal development in children with various diseases, disorders, or brain injuries.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Conformational coupling by trans-phosphorylation in calcium calmodulin dependent kinase II
The calcium calmodulin dependent protein kinase II (CaMKII) is a dodecameric holoenzyme important for encoding memory. Its activation, triggered by binding of calcium calmodulin, persists autonomously after calmodulin dissociation. One (receiver) kinase captures and subsequently phosphorylates the regulatory domain peptide of a donor kinase forming a chained dimer as a first stage of autonomous activation. Protein dynamics simulations examined the conformational changes triggered by dimer formation and phosphorylation, aimed to provide a molecular rationale for human mutations that result in learning disabilities. Ensembles generated from X-ray crystal structures were characterized by network centrality and community analysis. Mutual information related collective motions to local fragment dynamics encoded with a structural alphabet. Implicit solvent tCONCOORD conformational ensembles revealed the dynamic architecture of Inactive kinase do-mains was co-opted in the activated dimer but the network hub shifted from the nucleotide binding cleft to the captured peptide. Explicit solvent molecular dynamics (MD) showed nucleotide and substrate binding determinants formed coupled nodes in long-range signal relays between regulatory peptides in the dimer. Strain in the extended captured peptide was balanced by reduced flexibility of the receiver kinase C-lobe core. The relays were organized around a hydrophobic patch between the captured peptide and a key binding helix. The human mutations aligned along the relays. Thus, these mutations could disrupt the allosteric network alternatively, or in addition, to altered binding affinities. Non-binding protein sectors distant from the binding sites mediated the allosteric signalling; providing possible targets for inhibitor design. Phosphorylation of the peptide modulated the dielectric of its binding pocket to strengthen the patch, non-binding sectors, domain interface and temporal correlations between parallel relays. These results provide the molecular details underlying the reported positive kinase cooperativity to enrich discussion on how autonomous activation by phosphorylation leads to long-term behavioural effects.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Transcriptomic correlates of electrophysiological and morphological diversity within and across neuron types
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 Patch-seq 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 bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Ontological Dimensions of Cognitive-Neural Mappings
The growing literature reporting results of cognitive-neural mappings has increased calls for an adequate organizing ontology, or taxonomy, of these mappings. This enterprise is non-trivial, as relevant dimensions that might contribute to such an ontology are not yet agreed upon. We propose that any candidate dimensions should be evaluated on their ability to explain observed differences in functional neuroimaging activation patterns. In this study, we use a large sample of task-based functional magnetic resonance imaging (task-fMRI) results and a data-driven strategy to identify these dimensions. First, using a data-driven dimension reduction approach and multivariate distance matrix regression (MDMR), we quantify the variance among activation maps that is explained by existing ontological dimensions. We find that 'task paradigm' categories explain the most variance among task-activation maps than other dimensions, including latent cognitive categories. Surprisingly, 'study ID', or the study from which each activation map was reported, explained close to 50% of the variance in activation patterns. Using a clustering approach that allows for overlapping clusters, we derived data-driven latent activation states, associated with re-occurring configurations of the canonical fronto-parietal/salience, sensory-motor, and default mode network activation patterns. Importantly, with only four data-driven latent dimensions, one can explain greater variance among activation maps than all conventional ontological dimensions combined. These latent dimensions may inform a data-driven cognitive ontology, and suggest that current descriptions of cognitive processes and the tasks used to elicit them do not accurately reflect activation patterns commonly observed in the human brain.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Reproducibility of functional brain alterations in major depressive disorder: evidence from a multisite resting-state functional MRI study with 1,434 individuals
Resting-state functional MRI (R-fMRI) studies have demonstrated widespread alterations in brain function in patients with major depressive disorder (MDD). However, a clear and consistent conclusion regarding a repeatable pattern of MDD-relevant alterations is still limited due to the scarcity of large-sample, multisite datasets. Here, we address this issue by including a large R-fMRI dataset with 1,434 participants (709 patients with MDD and 725 healthy controls) from five centers in China. Individual functional activity maps that represent very local to long-range connections are computed using the amplitude of low-frequency fluctuations, regional homogeneity and distance-related functional connectivity strength. The reproducibility analyses involve different statistical strategies, global signal regression, across-center consistency, clinical variables, and sample size. We observed significant hypoactivity in the orbitofrontal, sensorimotor, and visual cortices and hyperactivity in the frontoparietal cortices in MDD patients compared to the controls. These alterations are not affected by different statistical analysis strategies, global signal regression and medication status and are generally reproducible across centers. However, these between-group differences are partially influenced by the episode status and the age of disease onset in patients, and the brain-clinical variable relationship exhibits poor cross-center reproducibility. Bootstrap analyses reveal that at least 400 subjects in each group are required to replicate significant alterations (an extent threshold of P<.05 and a height threshold of P<.001) at 50% reproducibility. Together, these results highlight reproducible patterns of functional alterations in MDD and relevant influencing factors, which provides crucial guidance for future neuroimaging studies of this disorder.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Tau pathology in early Alzheimer\'s disease disrupts selective neurophysiological networks dynamics
The role of aggregation of misfolded Tau protein in the pathogenesis of Alzheimer's disease is the subject of rapid biomarker development and new therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography (E/MEG) in combination with [18F]AV1451 PET scanning to quantify Tau-dependent network disruption. Using a graph theoretical approach to MEG connectivity, we quantified nodal measures of functional segregation, centrality and efficiency of information transfer. We correlated these metrics against the nodes' uptake of [18F]AV1451. There were both regional- and frequency-specific effects of Tau levels on the efficiency of information transfer and network segregation in early AD. Tau correlated with temporal regional participation coefficient (in delta, theta, beta bands); and temporal lobar eigenvector centrality (in theta, alpha, beta bands), but greater eccentricity at higher frequencies (gamma). The results support the translational development of neurophysiological "signatures" as biomarkers of Alzheimer's disease, with potential to facilitate experimental medicines studies.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Thalamus drives two complementary input strata of the neocortex in parallel
Sensory information enters the neocortex via thalamocortical axons that define the major 'input' layer 4. The same thalamocortical axons, however, additionally innervate the deep 'output' layers 5/6. How such bistratification impacts cortical processing remains unknown. Here, we find a class of neurons that cluster specifically around thalamocortical axons at the layer 5/6 border. We show that these border stratum cells are characterized by extensive horizontal axons, that they receive strong convergent input from the thalamus, and that this input is sufficient to drive reliable sensory-evoked responses, which precede those in layer 4. These cells are hence strategically placed to amplify and relay thalamocortical inputs across the cortical area, for example to drive the fast onsets of cortical output patterns. Layer 4 is therefore not the sole starting point of cortical processing. Instead, parallel activation of layer 4 and the border stratum is necessary to broadcast information out of the neocortex.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Distinct genetic signatures of cortical and subcortical regions associated with human memory
Despite the discovery of gene variants linked to memory performance, understanding the genetic basis of human memory remains a challenge. Here, we devised a framework combining human transcriptome data and a functional neuroimaging map to uncover the genetic signatures of memory in functionally-defined cortical and subcortical memory regions. Results were validated with animal literature and our framework proved to be highly effective and specific to the targeted cognitive function versus a control function. Genes preferentially expressed in cortical memory regions are linked to associative learning and ribosome biogenesis. Genes expressed in subcortical memory regions are associated with synaptic signaling and epigenetic processes. Cortical and subcortical regions share a number of memory-related biological processes and genes, e.g. translational initiation and GRIN1. Thus, cortical and subcortical memory regions exhibit distinct genetic signatures that potentially reflect functional differences in health and disease, and propose gene candidates for the targeted treatment of memory disorders.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Heartbeat evokes a dynamically changing cortical theta-synchronized network in the resting state
In the resting state, heartbeats evoke cortical responses called heartbeat-evoked responses (HERs). While previous studies reported regional level HERs, researchers have not determined how heartbeat is processed at the cortical network level. Using resting-state magnetoencephalography data from 87 human subjects of both genders provided by the Human Connectome Project, we first showed that heartbeat increases the phase synchronization between cortical regions in the theta frequency, which forms a network structure, and we called this network a heartbeat-evoked network (HEN). The HEN was not an artefactual increase in phase synchronization. The HEN was partitioned into three modules with connector hubs in each module. The first module contained major interoception-related regions and thus was called a visceromotor-interoceptive network (VIN) displaying the strongest synchronization among modules, suggesting a major role for the VIN in processing heartbeat information. Two modules contained regions involved in the default mode network (DMN). The HEN structure was not fixed, but dynamically changed. The most prominent change was observed at approximately 200 ms after R-peak of the electrocardiogram, which was quantified based on the flexibility of the network. Furthermore, the strongest synchronization within VIN was observed before heartbeat stimulated the cortex, which might be related to the prediction of an afferent heartbeat signal, thus supporting an interoceptive coding framework. Based on our results, the heartbeat is processed at the network level, and this result provides a useful framework that may potentially explain previous results of the regional level HER modulation through network-level processing.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Affective reactivity during adolescence: Associations with age, puberty and testosterone
Adolescence is a period of heightened social engagement that is accompanied by normative changes in neural reactivity to affective stimuli. It is also a period of concurrent endocrine and physical changes associated with puberty. A growing body of research suggests that hormonal shifts during adolescence impact brain development, but minimal research in humans has examined the relationship between intra-individual changes in puberty and brain function. The current study examines linear and nonlinear changes in affective reactivity in a longitudinal sample of 82 adolescents who underwent three fMRI sessions between the ages of 9 and 18 years. Changes in response to affective facial stimuli were related to age, pubertal stage, and testosterone levels. Using multilevel modelling, we highlight extensive nonlinear development of socio-emotional responsivity across the brain. Results include mid-pubertal peaks in amygdala and hippocampus response to fearful expressions, as well as sex differences in regions subserving social and self-evaluative processes. However, testosterone levels exhibited inverse patterns of association with neural response compared to pubertal stage in females (e.g. U-shaped relationship with the amygdala and hippocampus). Findings highlight potentially unique roles of age, pubertal stage and testosterone on socio-emotional development during adolescence, as well as sex differences in these associations.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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A Spiking Neuron and Population Model based on the Growth Transform Dynamical System
This paper introduces a new spiking neuron model based on the Growth transform dynamical system, where the process of spike generation and encoding results from the optimization of a network/population energy functional. As a result, the population-level spiking dynamics are always stable and interpretable. In this paper, we show how the model can be configured to generate a wide range of neural dynamics reported in literature by modulating the model hyper-parameters in a manner that the network objective function, or the optimized solution of the system remains unaffected. A publicly available software tool implementing the proposed model can be used to explore a number of single-cell and population dynamics under different conditions and network configurations, and could serve as an important framework for building scalable, energy-efficient neuromorphic machine learning algorithms.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling
Long-lasting forms of synaptic plasticity such as synaptic scaling are critically dependent on transcription. Activity-dependent transcriptional dynamics in neurons, however, have not been fully characterized, because most previous efforts relied on measurement of steady-state mRNAs. Here, we profiled transcriptional dynamics of primary neuron cultures undergoing network activity shifts using nascent RNA sequencing. We found pervasive transcriptional changes, in which ~45% of expressed genes respond to network activity shifts. Notably, the majority of these genes respond to increases or decreases of network activity uniquely, rather than reciprocally. We further linked the chromatin regulator Retinoic acid induced 1 (RAI1), the Smith-Magenis Syndrome gene, to the specific transcriptional program driven by reduced network activity. Finally, we show that RAI1 is essential for homeostatic synaptic upscaling but not downscaling. These results demonstrate the utility of bona fide transcription profiling to discover mechanisms of activity-dependent chromatin remodeling that underlie normal and pathological synaptic plasticity.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Individual differences in the effects of priors on perception: a multi-paradigm approach
The present study investigated individual differences in how much subjects rely on prior information, such as expectations or knowledge, when faced with perceptual ambiguity. The behavioural performance of forty-four participants was measured on four different visual paradigms (Mooney face recognition, illusory contours, blur detection and representational momentum) in which priors have been shown to affect perception. In addition, questionnaires were used to measure autistic and schizotypal traits in the non-clinical population. We hypothesized that someone who in the face of ambiguous or noisy perceptual input relies heavily on priors, would exhibit this tendency across a variety of tasks. This general pattern would then be reflected in high pairwise correlations between the behavioural measures and an emerging common factor. On the contrary, our results imply that there is no single factor that explains the individual differences present in the aforementioned tasks, as further evidenced by the overall lack of robust correlations between the separate paradigms. Instead, a two-factor structure reflecting differences in the hierarchy of perceptual processing was the best fit for explaining the individual variance in these tasks. This lends support to the notion that mechanisms underlying the effects of priors likely originate from several independent sources and that it is important to consider the role of specific tasks and stimuli more carefully when reporting effects of priors on perception.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Ethanol-induced conditioned place preference and aversion differentially alter plasticity in the bed nucleus of stria terminalis
Contextual cues associated with drugs of abuse, such as ethanol, can trigger craving and drug seeking behavior. Pavlovian procedures, such as place conditioning, have been widely used to study the rewarding/aversive properties of drugs and the association between environmental cues and drug seeking. Previous research has shown that ethanol as an unconditioned stimulus can induce a strong conditioned place preference (CPP) or aversion (CPA) in rodents. However, the neural mechanisms underlying ethanol induced reward and aversion have not been thoroughly investigated. The bed nucleus of the stria terminalis (BNST), an integral part of the extended amygdala, is engaged by both rewarding and aversive stimuli and plays a role in ethanol seeking behavior. Here, we used ex-vivo slice physiology to probe learning-induced synaptic plasticity in the BNST following ethanol-induced CPP and CPA. Male DBA/2J mice (2-3 months old) were conditioned using previously reported ethanol-induced CPP/CPA procedures. Ethanol-induced CPP was associated with increased neuronal excitability in the ventral BNST (vBNST). Conversely, ethanol-induced CPA resulted in a significant decrease in spontaneous glutamatergic transmission without alterations in GABAergic signaling. Ethanol-CPA also led to significant increase in paired pulse ratio at excitatory synapses, suggestive of a decrease in presynaptic glutamate release. Collectively, these data demonstrate that the vBNST is involved in the modulation of contextual learning associated with both the rewarding and the aversive properties of ethanol in mice.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Thermodynamic model of gene regulation for the Or59b olfactory receptor in <i>Drosophila</i>

by Alejandra González, Shadi Jafari, Alberto Zenere, Mattias Alenius, Claudio Altafini
Complex eukaryotic promoters normally contain multiple cis-regulatory sequences for different transcription factors (TFs). The binding patterns of the TFs to these sites, as well as the way the TFs interact with each other and with the RNA polymerase (RNAp), lead to combinatorial problems rarely understood in detail, especially under varying epigenetic conditions. The aim of this paper is to build a model describing how the main regulatory cluster of the olfactory receptor Or59b drives transcription of this gene in Drosophila. The cluster-driven expression of this gene is represented as the equilibrium probability of RNAp being bound to the promoter region, using a statistical thermodynamic approach. The RNAp equilibrium probability is computed in terms of the occupancy probabilities of the single TFs of the cluster to the corresponding binding sites, and of the interaction rules among TFs and RNAp, using experimental data of Or59b expression to tune the model parameters. The model reproduces correctly the changes in RNAp binding probability induced by various mutation of specific sites and epigenetic modifications. Some of its predictions have also been validated in novel experiments.
in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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Modeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor

by Keesha E. Erickson, Oleksii S. Rukhlenko, Md Shahinuzzaman, Kalina P. Slavkova, Yen Ting Lin, Ryan Suderman, Edward C. Stites, Marian Anghel, Richard G. Posner, Dipak Barua, Boris N. Kholodenko, William S. Hlavacek
Receptor tyrosine kinases (RTKs) typically contain multiple autophosphorylation sites in their cytoplasmic domains. Once activated, these autophosphorylation sites can recruit downstream signaling proteins containing Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains, which recognize phosphotyrosine-containing short linear motifs (SLiMs). These domains and SLiMs have polyspecific or promiscuous binding activities. Thus, multiple signaling proteins may compete for binding to a common SLiM and vice versa. To investigate the effects of competition on RTK signaling, we used a rule-based modeling approach to develop and analyze models for ligand-induced recruitment of SH2/PTB domain-containing proteins to autophosphorylation sites in the insulin-like growth factor 1 (IGF1) receptor (IGF1R). Models were parameterized using published datasets reporting protein copy numbers and site-specific binding affinities. Simulations were facilitated by a novel application of model restructuration, to reduce redundancy in rule-derived equations. We compare predictions obtained via numerical simulation of the model to those obtained through simple prediction methods, such as through an analytical approximation, or ranking by copy number and/or K_D value, and find that the simple methods are unable to recapitulate the predictions of numerical simulations. We created 45 cell line-specific models that demonstrate how early events in IGF1R signaling depend on the protein abundance profile of a cell. Simulations, facilitated by model restructuration, identified pairs of IGF1R binding partners that are recruited in anti-correlated and correlated fashions, despite no inclusion of cooperativity in our models. This work shows that the outcome of competition depends on the physicochemical parameters that characterize pairwise interactions, as well as network properties, including network connectivity and the relative abundances of competitors.
in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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Ten simple rules on how to create open access and reproducible molecular simulations of biological systems

by Arne Elofsson, Berk Hess, Erik Lindahl, Alexey Onufriev, David van der Spoel, Anders Wallqvist

in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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STRFs in primary auditory cortex emerge from masking-based statistics of natural sounds

by Abdul-Saboor Sheikh, Nicol S. Harper, Jakob Drefs, Yosef Singer, Zhenwen Dai, Richard E. Turner, Jörg Lücke
We investigate how the neural processing in auditory cortex is shaped by the statistics of natural sounds. Hypothesising that auditory cortex (A1) represents the structural primitives out of which sounds are composed, we employ a statistical model to extract such components. The input to the model are cochleagrams which approximate the non-linear transformations a sound undergoes from the outer ear, through the cochlea to the auditory nerve. Cochleagram components do not superimpose linearly, but rather according to a rule which can be approximated using the max function. This is a consequence of the compression inherent in the cochleagram and the sparsity of natural sounds. Furthermore, cochleagrams do not have negative values. Cochleagrams are therefore not matched well by the assumptions of standard linear approaches such as sparse coding or ICA. We therefore consider a new encoding approach for natural sounds, which combines a model of early auditory processing with maximal causes analysis (MCA), a sparse coding model which captures both the non-linear combination rule and non-negativity of the data. An efficient truncated EM algorithm is used to fit the MCA model to cochleagram data. We characterize the generative fields (GFs) inferred by MCA with respect to in vivo neural responses in A1 by applying reverse correlation to estimate spectro-temporal receptive fields (STRFs) implied by the learned GFs. Despite the GFs being non-negative, the STRF estimates are found to contain both positive and negative subfields, where the negative subfields can be attributed to explaining away effects as captured by the applied inference method. A direct comparison with ferret A1 shows many similar forms, and the spectral and temporal modulation tuning of both ferret and model STRFs show similar ranges over the population. In summary, our model represents an alternative to linear approaches for biological auditory encoding while it captures salient data properties and links inhibitory subfields to explaining away effects.
in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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Sequential infection experiments for quantifying innate and adaptive immunity during influenza infection

by Ada W. C. Yan, Sophie G. Zaloumis, Julie A. Simpson, James M. McCaw
Laboratory models are often used to understand the interaction of related pathogens via host immunity. For example, recent experiments where ferrets were exposed to two influenza strains within a short period of time have shown how the effects of cross-immunity vary with the time between exposures and the specific strains used. On the other hand, studies of the workings of different arms of the immune response, and their relative importance, typically use experiments involving a single infection. However, inferring the relative importance of different immune components from this type of data is challenging. Using simulations and mathematical modelling, here we investigate whether the sequential infection experiment design can be used not only to determine immune components contributing to cross-protection, but also to gain insight into the immune response during a single infection. We show that virological data from sequential infection experiments can be used to accurately extract the timing and extent of cross-protection. Moreover, the broad immune components responsible for such cross-protection can be determined. Such data can also be used to infer the timing and strength of some immune components in controlling a primary infection, even in the absence of serological data. By contrast, single infection data cannot be used to reliably recover this information. Hence, sequential infection data enhances our understanding of the mechanisms underlying the control and resolution of infection, and generates new insight into how previous exposure influences the time course of a subsequent infection.
in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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Longitudinal tau accumulation and atrophy in aging and alzheimer disease

Objective

To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy.

Methods

Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B [PiB]⁺, age = 77.6 ± 4.6 years, 25 female [F]/17 male [M]) and 19 PiB⁺ patients with AD (age = 63.1 ± 10.3 years, 12 F/7 M) over 1 to 3 years of follow‐up. FTP change, structural MRI measures of atrophy, and cross‐modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated.

Results

Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow‐up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status.

Interpretation

Our findings indicate that tau accumulates even in amyloid‐negative healthy OA and this process can be measured with in vivo tau‐PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy. Ann Neurol 2019; 1–12

in Wiley: Annals of Neurology: Table of Contents on January 17, 2019 06:02 PM.
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Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura

Amyloid‐β transmission has been described in patients both with and without iatrogenic Creutzfeldt–Jakob disease; however, there is little information regarding the clinical impact of this acquired amyloid‐β pathology during life. Here, for the first time, we describe in detail the clinical and neuroimaging findings in 3 patients with early onset symptomatic amyloid‐β cerebral amyloid angiopathy following childhood exposure to cadaveric dura (by neurosurgical grafting in 2 patients and tumor embolization in a third). Our observations provide further in vivo evidence that cerebral amyloid angiopathy might be caused by transmission of amyloid‐β seeds (prions) present in cadaveric dura and have diagnostic relevance for younger patients presenting with suspected cerebral amyloid angiopathy. Ann Neurol 2019; 1–7

in Wiley: Annals of Neurology: Table of Contents on January 17, 2019 06:00 PM.
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Not all cortical expansions are the same: the coevolution of the neocortex and the dorsal thalamus in mammals

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Andrew C Halley, Leah Krubitzer
A central question in comparative neurobiology concerns how evolution has produced brains with expanded neocortices, composed of more areas with unique connectivity and functional properties. Some mammalian lineages, such as primates, exhibit exceptionally large cortices relative to the amount of sensory inputs from the dorsal thalamus, and this expansion is associated with a larger number of distinct cortical areas, composing a larger proportion of the cortical sheet. We propose a link between the organization of the neocortex and its expansion relative to the size of the dorsal thalamus, based on a combination of work in comparative neuroanatomy and experimental research.

in ScienceDirect Publication: Current Opinion in Neurobiology on January 17, 2019 06:00 PM.
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Obstructive sleep apnea treatment, slow wave activity, and amyloid‐β

Obstructive sleep apnea (OSA) increases risk of dementia, a relationship that may be mediated by amyloid‐β (Aβ) and downstream Alzheimer disease pathology. We previously showed that OSA may impair Aβ clearance and affect the relationship between slow wave activity (SWA) and Aβ. In this study, SWA and CSF Aβ were measured in participants with OSA before and 1 to 4 months after treatment. OSA treatment increased SWA, and SWA was significantly correlated with lower Aβ after treatment. Greater improvement in OSA was associated with greater decreases in Aβ. We propose a model whereby OSA treatment may affect both Aβ release and clearance. Ann Neurol 2018

in Wiley: Annals of Neurology: Table of Contents on January 17, 2019 05:24 PM.
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Metabolic patterns and seizure outcomes following anterior temporal lobectomy

Objective

We investigated the relationship between the interictal metabolic patterns, the extent of resection of ¹⁸F‐fluorodeoxyglucose positron emission tomography (¹⁸FDG‐PET) hypometabolism, and seizure outcomes in patients with unilateral drug‐resistant mesial temporal lobe epilepsy (MTLE) following anterior temporal lobe (TL) resection.

Methods

Eighty‐two patients with hippocampal sclerosis or normal magnetic resonance imaging (MRI) findings, concordant ¹⁸FDG‐PET hypometabolism, and at least 2 years of postoperative follow‐up were included in this 2‐center study. The hypometabolic regions in each patient were identified with reference to 20 healthy controls (p < 0.005). The resected TL volume and the volume of resected TL PET hypometabolism (TLH) were calculated from the pre‐ and postoperative MRI scans coregistered with interictal ¹⁸FDG‐PET.

Results

Striking differences in metabolic patterns were observed depending on the lateralization of the epileptogenic TL. The extent of the ipsilateral TLH was significantly greater in left MTLE patients (p < 0.001), whereas right MTLE patients had significantly higher rates of contralateral (CTL) TLH (p = 0.016). In right MTLE patients, CTL hypometabolism was the strongest predictor of an unfavorable seizure outcome, associated with a 5‐fold increase in the likelihood of seizure recurrence (odds ratio [OR] = 4.90, 95% confidence interval [CI] = 1.07–22.39, p = 0.04). In left MTLE patients, greater extent of resection of ipsilateral TLH was associated with lower rates of seizure recurrence (p = 0.004) in univariate analysis; however, its predictive value did not reach statistical significance (OR = 0.96, 95% CI = 0.90–1.02, p = 0.19).

Interpretation

The difference in metabolic patterns depending on the lateralization of MTLE may represent distinct epileptic networks in patients with right versus left MTLE, and can guide preoperative counseling and surgical planning. Ann Neurol 2019; 1–10

in Wiley: Annals of Neurology: Table of Contents on January 17, 2019 05:23 PM.
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Visual processing in migraineurs depends on the migraine cycle

We investigated changes of after‐image duration in migraineurs and healthy controls (HCs) and throughout the migraine cycle to depict changes in the excitatory/inhibitory equilibrium within the visual cortex. Forty‐seven episodic (EMs) and 39 chronic migraineurs (CMs; interictal) were compared to 34 HCs for visual after‐image duration. Additionally, seven EMs were investigated every consecutive day over 20 to 32 days using the identical paradigm throughout the migraine cycle. Interictally, the after‐image duration was shorter compared to HCs, but significantly longer in the ictal compared to interictal phase. These data suggest an altered excitatory/inhibitory equilibrium in migraineurs, which oscillates over the migraine cycle.

in Wiley: Annals of Neurology: Table of Contents on January 17, 2019 05:16 PM.
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Gamma‐aminobutyric acidergic transmission underlies interictal epileptogenicity in pediatric focal cortical dysplasia

Objective

Dysregulation of γ‐aminobutyric acidergic (GABAergic) transmission has been reported in lesional acquired epilepsies (gliomas, hippocampal sclerosis). We investigated its involvement in a developmental disorder, human focal cortical dysplasia (FCD), focusing on chloride regulation driving GABAergic signals.

Methods

In vitro recordings of 47 human cortical acute slices from 11 pediatric patients who received operations for FCD were performed on multielectrode arrays. GABAergic receptors and chloride regulators were pharmacologically modulated. Immunostaining for chloride cotransporter KCC2 and interneurons were performed on recorded slices to correlate electrophysiology and expression patterns.

Results

FCD slices retain intrinsic epileptogenicity. Thirty‐six of 47 slices displayed spontaneous interictal discharges, along with a pattern specific to the histological subtypes. Ictal discharges were induced in proepileptic conditions in 6 of 8 slices in the areas generating spontaneous interictal discharges, with a transition to seizure involving the emergence of preictal discharges. Interictal discharges were sustained by GABAergic signaling, as a GABA_A receptor blocker stopped them in 2 of 3 slices. Blockade of NKCC1 Cl⁻ cotransporters further controlled interictal discharges in 9 of 12 cases, revealing a Cl⁻ dysregulation affecting actions of GABA. Immunohistochemistry highlighted decreased expression and changes in KCC2 subcellular localization and a decrease in the number of GAD67‐positive interneurons in regions generating interictal discharges.

Interpretation

Altered chloride cotransporter expression and changes in interneuron density in FCD may lead to paradoxical depolarization of pyramidal cells. Spontaneous interictal discharges are consequently mediated by GABAergic signals, and targeting chloride regulation in neurons may be considered for the development of new antiepileptic drugs. Ann Neurol 2019; 1–14

in Wiley: Annals of Neurology: Table of Contents on January 17, 2019 05:07 PM.
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Presetting of the Corticospinal Excitability in the Tibialis Anterior Muscle in Relation to Prediction of the Magnitude and Direction of Postural Perturbations
Kimiya Fujio, Hiroki Obata, Noritaka Kawashima, Kimitaka Nakazawa
in Frontiers in Human Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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A Versatile and Open-Source Rapid LED Switching System for One-Photon Imaging and Photo-Activation
Arne Battefeld, Marko A. Popovic, Dirk van der Werf, Maarten H. P. Kole
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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Entorhinal Neurons Exhibit Cue Locking in Rodent VR
Giulio Casali, Sarah Shipley, Charlie Dowell, Robin Hayman, Caswell Barry
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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The Neuroprotector Benzothiazepine CGP37157 Extends Lifespan in C. elegans Worms
Paloma García-Casas, Jessica Arias-del-Val, Pilar Alvarez-Illera, Aneta Wojnicz, Cristobal de los Ríos, Rosalba I. Fonteriz, Mayte Montero, Javier Alvarez
in Frontiers in Aging Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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Differential Associations of IL-4 With Hippocampal Subfields in Mild Cognitive Impairment and Alzheimer’s Disease
Virginia Boccardi, Eric Westman, Luca Pelini, Olof Lindberg, J-Sebastian Muehlboeck, Andrew Simmons, Roberto Tarducci, Piero Floridi, Pietro Chiarini, Hilkka Soininen, Iwona Kloszewska, Magda Tsolaki, Bruno Vellas, Christian Spenger, Lars-Olof Wahlund, Simon Lovestone, Patrizia Mecocci
in Frontiers in Aging Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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Fragile-X Syndrome Is Associated With NMDA Receptor Hypofunction and Reduced Dendritic Complexity in Mature Dentate Granule Cells
Suk-Yu Yau, Luis Bettio, Jason Chiu, Christine Chiu, Brian R. Christie
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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EZH2 Influences mdDA Neuronal Differentiation, Maintenance and Survival
Iris Wever, Lars von Oerthel, Cindy M. R. J. Wagemans, Marten P. Smidt
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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The Degree of Modulation of Beta Band Activity During Motor Planning Is Related to Trait Impulsivity
Charidimos Tzagarakis, Andrew Thompson, Robert D. Rogers, Giuseppe Pellizzer
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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The Effect of Dual Task on Attentional Performance in Children With ADHD
Simona Caldani, Milena Razuk, Mathilde Septier, José Angelo Barela, Richard Delorme, Eric Acquaviva, Maria Pia Bucci
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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Quantum Structures in Human Decision-making: Towards Quantum Expected Utility. (arXiv:1811.00875v1 [cs.AI] CROSS LISTED)

{\it Ellsberg thought experiments} and empirical confirmation of Ellsberg preferences pose serious challenges to {\it subjective expected utility theory} (SEUT). We have recently elaborated a quantum-theoretic framework for human decisions under uncertainty which satisfactorily copes with the Ellsberg paradox and other puzzles of SEUT. We apply here the quantum-theoretic framework to the {\it Ellsberg two-urn example}, showing that the paradox can be explained by assuming a state change of the conceptual entity that is the object of the decision ({\it decision-making}, or {\it DM}, {\it entity}) and representing subjective probabilities by quantum probabilities. We also model the empirical data we collected in a DM test on human participants within the theoretic framework above. The obtained results are relevant, as they provide a line to model real life, e.g., financial and medical, decisions that show the same empirical patterns as the two-urn experiment.

in q-bio.NC updates on arXiv.org on January 17, 2019 01:30 AM.
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Synapse maintenance is impacted by ATAT-2 tubulin acetyltransferase activity and the RPM-1 signaling hub
Synapse formation is comprised of target recognition, synapse assembly, and synapse maintenance. Maintaining established synaptic connections is essential for generating functional circuitry and synapse instability is a hallmark of neurodegenerative disease. While many molecules impact synapse formation generally, we know little about molecules that affect synapse maintenance in vivo. Using genetics and developmental time course analysis in C. elegans, we show that the a-tubulin acetyltransferase ATAT-2 and the signaling hub RPM-1 are required presynaptically to maintain stable synapses. Importantly, the enzymatic acetyltransferase activity of ATAT-2 is required for synapse maintenance. Our analysis revealed that RPM-1 is a hub in a genetic network composed of ATAT-2, PTRN-1 and DLK-1. In this network, ATAT-2 functions independent of the DLK-1 MAPK and likely acts downstream of RPM-1. Thus, our study reveals an important role for tubulin acetyltransferase activity in presynaptic maintenance, which occurs via the RPM-1/ATAT-2 pathway.
in eLife: latest articles on January 17, 2019 12:00 AM.
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Engineering a conserved RNA regulatory protein repurposes its biological function in vivo
PUF (PUmilio/FBF) RNA-binding proteins recognize distinct elements. In C. elegans, PUF-8 binds to an 8-nt motif and restricts proliferation in the germline. Conversely, FBF-2 recognizes a 9-nt element and promotes mitosis. To understand how motif divergence relates to biological function, we determined a crystal structure of PUF-8. Comparison of this structure to that of FBF-2 revealed a major difference in a central repeat. We devised a modified yeast 3-hybrid screen to identify mutations that confer recognition of an 8-nt element to FBF-2. We identified several such mutants and validated structurally and biochemically their binding to 8-nt RNA elements. Using genome engineering, we generated a mutant animal with a substitution in FBF-2 that confers preferential binding to the PUF-8 element. The mutant largely rescued overproliferation in animals that spontaneously generate tumors in the absence of puf-8. This work highlights the critical role of motif length in the specification of biological function.
in eLife: latest articles on January 17, 2019 12:00 AM.
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TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb
Comprehensively elucidating the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) latency is a priority to achieve a functional cure. As current 'shock' agents failed to efficiently reactivate the latent reservoir, it is important to discover new targets for developing more efficient latency-reversing agents (LRAs). Here we found that TRIM28 potently suppresses HIV-1 expression by utilizing both SUMO E3 ligase activity and epigenetic adaptor function. Through global site-specific SUMO-MS study and serial SUMOylation assays, we identified that P-TEFb catalytic subunit CDK9 is significantly SUMOylated by TRIM28 with SUMO4. The Lys44, Lys56 and Lys68 residues on CDK9 are SUMOylated by TRIM28, which inhibits CDK9 kinase activity or prevents P-TEFb assembly by directly blocking the interaction between CDK9 and Cyclin T1, subsequently inhibits viral transcription and contributes to HIV-1 latency. The manipulation of TRIM28 and its consequent SUMOylation pathway could be the target for developing LRAs.
in eLife: latest articles on January 17, 2019 12:00 AM.
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Nostril-specific and structure-based olfactory learning of chiral discrimination in human adults
Practice makes perfect. In human olfaction, such plasticity is generally assumed to occur at the level of cortical synthetic processing that shares information from both nostrils. Here we present findings that challenge this view. In two experiments, we trained human adults unirhinally for the discrimination between odor enantiomers over a course of about 10 to 11 days. Results showed that training-induced perceptual gain was restricted to the trained nostril yet partially generalized to untrained odor enantiomers in a structure- rather than quality- based manner. In other words, learning enhanced the differentiation of chirality (molecular configuration) as opposed to overall odor quality (odor object) per se. These findings argue that, unlike earlier beliefs, one nostril does not readily know what the other learns. Moreover, the initial analytical processing of the structural features of uninarial olfactory input remains plastic in human adults.
in eLife: latest articles on January 17, 2019 12:00 AM.
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CaImAn an open source tool for scalable calcium imaging data analysis
Advances in fluorescence microscopy enable monitoring larger brain areas in-vivo with finer time resolution. The resulting data rates require reproducible analysis pipelines that are reliable, fully automated, and scalable to datasets generated over the course of months. We present CaImAn, an open-source library for calcium imaging data analysis. CaImAn provides automatic and scalable methods to address problems common to pre-processing, including motion correction, neural activity identification, and registration across different sessions of data collection. It does this while requiring minimal user intervention, with good scalability on computers ranging from laptops to high-performance computing clusters. CaImAn is suitable for two-photon and one-photon imaging, and also enables real-time analysis on streaming data. To benchmark the performance of CaImAn we collected and combined a corpus of manual annotations from multiple labelers on nine mouse two-photon datasets. We demonstrate that CaImAn achieves near-human performance in detecting locations of active neurons.
in eLife: latest articles on January 17, 2019 12:00 AM.
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A Bundle of Mechanisms: Inner-Ear Hair-Cell Mechanotransduction
In the inner ear, the deflection of hair bundles, the sensory organelles of hair cells, activates mechanically-gated channels (MGCs). Hair bundles monitor orientation of the head, its angular and linear acceleration, and detect sound. Force applied to MGCs is shaped by intrinsic hair-bundle properties, by the mechanical load on the bundle, and by the filter imparted by the environment of the hair bundle. Channel gating and adaptation, the ability of the bundle to reset its operating point, contribute to hair-bundle mechanics.
in Trends in Neurosciences on January 17, 2019 12:00 AM.
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Long-Range Guidance of Spinal Commissural Axons by Netrin1 and Sonic Hedgehog from Midline Floor Plate Cells
Recent studies have queried the role of netrin1 from floor plate (FP-netrin1) in guiding commissural axons. Wu et al. show that, in spinal cord, FP-netrin1 is required and acts at long range to guide commissural axons, collaborating with Shh.
in Neuron on January 17, 2019 12:00 AM.
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Synergistic Activity of Floor-Plate- and Ventricular-Zone-Derived Netrin-1 in Spinal Cord Commissural Axon Guidance
Moreno-Bravo et al. use a conditional-knockout strategy and light sheet fluorescence microscopy to show that netrin-1 from ventricular zone progenitors and netrin-1 from the floor plate cooperate to guide spinal cord commissural axons to and across the midline.
in Neuron on January 17, 2019 12:00 AM.
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Correction to: Computing reward prediction errors and learning valence in the insect mushroom body
Following the publication of the original article [1], it was highlighted that an old version of the text for abstract P252 was published, thereby causing the text to no longer correspond with Fig. 1.
in Most Recent Articles: BMC Neuroscience on January 17, 2019 12:00 AM.
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Submicron Crystals of the Parkinson\'s Disease Substantia nigra: Calcium Oxalate, Titanium Dioxide and Iron Oxide
Parkinsons disease (PD) results of the death of dopaminergic neurons of the substantia nigra. When activated, the NLRP3 inflammasome of phagocytes releases inflammatory agents, their release resulting in the death of proximal cells. The hallmark protein of PD, aggregated -synuclein, is phagocytized and activates the NLRP3 inflammasome. Because crystalline particles are known to activate the NLRP3 inflammasome, to enhance -synuclein expression and aggregation in dopaminergic neurons and because their facets may mis-template adsorbed -synuclein, we probe here, by transmission electron microscopy (TEM), four human PD substantia nigra specimens for their crystalline particles. Samples weighing 5 mg of PD stages 1, 2, 4 and 5 were processed by proteolysis and centrifugation. TEM-grids were dipped in the centrifugate diluted to 1 mL and the dried films were searched for crystalline particles. Two types of crystalline particles, known to activate the NLRP3 inflammasome were found. Endogenous calcium oxalate, a downstream product of ascorbate and dopamine oxidation-produced hydrogen peroxide; and TiO2, the with pigment of foods and medications. The number-density of the NLRP-inflammasome activating crystalline particles found approached the reported about-equal number-densities of microglia and neuronal cells in the brain. The observations of COD and protein-coated TiO2 support two putative feedback loops, both leading to dopaminergic neuron death. In one, polymeric oxidized-dopamine catalyst accelerates H2O2-generation, the H2O2 indirectly oxidizing ascorbate in an ascorbate-fueled, oxalate-generating, loop the excess oxalate precipitating the subsequently inflammasome-activating COD crystals; In the second, protein-adsorbing facets of TiO2 mis-template the aggregation of -synuclein to produce inflammasome-activating mis-folded -synuclein.
in bioRxiv Subject Collection: Neuroscience on January 17, 2019 12:00 AM.
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The differential contribution of pacemaker neurons to synaptic transmission in the pyloric network of the Jonah crab, Cancer borealis
Many neurons receive synchronous input from heterogeneous presynaptic neurons with distinct properties. An instructive example is the crustacean stomatogastric pyloric circuit pacemaker group, consisting of the anterior burster (AB) and pyloric dilator (PD) neurons, which are active synchronously and exert a combined synaptic action on most pyloric follower neurons. Although the stomatogastric system of the crab Cancer borealis has become a preferred model system for exploration of cellular and synaptic basis of circuit dynamics, in this species, the identity of the PD neuron neurotransmitter and its contribution to the total pacemaker group synaptic output remain unexplored. We examined the synaptic properties of the crab PD neuron using a combination of single cell mRNA analysis, electrophysiology and pharmacology. The crab PD neuron expresses high levels of choline acetyltransferase and the vesicular acetylcholine transporter mRNAs, hallmarks of cholinergic neurons. Conversely, the AB neuron does not express either of these cholinergic markers, and expresses high levels of vesicular glutamate transporter mRNA, consistent with a glutamatergic phenotype. Notably, in the combined synapses to the LP and PY neurons, the major contribution is from the glutamatergic AB neuron and only between 25-30% of the synaptic strength is due to the PD neuron. However, there was no difference between the short-term synaptic plasticity in the total pacemaker synapse compared to that of the PD neuron alone. These findings provide a guide for similar explorations of heterogeneous synaptic connections in other systems and a baseline in this system for the exploration of the differential influence of neuromodulators.
in bioRxiv Subject Collection: Neuroscience on January 17, 2019 12:00 AM.
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Aβ-Positivity Predicts Cognitive Decline but Cognition Also Predicts Progression to Aβ-Positivity
Introduction: Biomarker positivity predicts cognitive decline and Alzheimer's dementia. But what predicts biomarker positivity? We hypothesized that cognitive function and p-tau would predict progression from normal to abnormal levels of {beta}-amyloid (A{beta}). Methods: Baseline cognition in 292 non-demented, A{beta}-negative Alzheimer's Disease Neuroimaging Initiative (ADNI) participants was measured with two cognitive composites and compared between those that progressed to A{beta}-positivity versus A{beta}-stable. Follow-up analyses included continuous CSF A{beta} and p-tau levels to examine subthreshold effects. Results: Continuously measured baseline subthreshold A{beta} and p-tau predicted progression to A{beta}-positivity, but both baseline cognitive measures predicted progression to A{beta}-positivity even after controlling for baseline biomarker levels. Discussion: Current A{beta} thresholds may be ignoring relevant subthreshold pathology. Importantly, cognitive function can be an important early predictor of future risk, even earlier than the key biomarkers as currently measured. Moreover, A-/T+ individuals may still be on the AD pathway because p-tau also predicted progression to positivity.
in bioRxiv Subject Collection: Neuroscience on January 17, 2019 12:00 AM.
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The Effect of Fucoidan on Cellular Oxidative Stress and the CatD-Bax Signaling Axis in MN9D Cells Damaged by 1-Methyl-4-Phenypyridinium
Zhigang Liang, Zhuli Liu, Xuwen Sun, Manli Tao, Xiao Xiao, Guoping Yu, Xiaomin Wang
in Frontiers in Aging Neuroscience | New and Recent Articles on January 16, 2019 06:00 PM.
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Erratum: Prekop et al., "Sox14 Is Required for a Specific Subset of Cerebello-Olivary Projections"

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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A Proposed Mechanism for Spontaneous Transitions between Interictal and Ictal Activity

Epileptic networks are characterized by two outputs: brief interictal spikes and rarer, more prolonged seizures. Although either output state is readily modeled in silico and induced experimentally, the transition mechanisms are unknown, in part because no models exhibit both output states spontaneously. In silico small-world neural networks were built using single-compartment neurons whose physiological parameters were derived from dual whole-cell recordings of pyramidal cells in organotypic hippocampal slice cultures that were generating spontaneous seizure-like activity. In silico, neurons were connected by abundant local synapses and rare long-distance synapses. Activity-dependent synaptic depression and gradual recovery delimited synchronous activity. Full synaptic recovery engendered interictal population spikes that spread via long-distance synapses. When synaptic recovery was incomplete, postsynaptic neurons required coincident activation of multiple presynaptic terminals to reach firing threshold. Only local connections were sufficiently dense to spread activity under these conditions. This coalesced network activity into traveling waves whose velocity varied with synaptic recovery. Seizures were comprised of sustained traveling waves that were similar to those recorded during experimental and human neocortical seizures. Sustained traveling waves occurred only when wave velocity, network dimensions, and the rate of synaptic recovery enabled wave reentry into previously depressed areas at precisely ictogenic levels of synaptic recovery. Wide-field, cellular-resolution GCamP7b calcium imaging demonstrated similar initial patterns of activation in the hippocampus, although the anatomical distribution of traveling waves of synaptic activation was altered by the pattern of synaptic connectivity in the organotypic hippocampal cultures.

SIGNIFICANCE STATEMENT When computerized distributed neural network models are required to generate both features of epileptic networks (i.e., spontaneous interictal population spikes and seizures), the network structure is substantially constrained. These constraints provide important new hypotheses regarding the nature of epileptic networks and mechanisms of seizure onset.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Tau Accumulation in Clinically Normal Older Adults Is Associated with Hippocampal Hyperactivity

Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-β proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-β accumulation, apolipoprotein 4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-β and tau accumulation) before clinical symptoms remains to be elucidated. Here, we studied 120 clinically normal older humans (80 females/40 males) enrolled in the Harvard Aging Brain Study. We measured functional magnetic resonance imaging (fMRI) activity during successful memory encoding and amyloid-β accumulation with PiB-positron emission tomography imaging. Additionally, we measured tau accumulation using AV1451 PET imaging in a subset of 87 participants. In this subset, we found that inferior temporal tau accumulation was associated with increased fMRI activity in the hippocampus, but showed no clear association with amyloid. Together, the findings support a hypothetical model of the evolution of preclinical AD that place hippocampal hyperactivity concurrent with spread of tau pathology to neocortical regions before clinical impairment.

SIGNIFICANCE STATEMENT The circumstances under which the hippocampus becomes hyperactive in preclinical stages of Alzheimer's disease (AD) have thus far remained elusive. Recent advances in positron emission tomography (PET) tracers now enable in vivo characterization of amyloid-β and tau accumulation. Here, we combine amyloid and tau PET with functional magnetic resonance imaging (fMRI) to examine the association between Alzheimer's disease pathology and memory-related brain activity in clinically normal older adults. We found an association between increased hippocampal activity and tau accumulation in the inferior temporal cortex. These data suggest that the pathogenesis of hippocampal hyperactivity occurs concurrent with the spread of tau pathology from the entorhinal cortex to the neocortex, before the clinical manifestations of Alzheimer's disease.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA–BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D_2/3 PET assessment using [¹¹C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D_2/3 receptors to BOLD response in the thalamo–striatal–cortical circuit, which supports WM functioning. Critically, the DA–BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA–BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA–BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.

SIGNIFICANCE STATEMENT Dopamine (DA) is a major neuromodulator in the CNS and plays a key role in several cognitive processes via modulating the blood oxygenation level-dependent (BOLD) signal. Some studies have shown a link between DA and BOLD, whereas others have failed to observe such a relationship. A possible reason for the discrepancy is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. We examined the relationship of DA to BOLD response during working memory under three load conditions and found that the DA–BOLD association is expressed in a load-dependent fashion. These findings may help explain the disproportionate impairment evident in more effortful cognitive tasks in normal aging and in those suffering dopamine-dependent neurodegenerative diseases (e.g., Parkinson's disease).

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Electrical Stimulation Over Human Posterior Parietal Cortex Selectively Enhances the Capacity of Visual Short-Term Memory

Visual short-term memory (VSTM) provides an on-line mental space for incoming sensory information to be temporally maintained to carry out complex behavioral tasks. Despite its essential functions, the capacity at which VSTM could maintain sensory information is limited (i.e., VSTM can hold only about three to four visual items at once). Moreover, the quality of sensory representation (i.e., precision) degrades as more information has to be maintained in VSTM. Correlational evidence suggests that the level and the pattern of neural activity measured in the posterior parietal cortex (PPC) track both VSTM capacity and precision. However, the causal contributions of the PPC to these different VSTM operations are unclear. Here, we tested whether stimulating the PPC with transcranial direct current stimulation (tDCS) could increase VSTM capacity or precision. We found that stimulating the PPC in male and female human participants selectively enhanced VSTM capacity when the number of memory items exceeded capacity limit, without significant effects on VSTM precision. Moreover, this enhancement of VSTM capacity is region specific as stimulating the prefrontal cortex did not change VSTM capacity or precision. Null stimulation effects in the sensory memory condition confirmed that the tDCS-induced enhancement of VSTM capacity was not simply due to changes in sensory or attentional processes. Altogether, these results provide causal evidence suggesting that the PPC has a more dominant role in supporting the storage capacity of VSTM compared with maintaining the quality of sensory representations. Furthermore, tDCS could be used as a promising noninvasive method to enhance this PPC VSTM-related function.

SIGNIFICANCE STATEMENT Correlational evidence from neuroimaging and electrophysiology suggests that the posterior parietal cortex (PPC) supports the storage capacity of visual short-term memory (VSTM) and the precision of sensory representations maintained in VSTM. However, the causal contributions of the PPC to these different VSTM functions were unclear. Here, we found that electrical stimulation over the PPC selectively enhanced VSTM capacity without changing VSTM precision. Overall, our findings suggest that the PPC has a dominant and causal role in supporting the storage capacity of VSTM.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Balancing Prediction and Sensory Input in Speech Comprehension: The Spatiotemporal Dynamics of Word Recognition in Context

Spoken word recognition in context is remarkably fast and accurate, with recognition times of ~200 ms, typically well before the end of the word. The neurocomputational mechanisms underlying these contextual effects are still poorly understood. This study combines source-localized electroencephalographic and magnetoencephalographic (EMEG) measures of real-time brain activity with multivariate representational similarity analysis to determine directly the timing and computational content of the processes evoked as spoken words are heard in context, and to evaluate the respective roles of bottom-up and predictive processing mechanisms in the integration of sensory and contextual constraints. Male and female human participants heard simple (modifier-noun) English phrases that varied in the degree of semantic constraint that the modifier (W1) exerted on the noun (W2), as in pairs, such as "yellow banana." We used gating tasks to generate estimates of the probabilistic predictions generated by these constraints as well as measures of their interaction with the bottom-up perceptual input for W2. Representation similarity analysis models of these measures were tested against electroencephalographic and magnetoencephalographic brain data across a bilateral fronto-temporo-parietal language network. Consistent with probabilistic predictive processing accounts, we found early activation of semantic constraints in frontal cortex (LBA45) as W1 was heard. The effects of these constraints (at 100 ms after W2 onset in left middle temporal gyrus and at 140 ms in left Heschl's gyrus) were only detectable, however, after the initial phonemes of W2 had been heard. Within an overall predictive processing framework, bottom-up sensory inputs are still required to achieve early and robust spoken word recognition in context.

SIGNIFICANCE STATEMENT Human listeners recognize spoken words in natural speech contexts with remarkable speed and accuracy, often identifying a word well before all of it has been heard. In this study, we investigate the brain systems that support this important capacity, using neuroimaging techniques that can track real-time brain activity during speech comprehension. This makes it possible to locate the brain areas that generate predictions about upcoming words and to show how these expectations are integrated with the evidence provided by the speech being heard. We use the timing and localization of these effects to provide the most specific account to date of how the brain achieves an optimal balance between prediction and sensory input in the interpretation of spoken language.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors in male rats, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of G_q signaling, but not G_s signaling, in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory G_i/o signaling in DA neurons blunted the reinforcing and priming effects of cocaine, reduced stress-potentiated reinstatement, and altered behavioral strategies for cocaine seeking and taking. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein-signaling cascades, and DA neuron efferent targets, highlighting their multifaceted roles in addiction.

SIGNIFICANCE STATEMENT G-protein-coupled receptors are crucial modulators of ventral tegmental area (VTA) dopamine neuron activity, but how this metabotropic signaling impacts the complex roles of dopamine in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs (designer receptors exclusively activated by designer drugs) during a variety of cocaine-seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. G_q and G_s stimulation activated dopamine neurons, but only G_q stimulation robustly enhanced cocaine seeking. G_i/o inhibitory signaling reduced some, but not all, types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and point to potential new approaches for intervening in these processes to treat addiction.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Ipsilateral-Dominant Control of Limb Movements in Rodent Posterior Parietal Cortex

It is well known that the posterior parietal cortex (PPC) and frontal motor cortices in primates preferentially control voluntary movements of contralateral limbs. The PPC of rats has been defined based on patterns of thalamic and cortical connectivity. The anatomical characteristics of this area suggest that it may be homologous to the PPC of primates. However, its functional roles in voluntary forelimb movements have not been well understood, particularly in the lateralization of motor limb representation; that is, the limb-specific activity representations for right and left forelimb movements. We examined functional spike activity of the PPC and two motor cortices, the primary motor cortex (M1) and the secondary motor cortex (M2), when head-fixed male rats performed right or left unilateral movements. Unlike primates, PPC neurons in rodents were found to preferentially represent ipsilateral forelimb movements, in contrast to the contralateral preference of M1 and M2 neurons. Consistent with these observations, optogenetic activation of PPC and motor cortices, respectively, evoked ipsilaterally and contralaterally biased forelimb movements. Finally, we examined the effects of optogenetic manipulation on task performance. PPC or M1 inhibition by optogenetic GABA release shifted the behavioral limb preference contralaterally or ipsilaterally, respectively. In addition, weak optogenetic PPC activation, which was insufficient to evoke motor responses by itself, shifted the preference ipsilaterally; although similar M1 activation showed no effects on task performance. These paradoxical observations suggest that the PPC plays evolutionarily different roles in forelimb control between primates and rodents.

SIGNIFICANCE STATEMENT In rodents, the primary and secondary motor cortices (M1 and M2, respectively) are involved in voluntary movements with contralateral preference. However, it remains unclear whether and how the posterior parietal cortex (PPC) participates in controlling multiple limb movements. We recorded functional activity from these areas using a behavioral task to monitor movements of the right and left forelimbs separately. PPC neurons preferentially represented ipsilateral forelimb movements and optogenetic PPC activation evoked ipsilaterally biased forelimb movements. Optogenetic PPC inhibition via GABA release shifted the behavioral limb preference contralaterally during task performance, whereas weak optogenetic PPC activation, which was insufficient to evoke motor responses by itself, shifted the preference ipsilaterally. Our findings suggest rodent PPC contributes to ipsilaterally biased motor response and/or planning.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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{alpha}2A-Adrenergic Receptor Activation Decreases Parabrachial Nucleus Excitatory Drive onto BNST CRF Neurons and Reduces Their Activity In Vivo

Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α_2A-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α_2A-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α_2A-AR is a G_i-linked GPCR, we assessed the impact of activating the G_i-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced Fos in BNST Crh neurons. Further, using Prkcd as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of Prkcd/Crh in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α_2A-AR activation suppresses the in vivo activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons.

SIGNIFICANCE STATEMENT Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α_2A-AR agonist guanfacine reduces activity of these cells in vivo, and reduces excitatory PBN inputs onto these cells ex vivo. Additionally, we uncover a novel sex-dependent coexpression of Prkcd with Crh in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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AGRP Neurons Project to the Medial Preoptic Area and Modulate Maternal Nest-Building

AGRP (agouti-related neuropeptide) expressing inhibitory neurons sense caloric needs of an animal to coordinate homeostatic feeding. Recent evidence suggests that AGRP neurons also suppress competing actions and motivations to mediate adaptive behavioral selection during starvation. Here, in adult mice of both sexes we show that AGRP neurons form inhibitory synapses onto ~30% neurons in the medial preoptic area (mPOA), a region critical for maternal care. Remarkably, optogenetically stimulating AGRP neurons decreases maternal nest-building while minimally affecting pup retrieval, partly recapitulating suppression of maternal behaviors during food restriction. In parallel, optogenetically stimulating AGRP projections to the mPOA or to the paraventricular nucleus of hypothalamus but not to the LHA (lateral hypothalamus area) similarly decreases maternal nest-building. Chemogenetic inhibition of mPOA neurons that express Vgat (vesicular GABA transporter), the population targeted by AGRP terminals, also decreases maternal nest-building. In comparison, chemogenetic inhibition of neurons in the LHA that express vesicular glutamate transporter 2, another hypothalamic neuronal population critical for feeding and innate drives, is ineffective. Importantly, nest-building during low temperature thermal challenge is not affected by optogenetic stimulation of AGRP->mPOA projections. Finally, via optogenetic activation and inhibition we show that distinctive subsets of mPOA Vgat+ neurons likely underlie pup retrieval and maternal nest-building. Together, these results show that AGRP neurons can modulate maternal nest-building, in part through direct projections to the mPOA. This study corroborates other recent discoveries and underscores the broad functions that AGRP neurons play in antagonizing rivalry motivations to modulate behavioral outputs during hunger.

SIGNIFICANCE STATEMENT In order for animals to initiate ethologically appropriate behaviors, they must typically decide between behavioral repertoires driven by multiple and often conflicting internal states. How neural pathways underlying individual behaviors interact to coherently modulate behavioral outputs, in particular to achieve a proper balance between behaviors that serve immediate individual needs versus those that benefit the propagation of the species, remains poorly understood. Here, by investigating projections from a neuronal population known to drive hunger behaviors to a brain region critical for maternal care, we show that activation of AGRP->mPOA projections in females dramatically inhibits maternal nest-building while leaving mostly intact pup retrieval behavior. Our findings shed new light on neural organization of behaviors and neural mechanisms that coordinate behavioral selection.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Locus Coeruleus Phasic, But Not Tonic, Activation Initiates Global Remapping in a Familiar Environment

Locus coeruleus (LC) neurons, the source of hippocampal norepinephrine (NE), are activated by novelty and changes in environmental contingencies. Based on the role of monoamines in reconfiguring invertebrate networks, and data from mammalian systems, a network reset hypothesis for the effects of LC activation has been proposed. We used the cellular compartmental analysis of temporal FISH technique based on the cellular distribution of immediate early genes to examine the effect of LC activation and inactivation, on regional hippocampal maps in male rats, when LC activity was manipulated just before placement in a second familiar (A/A) and/or novel environment (A/B). We found that bilateral phasic, but not tonic, activation of LC reset hippocampal maps in the A/A condition, whereas silencing the LC with clonidine before placement in the A/B condition blocked map reset and a familiar map emerged in the dentate gyrus, proximal and distal CA1, and CA3c. However, CA3a and CA3b encoded the novel environment. These results support a role for phasic LC responses in generating novel hippocampal sequences during memory encoding and, potentially, memory updating. The silencing experiments suggest that novel environments may not be recognized as different by dentate gyrus and CA1 without LC input. The functional distinction between phasic and tonic LC activity argues that these parameters are critical for determining network changes. These data are consistent with the hippocampus activating internal network representations to encode novel experiential episodes and suggest LC input is critical for this role.

SIGNIFICANCE STATEMENT Burst activation of the broadly projecting novelty signaling system of the locus coeruleus initiates new network representations throughout the hippocampus despite unchanged external environments. Tonic activation does not alter network representations in the same condition. This suggests differences in the temporal parameters of neuromodulator network activation are critical for neuromodulator function. Silencing this novelty signaling system prevented the appearance of new network representations in a novel environment. Instead, familiar representations were expressed in a subset of hippocampal areas, with another subset encoding the novel environment. This "being in two places at once" argues for independent functional regions within the hippocampus. These experiments strengthen the view that internal states are major determinants of the brain's construction of environmental representations.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Occurrence of Hippocampal Ripples is Associated with Activity Suppression in the Mediodorsal Thalamic Nucleus

Forming reliable memories requires coordinated activity within distributed brain networks. At present, neural mechanisms underlying systems-level consolidation of declarative memory beyond the hippocampal–prefrontal interactions remain largely unexplored. The mediodorsal thalamic nucleus (MD) is reciprocally connected with the medial prefrontal cortex (mPFC) and also receives inputs from parahippocampal regions. The MD may thus modulate functional connectivity between the hippocampus and the mPFC at different stages of information processing. Here, we characterized, in freely behaving Sprague Dawley male rats, the MD neural activity around hippocampal ripples, indicators of memory replay and hippocampal–cortical information transfer. Overall, the MD firing rate was transiently (0.76 ± 0.06 s) decreased around ripples, with the MD activity suppression preceding the ripple onset for 0.41 ± 0.04 s (range, 0.01–0.95 s). The degree of MD modulation correlated with ripple amplitude, differed across behavioral states, and also depended on the dynamics of hippocampal–cortical population activity. The MD suppression was the strongest and the most consistent during awake ripples. During non–rapid eye movement sleep, MD firing rate decreased around spindle-uncoupled ripples, but increased around spindle-coupled ripples. Our results suggest a competitive interaction between the thalamocortical and hippocampal–cortical networks supporting "on-line" and "off-line" information processing, respectively. We hypothesize that thalamic activity suppression during spindle-uncoupled ripples is favorable for memory replay, as it reduces interference from sensory relay. In turn, the thalamic input during hippocampal–cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer. Both predictions need to be tested in future experiments.

SIGNIFICANCE STATEMENT Systems mechanisms of declarative memory consolidation beyond the hippocampal–prefrontal interactions remain largely unexplored. The connectivity of the mediodorsal thalamic nucleus (MD) with extrahippocampal regions and with medial prefrontal cortex underlies its role in execution of diverse cognitive functions. However, little is known about the MD involvement in "off-line" consolidation. We found that MD neural activity was transiently suppressed around hippocampal ripples, except for ripples co-occurring with sleep spindles, when the MD activity was elevated. The thalamic activity suppression at times of spindle-uncoupled ripples may be favorable for memory replay, as it reduces interference with sensory relay. In turn, the thalamic input during hippocampal–cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Histamine H1 Receptor Contributes to Vestibular Compensation

Vestibular compensation is responsible for the spontaneous recovery of postural, locomotor, and oculomotor dysfunctions in patients with peripheral vestibular lesion or posterior circulation stroke. Mechanism investigation of vestibular compensation is of great importance in both facilitating recovery of vestibular function and understanding the postlesion functional plasticity in the adult CNS. Here, we report that postsynaptic histamine H1 receptor contributes greatly to facilitating vestibular compensation. The expression of H1 receptor is restrictedly increased in the ipsilesional rather than contralesional GABAergic projection neurons in the medial vestibular nucleus (MVN), one of the most important centers for vestibular compensation, in unilateral labyrinthectomized male rats. Furthermore, H1 receptor mediates an asymmetric excitation of the commissural GABAergic but not glutamatergic neurons in the ipsilesional MVN, which may help to rebalance bilateral vestibular systems and promote vestibular compensation. Selective blockage of H1 receptor in the MVN significantly retards the recovery of both static and dynamic vestibular symptoms following unilateral labyrinthectomy, and remarkably attenuates the facilitation of betahistine, whose effect has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, on vestibular compensation. These results reveal a previously unknown role for histamine H1 receptor in vestibular compensation and amelioration of vestibular motor deficits, as well as an involvement of H1 receptor in potential therapeutic effects of betahistine. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery in the CNS, but also a novel potential therapeutic target for vestibular disorders.

SIGNIFICANCE STATEMENT Vestibular disorders manifest postural imbalance, nystagmus, and vertigo. Vestibular compensation is critical for facilitating recovery from vestibular disorders, and of great importance in understanding the postlesion functional plasticity in the adult CNS. Here, we show that postsynaptic H1 receptor in the medial vestibular nucleus (MVN) contributes greatly to the recovery of both static and dynamic symptoms following unilateral vestibular lesion. H1 receptor selectively mediates the asymmetric activation of commissural inhibitory system in the ipsilesional MVN and actively promotes vestibular compensation. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery of CNS, but also a novel potential therapeutic target for promoting vestibular compensation and ameliorating vestibular disorders.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Dendritic Spines in Early Postnatal Fragile X Mice Are Insensitive to Novel Sensory Experience

Autism spectrum disorders are often associated with atypical sensory processing and sensory hypersensitivity, which can lead to maladaptive behaviors, such as tactile defensiveness. Such altered sensory perception in autism spectrum disorders could arise from disruptions in experience-dependent maturation of circuits during early brain development. Here, we tested the hypothesis that synaptic structures of primary somatosensory cortex (S1) neurons in Fragile X syndrome (FXS), which is a common inherited cause of autism, are not modulated by novel sensory information during development. We used chronic in vivo two-photon microscopy to image dendritic spines and axon "en passant" boutons of layer 2/3 pyramidal neurons in S1 of male and female WT and Fmr1 KO mice, a model of FXS. We found that a brief (overnight) exposure to dramatically enhance sensory inputs in the second postnatal week led to a significant increase in spine density in WT mice, but not in Fmr1 KO mice. In contrast, axon "en passant" boutons dynamics were impervious to this novel sensory experience in mice of both genotypes. We surmise that the inability of Fmr1 KO mice to modulate postsynaptic dynamics in response to increased sensory input, at a time when sensory information processing first comes online in S1 cortex, could play a role in altered sensory processing in FXS.

SIGNIFICANCE STATEMENT Very few longitudinal in vivo imaging studies have investigated synaptic structure and dynamics in early postnatal mice. Moreover, those studies tend to focus on the effects of sensory input deprivation, a process that rarely occurs during normal brain development. Early postnatal imaging experiments are critical because a variety of neurodevelopmental disorders, including those characterized by autism, could result from alterations in how circuits are shaped by incoming sensory inputs during critical periods of development. In this study, we focused on a mouse model of Fragile X syndrome and demonstrate how dendritic spines are insensitive to a brief period of novel sensory experience.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain

Nociceptors, sensory neurons in the DRG that detect damaging or potentially damaging stimuli, are key drivers of neuropathic pain. Injury to these neurons causes activation of translation regulation signaling, including the mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase interacting kinase (MNK) eukaryotic initiation factor (eIF) 4E pathways. This is a mechanism driving changes in excitability of nociceptors that is critical for the generation of chronic pain states; however, the mRNAs that are translated to lead to this plasticity have not been elucidated. To address this gap in knowledge, we used translating ribosome affinity purification in male and female mice to comprehensively characterize mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain (CIPN) caused by paclitaxel treatment. This unbiased method creates a new resource for the field, confirms many findings in the CIPN literature and also find extensive evidence for new target mechanisms that may cause CIPN. We provide evidence that an underlying mechanism of CIPN is sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling. This demonstrates a novel translation regulation signaling circuit wherein MNK1-eIF4E activity drives mTORC1 via control of RagA translation. CIPN and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We identify a novel translational circuit for the genesis of neuropathic pain caused by chemotherapy with important implications for therapeutics.

SIGNIFICANCE STATEMENT Neuropathic pain affects up to 10% of the population, but its underlying mechanisms are incompletely understood, leading to poor treatment outcomes. We used translating ribosome affinity purification technology to create a comprehensive translational profile of DRG nociceptors in naive mice and at the peak of neuropathic pain induced by paclitaxel treatment. We reveal new insight into how mechanistic target of rapamycin complex 1 is activated in neuropathic pain pointing to a key role of MNK1-eIF4E-mediated translation of a complex of mRNAs that control mechanistic target of rapamycin complex 1 signaling at the surface of the lysosome. We validate this finding using genetic and pharmacological techniques. Our work strongly suggests that MNK1-eIF4E signaling drives CIPN and that a drug in human clinical trials, eFT508, may be a new therapeutic for neuropathic pain.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Resilience to Pain: A Peripheral Component Identified Using Induced Pluripotent Stem Cells and Dynamic Clamp

Pain is a complex process that involves both detection in the peripheral nervous system and perception in the CNS. Individual-to-individual differences in pain are well documented, but not well understood. Here we capitalized on inherited erythromelalgia (IEM), a well characterized human genetic model of chronic pain, and studied a unique family containing related IEM subjects with the same disease-causing Na_V1.7 mutation, which is known to make dorsal root ganglion (DRG) neurons hyperexcitable, but different pain profiles (affected son with severe pain, affected mother with moderate pain, and an unaffected father). We show, first, that, at least in some cases, relative sensitivity to pain can be modeled in subject-specific induced pluripotent stem cell (iPSC)-derived sensory neurons in vitro; second, that, in some cases, mechanisms operating in peripheral sensory neurons contribute to interindividual differences in pain; and third, using whole exome sequencing (WES) and dynamic clamp, we show that it is possible to pinpoint a specific variant of another gene, KCNQ in this particular kindred, that modulates the excitability of iPSC-derived sensory neurons in this family. While different gene variants may modulate DRG neuron excitability and thereby contribute to interindividual differences in pain in other families, this study shows that subject-specific iPSCs can be used to model interindividual differences in pain. We further provide proof-of-principle that iPSCs, WES, and dynamic clamp can be used to investigate peripheral mechanisms and pinpoint specific gene variants that modulate pain signaling and contribute to interindividual differences in pain.

SIGNIFICANCE STATEMENT Individual-to-individual differences in pain are well documented, but not well understood. In this study, we show, first, that, at least in some cases, relative sensitivity to pain can be modeled in subject-specific induced pluripotent stem cell-derived sensory neurons in vitro; second, that, in some cases, mechanisms operating in peripheral sensory neurons contribute to interindividual differences in pain; and third, using whole exome sequencing and dynamic clamp, we show that it is possible to pinpoint a specific gene variant that modulates pain signaling and contributes to interindividual differences in pain.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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This Week in The Journal

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Solving a specificity mystery
Differences in the kinetics of G protein activation can explain why only some receptors can activate potassium ion channels called GIRKs.
in eLife: latest articles on January 16, 2019 12:00 AM.
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Targeting mutant estrogen receptors
A drug used in hormone replacement therapy can target estrogen receptors that have become resistant to breast cancer treatments.
in eLife: latest articles on January 16, 2019 12:00 AM.
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The presence and absence of periplasmic rings in bacterial flagellar motors correlates with stator type
The bacterial flagellar motor, a cell-envelope-embedded macromolecular machine that functions as a cellular propeller, exhibits significant structural variability between species. Different torque-generating stator modules allow motors to operate in different pH, salt or viscosity levels. How such diversity evolved is unknown. Here we use electron cryo-tomography to determine the in situ macromolecular structures of three Gammaproteobacteria motors: Legionella pneumophila, Pseudomonas aeruginosa, and Shewanella oneidensis, providing the first views of intact motors with dual stator systems. Complementing our imaging with bioinformatics analysis, we find a correlation between the motor's stator system and its structural elaboration. Motors with a single H⁺-driven stator have only the core periplasmic P- and L-rings; those with dual H⁺-driven stators have an elaborated P-ring; and motors with Na⁺orNa⁺/H⁺-driven stators have both their P- and L-rings embellished. Our results suggest an evolution of structural elaboration that may have enabled pathogenic bacteria to colonize higher-viscosity environments in animal hosts.
in eLife: latest articles on January 16, 2019 12:00 AM.
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Structural basis of Ca²⁺-dependent activation and lipid transport by a TMEM16 scramblase
The lipid distribution of plasma membranes of eukaryotic cells is asymmetric and phospholipid scramblases disrupt this asymmetry by mediating the rapid, nonselective transport of lipids down their concentration gradients. As a result, phosphatidylserine is exposed to the outer leaflet of membrane, an important step in extracellular signaling networks controlling processes such as apoptosis, blood coagulation, membrane fusion and repair. Several TMEM16 family members have been identified as Ca²⁺-activated scramblases but the mechanisms underlying their Ca²⁺-dependent gating and their effects on the surrounding lipid bilayer remain poorly understood. Here we describe three high-resolution cryo-electron microscopy structures of a fungal scramblase from Aspergillus fumigatus, afTMEM16, reconstituted in lipid nanodiscs. These structures reveal that Ca²⁺-dependent activation of the scramblase entails global rearrangement of the transmembrane and cytosolic domains. These structures, together with functional experiments, suggest that activation of the protein thins the membrane near the transport pathway to facilitate rapid transbilayer lipid movement.
in eLife: latest articles on January 16, 2019 12:00 AM.
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Reprogramming the antigen specificity of B cells using genome-editing technologies
We have developed a method to introduce novel paratopes into the human antibody repertoire by modifying the immunoglobulin (Ig) genes of mature B cells directly using genome editing technologies. We used CRISPR-Cas9 in a homology directed repair strategy, to replace the heavy chain (HC) variable region in B cell lines with that from an HIV broadly neutralizing antibody, PG9. Our strategy is designed to function in cells that have undergone VDJ recombination using any combination of variable (V), diversity (D) and joining (J) genes. The modified locus expresses PG9 HC which pairs with native light chains resulting in the cell surface expression of HIV specific B cell receptors (BCRs). Endogenous activation-induced cytidine deaminase (AID) in engineered cells allowed for Ig class switching and generated BCR variants with improved anti-HIV neutralizing activity. Thus, BCRs engineered in this way retain the genetic flexibility normally required for affinity maturation during adaptive immune responses. Peripheral blood derived primary B cells from three different donors were edited using this strategy. Engineered cells could bind the PG9 epitope by FACS and sequenced mRNA from these cells showed PG9 HC expressed as several different isotypes after culture with CD40 ligand and IL-4.
in eLife: latest articles on January 16, 2019 12:00 AM.
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Schwann cells, but not Oligodendrocytes, Depend Strictly on Dynamin 2 Function
Myelination requires extensive plasma membrane rearrangements, implying that molecules controlling membrane dynamics play prominent roles. The large GTPase dynamin 2 (DNM2) is a well-known regulator of membrane remodeling, membrane fission, and vesicular trafficking. Here, we genetically ablated Dnm2 in Schwann cells (SCs) and in oligodendrocytes of mice. Dnm2 deletion in developing SCs resulted in severely impaired axonal sorting and myelination onset. Induced Dnm2 deletion in adult SCs caused a rapidly-developing peripheral neuropathy with abundant demyelination. In both experimental settings, mutant SCs underwent prominent cell death, at least partially due to cytokinesis failure. Strikingly, when Dnm2 was deleted in adult SCs, non-recombined SCs still expressing DNM2 were able to remyelinate fast and efficiently, accompanied by neuropathy remission. These findings reveal a remarkable self-healing capability of peripheral nerves that are affected by SC loss. In the central nervous system, however, we found no major defects upon Dnm2 deletion in oligodendrocytes.
in eLife: latest articles on January 16, 2019 12:00 AM.
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Light-activated Frizzled7 reveals a permissive role of non-canonical Wnt signaling in mesendoderm cell migration
Non-canonical Wnt-signaling plays a central role for coordinated cell polarization and directed migration in metazoan development. While spatiotemporally restricted activation of non-canonical Wnt-signaling drives cell polarization in epithelial tissues, it remains unclear whether such instructive activity is also critical for directed mesenchymal cell migration. Here, we developed a light-activated version of the non-canonical Wnt receptor Frizzled 7 (Fz7) to analyze how restricted activation of non-canonical Wnt-signaling affects directed anterior axial mesendoderm (prechordal plate, ppl) cell migration within the zebrafish gastrula. We found that Fz7 signaling is required for ppl cell protrusion formation and migration, and that spatiotemporally restricted ectopic activation is capable of redirecting their migration. Finally, we show that uniform activation of Fz7 signaling in ppl cells fully rescues defective directed cell migration in fz7 mutant embryos. Together, our findings reveal that in contrast to the situation in epithelial cells, non-canonical Wnt-signaling functions permissively rather than instructively in directed mesenchymal cell migration during gastrulation.
in eLife: latest articles on January 16, 2019 12:00 AM.
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Pat1 promotes processing body assembly by enhancing the phase separation of the DEAD-box ATPase Dhh1 and RNA
Processing bodies (PBs) are cytoplasmic mRNP granules that assemble via liquid-liquid phase separation and are implicated in the decay or storage of mRNAs. How PB assembly is regulated in cells remains unclear. Previously, we identified the ATPase activity of the DEAD-box protein Dhh1 as a key regulator of PB dynamics and demonstrated that Not1, an activator of the Dhh1 ATPase and member of the CCR4-NOT deadenylase complex inhibits PB assembly in vivo (Mugler et al., 2016). Here, we show that the PB component Pat1 antagonizes Not1 and promotes PB assembly via its direct interaction with Dhh1. Intriguingly, in vivo PB dynamics can be recapitulated in vitro, since Pat1 enhances the phase separation of Dhh1 and RNA into liquid droplets, whereas Not1 reverses Pat1-Dhh1-RNA condensation. Overall, our results uncover a function of Pat1 in promoting the multimerization of Dhh1 on mRNA, thereby aiding the assembly of large multivalent mRNP granules that are PBs.
in eLife: latest articles on January 16, 2019 12:00 AM.
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Gut Microbes Join the Social Network
The gut microbiome is increasingly implicated in the regulation of social behavior across model organisms. In this issue of Neuron, Sgritta et al. (2018) examine the role of the gut microbiome in social reward circuits and sociability in three mouse models of autism spectrum disorder.
in Neuron on January 16, 2019 12:00 AM.
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A TREK to Translate Genetics to Mechanisms of Migraine
In this issue of Neuron, Royal et al. (2018) find that a mutant form of the TRESK ion channel linked to migraine undergoes alternative translation to produce an inhibitory protein that blocks TREK channels, leading to neuronal hyperexcitability and migraine in rodents.
in Neuron on January 16, 2019 12:00 AM.
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Engram Excitement
Engram cells can encode and switch between multiple mnemonic functions, but how they intrinsically do so is unknown. Pignatelli, Ryan, and colleagues show that upon memory recall, the engram’s excitability is transiently elevated, allowing its bearer to adapt to changing environments.
in Neuron on January 16, 2019 12:00 AM.
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The Puzzling Pulvinar
The functional role of the pulvinar, with its widespread cortical connectivity, has remained elusive. In this issue of Neuron, Jaramillo et al. (2019) provide a computational roadmap for how the pulvinar might influence various cognitive behaviors across multiple large-scale networks.
in Neuron on January 16, 2019 12:00 AM.
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Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer’s Disease
(Neuron 99, 925–940.e1–e7; September 5, 2018)
in Neuron on January 16, 2019 12:00 AM.
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Crosstalk of Local Translation and Mitochondria: Powering Plasticity in Axons and Dendrites
Two papers in Cell uncover reciprocal crosstalk of local translation and mitochondria in neurons. Rangaraju et al. (2019) observe tethered compartments of stable mitochondria in dendrites that provide a local energy supply for mRNA translation at synapses. Cioni et al. (2019) report a novel association of axonal RNA granules with Rab7a-late endosomes that provides a platform for local translation supporting mitochondria.
in Neuron on January 16, 2019 12:00 AM.
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Expectancy-Related Changes in Dopaminergic Error Signals Are Impaired by Cocaine Self-Administration
In the current study, Takahashi et al. show that prior cocaine use causes lasting changes in dopaminergic errors, consistent with diminished predictive input. These changes may play a role in long-term sequellae of drug use, such as relapse, which define addiction.
in Neuron on January 16, 2019 12:00 AM.
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On identifying collective displacements in apo-proteins that reveal eventual binding pathways

by Dheeraj Dube, Navjeet Ahalawat, Himanshu Khandelia, Jagannath Mondal, Surajit Sengupta
Binding of small molecules to proteins often involves large conformational changes in the latter, which open up pathways to the binding site. Observing and pinpointing these rare events in large scale, all-atom, computations of specific protein-ligand complexes, is expensive and to a great extent serendipitous. Further, relevant collective variables which characterise specific binding or un-binding scenarios are still difficult to identify despite the large body of work on the subject. Here, we show that possible primary and secondary binding pathways can be discovered from short simulations of the apo-protein without waiting for an actual binding event to occur. We use a projection formalism, introduced earlier to study deformation in solids, to analyse local atomic displacements into two mutually orthogonal subspaces—those which are “affine” i.e. expressible as a homogeneous deformation of the native structure, and those which are not. The susceptibility to non-affine displacements among the various residues in the apo- protein is then shown to correlate with typical binding pathways and sites crucial for allosteric modifications. We validate our observation with all-atom computations of three proteins, T4-Lysozyme, Src kinase and Cytochrome P450.
in PLOS Computational Biology: New Articles on January 15, 2019 10:00 PM.
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The finite state projection based Fisher information matrix approach to estimate information and optimize single-cell experiments

by Zachary R Fox, Brian Munsky
Modern optical imaging experiments not only measure single-cell and single-molecule dynamics with high precision, but they can also perturb the cellular environment in myriad controlled and novel settings. Techniques, such as single-molecule fluorescence in-situ hybridization, microfluidics, and optogenetics, have opened the door to a large number of potential experiments, which begs the question of how to choose the best possible experiment. The Fisher information matrix (FIM) estimates how well potential experiments will constrain model parameters and can be used to design optimal experiments. Here, we introduce the finite state projection (FSP) based FIM, which uses the formalism of the chemical master equation to derive and compute the FIM. The FSP-FIM makes no assumptions about the distribution shapes of single-cell data, and it does not require precise measurements of higher order moments of such distributions. We validate the FSP-FIM against well-known Fisher information results for the simple case of constitutive gene expression. We then use numerical simulations to demonstrate the use of the FSP-FIM to optimize the timing of single-cell experiments with more complex, non-Gaussian fluctuations. We validate optimal simulated experiments determined using the FSP-FIM with Monte-Carlo approaches and contrast these to experiment designs chosen by traditional analyses that assume Gaussian fluctuations or use the central limit theorem. By systematically designing experiments to use all of the measurable fluctuations, our method enables a key step to improve co-design of experiments and quantitative models.
in PLOS Computational Biology: New Articles on January 15, 2019 10:00 PM.
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Sexually dimorphic vasopressin cells modulate social investigation and communication in sex-specific ways
Abstract
The neuropeptide arginine-vasopressin (AVP) has long been implicated in the regulation of social behavior and communication, but precisely which AVP cell groups are involved is largely unknown. To address if the sexually dimorphic AVP cell group in the bed nucleus of the stria terminalis (BNST) is important for social communication, we deleted BNST AVP cells by viral delivery of a Cre-dependent caspase-3 cell-death construct in AVP-iCre positive mice using AVP-iCre negative littermate as controls, and assessed social, sexual, aggressive and anxiety-related behaviors. In males, lesioning BNST AVP cells reduced social investigation of other males and increased urine marking in the presence of a live female, without altering ultrasonic vocalizations, resident-intruder aggression, copulatory behavior, anxiety, or investigation of females or their odor cues. In females, which have significantly fewer AVP cells in the BNST, these injections influenced copulatory behavior but otherwise had minimal effects on social behavior and communication, indicating that these cells contribute to sex differences in social behavioral function.
Significance Statement Despite over thirty years of indirect evidence implicating sexually-dimorphic arginine vasopressin (AVP) cells within the bed nucleus of the stria terminalis (BNST) in the control of social and anxiety-related behavior in mammals, the function of these cells has never been directly tested. Here, we show that deletion of these cells in male, but not female, mice reduce investigation of same-sex conspecifics and alter social communication without changing aggressive and anxiety-related behaviors. Although AVP cell deletion in the BNST did not alter male copulatory behavior, it impaired female sexual behavior. These results indicate that sexually-dimorphic AVP cells in the BNST drive specific aspects of sexually-differentiated social investigation, behavior, and communication.

in RSS PAP on January 15, 2019 05:35 PM.
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Microglia are effector cells of CD47-SIRP{alpha} antiphagocytic axis disruption against glioblastoma [Immunology and Inflammation]
Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5 [Immunology and Inflammation]
Natural killer (NK) cells are important component of innate immunity and also contribute to activating and reshaping the adaptive immune responses. The functions of NK cells are modulated by multiple inhibitory and stimulatory receptors. Among these receptors, the activating receptor CD226 (DNAM-1) mediates NK cell activation via binding to its...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Phosphatase PP2A is essential for TH17 differentiation [Immunology and Inflammation]
Phosphatase PP2A expression levels are positively correlated to the clinical severity of systemic lupus erythematosus (SLE) and IL17A cytokine overproduction, indicating a potential role of PP2A in controlling TH17 differentiation and inflammation. By generating a mouse strain with ablation of the catalytic subunit α of PP2A in peripheral mature T...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Correction for Zella et al., Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperon protein, has broad oncogenic properties [Correction]
MICROBIOLOGY Correction for “Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperon protein, has broad oncogenic properties,” by Davide Zella, Sabrina Curreli, Francesca Benedetti, Selvi Krishnan, Fiorenza Cocchi, Olga S. Latinovic, Frank Denaro, Fabio Romerio, Muhammad Djavani, Man E. Charurat, Joseph L. Bryant, Hervé Tettelin, and Robert...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Correction for Terui et al., Metapopulation stability in branching river networks [Correction]
ECOLOGY Correction for “Metapopulation stability in branching river networks,” by Akira Terui, Nobuo Ishiyama, Hirokazu Urabe, Satoru Ono, Jacques C. Finlay, and Futoshi Nakamura, which was first published June 12, 2018; 10.1073/pnas.1800060115 (Proc Natl Acad Sci USA 115:E5963–E5969). The authors wish to note the following: “While extending a theoretical framework...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Correction for Paluck et al., Changing climates of conflict: A social network experiment in 56 schools [Correction]
PSYCHOLOGICAL AND COGNITIVE SCIENCES Correction for “Changing climates of conflict: A social network experiment in 56 schools,” by Elizabeth Levy Paluck, Hana Shepherd, and Peter M. Aronow, which was first published January 4, 2016; 10.1073/pnas.1514483113 (Proc Natl Acad Sci USA 113:566–571). The authors note that the following statement should be...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Correction for Li et al., Pressure-induced phase transitions and superconductivity in a black phosphorus single crystal [Correction]
PHYSICS Correction for “Pressure-induced phase transitions and superconductivity in a black phosphorus single crystal,” by Xiang Li, Jianping Sun, Prashant Shahi, Miao Gao, Allan H. MacDonald, Yoshiya Uwatoko, Tao Xiang, John B. Goodenough, Jinguang Cheng, and Jianshi Zhou, which was first published September 14, 2018; 10.1073/pnas.1810726115 (Proc Natl Acad Sci...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Conotoxin {kappa}M-RIIIJ, a tool targeting asymmetric heteromeric Kv1 channels [Neuroscience]
The vast complexity of native heteromeric K+ channels is largely unexplored. Defining the composition and subunit arrangement of individual subunits in native heteromeric K+ channels and establishing their physiological roles is experimentally challenging. Here we systematically explored this “zone of ignorance” in molecular neuroscience. Venom components, such as peptide toxins,...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Ca2+-activated Cl- current ensures robust and reliable signal amplification in vertebrate olfactory receptor neurons [Biophysics and Computational Biology]
Activation of most primary sensory neurons results in transduction currents that are carried by cations. One notable exception is the vertebrate olfactory receptor neuron (ORN), where the transduction current is carried largely by the anion Cl−. However, it remains unclear why ORNs use an anionic current for signal amplification. We...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Regulation of acetate metabolism and coordination with the TCA cycle via a processed small RNA [Microbiology]
Bacterial regulatory small RNAs act as crucial regulators in central carbon metabolism by modulating translation initiation and degradation of target mRNAs in metabolic pathways. Here, we demonstrate that a noncoding small RNA, SdhX, is produced by RNase E-dependent processing from the 3′UTR of the sdhCDAB-sucABCD operon, encoding enzymes of the...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Herpes simplex virus 1 ICP8 mutant lacking annealing activity is deficient for viral DNA replication [Microbiology]
Most DNA viruses that use recombination-dependent mechanisms to replicate their DNA encode a single-strand annealing protein (SSAP). The herpes simplex virus (HSV) single-strand DNA binding protein (SSB), ICP8, is the central player in all stages of DNA replication. ICP8 is a classical replicative SSB and interacts physically and/or functionally with...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response [Microbiology]
Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Rigidification of the Escherichia coli cytoplasm by the human antimicrobial peptide LL-37 revealed by superresolution fluorescence microscopy [Microbiology]
Superresolution, single-particle tracking reveals effects of the cationic antimicrobial peptide LL-37 on the Escherichia coli cytoplasm. Seconds after LL-37 penetrates the cytoplasmic membrane, the chromosomal DNA becomes rigidified on a length scale of ∼30 nm, evidenced by the loss of jiggling motion of specific DNA markers. The diffusive motion of...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Unregulated antigen-presenting cell activation by T cells breaks self tolerance [Immunology and Inflammation]
T cells proliferate vigorously following acute depletion of CD4+ Foxp3+ T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficient Rag1−/− hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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RNA-binding protein YTHDF3 suppresses interferon-dependent antiviral responses by promoting FOXO3 translation [Immunology and Inflammation]
IFN–stimulated genes (ISGs) are essential effectors of the IFN-dependent antiviral immune response. Dysregulation of ISG expression can cause dysfunctional antiviral responses and autoimmune disorders. Epitranscriptomic regulation, such as N6-methyladenosine (m6A) modification of mRNAs, plays key roles in diverse biological processes. Here, we found that the m6A “reader” YT521-B homology domain-containing...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases [Immunology and Inflammation]
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo [Genetics]
DICER1 gene alterations and decreased expression are associated with developmental disorders and diseases in humans. Oscillation of Dicer1 phosphorylation and dephosphorylation regulates its function during the oocyte-to-embryo transition in Caenorhabditis elegans. Dicer1 is also phosphorylated upon FGF stimulation at conserved serines in mouse embryonic fibroblasts and HEK293 cells. However, whether...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Blacklisting variants common in private cohorts but not in public databases optimizes human exome analysis [Genetics]
Computational analyses of human patient exomes aim to filter out as many nonpathogenic genetic variants (NPVs) as possible, without removing the true disease-causing mutations. This involves comparing the patient’s exome with public databases to remove reported variants inconsistent with disease prevalence, mode of inheritance, or clinical penetrance. However, variants frequent...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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HIV peptidome-wide association study reveals patient-specific epitope repertoires associated with HIV control [Genetics]
Genetic variation in the peptide-binding groove of the highly polymorphic HLA class I molecules has repeatedly been associated with HIV-1 control and progression to AIDS, accounting for up to 12% of the variation in HIV-1 set point viral load (spVL). This suggests a key role in disease control for HLA...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Novel genetic code and record-setting AT-richness in the highly reduced plastid genome of the holoparasitic plant Balanophora [Evolution]
Plastid genomes (plastomes) vary enormously in size and gene content among the many lineages of nonphotosynthetic plants, but key lineages remain unexplored. We therefore investigated plastome sequence and expression in the holoparasitic and morphologically bizarre Balanophoraceae. The two Balanophora plastomes examined are remarkable, exhibiting features rarely if ever seen before...
in Proceedings of the National Academy of Sciences Recent Issues on January 15, 2019 05:06 PM.
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Modern genomic tools reveal the structural and cellular diversity of cnidarian nervous systems

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Fabian Rentzsch, Celina Juliano, Brigitte Galliot
Cnidarians shared a common ancestor with bilaterians more than 600 million years ago. This sister group relationship gives them an informative phylogenetic position for understanding the fascinating morphological and molecular cell type diversity of bilaterian nervous systems. Moreover, cnidarians display novel features such as endodermal neurogenesis and independently evolved centralizations, which provide a platform for understanding the evolution of nervous system innovations. In recent years, the application of modern genomic tools has significantly advanced our understanding of cnidarian nervous system structure and function. For example, transgenic reporter lines and gene knockdown experiments in several cnidarian species reveal a significant degree of conservation in the neurogenesis gene regulatory program, while single cell RNA sequencing projects are providing a much deeper understanding of cnidarian neural cell type diversity. At the level of neural function, the physiological properties of ion channels have been described and calcium imaging of the nervous system in whole animals has allowed for the identification of neural circuits underlying specific behaviours. Cnidarians have arrived in the modern era of molecular neurobiology and are primed to provide exciting new insights into the early evolution of nervous systems.

in ScienceDirect Publication: Current Opinion in Neurobiology on January 15, 2019 12:00 PM.
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The Relevancy of Data Regarding the Metabolism of Iron to Our Understanding of Deregulated Mechanisms in ALS; Hypotheses and Pitfalls
Camille Petillon, Rudolf Hergesheimer, Hervé Puy, Philippe Corcia, Patrick Vourc’h, Christian Andres, Zoubida Karim, Hélène Blasco
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 15, 2019 12:00 PM.
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The Transcription Factor Function of Parkin: Breaking the Dogma
Cristine Alves da Costa, Eric Duplan, Lila Rouland, Frédéric Checler
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 15, 2019 12:00 PM.
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Abnormal Cortico-Cerebellar Functional Connectivity in Autism Spectrum Disorder
Taiane Coelho Ramos, Joana Bisol Balardin, João Ricardo Sato, André Fujita
in Frontiers in Systems Neuroscience | New and Recent Articles on January 15, 2019 12:00 PM.
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Synaptotagmin Ca2+ Sensors and Their Spatial Coupling to Presynaptic Cav Channels in Central Cortical Synapses
Grit Bornschein, Hartmut Schmidt
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 15, 2019 12:00 PM.
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Visual and Vestibular Inputs Affect Muscle Synergies Responsible for Body Extension and Stabilization in Sit-to-Stand Motion
Kazunori Yoshida, Qi An, Arito Yozu, Ryosuke Chiba, Kaoru Takakusaki, Hiroshi Yamakawa, Yusuke Tamura, Atsushi Yamashita, Hajime Asama
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 15, 2019 12:00 PM.
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Advances in Nano Neuroscience: From Nanomaterials to Nanotools
Niccolò Paolo Pampaloni, Michele Giugliano, Denis Scaini, Laura Ballerini, Rossana Rauti
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 15, 2019 12:00 PM.
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A Novel Optimization Framework to Improve the Computational Cost of Muscle Activation Prediction for a Neuromusculoskeletal System
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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Advancing System Performance with Redundancy: From Biological to Artificial Designs
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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State-Space Representations of Deep Neural Networks
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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Gradient Descent with Identity Initialization Efficiently Learns Positive-definite Linear Transformations by Deep Residual Networks
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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Scalable and Flexible Unsupervised Feature Selection
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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Forgetting Memories and Their Attractiveness
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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EEG-Based Neurocognitive Metrics May Predict Simulated and On-Road Driving Performance in Older Drivers
Greg Rupp, Chris Berka, Amir H. Meghdadi, Marija Stevanović Karić, Marc Casillas, Stephanie Smith, Theodore Rosenthal, Kevin McShea, Emily Sones, Thomas D. Marcotte
in Frontiers in Human Neuroscience | New and Recent Articles on January 15, 2019 06:00 AM.
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Cerebellum, Predictions and Errors
Laurentiu S. Popa, Timothy J. Ebner
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 15, 2019 06:00 AM.
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Executive Functions in Alzheimer Disease: A Systematic Review
Angela Guarino, Francesca Favieri, Ilaria Boncompagni, Francesca Agostini, Micaela Cantone, Maria Casagrande
in Frontiers in Aging Neuroscience | New and Recent Articles on January 15, 2019 06:00 AM.
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Cannabinoid Ligands Targeting TRP Channels
Chanté Muller, Paula Morales, Patricia H. Reggio
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 15, 2019 06:00 AM.
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Increased Vesicular Monoamine Transporter 2 (VMAT2) and Dopamine Transporter (DAT) Expression in Adolescent Brain Development: A Longitudinal Micro-PET/CT Study in Rodent
Donglang Jiang, Xiuhong Lu, Zijing Li, Nicklas Rydberg, Chuantao Zuo, Fangyu Peng, Fengchun Hua, Yihui Guan, Fang Xie
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 15, 2019 06:00 AM.
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Dominant Patterns of Information Flow in the Propagation of the Neuromagnetic Somatosensory Steady-State Response
Vasily A. Vakorin, Bernhard Ross, Sam M. Doesburg, Urs Ribary, Anthony R. McIntosh
in Frontiers in Neural Circuits | New and Recent Articles on January 15, 2019 06:00 AM.
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How to correctly quantify neuronal phase-response curves from noisy recordings. (arXiv:1901.04399v1 [q-bio.NC])

At the level of individual neurons, various coding properties can be inferred from the input-output relationship of a cell. For small inputs, this relation is captured by the phase-response curve (PRC), which measures the effect of a small perturbation on the timing of the subsequent spike. Experimentally, however, an accurate experimental estimation of PRCs is challenging. Despite elaborate measurement efforts, experimental PRC estimates often cannot be related to those from modeling studies. In particular, experimental PRCs rarely resemble the generic PRC expected close to spike initiation, which is indicative of the underlying spike-onset bifurcation. Here, we show for conductance-based model neurons that the correspondence between theoretical and measured phase-response curve is lost when the stimuli used for the estimation are too large. In this case, the derived phase-response curve is distorted beyond recognition and takes on a generic shape that reflects the measurement protocol, but not the real neuronal dynamics. We discuss how to identify appropriate stimulus strengths for perturbation and noise-stimulation methods, which permit to estimate PRCs that reliably reflect the spike-onset bifurcation -- a task that is particularly difficult if a lower bound for the stimulus amplitude is dictated by prominent intrinsic neuronal noise.

in q-bio.NC updates on arXiv.org on January 15, 2019 01:30 AM.
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Optimal decoding of dynamic stimuli encoded by heterogeneous populations of spiking neurons - a closed form approximation. (arXiv:1901.04094v1 [q-bio.NC])

Neural decoding may be formulated as dynamic state estimation (filtering) based on point process observations, a generally intractable problem. Numerical sampling techniques are often practically useful for the decoding of real neural data. However, they are less useful as theoretical tools for modeling and understanding sensory neural systems, since they lead to limited conceptual insight about optimal encoding and decoding strategies. We consider sensory neural populations characterized by a distribution over neuron parameters. We develop an analytically tractable Bayesian approximation to optimal filtering based on the observation of spiking activity, that greatly facilitates the analysis of optimal encoding in situations deviating from common assumptions of uniform coding. Continuous distributions are used to approximate large populations with few parameters, resulting in a filter whose complexity does not grow with the population size, and allowing optimization of population parameters rather than individual tuning functions. Numerical comparison with particle filtering demonstrates the quality of the approximation. The analytic framework leads to insights which are difficult to obtain from numerical algorithms, and is consistent with biological observations about the distribution of sensory cells' preferred stimuli.

in q-bio.NC updates on arXiv.org on January 15, 2019 01:30 AM.
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Formation of three-dimensional auditory space. (arXiv:1901.03990v1 [q-bio.NC])

Human listeners need to permanently interact with their three-dimensional (3-D) environment. To this end, they require efficient perceptual mechanisms to form a sufficiently accurate 3-D auditory space. In this chapter, we discuss the formation of the 3-D auditory space from various perspectives. The aim is to show the link between cognition, acoustics, neurophysiology, and psychophysics, when it comes to spatial hearing. First, we present recent cognitive concepts for creating internal models of the complex auditory environment. Second, we describe the acoustic signals available at our ears and discuss the spatial information they convey. Third, we look into neurophysiology, seeking for the neural substrates of the 3-D auditory space. Finally, we elaborate on psychophysical spatial tasks and percepts that are possible just because of the formation of the auditory space.

in q-bio.NC updates on arXiv.org on January 15, 2019 01:30 AM.
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Publisher Correction: Midbrain activity can explain perceptual decisions during an attention task

Publisher Correction: Midbrain activity can explain perceptual decisions during an attention task
Publisher Correction: Midbrain activity can explain perceptual decisions during an attention task, Published online: 15 January 2019; doi:10.1038/s41593-018-0319-6
Publisher Correction: Midbrain activity can explain perceptual decisions during an attention task
in Nature Neuroscience - Issue - nature.com science feeds on January 15, 2019 12:00 AM.
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The control of release probability at nerve terminals

The control of release probability at nerve terminals
The control of release probability at nerve terminals, Published online: 15 January 2019; doi:10.1038/s41583-018-0111-3
Neurosecretion is controlled by SNAREs and SNARE-binding proteins and is initiated by the influx of Ca2+ ions through voltage-gated calcium channels (VGCCs). In this Review, Dittman and Ryan discuss progress in our understanding of the molecular mechanisms underlying the function of VGCCs and fusion machinery.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 15, 2019 12:00 AM.
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Functional Synaptic Architecture of Callosal Inputs in Mouse Primary Visual Cortex
Lee et al. examine the functional synaptic organization of callosal projections onto layer 2/3 pyramidal neurons in the primary visual cortices of mice. They find that callosal and intra-cortical inputs with similar orientation preference cluster together on short dendritic segments.
in Neuron on January 15, 2019 12:00 AM.
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Cholinergic Interneurons Amplify Thalamostriatal Excitation of Striatal Indirect Pathway Neurons in Parkinson’s Disease Models
Tanimura et al. found that motor-learning deficits in a mouse model of PD were triggered by adaptations in the thalamostriatal circuitry. Cholinergic interneuron activation of nicotinic acetylcholine receptors on thalamostriatal axons was key to the adaptation.
in Neuron on January 15, 2019 12:00 AM.
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PAIRUP-MS: Pathway analysis and imputation to relate unknowns in profiles from mass spectrometry-based metabolite data

by Yu-Han H. Hsu, Claire Churchhouse, Tune H. Pers, Josep M. Mercader, Andres Metspalu, Krista Fischer, Kristen Fortney, Eric K. Morgen, Clicerio Gonzalez, Maria E. Gonzalez, Tonu Esko, Joel N. Hirschhorn
Metabolomics is a powerful approach for discovering biomarkers and for characterizing the biochemical consequences of genetic variation. While untargeted metabolite profiling can measure thousands of signals in a single experiment, many biologically meaningful signals cannot be readily identified as known metabolites nor compared across datasets, making it difficult to infer biology and to conduct well-powered meta-analyses across studies. To overcome these challenges, we developed a suite of computational methods, PAIRUP-MS, to match metabolite signals across mass spectrometry-based profiling datasets and to generate metabolic pathway annotations for these signals. To pair up signals measured in different datasets, where retention times (RT) are often not comparable or even available, we implemented an imputation-based approach that only requires mass-to-charge ratios (m/z). As validation, we treated each shared known metabolite as an unmatched signal and showed that PAIRUP-MS correctly matched 70–88% of these metabolites from among thousands of signals, equaling or outperforming a standard m/z- and RT-based approach. We performed further validation using genetic data: the most stringent set of matched signals and shared knowns showed comparable consistency of genetic associations across datasets. Next, we developed a pathway reconstitution method to annotate unknown signals using curated metabolic pathways containing known metabolites. We performed genetic validation for the generated annotations, showing that annotated signals associated with gene variants were more likely to be enriched for pathways functionally related to the genes compared to random expectation. Finally, we applied PAIRUP-MS to study associations between metabolites and genetic variants or body mass index (BMI) across multiple datasets, identifying up to ~6 times more significant signals and many more BMI-associated pathways compared to the standard practice of only analyzing known metabolites. These results demonstrate that PAIRUP-MS enables analysis of unknown signals in a robust, biologically meaningful manner and provides a path to more comprehensive, well-powered studies of untargeted metabolomics data.
in PLOS Computational Biology: New Articles on January 14, 2019 10:00 PM.
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Deep image reconstruction from human brain activity

by Guohua Shen, Tomoyasu Horikawa, Kei Majima, Yukiyasu Kamitani
The mental contents of perception and imagery are thought to be encoded in hierarchical representations in the brain, but previous attempts to visualize perceptual contents have failed to capitalize on multiple levels of the hierarchy, leaving it challenging to reconstruct internal imagery. Recent work showed that visual cortical activity measured by functional magnetic resonance imaging (fMRI) can be decoded (translated) into the hierarchical features of a pre-trained deep neural network (DNN) for the same input image, providing a way to make use of the information from hierarchical visual features. Here, we present a novel image reconstruction method, in which the pixel values of an image are optimized to make its DNN features similar to those decoded from human brain activity at multiple layers. We found that our method was able to reliably produce reconstructions that resembled the viewed natural images. A natural image prior introduced by a deep generator neural network effectively rendered semantically meaningful details to the reconstructions. Human judgment of the reconstructions supported the effectiveness of combining multiple DNN layers to enhance the visual quality of generated images. While our model was solely trained with natural images, it successfully generalized to artificial shapes, indicating that our model was not simply matching to exemplars. The same analysis applied to mental imagery demonstrated rudimentary reconstructions of the subjective content. Our results suggest that our method can effectively combine hierarchical neural representations to reconstruct perceptual and subjective images, providing a new window into the internal contents of the brain.
in PLOS Computational Biology: New Articles on January 14, 2019 10:00 PM.
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Transsacadic Information and Corollary Discharge in Local Field Potentials of Macaque V1
Michael A. Paradiso, Seth Akers-Campbell, Octavio Ruiz, James E. Niemeyer, Stuart Geman, Jackson Loper
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 14, 2019 06:00 PM.
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EEG Phase Synchronization in Persons With Depression Subjected to Transcranial Magnetic Stimulation
Urszula Zuchowicz, Agata Wozniak-Kwasniewska, David Szekely, Elzbieta Olejarczyk, Olivier David
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 14, 2019 06:00 PM.
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Postmeal optogenetic inhibition of dorsal or ventral hippocampal pyramidal neurons increases future intake
Abstract
Memory of a recently eaten meal can serve as a powerful mechanism for controlling future eating behavior because it provides a record of intake that likely outlasts most physiological signals generated by the meal. In support, impairing the encoding of a meal in humans increases the amount ingested at the next eating episode. However, the brain regions that mediate the inhibitory effects of memory on future intake are unknown. In the present study, we tested the hypothesis that dorsal (dHC) and ventral hippocampal (vHC) glutamatergic pyramidal neurons play a critical role in the inhibition of energy intake during the postprandial period by optogenetically inhibiting these neurons at specific times relative to a meal. Male Sprague-Dawley rats were given viral vectors containing CaMKIIα-eArchT3.0-eYFP or CaMKIIα-GFP and fiber optic probes into dHC of one hemisphere and vHC of the other. Compared to intake on a day in which illumination was not given, inhibition of dHC or vHC glutamatergic neurons after the end of a chow, sucrose, or saccharin meal accelerated the onset of the next meal and increased the amount consumed during that next meal when the neurons were no longer inhibited. Inhibition given during a meal did not affect the amount consumed during that meal or the next one but did hasten meal initiation. These data show that dHC and vHC glutamatergic neuronal activity during the postprandial period is critical for limiting subsequent ingestion and suggest that these neurons inhibit future intake by consolidating the memory of the preceding meal.
Significance statement Memory of a recently eaten meal provides a lasting record of recent intake and limits subsequent ingestion; however, the neural mechanisms underlying these mnemonic effects remain unknown. Here, we show that optogenetic inhibition of dorsal or ventral hippocampal pyramidal neurons induced after the end of a sucrose, chow or saccharin meal, when the memory of the meal would be undergoing consolidation, accelerated the initiation of the next meal and, importantly, increased the amount consumed during that next meal when the neurons were no longer inhibited. These findings show that principal hippocampal neurons limit future intake and suggest that they do so by consolidating the memory of the preceding meal.

in RSS PAP on January 14, 2019 05:49 PM.
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Cell-Type-Specific Changes in Intrinsic Excitability in the Subiculum following Learning and Exposure to Novel Environmental Contexts
Abstract
The subiculum is the main target of the hippocampal region CA1 and is the principle output region of the hippocampus. The subiculum is critical to learning and memory, although it has been relatively understudied. There are two functional types of principle neurons within the subiculum: regular spiking (RS) and burst spiking (BS) neurons. To determine whether these cell types are differentially modified by learning-related experience, we performed whole-cell patch clamp recordings from male mouse brain slices following contextual fear conditioning (FC) and memory retrieval relative to a number of control behavioral paradigms. RS cells, but not BS cells, displayed a greater degree of experience-related plasticity in intrinsic excitability measures [afterhyperpolarization (AHP), input resistance (R_input), current required to elicit a spike], with fear conditioned animals having generally more excitable RS cells compared to naïve controls. Furthermore, we found that the relative proportion of RS to BS neurons is modified by the type of exposure, with the lowest proportion of BS subicular cells occurring in animals that underwent contextual FC followed by a retrieval test. These studies indicate that pyramidal neurons in the subiculum undergo experience- and learning-related plasticity in intrinsic properties in a cell-type-specific manner. As BS and RS cells are thought to convey distinct types of information, this plasticity may be particularly important in encoding, consolidating, and recalling spatial information by modulating information flow from the hippocampus to cortical regions.

in eNeuro current issue on January 14, 2019 05:30 PM.
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PINK1 Interacts with VCP/p97 and Activates PKA to Promote NSFL1C/p47 Phosphorylation and Dendritic Arborization in Neurons

While PTEN-induced kinase 1 (PINK1) is well characterized for its role in mitochondrial homeostasis, much less is known concerning its ability to prevent synaptodendritic degeneration. Using unbiased proteomic methods, we identified valosin-containing protein (VCP) as a major PINK1-interacting protein. RNAi studies demonstrate that both VCP and its cofactor NSFL1C/p47 are necessary for the ability of PINK1 to increase dendritic complexity. Moreover, PINK1 regulates phosphorylation of p47, but not the VCP co-factor UFD1. Although neither VCP nor p47 interact directly with PKA, we found that PINK1 binds and phosphorylates the catalytic subunit of PKA at T197 [PKA_cat(pT197)], a site known to activate the PKA holoenzyme. PKA in turn phosphorylates p47 at a novel site (S176) to regulate dendritic complexity. Given that PINK1 physically interacts with both the PKA holoenzyme and the VCP-p47 complex to promote dendritic arborization, we propose that PINK1 scaffolds a novel PINK1-VCP-PKA-p47 signaling pathway to orchestrate dendritogenesis in neurons. These findings highlight an important mechanism by which proteins genetically implicated in Parkinson’s disease (PD; PINK1) and frontotemporal dementia (FTD; VCP) interact to support the health and maintenance of neuronal arbors.

in eNeuro current issue on January 14, 2019 05:30 PM.
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Longitudinal Changes in Semantic Concreteness in Semantic Variant Primary Progressive Aphasia (svPPA)
Abstract
This study examines longitudinal changes in the concreteness of nouns produced by human patients with semantic variant primary progressive aphasia (svPPA). Cross-sectional studies show that patients with svPPA demonstrate severe loss of concrete noun knowledge linked to atrophy of the left ventral temporal lobe. It is unknown how disease spread and duration affect the magnitude of the concreteness impairment in svPPA. We evaluate longitudinal spoken production of concrete nouns in svPPA, and relate this to changes in longitudinal MRI measures of gray matter (GM). Noun concreteness in svPPA is compared to that of behavioral variant frontotemporal dementia (bvFTD) patients, who typically demonstrate highly concrete speech. We elicited naturalistic speech samples at two time points (time 1 and time 2) in patients with svPPA (n = 11) and bvFTD (n = 15) through descriptions of the Cookie Theft picture and evaluated each spoken noun for concreteness. Compared to bvFTD patients whose noun production remained highly concrete throughout the testing period, mixed-effects models revealed that noun concreteness significantly decreased as disease progressed in svPPA. We also measured longitudinal changes to GM in a subset of svPPA patients (n = 7), who showed significant decline in the left and right temporal and frontal regions. Regression analyses revealed that longitudinal GM atrophy in the right fusiform and parahippocampal gyri and the left superior temporal gyrus was related to decreasing noun concreteness. These results suggest that progressive atrophy of the ventral temporal lobe in svPPA contributes to declining concrete noun production over time.

in eNeuro current issue on January 14, 2019 05:30 PM.
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The Positive Brain – Resting State Functional Connectivity in Highly Vital and Flourishing Individuals
Florens Goldbeck, Alina Haipt, David Rosenbaum, Tim Rohe, Andreas J. Fallgatter, Martin Hautzinger, Ann-Christine Ehlis
in Frontiers in Human Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Analysis of Metabolic Alterations Related to Pathogenic Process of Diabetic Encephalopathy Rats
Minjian Dong, Mengqian Ren, Chen Li, Xi Zhang, Changwei Yang, Liangcai Zhao, Hongchang Gao
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Chronic Ethanol Consumption Impairs the Tactile-Evoked Long-Term Depression at Cerebellar Molecular Layer Interneuron-Purkinje Cell Synapses in vivo in Mice
Da-Yong Li, Yan-Hua Bing, Chun-Ping Chu, Xun Cui, Song-Biao Cui, De-Lai Qiu, Li-Da Su
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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A Flow Cytometry-Based Approach for the Isolation and Characterization of Neural Stem Cell Primary Cilia
Sara Monaco, Katja Baur, Andrea Hellwig, Gabriele Hölzl-Wenig, Claudia Mandl, Francesca Ciccolini
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Sirtuin 1 and Autophagy Attenuate Cisplatin-Induced Hair Cell Death in the Mouse Cochlea and Zebrafish Lateral Line
Jiaqi Pang, Hao Xiong, Ting Zhan, Gui Cheng, Haiying Jia, Yongyi Ye, Zhongwu Su, Hongyu Chen, Hanqing Lin, Lan Lai, Yongkang Ou, Yaodong Xu, Suijun Chen, Qiuhong Huang, Maojin Liang, Yuexin Cai, Xueyuan Zhang, Xiaoding Xu, Yiqing Zheng, Haidi Yang
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Increased DJ-1 and α-Synuclein in Plasma Neural-Derived Exosomes as Potential Markers for Parkinson’s Disease
Zhen-Hua Zhao, Zhi-Ting Chen, Rui-Ling Zhou, Xu Zhang, Qin-Yong Ye, Yin-Zhou Wang
in Frontiers in Aging Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Circular RNA Expression Alteration and Bioinformatics Analysis in Rats After Traumatic Spinal Cord Injury
Chuan Qin, Chang-Bin Liu, De-Gang Yang, Feng Gao, Xin Zhang, Chao Zhang, Liang-Jie Du, Ming-Liang Yang, Jian-Jun Li
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Common CHD8 Genomic Targets Contrast With Model-Specific Transcriptional Impacts of CHD8 Haploinsufficiency
A. Ayanna Wade, Kenneth Lim, Rinaldo Catta-Preta, Alex S. Nord
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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White Matter Microstructure Associations of Cognitive and Visuomotor Control in Children: A Sensory Processing Perspective
Annie Brandes-Aitken, Joaquin A. Anguera, Yi-Shin Chang, Carly Demopoulos, Julia P. Owen, Adam Gazzaley, Pratik Mukherjee, Elysa J. Marco
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Test-Retest Reliability of Diffusion Measures Extracted Along White Matter Language Fiber Bundles Using HARDI-Based Tractography
Mariem Boukadi, Karine Marcotte, Christophe Bedetti, Jean-Christophe Houde, Alex Desautels, Samuel Deslauriers-Gauthier, Marianne Chapleau, Arnaud Boré, Maxime Descoteaux, Simona M. Brambati
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 14, 2019 06:00 AM.
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A Clinical Report of Two Cases of Cryptogenic Brain Abscess and a Relevant Literature Review
Wei Zhou, Xuefei Shao, Xiaochun Jiang
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 14, 2019 06:00 AM.
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Crosstalk Between Autophagy and Cerebral Ischemia
Yulin Sun, Yuanhan Zhu, Xiaojun Zhong, Xinle Chen, Jun Wang, Guozheng Ying
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 14, 2019 06:00 AM.
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Modeling the Effect of Environmental Geometries on Grid Cell Representations
Samyukta Jayakumar, Rukhmani Narayanamurthy, Reshma Ramesh, Karthik Soman, Vignesh Muralidharan, V. Srinivasa Chakravarthy
in Frontiers in Neural Circuits | New and Recent Articles on January 14, 2019 06:00 AM.
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The Organization and Connections of Second Somatosensory Cortex in the Agouti
Lucidia F. Santiago, Marco Aurelio M. Freire, Cristovam W. Picanço-Diniz, João G. Franca, Antonio Pereira
in Frontiers in Neuroanatomy | New and Recent Articles on January 14, 2019 06:00 AM.
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DIVE: A spatiotemporal progression model of brain pathology in neurodegenerative disorders. (arXiv:1901.03553v1 [cs.CV])

Here we present DIVE: Data-driven Inference of Vertexwise Evolution. DIVE is an image-based disease progression model with single-vertex resolution, designed to reconstruct long-term patterns of brain pathology from short-term longitudinal data sets. DIVE clusters vertex-wise biomarker measurements on the cortical surface that have similar temporal dynamics across a patient population, and concurrently estimates an average trajectory of vertex measurements in each cluster. DIVE uniquely outputs a parcellation of the cortex into areas with common progression patterns, leading to a new signature for individual diseases. DIVE further estimates the disease stage and progression speed for every visit of every subject, potentially enhancing stratification for clinical trials or management. On simulated data, DIVE can recover ground truth clusters and their underlying trajectory, provided the average trajectories are sufficiently different between clusters. We demonstrate DIVE on data from two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Dementia Research Centre (DRC), UK, containing patients with Posterior Cortical Atrophy (PCA) as well as typical Alzheimer's disease (tAD). DIVE finds similar spatial patterns of atrophy for tAD subjects in the two independent datasets (ADNI and DRC), and further reveals distinct patterns of pathology in different diseases (tAD vs PCA) and for distinct types of biomarker data: cortical thickness from Magnetic Resonance Imaging (MRI) vs amyloid load from Positron Emission Tomography (PET). Finally, DIVE can be used to estimate a fine-grained spatial distribution of pathology in the brain using any kind of voxelwise or vertexwise measures including Jacobian compression maps, fractional anisotropy (FA) maps from diffusion imaging or other PET measures. DIVE source code is available online: https://github.com/mrazvan22/dive

in q-bio.NC updates on arXiv.org on January 14, 2019 01:30 AM.
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Progress in Brain Computer Interfaces: Challenges and Trends. (arXiv:1901.03442v1 [cs.HC])

Brain computer interfaces (BCI) provide a direct communication link between the brain and a computer or other external devices. They offer an extended degree of freedom either by strengthening or by substituting human peripheral working capacity and have potential applications in various fields such as rehabilitation, affective computing, robotics, gaming and artificial intelligence. Significant research efforts on a global scale have delivered common platforms for technology standardization and help tackle highly complex and nonlinear brain dynamics and related feature extraction and classification challenges. Psycho-neurophysiological phenomena and their impact on brain signals impose another challenge for BCI researchers to transform the technology from laboratory experiments to plug-and-play daily life. This review summarizes progress in BCI field and highlights critical challenges.

in q-bio.NC updates on arXiv.org on January 14, 2019 01:30 AM.
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Time is just a memory

Time is just a memory
Time is just a memory, Published online: 14 January 2019; doi:10.1038/s41593-018-0331-x
Experience unfolds continuously in time, but we remember discrete sequences of events. In this issue of Nature Neuroscience, Montchal et al. describe brain activity patterns that predict how well people remember precisely when recent events occurred. Converging evidence suggests that homologous neural machinery structures temporal representations in rats and people.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Task representations in neural networks trained to perform many cognitive tasks

Task representations in neural networks trained to perform many cognitive tasks
Task representations in neural networks trained to perform many cognitive tasks, Published online: 14 January 2019; doi:10.1038/s41593-018-0310-2
Prefrontal cortex can be flexibly engaged in many different tasks. Yang et al. trained an artificial neural network to solve 20 cognitive tasks. Functionally specialized modules and compositional representations emerged in the network after training.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Cortical microcircuitry of performance monitoring

Cortical microcircuitry of performance monitoring
Cortical microcircuitry of performance monitoring, Published online: 14 January 2019; doi:10.1038/s41593-018-0309-8
Concurrently recording neural spiking across cortical layers in a medial frontal area with EEG reveals the microcircuitry of error and reward signals, showing how neural circuits can realize executive control and produce error-related negativity.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Active control of arousal by a locus coeruleus GABAergic circuit

Active control of arousal by a locus coeruleus GABAergic circuit
Active control of arousal by a locus coeruleus GABAergic circuit, Published online: 14 January 2019; doi:10.1038/s41593-018-0305-z
The authors describe a local population of GABAergic neurons that directly inhibits locus coeruleus noradrenergic neurons. They show how this circuit regulates arousal gain and tone.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Precise temporal memories are supported by the lateral entorhinal cortex in humans

Precise temporal memories are supported by the lateral entorhinal cortex in humans
Precise temporal memories are supported by the lateral entorhinal cortex in humans, Published online: 14 January 2019; doi:10.1038/s41593-018-0303-1
In the lateral entorhinal cortex, high-precision judgments related to timing were associated with greater blood-oxygen-level-dependent fMRI activity than low-precision time judgments. This brain region may be involved in memory for when events occur.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair

ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair
ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair, Published online: 14 January 2019; doi:10.1038/s41593-018-0300-4
Klim et al. illuminate pathomechanisms of ALS using pluripotent stem cells to identify transcripts altered in human motor neurons by perturbations to ALS protein TDP-43, finding the microtubule regulator STMN2 highly sensitive to TDP-43 malfunctions.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Neuronal brain-region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability

Neuronal brain-region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability
Neuronal brain-region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability, Published online: 14 January 2019; doi:10.1038/s41593-018-0297-8
An extensive profile of DNA methylation in neuronal and non-neuronal cells across four brain regions is reported, showing that differential epigenetic marks are enriched for DNA variants associated with neuropsychiatric traits.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration

Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration
Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration, Published online: 14 January 2019; doi:10.1038/s41593-018-0293-z
The mRNA encoding stathmin-2, a protein implicated in axonal growth, is shown to be widely suppressed by premature polyadenylation in both sporadic and C9orf72 ALS through a mechanism directly dependent on loss of nuclear TDP-43 in motor neurons.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis

Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis
Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis, Published online: 14 January 2019; doi:10.1038/s41583-018-0113-1
Understanding the complex interplay of cells that protect neurons early in Alzheimer disease but later contribute to neurodegeneration is important for developing effective therapeutics. In this Review, Henstridge and colleagues discuss the contributions of multiple cell types to disease pathogenesis.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Ionotropic Receptors Specify the Morphogenesis of Phasic Sensors Controlling Rapid Thermal Preference in Drosophila
Budelli et al. find Drosophila thermoregulatory behavior is driven by a combination of heating and cooling detectors rather than hot- and cold-labeled lines. They further show Ionotropic Receptors not only confer thermosensitivity but also specify the thermoreceptor’s complex dendritic morphology.
in Neuron on January 14, 2019 12:00 AM.
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Oligodendrocyte Progenitor Cells Become Regionally Diverse and Heterogeneous with Age
Spitzer et al. show that oligodendrocyte progenitor cells (OPCs) acquire ion channels and sensitivity to neuronal activity that differ between region and age. The onset and decline of ion channels follow developmental milestones. This heterogeneity indicates different functional states of OPCs.
in Neuron on January 14, 2019 12:00 AM.
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DNA damage signatures in peripheral blood cells as biomarkers in prodromal huntington disease

Easily accessible biomarkers in Huntington disease (HD) are actively searched. We investigated telomere length and DNA double‐strand breaks (histone variant pγ‐H2AX) as predictive disease biomarkers in peripheral blood mononuclear cells (PBMC) from 25 premanifest subjects, 58 HD patients with similar CAG expansion in the huntingtin gene (HTT), and 44 healthy controls (HC). PBMC from the pre‐HD and HD groups showed shorter telomeres (p < 0.0001) and a significant increase of pγ‐H2AX compared to the controls (p < 0.0001). The levels of pγ‐H2AX correlated robustly with the presence of the mutated gene in pre‐HD and HD. The availability of a potentially reversible biomarker (pγ‐H2AX) in the premanifest stage of HD, negligible in HC, provides a novel tool to monitor premanifest subjects and find patient‐specific drugs. Ann Neurol 2018;00:1–6

in Wiley: Annals of Neurology: Table of Contents on January 13, 2019 07:08 PM.
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Correction: clusterExperiment and RSEC: A Bioconductor package and framework for clustering of single-cell and other large gene expression datasets

by The PLOS Computational Biology Staff

in PLOS Computational Biology: New Articles on January 11, 2019 10:00 PM.
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Hypomyelination and Oligodendroglial Alterations in a Mouse Model of Autism Spectrum Disorder
Mariana Graciarena, Araceli Seiffe, Brahim Nait-Oumesmar, Amaicha M. Depino
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 11, 2019 06:00 PM.
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Dual-Model Radiomic Biomarkers Predict Development of Mild Cognitive Impairment Progression to Alzheimer’s Disease
Hucheng Zhou, Jiehui Jiang, Jiaying Lu, Min Wang, Huiwei Zhang, Chuantao Zuo, Alzheimer’s Disease Neuroimaging Initiative
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 11, 2019 06:00 PM.
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Pain-Related Fear--Dissociable Neural Sources of Different Fear Constructs
Abstract
Fear of pain demonstrates significant prognostic value regarding the development of persistent musculoskeletal pain and disability. Its assessment often relies on self-report measures of pain-related fear by a variety of questionnaires. However, based either on "fear of movement/(re)injury/kinesiophobia," "fear avoidance beliefs," or "pain anxiety," pain-related fear constructs plausibly differ while it is unclear how specific the questionnaires are in assessing these different constructs. Furthermore, the relationship of pain-related fear to other anxiety measures such as state or trait anxiety remains ambiguous. Advances in neuroimaging such as machine learning on brain activity patterns recorded by functional magnetic resonance imaging might help to dissect commonalities or differences across pain-related fear constructs. We applied a pattern regression approach in 20 human patients with nonspecific chronic low back pain to reveal predictive relationships between fear-related neural pattern information and different pain-related fear questionnaires. More specifically, the applied multiple kernel learning approach allowed the generation of models to predict the questionnaire scores based on a hierarchical ranking of fear-related neural patterns induced by viewing videos of activities potentially harmful for the back. We sought to find evidence for or against overlapping pain-related fear constructs by comparing the questionnaire prediction models according to their predictive abilities and associated neural contributors. By demonstrating evidence of nonoverlapping neural predictors within fear-processing regions, the results underpin the diversity of pain-related fear constructs. This neuroscientific approach might ultimately help to further understand and dissect psychological pain-related fear constructs.

in eNeuro current issue on January 11, 2019 05:30 PM.
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Neuronal Correlations in MT and MST Impair Population Decoding of Opposite Directions of Random Dot Motion
Abstract
The study of neuronal responses to random-dot motion patterns has provided some of the most valuable insights into how the activity of neurons is related to perception. In the opposite directions of motion paradigm, the motion signal strength is decreased by manipulating the coherence of random dot patterns to examine how well the activity of single neurons represents the direction of motion. To extend this paradigm to populations of neurons, studies have used modelling based on data from pairs of neurons, but several important questions require further investigation with larger neuronal datasets. We recorded neuronal populations in the middle temporal (MT) and medial superior temporal (MST) areas of anaesthetized marmosets with electrode arrays, while varying the coherence of random dot patterns in two opposite directions of motion (left and right). Using the spike rates of simultaneously recorded neurons, we decoded the direction of motion at each level of coherence with linear classifiers. We found that the presence of correlations had a detrimental effect to decoding performance, but that learning the correlation structure produced better decoding performance compared to decoders that ignored the correlation structure. We also found that reducing motion coherence increased neuronal correlations, but decoders did not need to be optimized for each coherence level. Finally, we showed that decoder weights depend of left-right selectivity at 100% coherence, rather than the preferred direction. These results have implications for understanding how the information encoded by populations of neurons is affected by correlations in spiking activity.

in eNeuro current issue on January 11, 2019 05:30 PM.
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Gamma oscillations in the basolateral amygdala: biophysical mechanisms and computational consequences
Abstract
The basolateral nucleus of the amygdala (BL) is thought to support numerous emotional behaviors through specific microcircuits. These are often thought to be comprised of feedforward networks of principal cells and interneurons. Neither well-understood nor often considered are recurrent and feedback connections, which likely engender oscillatory dynamics within BL. Indeed, oscillations in the gamma frequency range (40-100 Hz) are known to occur in the BL, and yet their origin and effect on local circuits remains unknown. To address this, we constructed a biophysically and anatomically detailed model of the rat BL and its local field potential based on the physiological and anatomical literature, along with in vivo and in vitro data we collected on the activities of neurons within the rat BL. Remarkably, the model produced intermittent gamma oscillations (~50-70 Hz) whose properties matched those recorded in vivo, including their entrainment of spiking. BL gamma-band oscillations were generated by the intrinsic circuitry, depending upon reciprocal interactions between principal cells and fast-spiking interneurons, while connections within these cell types affected the rhythm’s frequency. The model allowed us to conduct experimentally impossible tests to characterize the synaptic and spatial properties of gamma. The entrainment of individual neurons to gamma depended on the number of afferent connections they received, and gamma bursts were spatially restricted in the BL. Importantly, the gamma rhythm synchronized principal cells and mediated competition between ensembles. Together, these results indicate that the recurrent connectivity of BL expands its computational and communication repertoire.
Significant Statement Using in vitro and in vivo data we develop the first large-scale biophysically and anatomically realistic model of the basolateral amygdala nucleus (BL), which reproduces the dynamics of the in vivo local field potential (LFP). Significantly, it predicts that BL intrinsically generates the transient gamma oscillations observed in vivo. The model permitted exploration of the poorly understood synaptic mechanisms underlying gamma genesis in BL, and the model's ability to compute LFPs at arbitrary numbers of recording sites provided insights into the characteristics of the spatial properties of gamma bursts. Furthermore, we show how gamma synchronizes principal cells to overcome their low firing rates while simultaneously promoting competition, potentially impacting their afferent selectivity and efferent drive, and thus emotional behavior.

in RSS PAP on January 11, 2019 05:16 PM.
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Abundant GAD‐reactive B cells in GAD‐antibody‐associated neurological disorders

ABSTRACT

High levels of antibodies against glutamic acid decarboxylase (GAD) are observed in patients with different neurological disorders, but cells producing these auto‐antibodies are largely unexplored. We detect circulating GAD‐reactive B cells in peripheral blood that readily differentiate into antibody‐producing cells. These cells are highly elevated in most patients with GAD‐antibody‐associated disorders (n=15) compared to controls (n=19). They mainly produce GAD65‐antibodies of the IgG1 and IgG4 subclasses and are as abundant as B cells reactive for common recall antigens. Bone marrow cells represent an additional source of GAD‐antibodies. The identification of GAD‐antibody‐producing cells has implications for the selection of cell‐specific biologics.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on January 11, 2019 05:02 PM.
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APRIL‐mediated anti‐inflammatory response of astrocytes in multiple sclerosis

Abstract

Objective

the two related TNF members APRIL and BAFF are currently targeted in autoimmune diseases as B‐cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to an unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.

Methods

APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.

Results

APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan (CSPG) bearing sometimes chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing sufficient amount of IL‐10 to dampen antigen‐specific T‐cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset had also an effect.

Interpretation

our data show that APRIL mediates an anti‐inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on January 11, 2019 05:02 PM.
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Brain and cord imaging features in neuromyelitis optica spectrum disorders

Abstract

Objectives

To validate imaging features able to discriminate neuromyelitis optica spectrum disorders from multiple sclerosis with conventional MRI.

Methods

In this cross‐sectional study, brain and spinal cord scans were evaluated from 116 neuromyelitis optica spectrum disorders patients (98 seropositive and 18 seronegative) in chronic disease phase and 65 age‐, sex‐ and disease duration‐matched multiple sclerosis patients. To identify independent predictors of neuromyelitis optica diagnosis, after assessing the prevalence of typical/atypical findings, the original cohort was 2:1 randomized in a training sample (where a multivariate logistic regression analysis was run) and a validation sample (where the performance of the selected variables was tested and validated).

Results

Typical brain lesions occurred in 50.9% of neuromyelitis optica patients (18.1% brainstem periventricular/periaqueductal; 32.7% periependymal along lateral ventricles, 3.4% large hemispheric; 6.0% diencephalic; 4.3% cortico‐spinal tract), 72.2% had spinal cord lesions (46.3% long transverse myelitis, 36.1% short transverse myelitis) 37.1% satisfied 2010 McDonald criteria and none had cortical lesions. Fulfillment of at least 2/5 of: absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson's fingers, presence of long transverse myelitis or presence of periependymal lesions along lateral ventricles, discriminated neuromyelitis optica patients in both training (sensitivity [95% confidence interval ]=0.92 [0.84‐0.97], specificity=0.91 [0.78‐0.97]) and validation samples (sensitivity=0.82 [0.66‐0.92], specificity=0.91 [0.71‐0.99]). MRI findings and criteria performance were similar irrespective of serostatus.

Interpretation

Although up to 50% of neuromyelitis optica patients have no typical lesions and a relatively high percentage of them satisfies multiple sclerosis criteria, several easily applicable imaging features can help to identify neuromyelitis optica from multiple sclerosis.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on January 11, 2019 05:02 PM.
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Amyloid‐β Immunotherapy for Alzheimer's Disease – Is It Now A Long Shot…?

Abstract

The amyloid‐β (Aβ) cascade hypothesis of Alzheimer's disease (AD) holds that brain accumulation of Aβ initiates the disease process. Accordingly, drug research has targeted Aβ production, clearance or deposition as therapeutic strategies. Unfortunately, candidate drugs have failed to show clinical benefit in established, early or prodromal disease, or those with high AD risk. Currently, monoclonal antibodies specifically directed against the most neurotoxic Aβ forms are undergoing large scale trials to confirm initially encouraging results. However, recent findings on the normal physiology of Aβ suggest that accumulation may be compensatory rather than the pathological initiator. If this is true, alternative strategies will be needed to defeat this devastating disease.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on January 11, 2019 05:01 PM.
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Cerebellar degeneration correlates with motor symptoms in Huntington's disease

ABSTRACT

Objective

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by variable motor and behavioural symptoms attributed to major neuropathology of mainly the basal ganglia and cerebral cortex. The role of the cerebellum, a brain region involved in the coordination of movements, in HD neuropathology has been controversial. This study utilises post‐mortem human brain tissue to investigate whether Purkinje cell degeneration in the neocerebellum is present in HD, and how this relates to disease symptom profiles.

Methods

Unbiased stereological counting methods were used to quantify the total number of Purkinje cells in 15 HD cases and 8 neurologically normal control cases. Based on their predominant symptoms, the HD cases were categorised into two groups: “motor” or “mood”.

Results

The results demonstrated a significant 43% loss of Purkinje cells in HD cases with predominantly motor symptoms, and no cell loss in cases showing a major mood phenotype. There was no significant correlation between Purkinje cell loss and striatal neuropathological grade, post‐mortem delay, CAG repeat in the IT15 gene or age at death.

Interpretation

This study shows a compelling relationship between Purkinje cell loss in the HD neocerebellum and the HD motor symptom phenotype, which, together with our previous human brain studies on the same HD cases, provide novel perspectives interrelating and correlating the variable cerebellar, basal ganglia and neocortical neuropathology with the variability of motor/mood symptom profiles in the human HD brain.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on January 11, 2019 05:01 PM.
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SLC13A3 variants cause acute reversible leukoencephalopathy and αKG accumulation

Abstract

Objective

SLC13A3 encodes the plasma membrane Na⁺/Dicarboxylate Cotransporter 3 (NaDC3), which imports inside the cell four to six carbon dicarboxylates as well as N‐acetylaspartate (NAA). SLC13A3 is mainly expressed in kidney, in astrocytes and in the choroid plexus. We describe two unrelated patients presenting with acute, reversible (and recurrent in one) neurological deterioration during a febrile illness. Both patients exhibited a reversible leukoencephalopathy and a markedly increased and persisting over time urinary excretion of α‐ketoglutarate (αKG). In one patient, increased cerebrospinal fluid NAA and dicarboxylates (including αKG) concentrations were observed. Extensive workup was unsuccessful and a genetic cause was suspected.

Methods

Whole exome sequencing (WES) was performed. Our teams were connected through GeneMatcher.

Results

WES analysis revealed variants in SLC13A3. A homozygous missense mutation (p.Ala254Asp) was found in the first patient. The second patient was heterozygous for another missense mutation (p.Gly548Ser) and an intronic mutation affecting splicing as demonstrated by RT‐PCR performed in muscle tissue (c.1016+3A>G). Mutations and segregation were confirmed by Sanger sequencing. Functional studies performed on HEK293T cells transiently transfected with wild type and mutant SLC13A3 indicated that the missense mutations caused a marked reduction in the capacity to transport αKG, succinate and NAA.

Interpretation

SLC13A3 deficiency causes acute and reversible leukoencephalopathy with marked accumulation of αKG. Urine organic acids (especially αKG and NAA) and SLC13A3 mutations should be screened in patients presenting with unexplained reversible leukoencephalopathy for which SLC13A3 deficiency is a novel differential diagnosis.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on January 11, 2019 05:00 PM.
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Decreased Intrinsic Functional Connectivity in First-Episode, Drug-Naive Adolescents With Generalized Anxiety Disorder
Fan Yang, Linlin Fan, Tianyi Zhai, Ying Lin, Yuyin Wang, Junji Ma, Mei Liao, Yan Zhang, Lingjiang Li, Linyan Su, Zhengjia Dai
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 12:00 PM.
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A Neurophysiological and Behavioral Assessment of Interventions Targeting Attention Bias and Sense of Control in Binge Drinking
Jessica E. Langbridge, Richard D. Jones, Juan J. Canales
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 12:00 PM.
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Memory Integration as a Challenge to the Consolidation/Reconsolidation Hypothesis: Similarities, Differences and Perspectives
Pascale Gisquet-Verrier, David C. Riccio
in Frontiers in Systems Neuroscience | New and Recent Articles on January 11, 2019 12:00 PM.
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Machine Learning Models for Multiparametric Glioma Grading With Quantitative Result Interpretations
Xiuying Wang, Dingqian Wang, Zhigang Yao, Bowen Xin, Bao Wang, Chuanjin Lan, Yejun Qin, Shangchen Xu, Dazhong He, Yingchao Liu
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 11, 2019 12:00 PM.
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Transcytosis to Cross the Blood Brain Barrier, New Advancements and Challenges
Victor M. Pulgar
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 11, 2019 12:00 PM.
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Tracking Neural Progenitor Cell Migration in the Rodent Brain Using Magnetic Resonance Imaging
Christiane L. Mallett, Dorela D. Shuboni-Mulligan, Erik M. Shapiro
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 11, 2019 12:00 PM.
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Tool Embodiment: The Tool’s Output Must Match the User’s Input
Veronica Weser, Dennis R. Proffitt
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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A Review of Acute Aerobic Exercise and Transcranial Direct Current Stimulation Effects on Cognitive Functions and Their Potential Synergies
Fabian Steinberg, Nils Henrik Pixa, Felipe Fregni
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Effects of Reciprocal Ia Inhibition on Contraction Intensity of Co-contraction
Ryo Hirabayashi, Mutsuaki Edama, Sho Kojima, Masatoshi Nakamura, Wataru Ito, Emi Nakamura, Takanori Kikumoto, Hideaki Onishi
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Improving Relationships by Elevating Positive Illusion and the Underlying Psychological and Neural Mechanisms
Hongwen Song, Yongjun Zhang, Lin Zuo, Xueli Chen, Gui Cao, Federico d’Oleire Uquillas, Xiaochu Zhang
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Current Status and Issues Regarding Pre-processing of fNIRS Neuroimaging Data: An Investigation of Diverse Signal Filtering Methods Within a General Linear Model Framework
Paola Pinti, Felix Scholkmann, Antonia Hamilton, Paul Burgess, Ilias Tachtsidis
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Targeting MAPK Pathways by Naringenin Modulates Microglia M1/M2 Polarization in Lipopolysaccharide-Stimulated Cultures
Bei Zhang, Yi-Zheng Wei, Guo-Qing Wang, Dai-Di Li, Jing-Shan Shi, Feng Zhang
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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The Role of BDNF in Peripheral Nerve Regeneration: Activity-Dependent Treatments and Val66Met
Claire Emma McGregor, Arthur W. English
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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The Expression of Transcription Factors Mecp2 and CREB Is Modulated in Inflammatory Pelvic Pain
Alison Xiaoqiao Xie, Xiao-Qing Pan, Randall B. Meacham, Anna P. Malykhina
in Frontiers in Systems Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Neuropeptides Exert Neuroprotective Effects in Alzheimer's Disease
Xin-Yi Chen, Yi-Feng Du, Lei Chen
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Clinical Value of Machine Learning in the Automated Detection of Focal Cortical Dysplasia Using Quantitative Multimodal Surface-Based Features
Jia-Jie Mo, Jian-Guo Zhang, Wen-Ling Li, Chao Chen, Na-Jing Zhou, Wen-Han Hu, Chao Zhang, Yao Wang, Xiu Wang, Chang Liu, Bao-Tian Zhao, Jun-Jian Zhou, Kai Zhang
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 11, 2019 06:00 AM.
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A Framework for Intelligence and Cortical Function Based on Grid Cells in the Neocortex
Jeff Hawkins, Marcus Lewis, Mirko Klukas, Scott Purdy, Subutai Ahmad
in Frontiers in Neural Circuits | New and Recent Articles on January 11, 2019 06:00 AM.
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DEFiNE: A Method for Enhancement and Quantification of Fluorescently Labeled Axons
Jeanne M. Powell, Nicholas W. Plummer, Erica L. Scappini, Charles J. Tucker, Patricia Jensen
in Frontiers in Neuroanatomy | New and Recent Articles on January 11, 2019 06:00 AM.
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Toward a Common Terminology for the Thalamus
Jürgen K. Mai, Milan Majtanik
in Frontiers in Neuroanatomy | New and Recent Articles on January 11, 2019 06:00 AM.
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COMPASS: An Open-Source, General-Purpose Software Toolkit for Computational Psychiatry
Ali Yousefi, Angelique C. Paulk, Ishita Basu, Jonathan L. Mirsky, Darin D. Dougherty, Emad N. Eskandar, Uri T. Eden, Alik S. Widge
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 11, 2019 06:00 AM.
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An Analysis of the Accuracy of the P300 BCI. (arXiv:1901.03299v1 [eess.SP])

The P300 Brain-Computer Interface (BCI) is a well-established communication channel for severely disabled people. The P300 event-related potential is mostly characterized by its amplitude or its area, which correlate with the spelling accuracy of the P300 speller. Here, we introduce a novel approach for estimating the efficiency of this BCI by considering the P300 signal-to-noise ratio (SNR), a parameter that estimates the spatial and temporal noise levels and has a significantly stronger correlation with spelling accuracy. Furthermore, we suggest a Gaussian noise model, which utilizes the P300 event-related potential SNR to predict spelling accuracy under various conditions for LDA-based classification. We demonstrate the utility of this analysis using real data and discuss its potential applications, such as speeding up the process of electrode selection.

in q-bio.NC updates on arXiv.org on January 11, 2019 01:30 AM.
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Brain Electrical Stimulation for Animal Navigation. (arXiv:1901.02943v1 [q-bio.NC])

The brain stimulation and its widespread use is one of the most important subjects in studies of neurophysiology. In brain electrical stimulation methods, following the surgery and electrode implantation, electrodes send electrical impulses to the specific targets in the brain. The use of this stimulation method is provided therapeutic benefits for treatment chronic pain, essential tremor, Parkinsons disease, major depression, and neurological movement disorder syndrome (dystonia). One area in which advancements have been recently made is in controlling the movement and navigation of animals in a specific pathway. It is important to identify brain targets in order to stimulate appropriate brain regions for all the applications listed above. An animal navigation system based on brain electrical stimulation is used to develop new behavioral models for the aim of creating a platform for interacting with the animal nervous system in the spatial learning task. In the context of animal navigation the electrical stimulation has been used either as creating virtual sensation for movement guidance or virtual reward for movement motivation. In this paper, different approaches and techniques of brain electrical stimulation for this application has been reviewed.

Keywords: Rat Robot, Brain Computer Interface, Electrical Stimulation, Cyborg Intelligence, Brain to Brain Interface

in q-bio.NC updates on arXiv.org on January 11, 2019 01:30 AM.
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Revealing interpretable object representations from human behavior. (arXiv:1901.02915v1 [stat.ML])

To study how mental object representations are related to behavior, we estimated sparse, non-negative representations of objects using human behavioral judgments on images representative of 1,854 object categories. These representations predicted a latent similarity structure between objects, which captured most of the explainable variance in human behavioral judgments. Individual dimensions in the low-dimensional embedding were found to be highly reproducible and interpretable as conveying degrees of taxonomic membership, functionality, and perceptual attributes. We further demonstrated the predictive power of the embeddings for explaining other forms of human behavior, including categorization, typicality judgments, and feature ratings, suggesting that the dimensions reflect human conceptual representations of objects beyond the specific task.

in q-bio.NC updates on arXiv.org on January 11, 2019 01:30 AM.
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Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer

by Deena M. A. Gendoo, Robert E. Denroche, Amy Zhang, Nikolina Radulovich, Gun Ho Jang, Mathieu Lemire, Sandra Fischer, Dianne Chadwick, Ilinca M. Lungu, Emin Ibrahimov, Ping-Jiang Cao, Lincoln D. Stein, Julie M. Wilson, John M. S. Bartlett, Ming-Sound Tsao, Neesha Dhani, David Hedley, Steven Gallinger, Benjamin Haibe-Kains
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 ‘trios’ of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity.
in PLOS Computational Biology: New Articles on January 10, 2019 10:00 PM.
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Computational translation of genomic responses from experimental model systems to humans

by Douglas K. Brubaker, Elizabeth A. Proctor, Kevin M. Haigis, Douglas A. Lauffenburger
The high failure rate of therapeutics showing promise in mouse models to translate to patients is a pressing challenge in biomedical science. Though retrospective studies have examined the fidelity of mouse models to their respective human conditions, approaches for prospective translation of insights from mouse models to patients remain relatively unexplored. Here, we develop a semi-supervised learning approach for inference of disease-associated human differentially expressed genes and pathways from mouse model experiments. We examined 36 transcriptomic case studies where comparable phenotypes were available for mouse and human inflammatory diseases and assessed multiple computational approaches for inferring human biology from mouse datasets. We found that semi-supervised training of a neural network identified significantly more true human biological associations than interpreting mouse experiments directly. Evaluating the experimental design of mouse experiments where our model was most successful revealed principles of experimental design that may improve translational performance. Our study shows that when prospectively evaluating biological associations in mouse studies, semi-supervised learning approaches, combining mouse and human data for biological inference, provide the most accurate assessment of human in vivo disease processes. Finally, we proffer a delineation of four categories of model system-to-human “Translation Problems” defined by the resolution and coverage of the datasets available for molecular insight translation and suggest that the task of translating insights from model systems to human disease contexts may be better accomplished by a combination of translation-minded experimental design and computational approaches.
in PLOS Computational Biology: New Articles on January 10, 2019 10:00 PM.
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Improvement of Mesenchymal Stem Cell Immunomodulatory Properties by Heat-Killed Propionibacterium acnes via TLR2
Gabriela da Paz Silveira, Mayari Eika Ishimura, Daniela Teixeira, Layla Tesla Galindo, Agnes Araujo Sardinha, Marimelia Porcionatto, Ieda Maria Longo-Maugéri
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 10, 2019 06:00 PM.
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Corrigendum: Dysregulation of MicroRNAs and Target Genes Networks in Peripheral Blood of Patients With Sporadic Amyotrophic Lateral Sclerosis
Maria Liguori, Nicoletta Nuzziello, Alessandro Introna, Arianna Consiglio, Flavio Licciulli, Eustachio D'Errico, Antonio Scarafino, Eugenio Distaso, Isabella L. Simone
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 10, 2019 06:00 PM.
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Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice
Zinah Wassouf, Thomas Hentrich, Nicolas Casadei, Mirko Jaumann, Marlies Knipper, Olaf Riess, Julia M. Schulze-Hentrich
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 10, 2019 06:00 PM.
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Trigeminal nerve transection-induced neuroplastic changes in the somatosensory and insular cortices in a rat ectopic pain model
Abstract
The primary sensory cortex processes competitive sensory inputs. Ablation of these competitive inputs induces neuroplastic changes in local cortical circuits. However, information concerning cortical plasticity induced by a disturbance of competitive nociceptive inputs is limited. Nociceptive information from the maxillary and mandibular molar pulps converges at the border between the ventral secondary somatosensory cortex (S2) and insular oral region (IOR), therefore S2/IOR is a suitable target for examining the cortical changes induced by a disturbance of noxious inputs, which often causes neuropathic pain and allodynia. We focused on the plastic changes in S2/IOR excitation in a model of rats subjected to inferior alveolar nerve transection (IANX). Our optical imaging using a voltage-sensitive dye revealed that the maxillary molar pulp stimulation-induced excitatory propagation was expanded 1-2 weeks after IANX at the macroscopic level. At the cellular level, based on Ca²⁺ imaging using two-photon microscopy, the amplitude of the Ca²⁺ responses and the number of responding neurons in S2/IOR increased in both excitatory and inhibitory neurons. The in vitro laser scanning photostimulation revealed that layer II/III pyramidal and GABAergic fast-spiking neurons in S2/IOR received larger excitatory inputs from layer IV in the IANX models, which supports the findings obtained by the macroscopic and microscopic optical imaging. Furthermore, the inhibitory postsynaptic inputs to the pyramidal neurons were decreased in the IANX models, suggesting suppression of inhibitory synaptic transmission onto excitatory neurons. These results suggest that IANX induces plastic changes in S2/IOR by changing the local excitatory and inhibitory circuits. (246/250 words)
Significance statement The inferior alveolar nerve (IAN), a mandibular branch of the trigeminal nerve, innervates the orofacial region, including the tooth pulps. IAN transection (IANX) induces allodynia in the maxillary nerve-projecting region. This study demonstrates the facilitation of excitatory propagation in the secondary somatosensory cortex (S2) and insular oral region (IOR) following maxillary molar tooth pulp stimulation in IANX rats. Both pyramidal and fast-spiking neurons in layer II/III S2/IOR of IANX rats received larger glutamatergic excitatory inputs from the deeper layers. Reduction of GABA_A receptor-mediated IPSCs in pyramidal neurons of IANX rats may contribute to the facilitated excitation in S2/IOR. These findings suggest that GABAergic neurons in S2/IOR could be a therapeutic target for ectopic pain in the orofacial region. (118/120 words)

in RSS PAP on January 10, 2019 05:23 PM.
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Methamphetamine self-administration elicits sex related changes in postsynaptic glutamate transmission in the prefrontal cortex
Abstract
Pre-clinical and clinical research has shown that females are more vulnerable to the rewarding effects of stimulants, and it has been proposed that estrogens may play a role in this enhanced sensitivity; however sex differences in methamphetamine (METH)-induced neuroplasticity have not been explored. To address this gap in knowledge we recorded from the prelimbic area of the prefrontal cortex (PFC) of male and females rats following long access METH self-administration (SA) and investigated the resulting long-term synaptic neuroadaptations. Males and females took similar amounts of METH during self-administration; however, female rats exhibit significant synaptic baseline differences when compared to males. Furthermore, females exhibited a significant increase in evoked excitatory currents. This increase in evoked glutamate was correlated with increases in NMDA currents and was not affected by application of a GluN2B selective blocker. We propose that METH SA selectively upregulates GluN2B-lacking NMDAR in the PFC of female rats. Our results may provide a mechanistic explanation for the sex differences reported for METH addiction in females.
Significance Statement The rate of methamphetamine (METH) addiction is second only to heroin, and use trends are on the rise. Like other drugs of abuse, there are known sex differences in METH addiction, however if these differences result from sex differences in pharmacokinetics, neurophysiology, and/or drug-induced neuroplasticity has not been established. Here we assessed METH self-administration induced neuroadaptations in synaptic physiology using electrophysiological measures in prefrontal cortical brain slices of male and female rats. We are the first to report, to our knowledge, that cortical baseline and METH-induced synaptic responses are different between male and female rats. Our results may provide a mechanistic explanation for the sex differences reported for METH addiction in females and highlight the possibility that sex-specific treatment strategies may be required to address METH-induced neuroplasticity.

in RSS PAP on January 10, 2019 05:23 PM.
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Isoflurane inhibits dopaminergic synaptic vesicle exocytosis coupled to CaV2.1 and CaV2.2 in rat midbrain neurons
ABSTRACT
Volatile anesthetics affect neuronal signaling by poorly understood mechanisms. Activation of central dopaminergic pathways has been implicated in emergence from general anesthesia. The volatile anesthetic isoflurane differentially inhibits glutamatergic and GABAergic synaptic vesicle exocytosis by reducing presynaptic Ca²⁺ influx without affecting the Ca²⁺-exocytosis relationship, but its effects on dopaminergic exocytosis are unclear. We tested the hypothesis that isoflurane inhibits exocytosis in dopaminergic neurons. We used electrical stimulation or depolarization by elevated extracellular KCl to evoke exocytosis measured by quantitative live-cell fluorescence imaging in cultured rat ventral tegmental area neurons. Using trains of electrically evoked action potentials (APs), isoflurane inhibited exocytosis in dopaminergic neurons to a greater extent (30 ± 4% inhibition; p < 0.0001) than in non-dopaminergic neurons (15 ± 5% inhibition; p = 0.014). Isoflurane also inhibited exocytosis evoked by elevated KCl in dopaminergic neurons (35 ± 6% inhibition; p = 0.0007), but not in non-dopaminergic neurons (2 ± 4% inhibition). Pharmacological isolation of presynaptic Ca²⁺ channel subtypes showed that isoflurane inhibited KCl-evoked exocytosis mediated exclusively by either Ca_V2.1 (P/Q-type Ca²⁺ channels) (30 ± 5% inhibition; p = 0.0002) or by Ca_V2.2 (N-type Ca²⁺ channels) (35 ± 11% inhibition; p = 0.015). Additionally, isoflurane inhibited single AP-evoked Ca²⁺ influx by 41 ± 3% and single AP-evoked exocytosis by 34 ± 6%. Comparable reductions in exocytosis and Ca²⁺ influx were produced by lowering extracellular [Ca²⁺]. Thus, isoflurane inhibits exocytosis from dopaminergic neurons by a mechanism distinct from that in non-dopaminergic neurons involving reduced Ca²⁺ entry through Ca_V2.1 and/or Ca_V2.2.
SIGNIFICANCE STATEMENT Despite their medical importance, the mechanisms of action of general anesthetics have not been fully elucidated. Isoflurane, a widely used volatile anesthetic, inhibits voltage-gated sodium channels and differentially inhibits synaptic vesicle exocytosis depending on neurotransmitter phenotype. Here we show that in dopaminergic neurons of the ventral tegmental area isoflurane acts via a sodium channel-independent mechanism to inhibit synaptic vesicle exocytosis in proportion to reduced presynaptic Ca²⁺ flux mediated by Ca_V2.1 and/or Ca_V2.2, in contrast to its effects in non-dopaminergic neurons. These findings provide a synaptic mechanism for the observed role of reduced dopamine release in anesthetic-induced unconsciousness, and implicate presynaptic Ca²⁺ channels of dopaminergic neurons as important targets of isoflurane.

in RSS PAP on January 10, 2019 05:23 PM.
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Multimodal Characterization of Neural Networks Using Highly Transparent Electrode Arrays

Transparent and flexible materials are attractive for a wide range of emerging bioelectronic applications. These include neural interfacing devices for both recording and stimulation, where low electrochemical electrode impedance is valuable. Here the conducting polymer poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is used to fabricate electrodes that are small enough to allow unencumbered optical access for imaging a large cell population with two-photon (2P) microscopy, yet provide low impedance for simultaneous high quality recordings of neural activity in vivo. To demonstrate this, pathophysiological activity was induced in the mouse cortex using 4-aminopyridine (4AP), and the resulting electrical activity was detected with the PEDOT:PSS-based probe while imaging calcium activity directly below the probe area. The induced calcium activity of the neuronal network as measured by the fluorescence change in the cells correlated well with the electrophysiological recordings from the cortical grid of PEDOT:PSS microelectrodes. Our approach provides a valuable vehicle for complementing classical high temporal resolution electrophysiological analysis with optical imaging.

in eNeuro current issue on January 10, 2019 05:11 PM.
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Nociceptin/Orphanin-FQ Inhibits Gonadotropin-Releasing Hormone Neurons via G-Protein-Gated Inwardly Rectifying Potassium Channels
Abstract
The pulsatile release of gonadotropin-releasing hormone (GnRH) is a key feature of the hypothalamic–pituitary–gonadal axis. Kisspeptin neurons in the arcuate nucleus (ARC) trigger GnRH neuronal activity, but how GnRH neurons return to baseline electrical activity is unknown. Nociceptin/orphanin-FQ (OFQ) is an inhibitory neuromodulator. ARC proopiomelanocortin (POMC) neurons, known to receive inputs from ARC kisspeptin neurons, contact GnRH neurons and coexpress OFQ in the rat. In the present study, the effect of OFQ(1-13) on GnRH neurons was determined in the mouse. We identified transcripts for the OFQ receptor [opioid receptor like 1 (ORL1)] in GnRH neurons, and, using two-model systems (explants and slices), we found that OFQ exerted a potent inhibition on GnRH neurons, with or without excitatory inputs. We confirmed that the inhibition was mediated by ORL1 via G_i/o-protein coupling. The inhibition, occurring independently of levels of intracellular cyclic adenosine monophosphate, was sensitive to inwardly rectifying potassium channels. The only specific blocker of G_i/o-protein-coupled inwardly rectifying potassium (GIRK) channels, tertiapin-Q (TPNQ), was ineffective in the inhibition of OFQ. Two GIRK activators, one sharing the binding site of TPNQ and one active only on GIRK1-containing GIRK channels, failed to trigger an inhibition. In contrast, protein kinase C phosphorylation activation, known to inhibit GIRK2-mediated currents, prevented the OFQ inhibition. These results indicate a specific combination of GIRK subunits, GIRK2/3 in GnRH neurons. In vivo, double-labeled OFQ/POMC fibers were found in the vicinity of GnRH neurons, and OFQ fibers apposed GnRH neurons. Together, this study brings to light a potent neuromodulator of GnRH neurons.

in eNeuro current issue on January 10, 2019 05:11 PM.
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Single cell RNA-sequencing: replicability of cell types

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Megan Crow, Jesse Gillis
Recent technical advances have enabled transcriptomics experiments at an unprecedented scale, and single-cell profiles from neural tissue are accumulating rapidly. There has been considerable effort to use these profiles to understand cell diversity, primarily through unsupervised clustering and differential expression analysis. However, current practices to validate these findings vary. In this review, we describe recent efforts to evaluate clusters from single-cell RNA-sequencing data, and provide a framework for considering current evidence and practices in terms of their capacity to establish principles of cell biology. Single-cell RNA-sequencing has already transformed neuroscience. By facilitating detailed comparative and genetic perturbation analyses, it may provide the tools to uncover fundamental mechanisms of neural diversity throughout the tree of life.

in ScienceDirect Publication: Current Opinion in Neurobiology on January 10, 2019 12:00 PM.
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Correlated MRI and Ultramicroscopy (MR-UM) of Brain Tumors Reveals Vast Heterogeneity of Tumor Infiltration and Neoangiogenesis in Preclinical Models and Human Disease
Michael O. Breckwoldt, Julia Bode, Felix Sahm, Thomas Krüwel, Gergely Solecki, Artur Hahn, Peter Wirthschaft, Anna S. Berghoff, Maximilian Haas, Varun Venkataramani, Andreas von Deimling, Wolfgang Wick, Christel Herold-Mende, Sabine Heiland, Michael Platten, Martin Bendszus, Felix T. Kurz, Frank Winkler, Björn Tews
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 10, 2019 12:00 PM.
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Parkinsonian Neurotoxins Impair the Pro-inflammatory Response of Glial Cells
Neus Rabaneda-Lombarte, Efren Xicoy-Espaulella, Joan Serratosa, Josep Saura, Carme Solà
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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High-Altitude Cognitive Impairment Is Prevented by Enriched Environment Including Exercise via VEGF Signaling
Christina Koester-Hegmann, Harkaitz Bengoetxea, Dmitry Kosenkov, Markus Thiersch, Thomas Haider, Max Gassmann, Edith M. Schneider Gasser
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Extracellular Vesicles Secreted by Astroglial Cells Transport Apolipoprotein D to Neurons and Mediate Neuronal Survival Upon Oxidative Stress
Raquel Pascua-Maestro, Esperanza González, Concepción Lillo, Maria D. Ganfornina, Juan Manuel Falcón-Pérez, Diego Sanchez
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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CSF1R Stimulation Promotes Increased Neuroprotection by CD11c+ Microglia in EAE
Agnieszka Wlodarczyk, Anouk Benmamar-Badel, Oriane Cédile, Kirstine Nolling Jensen, Isabella Kramer, Nick Boe Elsborg, Trevor Owens
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Choice of Alternative Polyadenylation Sites, Mediated by the RNA-Binding Protein Elavl3, Plays a Role in Differentiation of Inhibitory Neuronal Progenitors
Elena Grassi, Roberto Santoro, Alessandro Umbach, Anna Grosso, Salvatore Oliviero, Francesco Neri, Luciano Conti, Ugo Ala, Paolo Provero, Ferdinando DiCunto, Giorgio R. Merlo
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Commentary: Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer's Disease
Janusz K. Rybakowski
in Frontiers in Aging Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Precuneus Dysfunction in Parkinson’s Disease With Mild Cognitive Impairment
Xiuqin Jia, Ying Li, Kuncheng Li, Peipeng Liang, Xiaolan Fu
in Frontiers in Aging Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Experience-Dependent Effects of Muscimol-Induced Hippocampal Excitation on Mnemonic Discrimination
Sarah A. Johnson, Sean M. Turner, Katelyn N. Lubke, Tara L. Cooper, Kaeli E. Fertal, Jennifer L. Bizon, Andrew P. Maurer, Sara N. Burke
in Frontiers in Systems Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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A Key Role for Subiculum-Fornix Connectivity in Recollection in Older Age
Naomi Hartopp, Paul Wright, Nicola J. Ray, Tavia E. Evans, Claudia Metzler-Baddeley, John P. Aggleton, Michael J. O’Sullivan
in Frontiers in Systems Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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What Can Computational Models Contribute to Neuroimaging Data Analytics?
Oleksandr V. Popovych, Thanos Manos, Felix Hoffstaedter, Simon B. Eickhoff
in Frontiers in Systems Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Topological Properties of Resting-State fMRI Functional Networks Improve Machine Learning-Based Autism Classification
Amirali Kazeminejad, Roberto C. Sotero
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 10, 2019 06:00 AM.
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Tau and mTOR: The Hotspots for Multifarious Diseases in Alzheimer's Development
Zeba Mueed, Pallavi Tandon, Sanjeev Kumar Maurya, Ravi Deval, Mohammad A. Kamal, Nitesh Kumar Poddar
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 10, 2019 06:00 AM.
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Quantitative Analyses Help in Choosing Between Simultaneous vs. Separate EEG and fMRI
Maarten Schrooten, Rik Vandenberghe, Ronald Peeters, Patrick Dupont
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 10, 2019 06:00 AM.
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Optimizing Data for Modeling Neuronal Responses
Peter Zeidman, Samira M. Kazan, Nick Todd, Nikolaus Weiskopf, Karl J. Friston, Martina F. Callaghan
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 10, 2019 06:00 AM.
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Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration
Prahalathan Pichavaram, Chithra Devi Palani, Chintan Patel, Zhimin Xu, Esraa Shosha, Abdelrahman Y. Fouda, Ruth B. Caldwell, Subhadra Priya Narayanan
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 10, 2019 06:00 AM.
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A Single-Cell Level and Connectome-Derived Computational Model of the Drosophila Brain
Yu-Chi Huang, Cheng-Te Wang, Ta-Shun Su, Kuo-Wei Kao, Yen-Jen Lin, Chao-Chun Chuang, Ann-Shyn Chiang, Chung-Chuan Lo
in Frontiers in Neuroinformatics | New and Recent Articles on January 10, 2019 06:00 AM.
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Modeling the Encoding of Saccade Kinematic Metrics in the Purkinje Cell Layer of the Cerebellar Vermis
Hari Teja Kalidindi, Thomas George Thuruthel, Cecilia Laschi, Egidio Falotico
in Frontiers in Computational Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Saccade Velocity Driven Oscillatory Network Model of Grid Cells
Ankur Chauhan, Karthik Soman, V. Srinivasa Chakravarthy
in Frontiers in Computational Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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duneuro - A software toolbox for forward modeling in neuroscience. (arXiv:1901.02874v2 [cs.MS] UPDATED)

This paper describes duneuro, a software toolbox for forward modeling in neuroscience. Its purpose is to provide extendible and easy-to-use interfaces and enable a closer integration into existing analysis pipelines. It provides implementations of fitted and unfitted finite element methods and makes use of the Dune framework. The forward problems consist of the electroencephalography (EEG) and magnetoencephalography (MEG) forward problems. For the incorporation into existing analysis pipelines, Python and Matlab interfaces are provided. The practical use is demonstrated on a source analysis example of evoked potentials.

in q-bio.NC updates on arXiv.org on January 10, 2019 01:30 AM.
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Visual novelty, curiosity, and intrinsic reward in machine learning and the brain. (arXiv:1901.02478v1 [q-bio.NC])

A strong preference for novelty emerges in infancy and is prevalent across the animal kingdom. When incorporated into reinforcement-based machine learning algorithms, visual novelty can act as an intrinsic reward signal that vastly increases the efficiency of exploration and expedites learning, particularly in situations where external rewards are difficult to obtain. Here we review parallels between recent developments in novelty-driven machine learning algorithms and our understanding of how visual novelty is computed and signaled in the primate brain. We propose that in the visual system, novelty representations are not configured with the principal goal of detecting novel objects, but rather with the broader goal of flexibly generalizing novelty information across different states in the service of driving novelty-based learning.

in q-bio.NC updates on arXiv.org on January 10, 2019 01:30 AM.
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HCN2 Channels in Cholinergic Interneurons of Nucleus Accumbens Shell Regulate Depressive Behaviors
Cheng et al. show that decreased expression and function of HCN2 channels cause reduced ChI tonic activity in NAc shell that leads to depressive phenotypes. Targeting HCN2 channels to enhance ChI activity is sufficient to rescue depression.
in Neuron on January 10, 2019 12:00 AM.
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Rostral and Caudal Ventral Tegmental Area GABAergic Inputs to Different Dorsal Raphe Neurons Participate in Opioid Dependence
Li and Li et al. dissect the microcircuits between VTA GABAergic neurons and DRN neurons, identifying distinct pathways that specifically modulate morphine reward without affecting the analgesic effects of morphine.
in Neuron on January 10, 2019 12:00 AM.
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A computational knowledge-base elucidates the response of <i>Staphylococcus aureus</i> to different media types

by Yara Seif, Jonathan M. Monk, Nathan Mih, Hannah Tsunemoto, Saugat Poudel, Cristal Zuniga, Jared Broddrick, Karsten Zengler, Bernhard O. Palsson
S. aureus is classified as a serious threat pathogen and is a priority that guides the discovery and development of new antibiotics. Despite growing knowledge of S. aureus metabolic capabilities, our understanding of its systems-level responses to different media types remains incomplete. Here, we develop a manually reconstructed genome-scale model (GEM-PRO) of metabolism with 3D protein structures for S. aureus USA300 str. JE2 containing 854 genes, 1,440 reactions, 1,327 metabolites and 673 3-dimensional protein structures. Computations were in 85% agreement with gene essentiality data from random barcode transposon site sequencing (RB-TnSeq) and 68% agreement with experimental physiological data. Comparisons of computational predictions with experimental observations highlight: 1) cases of non-essential biomass precursors; 2) metabolic genes subject to transcriptional regulation involved in Staphyloxanthin biosynthesis; 3) the essentiality of purine and amino acid biosynthesis in synthetic physiological media; and 4) a switch to aerobic fermentation upon exposure to extracellular glucose elucidated as a result of integrating time-course of quantitative exo-metabolomics data. An up-to-date GEM-PRO thus serves as a knowledge-based platform to elucidate S. aureus’ metabolic response to its environment.
in PLOS Computational Biology: New Articles on January 09, 2019 10:00 PM.
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Using the drug-protein interactome to identify anti-ageing compounds for humans

by Matías Fuentealba, Handan Melike Dönertaş, Rhianna Williams, Johnathan Labbadia, Janet M. Thornton, Linda Partridge
Advancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established their association with ageing at multiple levels of biological action including pathways, functions and protein interactions. Finally, combining all the data, we calculated a ranked list of drugs that identified tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.
in PLOS Computational Biology: New Articles on January 09, 2019 10:00 PM.
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Electrophysiological Correlates of Absolute Pitch in a Passive Auditory Oddball Paradigm: a Direct Replication Attempt
Abstract
Humans with absolute pitch (AP) are able to effortlessly name the pitch class of a sound without an external reference. The association of labels with pitches cannot be entirely suppressed even if it interferes with task demands. This suggests a high level of automaticity of pitch labeling in AP. The automatic nature of AP was further investigated in a study by Rogenmoser et al. (2015). Using a passive auditory oddball paradigm in combination with electroencephalography, they observed electrophysiological differences between musicians with and without AP in response to piano tones. Specifically, the AP musicians showed a smaller P3a, an event-related potential (ERP) component presumably reflecting early attentional processes. In contrast, they did not find group differences in the mismatch negativity (MMN), an ERP component associated with auditory memory processes. They concluded that early cognitive processes are facilitated in AP during passive listening and are more important for AP than the preceding sensory processes. In our direct replication study on a larger sample of musicians with (n = 54, 27 females, 27 males) and without (n = 50, 24 females, 26 males) AP, we successfully replicated the non-significant effects of AP on the MMN. However, we could not replicate the significant effects for the P3a. Additional Bayes factor analyses revealed moderate to strong evidence (Bayes factor > 3) for the null hypothesis for both MMN and P3a. Therefore, the results of this replication study do not support the postulated importance of cognitive facilitation in AP during passive tone listening.

in eNeuro current issue on January 09, 2019 05:30 PM.
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Erratum: Chariker et al., "Rhythm and Synchrony in a Cortical Network Model"

in Journal of Neuroscience current issue on January 09, 2019 05:30 PM.
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Top-down and Bottom-up Regulated Auditory Phantom Perception

Auditory phantom percepts such as tinnitus are associated with auditory deafferentation. The idea is that auditory deafferentation limits the amount of information the brain can acquire to make sense of the world. Because of this, auditory deafferentation increases the uncertainty of the auditory environment. To minimize uncertainty, the deafferented brain will attempt to obtain or fill in the missing information. A proposed multiphase compensation model suggests two distinct types of bottom-up related tinnitus: an auditory cortex related tinnitus and a parahippocampal cortex related tinnitus. The weakness of this model is that it cannot explain why some people without hearing loss develop tinnitus, whereas conversely others with hearing loss do not develop tinnitus. In this human study, we provide evidence for a top-down type of tinnitus associated with a deficient noise-cancelling mechanism. A total of 72 participants (age: 40.96 ± 7.67 years; males: 48; females: 24) were recruited for this study. We demonstrate that top-down related tinnitus is related to a change in the pregenual anterior cingulate cortex that corresponds to increased activity in the auditory cortex. This is in accordance with the idea that tinnitus can have different generators as proposed in a recent model that suggests that different compensation mechanisms at a cortical level can be linked to phantom percepts.

SIGNIFICANCE STATEMENT Chronic tinnitus affects 15% of the population worldwide. The term "tinnitus" however represents a highly heterogeneous condition, as evidenced by the fact that there are no effective treatments or even an adequate understanding of the underlying neural mechanisms. Consistent with this idea, our research shows that tinnitus indeed has different subtypes related to hearing loss. In a human study tightly controlled for hearing loss, we establish a tinnitus subtype associated with a deficient top-down noise-cancelling mechanism, which distinguishes it from bottom-up subtypes. We demonstrate that top-down related tinnitus relates to a change in the pregenual anterior cingulate cortex that corresponds to increased activity in the auditory cortex, whereas bottom-up tinnitus instead relates to changes in the parahippocampal cortex.

in Journal of Neuroscience current issue on January 09, 2019 05:30 PM.
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Directing Voluntary Temporal Attention Increases Fixational Stability

Our visual input is constantly changing, but not all moments are equally relevant. Visual temporal attention, the prioritization of visual information at specific points in time, increases perceptual sensitivity at behaviorally relevant times. The dynamic processes underlying this increase are unclear. During fixation, humans make small eye movements called microsaccades, and inhibiting microsaccades improves perception of brief stimuli. Here, we investigated whether temporal attention changes the pattern of microsaccades in anticipation of brief stimuli. Human observers (female and male) judged stimuli presented within a short sequence. Observers were given either an informative precue to attend to one of the stimuli, which was likely to be probed, or an uninformative (neutral) precue. We found strong microsaccadic inhibition before the stimulus sequence, likely due to its predictable onset. Critically, this anticipatory inhibition was stronger when the first target in the sequence (T1) was precued (task-relevant) than when the precue was uninformative. Moreover, the timing of the last microsaccade before T1 and the first microsaccade after T1 shifted such that both occurred earlier when T1 was precued than when the precue was uninformative. Finally, the timing of the nearest pre- and post-T1 microsaccades affected task performance. Directing voluntary temporal attention therefore affects microsaccades, helping to stabilize fixation at the most relevant moments over and above the effect of predictability. Just as saccading to a relevant stimulus can be an overt correlate of the allocation of spatial attention, precisely timed gaze stabilization can be an overt correlate of the allocation of temporal attention.

SIGNIFICANCE STATEMENT We pay attention at moments in time when a relevant event is likely to occur. Such temporal attention improves our visual perception, but how it does so is not well understood. Here, we discovered a new behavioral correlate of voluntary, or goal-directed, temporal attention. We found that the pattern of small fixational eye movements called microsaccades changes around behaviorally relevant moments in a way that stabilizes the position of the eyes. Microsaccades during a brief visual stimulus can impair perception of that stimulus. Therefore, such fixation stabilization may contribute to the improvement of visual perception at attended times. This link suggests that, in addition to cortical areas, subcortical areas mediating eye movements may be recruited with temporal attention.

in Journal of Neuroscience current issue on January 09, 2019 05:30 PM.
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Neural Substrates of Cognitive Motor Interference During Walking; Peripheral and Central Mechanisms
Emad Al-Yahya, Wala’ Mahmoud, Daan Meester, Patrick Esser, Helen Dawes
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Parietal Activation Associated With Target-Directed Right Hand Movement Is Lateralized by Mirror Feedback to the Ipsilateral Hemisphere
Thushini Manuweera, Mathew Yarossi, Sergei Adamovich, Eugene Tunik
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Neural Network Connectivity During Post-encoding Rest: Linking Episodic Memory Encoding and Retrieval
Okka J. Risius, Oezguer A. Onur, Julian Dronse, Boris von Reutern, Nils Richter, Gereon R. Fink, Juraj Kukolja
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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EEG Frequency Bands in Psychiatric Disorders: A Review of Resting State Studies
Jennifer J. Newson, Tara C. Thiagarajan
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Behind the Scenes of Developmental Language Disorder: Time to Call Neuropsychology Back on Stage
Ekaterina Tomas, Constance Vissers
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Multimodal Simon Effect: A Multimodal Extension of the Diffusion Model for Conflict Tasks
Mohammad-Ali Nikouei Mahani, Karin Maria Bausenhart, Majid Nili Ahmadabadi, Rolf Ulrich
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Idebenone Alleviates Neuroinflammation and Modulates Microglial Polarization in LPS-Stimulated BV2 Cells and MPTP-Induced Parkinson’s Disease Mice
Aijuan Yan, Zhihua Liu, Lu Song, Xijin Wang, Yu Zhang, Na Wu, Jingya Lin, Ying Liu, Zhenguo Liu
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Activin Receptor-Like Kinase 1 Combined With VEGF-A Affects Migration and Proliferation of Endothelial Cells From Sporadic Human Cerebral AVMs
Qiang Hao, Hao Wang, Jun-Lin Lu, Li Ma, Xiao-Lin Chen, Xun Ye, Ya-Hui Zhao, Ming-Tao Li, Yu Chen, Yuan-Li Zhao
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Expression of Tmem119/Sall1 and Ccr2/CD69 in FACS-Sorted Microglia- and Monocyte/Macrophage-Enriched Cell Populations After Intracerebral Hemorrhage
Qian Li, Xi Lan, Xiaoning Han, Jian Wang
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Locus Coeruleus Optogenetic Light Activation Induces Long-Term Potentiation of Perforant Path Population Spike Amplitude in Rat Dentate Gyrus
Meghan A. L. Quinlan, Vanessa M. Strong, Darlene M. Skinner, Gerard M. Martin, Carolyn W. Harley, Susan G. Walling
in Frontiers in Systems Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Disruption of Otoferlin Alters the Mode of Exocytosis at the Mouse Inner Hair Cell Ribbon Synapse
Hideki Takago, Tomoko Oshima-Takago, Tobias Moser
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse
Laura Orio, Francisco Alen, Francisco Javier Pavón, Antonia Serrano, Borja García-Bueno
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Ferroptosis Contributes to Isoflurane Neurotoxicity
Yimeng Xia, Xiaoyun Sun, Yan Luo, Creed M. Stary
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Expression and Roles of the Immunoglobulin Superfamily Recognition Molecule Sidekick1 in Mouse Retina
Masahito Yamagata, Joshua R. Sanes
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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An Excitatory/Inhibitory Switch From Asymmetric Sensory Neurons Defines Postsynaptic Tuning for a Rapid Response to NaCl in Caenorhabditis elegans
Masahiro Kuramochi, Motomichi Doi
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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PKR: A Kinase to Remember
Shunit Gal-Ben-Ari, Iliana Barrera, Marcelo Ehrlich, Kobi Rosenblum
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Analysis of α-Synuclein Pathology in PINK1 Knockout Rat Brains
Rose B. Creed, Matthew S. Goldberg
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 09, 2019 06:00 AM.
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Impact of Caffeine Consumption on Type 2 Diabetes-Induced Spatial Memory Impairment and Neurochemical Alterations in the Hippocampus
João M. N. Duarte, Cecilia Skoug, Henrique B. Silva, Rui A. Carvalho, Rolf Gruetter, Rodrigo A. Cunha
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 09, 2019 06:00 AM.
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Impact of Traumatic Brain Injury on Neurogenesis
Laura B. Ngwenya, Steve C. Danzer
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on January 09, 2019 06:00 AM.
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Radiation Induces Distinct Changes in Defined Subpopulations of Neural Stem and Progenitor Cells in the Adult Hippocampus
Olga A. Mineyeva, Dmitri V. Bezriadnov, Alexander V. Kedrov, Alexander A. Lazutkin, Konstantin V. Anokhin, Grigori N. Enikolopov
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on January 09, 2019 06:00 AM.
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The Evaluation of Dynamic FDG-PET for Detecting Epileptic Foci and Analyzing Reduced Glucose Phosphorylation in Refractory Epilepsy
Yongxiang Tang, Jeih-San Liow, Zhimin Zhang, Jian Li, Tingting Long, Yulai Li, Beisha Tang, Shuo Hu
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 09, 2019 06:00 AM.
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Longitudinal Connectomes as a Candidate Progression Marker for Prodromal Parkinson’s Disease
Óscar Peña-Nogales, Timothy M. Ellmore, Rodrigo de Luis-García, Jessika Suescun, Mya C. Schiess, Luca Giancardo
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 09, 2019 06:00 AM.
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Memory Reinforcement and Attenuation by Activating the Human Locus Coeruleus via Transcutaneous Vagus Nerve Stimulation
Niels Hansen
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 09, 2019 06:00 AM.
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Bio-inspired Analysis of Deep Learning on Not-So-Big Data Using Data-Prototypes
Thalita F. Drumond, Thierry Viéville, Frédéric Alexandre
in Frontiers in Computational Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Understanding Sensory Information Processing Through Simultaneous Multi-area Population Recordings
Elizabeth Zavitz, Nicholas S. C. Price
in Frontiers in Neural Circuits | New and Recent Articles on January 09, 2019 06:00 AM.
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Relationship Between DTI Metrics and Cognitive Function in Alzheimer’s Disease
Chantel D. Mayo, Mauricio A. Garcia-Barrera, Erin L. Mazerolle, Lesley J. Ritchie, John D. Fisk, Jodie R. Gawryluk, Alzheimer’s Disease Neuroimaging Initiative
in Frontiers in Aging Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Differences in Cognitive-Motor Interference in Older Adults While Walking and Performing a Visual-Verbal Stroop Task
Bettina Wollesen, Claudia Voelcker-Rehage
in Frontiers in Aging Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Metabolite Profile of Alzheimer’s Disease in the Frontal Cortex as Analyzed by HRMAS 1H NMR
Yuzhong Zhang, Zhou Liu, Bing Ji, Lijian Liu, Shaoxiong Wu, Xiaowu Liu, Silun Wang, Liya Wang
in Frontiers in Aging Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Two-Photon Uncaging of Glutamate
Graham C. R. Ellis-Davies
in Frontiers in Synaptic Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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The role of AMPA receptor exchange in systems memory reconsolidation: A computational model. (arXiv:1901.02270v2 [q-bio.NC] UPDATED)

In the mammalian brain newly acquired memories depend on the hippocampus for maintenance and recall, but over time these functions are taken over by the neocortex through a process called systems consolidation. However, reactivation of a consolidated memory can induce a brief period of temporary hippocampus-dependence, followed by return to hippocampus-independence. Here we present a computational model that uses simulation of recently described mechanisms of synaptic plasticity to account for findings from the systems consolidation/reconsolidation literature and to make predictions for future research.

in q-bio.NC updates on arXiv.org on January 09, 2019 01:30 AM.
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Extracting impedance changes from a frequency multiplexed signal during neural activity in sciatic nerve of rat: preliminary study in-vitro. (arXiv:1901.02068v1 [q-bio.NC])

Objective: Establish suitable frequency spacing and demodulation steps to use when extracting impedance changes from frequency division multiplexed (FDM) carrier signals in peripheral nerve. Approach: Experiments were performed in-vitro on cadavers immediately following euthanasia. Neural activity was evoked via stimulation of nerves in the hind paw, while carrier signals were injected, and recordings obtained, with a dual ring nerve cuff implanted on the sciatic nerve. Frequency analysis of recorded compound action potentials (CAPs) and extracted impedance changes, with the latter obtained using established demodulation methods, were used to determine suitable frequency spacing of carrier signals, and bandpass filter (BPF) bandwidth and order, for a frequency multiplexed signal. Main results: CAPs and impedance changes were dominant in the frequency band 200 to 500 Hz and 100 to 200 Hz, respectively. A Tukey window was introduced to remove ringing from Gibbs phenomena. A +/- 750 Hz BPF bandwidth was selected to encompass 99.99 % of the frequency power of the impedance change. Modelling predicted a minimum BPF order of 16 for 2 kHz spacing, and 10 for 4 kHz spacing, were required to avoid ringing from the neighbouring carrier signal, while FDM experiments verified BPF orders of 12 and 8, respectively, were required. With a notch filter centred on the neighbouring signal, a BPF order of at least 6 or 4 was required for 2 and 4 kHz, respectively. Significance: The results establish drive frequency spacing and demodulation settings for use in FDM electrical impedance tomography (EIT) experiments, as well as a framework for their selection, and, for the first time, demonstrates the viability of FDM-EIT of neural activity on peripheral nerve, which will be a central aspect of future real-time neural-EIT systems and EIT-based neural prosthetics interfaces.

in q-bio.NC updates on arXiv.org on January 09, 2019 01:30 AM.
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Differential NOVA2-Mediated Splicing in Excitatory and Inhibitory Neurons Regulates Cortical Development and Cerebellar Function
cTag-CLIP provides a next-generation strategy to profile functional protein:RNA interactions at cell-specific resolution in vivo. Saito et al. show that differential NOVA2 regulatory actions on alternative splicing coupled to intron removal in different neurons.
in Neuron on January 09, 2019 12:00 AM.
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Pioneer Factor NeuroD1 Rearranges Transcriptional and Epigenetic Profiles to Execute Microglia-Neuron Conversion
Matsuda et al. report direct neuronal conversion of microglia induced by the expression of a single transcription factor, NeuroD1, which occupies bivalent epigenetic domains for neuronal gene induction. NeuroD1 can also converts microglia into neurons in the adult mouse striatum.
in Neuron on January 09, 2019 12:00 AM.
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Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

in Wiley: Annals of Neurology: Table of Contents on January 08, 2019 06:42 PM.
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Cerebro-Cerebellar Pathways for Verbal Working Memory
Monika Sobczak-Edmans, Yu-Chun Lo, Yung-Chin Hsu, Yu-Jen Chen, Fu Yu Kwok, Kai-Hsiang Chuang, Wen-Yih Isaac Tseng, S. H. Annabel Chen
in Frontiers in Human Neuroscience | New and Recent Articles on January 08, 2019 06:00 PM.
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Spectral Imprints of Working Memory for Everyday Associations in the Frontoparietal Network
Elizabeth L. Johnson, David King-Stephens, Peter B. Weber, Kenneth D. Laxer, Jack J. Lin, Robert T. Knight
in Frontiers in Systems Neuroscience | New and Recent Articles on January 08, 2019 06:00 PM.
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Group II Metabotropic Glutamate Receptors Mediate Presynaptic Inhibition of Excitatory Transmission in Pyramidal Neurons of the Human Cerebral Cortex
Marco Bocchio, Istvan P. Lukacs, Richard Stacey, Puneet Plaha, Vasileios Apostolopoulos, Laurent Livermore, Arjune Sen, Olaf Ansorge, Martin J. Gillies, Peter Somogyi, Marco Capogna
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 08, 2019 06:00 PM.
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18F-FDG-PET Detects Drastic Changes in Brain Metabolism in the Tg4–42 Model of Alzheimer’s Disease
Caroline Bouter, Philipp Henniges, Timon N. Franke, Caroline Irwin, Carsten Oliver Sahlmann, Marius E. Sichler, Nicola Beindorff, Thomas A. Bayer, Yvonne Bouter
in Frontiers in Aging Neuroscience | New and Recent Articles on January 08, 2019 06:00 PM.
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A Computational Model of Dual Competition between the Basal Ganglia and the Cortex
Abstract
We propose a model that includes interactions between the cortex, the basal ganglia (BG), and the thalamus based on a dual competition. We hypothesize that the striatum, the subthalamic nucleus (STN), the internal globus pallidus (GPi), the thalamus, and the cortex are involved in closed feedback loops through the hyperdirect and direct pathways. These loops support a competition process that results in the ability of BG to make a cognitive decision followed by a motor one. Considering lateral cortical interactions, another competition takes place inside the cortex allowing the latter to make a cognitive and a motor decision. We show how this dual competition endows the model with two regimes. One is driven by reinforcement learning and the other by Hebbian learning. The final decision is made according to a combination of these two mechanisms with a gradual transfer from the former to the latter. We confirmed these theoretical results on primates (Macaca mulatta) using a novel paradigm predicted by the model.

in eNeuro current issue on January 08, 2019 05:30 PM.
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The systemDrive: a Multisite, Multiregion Microdrive with Independent Drive Axis Angling for Chronic Multimodal Systems Neuroscience Recordings in Freely Behaving Animals

A multielectrode system that can address widely separated targets at multiple sites across multiple brain regions with independent implant angling is needed to investigate neural function and signaling in systems and circuits of small animals. Here, we present the systemDrive, a novel multisite, multiregion microdrive that is capable of moving microwire electrode bundles into targets along independent and nonparallel drive trajectories. Our design decouples the stereotaxic surgical placement of individual guide cannulas for each trajectory from the placement of a flexible drive structure. This separation enables placement of many microwire multitrodes along widely spaced and independent drive axes with user-set electrode trajectories and depths from a single microdrive body, and achieves stereotaxic precision with each. The system leverages tight tube–cannula tolerances and geometric constraints on flexible drive axes to ensure concentric alignment of electrode bundles within guide cannulas. Additionally, the headmount and microdrive both have an open-center design to allow for the placement of additional sensing modalities. This design is the first, in the context of small rodent chronic research, to provide the capability to finely position microwires through multiple widely distributed cell groups, each with stereotaxic precision, along arbitrary and nonparallel trajectories that are not restricted to emanate from a single source. We demonstrate the use of the systemDrive in male Long–Evans rats to observe simultaneous single-unit and multiunit activity from multiple widely separated sleep–wake regulatory brainstem cell groups, along with cortical and hippocampal activity, during free behavior over multiple many-day continuous recording periods.

in eNeuro current issue on January 08, 2019 05:30 PM.
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Electrophysiological Excitability and Parallel Fiber Synaptic Properties of Zebrin-Positive and -Negative Purkinje Cells in Lobule VIII of the Mouse Cerebellar Slice
Viet T. Nguyen-Minh, Khoa Tran-Anh, Yuanjun Luo, Izumi Sugihara
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 08, 2019 12:00 PM.
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An Empirical Comparison of Meta- and Mega-Analysis With Data From the ENIGMA Obsessive-Compulsive Disorder Working Group
Premika S. W. Boedhoe, Martijn W. Heymans, Lianne Schmaal, Yoshinari Abe, Pino Alonso, Stephanie H. Ameis, Alan Anticevic, Paul D. Arnold, Marcelo C. Batistuzzo, Francesco Benedetti, Jan C. Beucke, Irene Bollettini, Anushree Bose, Silvia Brem, Anna Calvo, Rosa Calvo, Yuqi Cheng, Kang Ik K. Cho, Valentina Ciullo, Sara Dallaspezia, Damiaan Denys, Jamie D. Feusner, Kate D. Fitzgerald, Jean-Paul Fouche, Egill A. Fridgeirsson, Patricia Gruner, Gregory L. Hanna, Derrek P. Hibar, Marcelo Q. Hoexter, Hao Hu, Chaim Huyser, Neda Jahanshad, Anthony James, Norbert Kathmann, Christian Kaufmann, Kathrin Koch, Jun Soo Kwon, Luisa Lazaro, Christine Lochner, Rachel Marsh, Ignacio Martínez-Zalacaín, David Mataix-Cols, José M. Menchón, Luciano Minuzzi, Astrid Morer, Takashi Nakamae, Tomohiro Nakao, Janardhanan C. Narayanaswamy, Seiji Nishida, Erika L. Nurmi, Joseph O'Neill, John Piacentini, Fabrizio Piras, Federica Piras, Y. C. Janardhan Reddy, Tim J. Reess, Yuki Sakai, Joao R. Sato, H. Blair Simpson, Noam Soreni, Carles Soriano-Mas, Gianfranco Spalletta, Michael C. Stevens, Philip R. Szeszko, David F. Tolin, Guido A. van Wingen, Ganesan Venkatasubramanian, Susanne Walitza, Zhen Wang, Je-Yeon Yun, ENIGMA-OCD Working-Group , Paul M. Thompson, Dan J. Stein, Odile A. van den Heuvel, Jos W. R. Twisk
in Frontiers in Neuroinformatics | New and Recent Articles on January 08, 2019 12:00 PM.
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On the Influence of Structural Connectivity on the Correlation Patterns and Network Synchronization
Parisa Sadat Nazemi, Yousef Jamali
in Frontiers in Computational Neuroscience | New and Recent Articles on January 08, 2019 12:00 PM.
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Minimal Circuit Model of Reward Prediction Error Computations and Effects of Nicotinic Modulations
Nicolas Deperrois, Victoria Moiseeva, Boris Gutkin
in Frontiers in Neural Circuits | New and Recent Articles on January 08, 2019 12:00 PM.
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Differences in Gene Expression Profiles and Phenotypes of Differentiated SH-SY5Y Neurons Stably Overexpressing Mitochondrial Ferritin
Anarmaa Mendsaikhan, Shigeko Takeuchi, Douglas G. Walker, Ikuo Tooyama
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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Mitochondrial Calcium Transporters Mediate Sensitivity to Noise-Induced Losses of Hair Cells and Cochlear Synapses
Xianren Wang, Yuanping Zhu, Haishan Long, Song Pan, Hao Xiong, Qiaojun Fang, Kayla Hill, Ruosha Lai, Hu Yuan, Su-Hua Sha
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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Oculomotor and Inhibitory Control in Dyslexia
Thomas D. W. Wilcockson, Diako Mardanbegi, Peter Sawyer, Hans Gellersen, Baiqiang Xia, Trevor J. Crawford
in Frontiers in Systems Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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The Cortical States of Wakefulness
James F. A. Poulet, Sylvain Crochet
in Frontiers in Systems Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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Effects of High-Definition Transcranial Direct Current Stimulation (HD-tDCS) of the Intraparietal Sulcus and Dorsolateral Prefrontal Cortex on Working Memory and Divided Attention
Stevan Nikolin, Shani Lauf, Colleen K. Loo, Donel Martin
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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Ceruloplasmin Plays a Neuroprotective Role in Cerebral Ischemia
Fari Ryan, Juan G. Zarruk, Lena Lößlein, Samuel David
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 08, 2019 06:00 AM.
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Postnatal Development of NPY and Somatostatin-28 Peptidergic Populations in the Human Angular Bundle
Sandra Cebada-Sánchez, Pilar Marcos Rabal, Ana María Insausti, Ricardo Insausti
in Frontiers in Neuroanatomy | New and Recent Articles on January 08, 2019 06:00 AM.
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Hacking the Brain: Triggering Neuroplasticity for Enhancing Musical Talent. (arXiv:1901.01362v1 [q-bio.NC])

In this paper, we analyze the cognitive improvements that can be achieved through hacking the brain and using neuroplasticity. Not all cases of neuroplasticity are useful, but exposure to gaming, for example, has proven conducive for learning. We will discuss cortical magnification and receptive field sizes, as well as topographic brain maps in the context of neuroplasticity. We finally propose more studies to be performed to improve musical talent and musical abilities.

in q-bio.NC updates on arXiv.org on January 08, 2019 01:30 AM.
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Adaptive Internal Models: Explaining the Oculomotor System and the Cerebellum. (arXiv:1901.01309v1 [q-bio.NC])

We propose a new model of the oculomotor system, particularly the vestibulo-ocular reflex, the optokinetic reflex, gaze fixation, and smooth pursuit. Our key insight is to exploit recent developments on adaptive internal models. The outcome is a simple model that includes the interactions between the brainstem and the cerebellum and that recovers behaviors from more than 15 oculomotor experiments. In addition, we put forward a thesis that the cerebellum embodies internal models of all persistent, exogenous reference and disturbance signals acting on the body and observable through the error signals it receives. Our proposed architecture is compared to feedback error learning, a variant of the computed torque method in robotics and currently the best developed computational architecture for the cerebellum.

in q-bio.NC updates on arXiv.org on January 08, 2019 01:30 AM.
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Publisher Correction: Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry

Publisher Correction: Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry
Publisher Correction: Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry, Published online: 08 January 2019; doi:10.1038/s41593-018-0306-y
Publisher Correction: Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry
in Nature Neuroscience - Issue - nature.com science feeds on January 08, 2019 12:00 AM.
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Layer-Specific Physiological Features and Interlaminar Interactions in the Primary Visual Cortex of the Mouse
The relationship between LFP patterns and single-neuron firing in the visual cortex is identified by Senzai et al. by using high-density silicon probe recordings, ICA-based LFP analysis, LFP-spike coupling, and spike transmission probability in freely moving mice.
in Neuron on January 08, 2019 12:00 AM.
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Calcium phosphate precipitation inhibits mitochondrial energy metabolism

by Sathyavani Malyala, Yizhu Zhang, Jasiel O. Strubbe, Jason N. Bazil
Early studies have shown that moderate levels of calcium overload can cause lower oxidative phosphorylation rates. However, the mechanistic interpretations of these findings were inadequate. And while the effect of excessive calcium overload on mitochondrial function is well appreciated, there has been little to no reports on the consequences of low to moderate calcium overload. To resolve this inadequacy, mitochondrial function from guinea pig hearts was quantified using several well-established methods including high-resolution respirometry and spectrofluorimetry and analyzed using mathematical modeling. We measured key mitochondrial variables such as respiration, mitochondrial membrane potential, buffer calcium, and substrate effects for a range of mitochondrial calcium loads from near zero to levels approaching mitochondrial permeability transition. In addition, we developed a computer model closely mimicking the experimental conditions and used this model to design experiments capable of eliminating many hypotheses generated from the data analysis. We subsequently performed those experiments and determined why mitochondrial ADP-stimulated respiration is significantly lowered during calcium overload. We found that when calcium phosphate levels, not matrix free calcium, reached sufficient levels, complex I activity is inhibited, and the rate of ATP synthesis is reduced. Our findings suggest that calcium phosphate granules form physical barriers that isolate complex I from NADH, disrupt complex I activity, or destabilize cristae and inhibit NADH-dependent respiration.
in PLOS Computational Biology: New Articles on January 07, 2019 10:00 PM.
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Protein—protein binding supersites

by Raji Viswanathan, Eduardo Fajardo, Gabriel Steinberg, Matthew Haller, Andras Fiser
The lack of a deep understanding of how proteins interact remains an important roadblock in advancing efforts to identify binding partners and uncover the corresponding regulatory mechanisms of the functions they mediate. Understanding protein-protein interactions is also essential for designing specific chemical modifications to develop new reagents and therapeutics. We explored the hypothesis of whether protein interaction sites serve as generic biding sites for non-cognate protein ligands, just as it has been observed for small-molecule-binding sites in the past. Using extensive computational docking experiments on a test set of 241 protein complexes, we found that indeed there is a strong preference for non-cognate ligands to bind to the cognate binding site of a receptor. This observation appears to be robust to variations in docking programs, types of non-cognate protein probes, sizes of binding patches, relative sizes of binding patches and full-length proteins, and the exploration of obligate and non-obligate complexes. The accuracy of the docking scoring function appears to play a role in defining the correct site. The frequency of interaction of unrelated probes recognizing the binding interface was utilized in a simple prediction algorithm that showed accuracy competitive with other state of the art methods.
in PLOS Computational Biology: New Articles on January 07, 2019 10:00 PM.
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Mutation, drift and selection in single-driver hematologic malignancy: Example of secondary myelodysplastic syndrome following treatment of inherited neutropenia

by Tomasz Wojdyla, Hrishikesh Mehta, Taly Glaubach, Roberto Bertolusso, Marta Iwanaszko, Rosemary Braun, Seth J. Corey, Marek Kimmel
Cancer development is driven by series of events involving mutations, which may become fixed in a tumor via genetic drift and selection. This process usually includes a limited number of driver (advantageous) mutations and a greater number of passenger (neutral or mildly deleterious) mutations. We focus on a real-world leukemia model evolving on the background of a germline mutation. Severe congenital neutropenia (SCN) evolves to secondary myelodysplastic syndrome (sMDS) and/or secondary acute myeloid leukemia (sAML) in 30–40%. The majority of SCN cases are due to a germline ELANE mutation. Acquired mutations in CSF3R occur in >70% sMDS/sAML associated with SCN. Hypotheses underlying our model are: an ELANE mutation causes SCN; CSF3R mutations occur spontaneously at a low rate; in fetal life, hematopoietic stem and progenitor cells expands quickly, resulting in a high probability of several tens to several hundreds of cells with CSF3R truncation mutations; therapeutic granulocyte colony-stimulating factor (G-CSF) administration early in life exerts a strong selective pressure, providing mutants with a growth advantage. Applying population genetics theory, we propose a novel two-phase model of disease development from SCN to sMDS. In Phase 1, hematopoietic tissues expand and produce tens to hundreds of stem cells with the CSF3R truncation mutation. Phase 2 occurs postnatally through adult stages with bone marrow production of granulocyte precursors and positive selection of mutants due to chronic G-CSF therapy to reverse the severe neutropenia. We predict the existence of the pool of cells with the mutated truncated receptor before G-CSF treatment begins. The model does not require increase in mutation rate under G-CSF treatment and agrees with age distribution of sMDS onset and clinical sequencing data.
in PLOS Computational Biology: New Articles on January 07, 2019 10:00 PM.
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Sour grapes and sweet victories: How actions shape preferences

by Fabien Vinckier, Lionel Rigoux, Irma T. Kurniawan, Chen Hu, Sacha Bourgeois-Gironde, Jean Daunizeau, Mathias Pessiglione
Classical decision theory postulates that choices proceed from subjective values assigned to the probable outcomes of alternative actions. Some authors have argued that opposite causality should also be envisaged, with choices influencing subsequent values expressed in desirability ratings. The idea is that agents may increase their ratings of items that they have chosen in the first place, which has been typically explained by the need to reduce cognitive dissonance. However, evidence in favor of this reverse causality has been the topic of intense debates that have not reached consensus so far. Here, we take a novel approach using Bayesian techniques to compare models in which choices arise from stable (but noisy) underlying values (one-way causality) versus models in which values are in turn influenced by choices (two-way causality). Moreover, we examined whether in addition to choices, other components of previous actions, such as the effort invested and the eventual action outcome (success or failure), could also impact subsequent values. Finally, we assessed whether the putative changes in values were only expressed in explicit ratings, or whether they would also affect other value-related behaviors such as subsequent choices. Behavioral data were obtained from healthy participants in a rating-choice-rating-choice-rating paradigm, where the choice task involves deciding whether or not to exert a given physical effort to obtain a particular food item. Bayesian selection favored two-way causality models, where changes in value due to previous actions affected subsequent ratings, choices and action outcomes. Altogether, these findings may help explain how values and actions drift when several decisions are made successively, hence highlighting some shortcomings of classical decision theory.
in PLOS Computational Biology: New Articles on January 07, 2019 10:00 PM.
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A Strategy for Discovery and Verification of Candidate Biomarkers in Cerebrospinal Fluid of Preclinical Alzheimer’s Disease
Xiaofang Zhong, Jingxin Wang, Cynthia Carlsson, Ozioma Okonkwo, Henrik Zetterberg, Lingjun Li
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 07, 2019 06:00 PM.
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Hippocampal Neurogenesis Reduces the Dimensionality of Sparsely Coded Representations to Enhance Memory Encoding
Anthony J. DeCostanzo, Chi Chung Alan Fung, Tomoki Fukai
in Frontiers in Computational Neuroscience | New and Recent Articles on January 07, 2019 06:00 PM.
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Large normal alleles of ATXN2 decrease age‐at‐onset in TTR‐FAP Val30Met patients

Abstract

Objective

Transthyretin (TTR) related familial amyloid polyneuropathy (FAP) is an autosomal dominant neurological disease, caused most frequently by a Val30Met (now classified as Val50Met) substitution in TTR. Age‐at‐onset (AO) ranges 19‐82 years and variability exists mostly between generations. Unstable oligonucleotide repeats in various genes are the mechanism behind several neurological diseases, found also to act as modifiers for other disorders. Our aim was to investigate whether large normal repeat alleles of ten genes, had a possible modifier effect in AO in Portuguese TTR‐FAP Val30Met families.

Methods

We analysed 329 Portuguese patients, from 123 families. Repeat length (at ATXN1, ATXN2, ATXN3, ATXN7, TBP, ATN1, HTT, JPH3, AR and DMPK) was assessed by single and multiplex PCR, using fluorescently‐labelled primers, followed by capillary electrophoresis. We used a family‐centred approach and generalized estimating equations (GEE) were used to account for AO correlation between family members.

Results

For ATXN2, the presence of at least one allele longer than 22 CAGs was significantly associated with an earlier onset in TTR‐FAP Val30Met, decreasing mean AO by 6 years (95% CI: [‐8.81; ‐2.19], p=0.001). No association was found for the remaining repeat loci.

Interpretation

Length of normal repeats at ATXN2 may modify AO in TTR‐FAP Val30Met and may function as a risk factor. This can be due to ATXN2 role in RNA metabolism and as a modulator of various cellular processes, including mitochondrial stress. This may have relevant implications for prognosis and the follow‐up of presymptomatic carriers.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on January 07, 2019 03:23 PM.
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Final Results of the RHAPSODY Trial: A Multi‐Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A‐APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke

Objective

Agonism of protease‐activated receptor (PAR) 1 by activated protein C (APC) provides neuro‐ and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A‐APC, reduces neurological injury and promotes vascular integrity; 3K3A‐APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A‐APC in ischemic stroke patients.

Methods

The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 μg/kg of 3K3A‐APC. After intravenous tissue plasminogen activator, intra‐arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates.

Results

Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest‐dose 3K3A‐APC tested, 540 μg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A‐APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066).

Interpretation

RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 μg/kg for the PAR1 active cytoprotectant, 3K3A‐APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation.

Clinical Trial Registration

Clinical Trial Registration‐URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. Ann Neurol 2018;00:1–12

in Wiley: Annals of Neurology: Table of Contents on January 07, 2019 11:36 AM.
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Vascular Risk and β‐Amyloid Are Synergistically Associated with Cortical Tau

Objective

Neuropathological studies have demonstrated that cerebrovascular disease and Alzheimer disease (AD) pathology frequently co‐occur in older adults. The extent to which cerebrovascular disease influences the progression of AD pathology remains unclear. Leveraging newly available positron emission tomography (PET) imaging, we examined whether a well‐validated measure of systemic vascular risk and β‐amyloid (Aβ) burden have an interactive association with regional tau burden.

Methods

Vascular risk was quantified at baseline in 152 clinically normal older adults (mean age = 73.5 ± 6.1 years) with the office‐based Framingham Heart Study cardiovascular disease risk algorithm (FHS‐CVD). We acquired Aβ (¹¹C‐Pittsburgh compound B) and tau (¹⁸F‐flortaucipir) PET imaging on the same participants. Aβ PET was performed at baseline; tau PET was acquired on average 2.98 ± 1.1 years later. Tau was measured in the entorhinal cortex (EC), an early site of tau deposition, and in the inferior temporal cortex (ITC), an early site of neocortical tau accumulation associated with AD. Linear regression models examined FHS‐CVD and Aβ as interactive predictors of tau deposition, adjusting for age, sex, APOE ε4 status, and the time interval between baseline and the tau PET scan.

Results

We observed a significant interaction between FHS‐CVD and Aβ burden on subsequently measured ITC tau (p < 0.001), whereby combined higher FHS‐CVD and elevated Aβ burden was associated with increased tau. The interaction was not significant for EC tau (p = 0.16).

Interpretation

Elevated vascular risk may influence tau burden when coupled with high Aβ burden. These results suggest a potential link between vascular risk and tau pathology in preclinical AD. Ann Neurol 2019; 1–8

in Wiley: Annals of Neurology: Table of Contents on January 07, 2019 11:35 AM.
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Neural basis of induced phantom limb pain relief

Objective

Phantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP‐related disease mechanisms. Noninvasive brain stimulation (NIBS) is used to modulate plasticity in various neuropathological diseases, including chronic pain. Although NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS‐induced PLP relief is needed for future implementation of such treatment and generalization to related conditions.

Methods

We used a within‐participants, double‐blind, and sham‐controlled design to alleviate PLP via task‐concurrent NIBS over the primary sensorimotor missing hand cortex (S1/M1). To specifically influence missing hand signal processing, amputees performed phantom hand movements during anodal transcranial direct current stimulation. Brain activity was monitored using neuroimaging during and after NIBS. PLP ratings were obtained throughout the week after stimulation.

Results

A single session of intervention NIBS significantly relieved PLP, with effects lasting at least 1 week. PLP relief associated with reduced activity in the S1/M1 missing hand cortex after stimulation. Critically, PLP relief and reduced S1/M1 activity correlated with preceding activity changes during stimulation in the mid‐ and posterior insula and secondary somatosensory cortex (S2).

Interpretation

The observed correlation between PLP relief and decreased S1/M1 activity confirms our previous findings linking PLP with increased S1/M1 activity. Our results further highlight the driving role of the mid‐ and posterior insula, as well as S2, in modulating PLP. Lastly, our novel PLP intervention using task‐concurrent NIBS opens new avenues for developing treatment for PLP and related pain conditions. Ann Neurol 2018;00:1–15

in Wiley: Annals of Neurology: Table of Contents on January 07, 2019 11:35 AM.
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Clinicopathology conference: 41‐year‐old woman with chronic relapsing meningitis

in Wiley: Annals of Neurology: Table of Contents on January 07, 2019 11:34 AM.
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Predicting Progression to Mild Cognitive Impairment

Despite much attention to the use of biomarkers for predicting Alzheimer disease, little information is available at the individual level. We used the population‐based Mayo Clinic Study of Aging to estimate absolute risk of cognitive impairment by biomarker group. Risk increased with age and any biomarker abnormality. For example, a 75‐year‐old with abnormal amyloid and cortical thinning biomarkers has about a 20% chance of cognitive impairment by age 80 years, whereas with normal biomarkers the chance is <10%. Persons with only one abnormal biomarker had similar intermediate risks. Ann Neurol 2018:1–6

in Wiley: Annals of Neurology: Table of Contents on January 07, 2019 11:34 AM.
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Respiration and Heart Rate Modulation Due to Competing Cognitive Tasks While Driving
Antonio R. Hidalgo-Muñoz, Adolphe J. Béquet, Mathis Astier-Juvenon, Guillaume Pépin, Alexandra Fort, Christophe Jallais, Hélène Tattegrain, Catherine Gabaude
in Frontiers in Human Neuroscience | New and Recent Articles on January 07, 2019 06:00 AM.
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Different Contexts in the Oddball Paradigm Induce Distinct Brain Networks in Generating the P300
Fali Li, Chanlin Yi, Yuanling Jiang, Yuanyuan Liao, Yajing Si, Jing Dai, Dezhong Yao, Yangsong Zhang, Peng Xu
in Frontiers in Human Neuroscience | New and Recent Articles on January 07, 2019 06:00 AM.
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Light-Induced Thiol Oxidation of Recoverin Affects Rhodopsin Desensitization
Evgeni Yu. Zernii, Aliya A. Nazipova, Ekaterina L. Nemashkalova, Alexey S. Kazakov, Olga S. Gancharova, Marina V. Serebryakova, Natalya K. Tikhomirova, Viktoriia E. Baksheeva, Vasiliy I. Vladimirov, Dmitry V. Zinchenko, Pavel P. Philippov, Ivan I. Senin, Sergei E. Permyakov
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 07, 2019 06:00 AM.
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Deep Learning Based Attenuation Correction of PET/MRI in Pediatric Brain Tumor Patients: Evaluation in a Clinical Setting
Claes Nøhr Ladefoged, Lisbeth Marner, Amalie Hindsholm, Ian Law, Liselotte Højgaard, Flemming Littrup Andersen
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 07, 2019 06:00 AM.
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Dynamic Alterations in Spontaneous Neural Activity in Multiple Brain Networks in Subacute Stroke Patients: A Resting-State fMRI Study
Jing Chen, Dalong Sun, Yonghui Shi, Wei Jin, Yanbin Wang, Qian Xi, Chuancheng Ren
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 07, 2019 06:00 AM.
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An Integrative Approach to Treat Parkinson's Disease: Ukgansan Complements L-Dopa by Ameliorating Dopaminergic Neuronal Damage and L-Dopa-Induced Dyskinesia in Mice
Eugene Huh, Jin Gyu Choi, Yeomoon Sim, Myung Sook Oh
in Frontiers in Aging Neuroscience | New and Recent Articles on January 07, 2019 06:00 AM.
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Gestational Exposure to Particulate Matter 2.5 (PM2.5) Leads to Spatial Memory Dysfunction and Neurodevelopmental Impairment in Hippocampus of Mice Offspring
Xinrui Zheng, Xia Wang, Tingting Wang, Hongxia Zhang, Hongjuan Wu, Can Zhang, Li Yu, Yingjun Guan
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on January 07, 2019 06:00 AM.
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Manganese Enhanced MRI for Use in Studying Neurodegenerative Diseases
Galit Saar, Alan P. Koretsky
in Frontiers in Neural Circuits | New and Recent Articles on January 07, 2019 06:00 AM.
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A Dual Role Hypothesis of the Cortico-Basal-Ganglia Pathways: Opponency and Temporal Difference Through Dopamine and Adenosine
Kenji Morita, Yasuo Kawaguchi
in Frontiers in Neural Circuits | New and Recent Articles on January 07, 2019 06:00 AM.
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Centrifugal Inputs to the Main Olfactory Bulb Revealed Through Whole Brain Circuit-Mapping
Krishnan Padmanabhan, Fumitaka Osakada, Anna Tarabrina, Erin Kizer, Edward M. Callaway, Fred H. Gage, Terrence J. Sejnowski
in Frontiers in Neuroanatomy | New and Recent Articles on January 07, 2019 06:00 AM.
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Personalised network modelling in epilepsy. (arXiv:1901.01024v1 [q-bio.NC])

Epilepsy is a disorder characterised by spontaneous, recurrent seizures. Both local and network abnormalities have been associated with epilepsy, and the exact processes generating seizures are thought to be heterogeneous and patient-specific. Due to the heterogeneity, treatments such as surgery and medication are not always effective in achieving full seizure control and choosing the best treatment for the individual patient can be challenging. Predictive models constrained by the patient's own data therefore offer the potential to assist in clinical decision making. In this chapter, we describe how personalised patient-derived networks from structural or functional connectivity can be incorporated into predictive models. We focus specifically on dynamical systems models which are composed of differential equations capable of simulating brain activity over time. Here we review recent studies which have used these models, constrained by patient data, to make personalised patient-specific predictions about seizure features (such as propagation patterns) or treatment outcomes (such as the success of surgical resection). Finally, we suggest future research directions for patient-specific network models in epilepsy, including their application to integrate information from multiple modalities, to predict long-term disease evolution, and to account for within-subject variability for treatment.

in q-bio.NC updates on arXiv.org on January 07, 2019 01:30 AM.
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A Unified Theory of Early Visual Representations from Retina to Cortex through Anatomically Constrained Deep CNNs. (arXiv:1901.00945v1 [q-bio.NC])

The visual system is hierarchically organized to process visual information in successive stages. Neural representations vary drastically across the first stages of visual processing: at the output of the retina, ganglion cell receptive fields (RFs) exhibit a clear antagonistic center-surround structure, whereas in the primary visual cortex, typical RFs are sharply tuned to a precise orientation. There is currently no unified theory explaining these differences in representations across layers. Here, using a deep convolutional neural network trained on image recognition as a model of the visual system, we show that such differences in representation can emerge as a direct consequence of different neural resource constraints on the retinal and cortical networks, and we find a single model from which both geometries spontaneously emerge at the appropriate stages of visual processing. The key constraint is a reduced number of neurons at the retinal output, consistent with the anatomy of the optic nerve as a stringent bottleneck. Second, we find that, for simple cortical networks, visual representations at the retinal output emerge as nonlinear and lossy feature detectors, whereas they emerge as linear and faithful encoders of the visual scene for more complex cortices. This result predicts that the retinas of small vertebrates should perform sophisticated nonlinear computations, extracting features directly relevant to behavior, whereas retinas of large animals such as primates should mostly encode the visual scene linearly and respond to a much broader range of stimuli. These predictions could reconcile the two seemingly incompatible views of the retina as either performing feature extraction or efficient coding of natural scenes, by suggesting that all vertebrates lie on a spectrum between these two objectives, depending on the degree of neural resources allocated to their visual system.

in q-bio.NC updates on arXiv.org on January 07, 2019 01:30 AM.
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Back to baseline: sleep recalibrates synapses

Back to baseline: sleep recalibrates synapses
Back to baseline: sleep recalibrates synapses, Published online: 07 January 2019; doi:10.1038/s41593-018-0327-6
In 2008, Vyazovskiy et al. published a seminal study demonstrating that sleep induces a widespread downscaling of synapses that counters the synaptic upscaling that occurred during prior wakefulness. The study laid the groundwork for current research into the ‘where’ and ‘when’ of homeostatic neuronal network regulation during sleep.
in Nature Neuroscience - Issue - nature.com science feeds on January 07, 2019 12:00 AM.
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Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE

Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE, Published online: 07 January 2019; doi:10.1038/s41593-018-0296-9
Loss of Trem2 function increases early amyloidogenesis by preventing microglial activation and clustering around amyloid seeds. As a consequence of reduced microglial ApoE production in the absence of Trem2 function, amyloid plaques contain less ApoE.
in Nature Neuroscience - Issue - nature.com science feeds on January 07, 2019 12:00 AM.
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Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons

Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons
Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons, Published online: 07 January 2019; doi:10.1038/s41593-018-0295-x
Using a dynamic time-course approach to model developmental trajectories in autism spectrum disorder, Schafer et al. identified aberrant gene network dynamics as a part of an ongoing process that is primed early in development.
in Nature Neuroscience - Issue - nature.com science feeds on January 07, 2019 12:00 AM.
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Hemispheric Module-Specific Influence of the X Chromosome on White Matter Connectivity: Evidence from Girls with Turner Syndrome

Abstract
Turner syndrome (TS) is caused by the congenital absence of all or part of one of the X chromosomes in females, offering a valuable human “knockout model” to study the functioning patterns of the X chromosome in the human brain. Little is known about whether and how the loss of the X chromosome influences the brain structural wiring patterns in human. We acquired a multimodal MRI dataset and cognitive assessments from 22 girls with TS and 21 age-matched control girls to address these questions. Hemispheric white matter (WM) networks and modules were derived using refined diffusion MRI tractography. Statistical comparisons revealed a reduced topological efficiency of both hemispheric networks and bilateral parietal modules in TS girls. Specifically, the efficiency of right parietal module significantly mediated the effect of the X chromosome on working memory performance, indicating that X chromosome loss impairs working memory performance by disrupting this module. Additionally, TS girls showed structural and functional connectivity decoupling across specific within- and between-modular connections, predominantly in the right hemisphere. These findings provide novel insights into the functional pathways in the brain that are regulated by the X chromosome and highlight a module-specific genetic contribution to WM connectivity in the human brain.
in Cerebral Cortex Advance Access on January 07, 2019 12:00 AM.
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I See Your Effort: Force-Related BOLD Effects in an Extended Action Execution–Observation Network Involving the Cerebellum

Abstract
Action observation (AO) is crucial for motor planning, imitation learning, and social interaction, but it is not clear whether and how an action execution–observation network (AEON) processes the effort of others engaged in performing actions. In this functional magnetic resonance imaging (fMRI) study, we used a “squeeze ball” task involving different grip forces to investigate whether AEON activation showed similar patterns when executing the task or observing others performing it. Both in action execution, AE (subjects performed the visuomotor task) and action observation, AO (subjects watched a video of the task being performed by someone else), the fMRI signal was detected in cerebral and cerebellar regions. These responses showed various relationships with force mapping onto specific areas of the sensorimotor and cognitive systems. Conjunction analysis of AE and AO was repeated for the “0th” order and linear and nonlinear responses, and revealed multiple AEON nodes remapping the detection of actions, and also effort, of another person onto the observer’s own cerebrocerebellar system. This result implies that the AEON exploits the cerebellum, which is known to process sensorimotor predictions and simulations, performing an internal assessment of forces and integrating information into high-level schemes, providing a crucial substrate for action imitation.
in Cerebral Cortex Open Access on January 07, 2019 12:00 AM.
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Enhanced Population Coding for Rewarded Choices in the Medial Frontal Cortex of the Mouse

Abstract
Instrumental behavior is characterized by the selection of actions based on the degree to which they lead to a desired outcome. However, we lack a detailed understanding of how rewarded actions are reinforced and preferentially implemented. In rodents, the medial frontal cortex is hypothesized to play an important role in this process, based in part on its capacity to encode chosen actions and their outcomes. We therefore asked how neural representations of choice and outcome might interact to facilitate instrumental behavior. To investigate this question, we imaged neural ensemble activity in layer 2/3 of the secondary motor region (M2) while mice engaged in a two-choice auditory discrimination task with probabilistic outcomes. Correct choices could result in one of three reward amounts (single, double or omitted reward), which allowed us to measure neural and behavioral effects of reward magnitude, as well as its categorical presence or absence. Single-unit and population decoding analyses revealed a consistent influence of outcome on choice signals in M2. Specifically, rewarded choices were more robustly encoded relative to unrewarded choices, with little dependence on the exact magnitude of reinforcement. Our results provide insight into the integration of past choices and outcomes in the rodent brain during instrumental behavior.
in Cerebral Cortex Advance Access on January 07, 2019 12:00 AM.
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Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms
The mesolimbic hypothesis has been a central dogma of schizophrenia for decades, positing that aberrant functioning of midbrain dopamine projections to limbic regions causes psychotic symptoms. Recently, however, advances in neuroimaging techniques have led to the unanticipated finding that dopaminergic dysfunction in schizophrenia is greatest within nigrostriatal pathways, implicating the dorsal striatum in the pathophysiology and calling into question the mesolimbic theory. At the same time our knowledge of striatal anatomy and function has progressed, suggesting new mechanisms via which striatal dysfunction may contribute to the symptoms of schizophrenia.
in Trends in Neurosciences on January 06, 2019 12:00 AM.
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Inhibitory effect of ultrasonic stimulation on the voltage-dependent potassium currents in rat hippocampal CA1 neurons
Transcranial ultrasonic stimulation is a novel noninvasive tool for neuromodulation, and has high spatial resolution and deep penetration. Although it can increase excitation of neurons, its effects on neuron ...
in Most Recent Articles: BMC Neuroscience on January 05, 2019 12:00 AM.
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Royal Jelly Alleviates Cognitive Deficits and β-Amyloid Accumulation in APP/PS1 Mouse Model Via Activation of the cAMP/PKA/CREB/BDNF Pathway and Inhibition of Neuronal Apoptosis
Mengmeng You, Yongming Pan, Yichen Liu, Yifan Chen, Yuqi Wu, Juanjuan Si, Kai Wang, Fuliang Hu
in Frontiers in Aging Neuroscience | New and Recent Articles on January 04, 2019 06:00 PM.
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Activity patterns in the neuropil of striatal cholinergic interneurons in freely moving mice represent their collective spiking dynamics
Abstract
Cholinergic interneurons (CINs) are believed to form synchronous cell assemblies that modulate the striatal microcircuitry and possibly orchestrate local dopamine release. We expressed GCaMP6s, a genetically encoded calcium indicator (GECIs), selectively in CINs, and used microendoscopes to visualize the putative CIN assemblies in the dorsal striatum of freely moving mice. The GECI fluorescence signal from the dorsal striatum was composed of signals from individual CIN somata that were engulfed by a widespread fluorescent neuropil. Bouts of synchronous activation of the cholinergic neuropil revealed patterns of activity that preceded the signal from individual somata. To investigate the nature of the neuropil signal and why it precedes the somatic signal, we target-patched GECI-expressing CINs in acute striatal slices in conjunction with multiphoton imaging or wide-field imaging that emulates the microendoscopes’ specifications. The ability to detect fluorescent transients associated with individual action potential was constrained by the long decay constant of GECIs (relative to common inorganic dyes) to slowly firing (< 2 spikes/s) CINs. The microendoscopes’ resolving power and sampling rate further diminished this ability. Additionally, we found that only back-propagating action potentials but not synchronous optogenetic activation of thalamic inputs elicited observable calcium transients in CIN dendrites. Our data suggest that only bursts of CIN activity (but not their tonic firing) are visible using endoscopic imaging, and that the neuropil patterns are a physiological measure of the collective recurrent CIN network spiking activity.
Significance Statement Cholinergic interneurons (CINs) are key modulators of the striatal microcircuitry that are necessary for assigning action value and behavioral flexibility. We present a first endoscopic imaging study of multiple molecularly identified CINs in freely moving mice. We reveal the presence of activity patterns in the CIN neuropil. We then use ex vivo electrophysiological and imaging techniques to show that the neuropil signal is the integrated fluorescence arising from the axo-dendritic arbors of CINs dispersed throughout the striatum. We conclude that the neuropil signal acts as a mean-field readout of the striatal CIN network activity.

in RSS PAP on January 04, 2019 05:39 PM.
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Neuron-Specific Gene 2 (NSG2) encodes an AMPA receptor interacting protein that modulates excitatory neurotransmission
Abstract
Neurons have evolved a number of unique protein-coding genes that regulate trafficking of protein complexes within small organelles throughout dendrites axons. Neuron specific gene 2 (NSG2) encodes for one of the most abundant proteins in the nervous system during perinatal development. NSG2 belongs to a family of small neuronal endosomal proteins but its function has remained uncharacterized to date. Here we show that NSG2 is found in discrete punctae restricted to the somatodendritic arbors of developing mouse and human neurons, and a significant proportion of NSG2 punctae colocalize with postsynaptic HOMER1 and surface-expressed AMPARs at excitatory synapses. Immunoprecipitation revealed that NSG2 physically interacts with both the GluA1 and GluA2 AMPAR subunits in mouse brain. Knockout of NSG2 in mouse hippocampal neurons selectively impaired the frequency of miniature excitatory postsynaptic currents (mEPSCs) and caused alterations in PSD95 expression at postsynaptic densities. In contrast, NSG2 overexpression caused a significant increase in the amplitude of mEPSCs as well as GluA2 surface expression. Thus, NSG2 functions as an AMPAR-binding protein that is required for normal synapse formation and/or maintenance, and has unique functions compared with other NSG family members.
Significance Statement Due to their morphological and functional complexity, neurons have evolved specialized proteins like those of the neuron-specific gene family (NSG1-3). Important developmental and synaptic functions have been attributed to NSG1/NEEP21 and NSG3/Calcyon while the function of NSG2/HMP19/NVTA2 has remained uncharacterized. Here we show that NSG2 localizes to a large proportion of excitatory synapses, interacts with AMPARs, and modulates their surface expression during synaptogenesis. Alterations of NSG2 expression affected both the amplitude and frequency of excitatory neurotransmission that is not compensated for by other NSG family members. Thus, NSG2 appears critical for excitatory synapse formation and/or maintenance and forced expression can promote increased synaptic efficacy.

in RSS PAP on January 04, 2019 05:39 PM.
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NMNAT proteins that limit Wallerian degeneration also regulate critical period plasticity in the visual cortex
Abstract
Many brain regions go through critical periods of development during which plasticity is enhanced. These critical periods are associated with extensive growth and retraction of thalamocortical and intracortical axons. Here, we investigated whether a signaling pathway that is central in Wallerian axon degeneration also regulates critical period plasticity in the primary visual cortex. Wallerian degeneration is characterized by rapid disintegration of axons once they are separated from the cell body. This degenerative process is initiated by reduced presence of cytoplasmic nicotinamide mononucleotide adenylyltransferases (NMNATs) and is strongly delayed in mice overexpressing cytoplasmic NMNAT proteins, such as Wld^S mutant mice producing a UBE4b-NMNAT1 fusion protein or NMNAT3 transgenic mice. Here we provide evidence that in Wld^S mice and NMNAT3-transgenic mice, ocular dominance plasticity in the developing visual cortex is reduced. This deficit is only observed during the second half of the critical period. Additionally, we detect an early increase of visual acuity in the primary visual cortex of Wld^S mice. We do not find evidence for Wallerian degeneration occurring during ocular dominance plasticity. Our findings suggest that NMNATs do not only regulate Wallerian degeneration during pathological conditions, but also control cellular events that mediate critical period plasticity during the physiological development of the cortex.
Significance statement Different forms of axon degeneration occur during development and neurodegenerative processes. A good understanding of the molecular and cellular events that regulate these forms of axon degeneration is essential to selectively modulate them for therapeutic purposes. This study shows that genes thought to be selectively involved in pathological axon degeneration are also involved in developmental plasticity, implying that these events are molecularly less separable than previously assumed.

in RSS PAP on January 04, 2019 05:39 PM.
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Coordination between Prefrontal Cortex Clock Gene Expression and Corticosterone Contributes to Enhanced Conditioned Fear Extinction Recall
Abstract
Post-traumatic stress disorder (PTSD) is associated with impaired conditioned fear extinction learning, a ventromedial prefrontal cortex (vmPFC)-dependent process. PTSD is also associated with dysregulation of vmPFC, circadian, and glucocorticoid hormone function. Rats have rhythmic clock gene expression in the vmPFC that requires appropriate diurnal circulatory patterns of corticosterone (CORT), suggesting the presence of CORT-entrained intrinsic circadian clock function within the PFC. We examined the role of vmPFC clock gene expression and its interaction with CORT profiles in regulation of auditory conditioned fear extinction learning. Extinction learning and recall were examined in male rats trained and tested either in the night (active phase) or in the day (inactive phase). Using a viral vector strategy, Per1 and Per2 clock gene expression were selectively knocked down within the vmPFC. Circulating CORT profiles were manipulated via adrenalectomy (ADX) ± diurnal and acute CORT replacement. Rats trained and tested during the night exhibited superior conditioned fear extinction recall that was absent in rats that had knock-down of vmPFC clock gene expression. Similarly, the superior nighttime extinction recall was absent in ADX rats, but restored in ADX rats given a combination of a diurnal pattern of CORT and acute elevation of CORT during the postextinction training consolidation period. Thus, conditioned fear extinction learning is regulated in a diurnal fashion that requires normal vmPFC clock gene expression and a combination of circadian and training-associated CORT. Strategic manipulation of these factors may enhance the therapeutic outcome of conditioned fear extinction related treatments in the clinical setting.

in eNeuro current issue on January 04, 2019 05:30 PM.
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Wave Turbulence and Energy Cascade in the Hippocampus
Alex Sheremet, Yu Qin, Jack P. Kennedy, Yuchen Zhou, Andrew P. Maurer
in Frontiers in Systems Neuroscience | New and Recent Articles on January 04, 2019 06:00 AM.
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Altered Functional Connectivity of Cerebello-Cortical Circuit in Multiple System Atrophy (Cerebellar-Type)
Shan Ren, Hao Zhang, Weimin Zheng, Ming Liu, Fang Gao, Zhiqun Wang, Zhigang Chen
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 04, 2019 06:00 AM.
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Electrophysiology Meets Printed Electronics: The Beginning of a Beautiful Friendship
Lilah Inzelberg, Yael Hanein
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 04, 2019 06:00 AM.
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Decoding Hand Kinematics from Local Field Potentials Using Long Short-Term Memory (LSTM) Network. (arXiv:1901.00708v1 [q-bio.NC])

Local field potential (LFP) has gained increasing interest as an alternative input signal for brain-machine interfaces (BMIs) due to its informative features, long-term stability, and low frequency content. However, despite these interesting properties, LFP-based BMIs have been reported to yield low decoding performances compared to spike-based BMIs. In this paper, we propose a new decoder based on long short-term memory (LSTM) network which aims to improve the decoding performance of LFP-based BMIs. We compare offline decoding performance of the proposed LSTM decoder to a commonly used Kalman filter (KF) decoder on hand kinematics prediction tasks from multichannel LFPs. We also benchmark the performance of LFP-driven LSTM decoder against KF decoder driven by two types of spike signals: single-unit activity (SUA) and multi-unit activity (MUA). Our results show that LFP-driven LSTM decoder achieves significantly better decoding performance than LFP-, SUA-, and MUA-driven KF decoders. This suggests that LFPs coupled with LSTM decoder could provide high decoding performance, robust, and low power BMIs.

in q-bio.NC updates on arXiv.org on January 04, 2019 01:30 AM.
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Deconstructing cortical folding: genetic, cellular and mechanical determinants

Deconstructing cortical folding: genetic, cellular and mechanical determinants
Deconstructing cortical folding: genetic, cellular and mechanical determinants, Published online: 04 January 2019; doi:10.1038/s41583-018-0112-2
Why is the human cerebral cortex folded? Llinares-Benadero and Borrell provide an overview of the mechanical, cellular and molecular factors — and the interactions among them — that influence cortical folding in gyrencephalic species.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 04, 2019 12:00 AM.
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Cortical Dysmaturation in Congenital Heart Disease
Congenital heart disease (CHD) is among the most common birth defects. Children with CHD frequently display long-term intellectual and behavioral disability. Emerging evidence indicates that cardiac anomalies lead to a reduction in cerebral oxygenation, which appears to profoundly impact on the maturation of cerebral regions responsible for higher-order cognitive functions. In this review we focus on the potential mechanisms by which dysregulation of cortical neuronal development during early life may lead to the significant cognitive impairments that commonly occur in children with CHD.
in Trends in Neurosciences on January 04, 2019 12:00 AM.
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Nestin Regulates Neurogenesis in Mice Through Notch Signaling From Astrocytes to Neural Stem Cells

Abstract
The intermediate filament (nanofilament) protein nestin is a marker of neural stem cells, but its role in neurogenesis, including adult neurogenesis, remains unclear. Here, we investigated the role of nestin in neurogenesis in adult nestin-deficient (Nes^–/–) mice. We found that the proliferation of Nes^–/– neural stem cells was not altered, but neurogenesis in the hippocampal dentate gyrus of Nes^–/– mice was increased. Surprisingly, the proneurogenic effect of nestin deficiency was mediated by its function in the astrocyte niche. Through its role in Notch signaling from astrocytes to neural stem cells, nestin negatively regulates neuronal differentiation and survival; however, its expression in neural stem cells is not required for normal neurogenesis. In behavioral studies, nestin deficiency in mice did not affect associative learning but was associated with impaired long-term memory.
in Cerebral Cortex Advance Access on January 03, 2019 12:00 AM.
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The modulation effect of non-invasive brain stimulation on cognitive function in patients with mild cognitive impairment: a systematic review and meta-analysis of randomized controlled trials
To prevent and control dementia, many scholars have focused on the transition stage between normal ageing and dementia, mild cognitive impairment (MCI) which is a key interventional target for dementia. Studie...
in Most Recent Articles: BMC Neuroscience on January 03, 2019 12:00 AM.
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Possible involvement of peripheral TRP channels in the hydrogen sulfide-induced hyperalgesia in diabetic rats
Peripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfide (H2S) is involved in diabetes-induced hyperalgesia and allodynia. However, the...
in Most Recent Articles: BMC Neuroscience on January 03, 2019 12:00 AM.
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Fixed Points of Competitive Threshold-Linear Networks
Neural Computation, Volume 31, Issue 1, Page 94-155, January 2019.

in MIT Press: Neural Computation: Table of Contents on January 02, 2019 07:06 AM.
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Decoding of Neural Data Using Cohomological Feature Extraction
Neural Computation, Volume 31, Issue 1, Page 68-93, January 2019.

in MIT Press: Neural Computation: Table of Contents on January 02, 2019 07:06 AM.
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The Exact VC Dimension of the WiSARD [math]-Tuple Classifier
Neural Computation, Volume 31, Issue 1, Page 176-207, January 2019.

in MIT Press: Neural Computation: Table of Contents on January 02, 2019 07:06 AM.
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Supervised Dimensionality Reduction on Grassmannian for Image Set Recognition
Neural Computation, Volume 31, Issue 1, Page 156-175, January 2019.

in MIT Press: Neural Computation: Table of Contents on January 02, 2019 07:06 AM.
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First Passage Time Memory Lifetimes for Simple, Multistate Synapses: Beyond the Eigenvector Requirement
Neural Computation, Volume 31, Issue 1, Page 8-67, January 2019.

in MIT Press: Neural Computation: Table of Contents on January 02, 2019 07:06 AM.
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Ten Simple Rules for Organizing and Running a Successful Intensive Two-Week Course
Neural Computation, Volume 31, Issue 1, Page 1-7, January 2019.

in MIT Press: Neural Computation: Table of Contents on January 02, 2019 07:06 AM.
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From sleeping to waking

From sleeping to waking
From sleeping to waking, Published online: 02 January 2019; doi:10.1038/s41583-018-0119-8
From sleeping to waking
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 02, 2019 12:00 AM.
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Seeds of change

Seeds of change
Seeds of change, Published online: 02 January 2019; doi:10.1038/s41583-018-0118-9
Seeds of change
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 02, 2019 12:00 AM.
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All wrapped up

All wrapped up
All wrapped up, Published online: 02 January 2019; doi:10.1038/s41583-018-0117-x
All wrapped up
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 02, 2019 12:00 AM.
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A glial contribution to ‘chemobrain’

A glial contribution to ‘chemobrain’
A glial contribution to ‘chemobrain’, Published online: 02 January 2019; doi:10.1038/s41583-018-0115-z
A mouse model reveals a central role for microglial activation and altered glial cell dynamics in the lasting neurological and cognitive dysfunction following methotrexate chemotherapy.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 02, 2019 12:00 AM.
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Interactive Regulation of Neuronal Development by Hippocampal Stem Cell Niche Populations
Microenvironment cues and cell-to-cell interactions balance stem cell quiescence with proliferation and direct neurogenesis in the adult hippocampal niche. Tang et al. report that hippocampal stem cells release feedback signals that regulate the dendritic complexity and activity of newborn neurons.
in Neuron on January 02, 2019 12:00 AM.
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The NeuroDev Study: Phenotypic and Genetic Characterization of Neurodevelopmental Disorders in Kenya and South Africa
The NeuroDev study will deeply phenotype cognition, behavior, dysmorphias, and neuromedical traits on an expected cohort of 5,600 Africans (1,800 child cases, 1,800 child controls, and 1,900 parents) and will collect whole blood for exome sequencing and biobanking.
in Neuron on January 02, 2019 12:00 AM.
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Editorial Board and Contents

in Trends in Neurosciences on January 01, 2019 12:00 AM.
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Phase separation as a mechanism for assembling dynamic postsynaptic density signalling complexes

Publication date: August 2019
Source: Current Opinion in Neurobiology, Volume 57
Author(s): Zhe Feng, Xudong Chen, Menglong Zeng, Mingjie Zhang
The postsynaptic density (PSD) is an electron dense, semi-membrane bound compartment that lies beneath postsynaptic membranes. This region is densely packed with thousands of proteins that are involved in extensive interactions. During synaptic plasticity, the PSD undergoes changes in size and composition along with changes in synaptic strength that lead to long term potentiation (LTP) or depression (LTD). It is therefore essential to understand the organization principles underlying PSD assembly and rearrangement. Here, we review exciting new findings from recent in vitro reconstitution studies and propose a hypothesis that liquid–liquid phase separation mediates PSD formation and regulation. We also discuss how the properties of PSD formed via phase separation might contribute to the biological functions observed from decades of researches. Finally, we highlight unanswered questions regarding PSD organization and how in vitro reconstitution systems may help to answer these questions in the coming years.

in ScienceDirect Publication: Current Opinion in Neurobiology on December 31, 2018 12:00 PM.
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Panoptic imaging of transparent mice reveals whole-body neuronal projections and skull–meninges connections

Panoptic imaging of transparent mice reveals whole-body neuronal projections and skull–meninges connections
Panoptic imaging of transparent mice reveals whole-body neuronal projections and skull–meninges connections, Published online: 31 December 2018; doi:10.1038/s41593-018-0301-3
A nanobody-based immunolabeling method, vDISCO, boosts the signal of fluorescent proteins and allows imaging of subcellular details in intact transparent mice. It uncovers neuronal projections and skull–meninges connections in whole adult mice.
in Nature Neuroscience - Issue - nature.com science feeds on December 31, 2018 12:00 AM.
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Rapamycin treatment increases hippocampal cell viability in an mTOR-independent manner during exposure to hypoxia mimetic, cobalt chloride
Cobalt chloride (CoCl2) induces chemical hypoxia through activation of hypoxia-inducible factor-1 alpha (HIF-1α). Mammalian target of rapamycin (mTOR) is a multifaceted protein capable of regulating cell growth, ...
in Most Recent Articles: BMC Neuroscience on December 29, 2018 12:00 AM.
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Corrigendum: Dissociation of Appetitive Overexpectation and Extinction in the Infralimbic Cortex

in Cerebral Cortex Advance Access on December 27, 2018 12:00 AM.
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Neural Interactions Underlying Visuomotor Associations in the Human Brain

Abstract
Rapid and flexible learning during behavioral choices is critical to our daily endeavors and constitutes a hallmark of dynamic reasoning. An important paradigm to examine flexible behavior involves learning new arbitrary associations mapping visual inputs to motor outputs. We conjectured that visuomotor rules are instantiated by translating visual signals into actions through dynamic interactions between visual, frontal and motor cortex. We evaluated the neural representation of such visuomotor rules by performing intracranial field potential recordings in epilepsy subjects during a rule-learning delayed match-to-behavior task. Learning new visuomotor mappings led to the emergence of specific responses associating visual signals with motor outputs in 3 anatomical clusters in frontal, anteroventral temporal and posterior parietal cortex. After learning, mapping selective signals during the delay period showed interactions with visual and motor signals. These observations provide initial steps towards elucidating the dynamic circuits underlying flexible behavior and how communication between subregions of frontal, temporal, and parietal cortex leads to rapid learning of task-relevant choices.
in Cerebral Cortex Advance Access on December 27, 2018 12:00 AM.
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Connectivity of Frontoparietal Regions Reveals Executive Attention and Consciousness Interactions

Abstract
The executive control network is involved in the voluntary control of novel and complex situations. Solving conflict situations or detecting errors have demonstrated to impair conscious perception of near-threshold stimuli. The aim of this study was to explore the neural mechanisms underlying executive control and its interaction with conscious perception using functional magnetic resonance imaging and diffusion-weighted imaging. To this end, we used a dual-task paradigm involving Stroop and conscious detection tasks with near-threshold stimuli. A set of prefrontal and frontoparietal regions were more strongly engaged for incongruent than congruent trials while a distributed set of frontoparietal regions showed stronger activation for consciously than nonconsciously perceived trials. Functional connectivity analysis revealed an interaction between executive control and conscious perception in frontal and parietal nodes. The microstructural properties of the middle branch of the superior longitudinal fasciculus were associated with neural measures of the interaction between executive control and consciousness. These results demonstrate that conscious perception and executive control share neural resources in frontoparietal networks, as proposed by some influential models.
in Cerebral Cortex Advance Access on December 27, 2018 12:00 AM.
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Waves of Maturation and Senescence in Micro-structural MRI Markers of Human Cortical Myelination over the Lifespan

Abstract
Seminal human brain histology work has demonstrated developmental waves of myelination. Here, using a micro-structural magnetic resonance imaging (MRI) marker linked to myelin, we studied fine-grained age differences to deduce waves of growth, stability, and decline of cortical myelination over the life-cycle. In 484 participants, aged 8–85 years, we fitted smooth growth curves to T1- to T2-weighted ratio in each of 360 regions from one of seven cytoarchitectonic classes. From the first derivatives of these generally inverted-U trajectories, we defined three milestones: the age at peak growth; the age at onset of a stable plateau; and the age at the onset of decline. Age at peak growth had a bimodal distribution comprising an early (pre-pubertal) wave of primary sensory and motor cortices and a later (post-pubertal) wave of association, insular and limbic cortices. Most regions reached stability in the 30-s but there was a second wave reaching stability in the 50-s. Age at onset of decline was also bimodal: in some right hemisphere regions, the curve declined from the 60-s, but in other left hemisphere regions, there was no significant decline from the stable plateau. These results are consistent with regionally heterogeneous waves of intracortical myelinogenesis and age-related demyelination.
in Cerebral Cortex Advance Access on December 27, 2018 12:00 AM.
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Thrombin contributes to the injury development and neurological deficit after acute subdural hemorrhage in rats only in collaboration with additional blood-derived factors
Acute subdural hemorrhage (ASDH) is a severe consequence of traumatic brain injury. The occurrence of subdural blood increases the lethality of these patients independent of the amount of blood or elevated int...
in Most Recent Articles: BMC Neuroscience on December 27, 2018 12:00 AM.
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NFBLab—A Versatile Software for Neurofeedback and Brain-Computer Interface Research
Nikolai Smetanin, Ksenia Volkova, Stanislav Zabodaev, Mikhail A. Lebedev, Alexei Ossadtchi
in Frontiers in Neuroinformatics | New and Recent Articles on December 24, 2018 12:00 PM.
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Direct Evidence for Prediction Signals in Frontal Cortex Independent of Prediction Error

Abstract
Predictive coding (PC) has been suggested as one of the main mechanisms used by brains to interact with complex environments. PC theories posit top-down prediction signals, which are compared with actual outcomes, yielding in turn prediction error (PE) signals, which are used, bottom-up, to modify the ensuing predictions. However, disentangling prediction from PE signals has been challenging. Critically, while many studies found indirect evidence for PC in the form of PE signals, direct evidence for the prediction signal is mostly lacking. Here, we provide clear evidence, obtained from intracranial cortical recordings in human surgical patients, that the human lateral prefrontal cortex evinces prediction signals while anticipating an event. Patients listened to task-irrelevant sequences of repetitive tones including infrequent predictable or unpredictable pitch deviants. The broadband high-frequency amplitude (HFA) was decreased prior to the onset of expected relative to unexpected deviants in the frontal cortex only, and its amplitude was sensitive to the increasing likelihood of deviants following longer trains of standards in the unpredictable condition. Single-trial HFA predicted deviations and correlated with poststimulus response to deviations. These results provide direct evidence for frontal cortex prediction signals independent of PE signals.
in Cerebral Cortex Advance Access on December 22, 2018 12:00 AM.
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Acquisition of Spatial Search Strategies and Reversal Learning in the Morris Water Maze Depend on Disparate Brain Functional Connectivity in Mice

Abstract
Learning has been proposed to coincide with changes in connections between brain regions. In the present study, we used resting-state fMRI (rsfMRI) to map brain-wide functional connectivity (FC) in mice that were trained in the hidden-platform version of the Morris water maze. C57BL6 mice were investigated in a small animal MRI scanner following 2, 10, or 15 days of acquisition learning, or 5 days of reversal learning. Spatial learning coincided with progressive and changing FC between telencephalic regions that have been implemented in spatial learning (such as hippocampus, cingulate, visual, and motor cortex). Search strategy assessment demonstrated that the use of cognitively advanced spatial strategies correlated positively with extensive telencephalic connectivity, whereas non-spatial strategies correlated negatively with connectivity. FC patterns were different and more extensive after reversal learning compared with after extended acquisition learning, which could explain why reversal learning has been shown to be more sensitive to subtle functional defects.
in Cerebral Cortex Advance Access on December 22, 2018 12:00 AM.
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Ceftriaxone Treatment Preserves Cortical Inhibitory Interneuron Function via Transient Salvage of GLT-1 in a Rat Traumatic Brain Injury Model

Abstract
Traumatic brain injury (TBI) results in a decrease in glutamate transporter-1 (GLT-1) expression, the major mechanism for glutamate removal from synapses. Coupled with an increase in glutamate release from dead and dying neurons, this causes an increase in extracellular glutamate. The ensuing glutamate excitotoxicity disproportionately damages vulnerable GABAergic parvalbumin-positive inhibitory interneurons, resulting in a progressively worsening cortical excitatory:inhibitory imbalance due to a loss of GABAergic inhibitory tone, as evidenced by chronic post-traumatic symptoms such as epilepsy, and supported by neuropathologic findings. This loss of intracortical inhibition can be measured and followed noninvasively using long-interval paired-pulse transcranial magnetic stimulation with mechanomyography (LI-ppTMS-MMG). Ceftriaxone, a β-lactam antibiotic, is a potent stimulator of the expression of rodent GLT-1 and would presumably decrease excitotoxic damage to GABAergic interneurons. It may thus be a viable antiepileptogenic intervention. Using a rat fluid percussion injury TBI model, we utilized LI-ppTMS-MMG, quantitative PCR, and immunohistochemistry to test whether ceftriaxone treatment preserves intracortical inhibition and cortical parvalbumin-positive inhibitory interneuron function after TBI in rat motor cortex. We show that neocortical GLT-1 gene and protein expression are significantly reduced 1 week after TBI, and this transient loss is mitigated by ceftriaxone. Importantly, whereas intracortical inhibition declines progressively after TBI, 1 week of post-TBI ceftriaxone treatment attenuates the loss of inhibition compared to saline-treated controls. This finding is accompanied by significantly higher parvalbumin gene and protein expression in ceftriaxone-treated injured rats. Our results highlight prospects for ceftriaxone as an intervention after TBI to prevent cortical inhibitory interneuron dysfunction, partly by preserving GLT-1 expression.
in Cerebral Cortex Advance Access on December 22, 2018 12:00 AM.
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Differential Representations of Perceived and Retrieved Visual Information in Hippocampus and Cortex

Abstract
Memory retrieval is thought to depend on interactions between hippocampus and cortex, but the nature of representation in these regions and their relationship remains unclear. Here, we performed an ultra-high field fMRI (7T) experiment, comprising perception, learning and retrieval sessions. We observed a fundamental difference between representations in hippocampus and high-level visual cortex during perception and retrieval. First, while object-selective posterior fusiform cortex showed consistent responses that allowed us to decode object identity across both perception and retrieval one day after learning, object decoding in hippocampus was much stronger during retrieval than perception. Second, in visual cortex but not hippocampus, there was consistency in response patterns between perception and retrieval, suggesting that substantial neural populations are shared for both perception and retrieval. Finally, the decoding in hippocampus during retrieval was not observed when retrieval was tested on the same day as learning suggesting that the retrieval process itself is not sufficient to elicit decodable object representations. Collectively, these findings suggest that while cortical representations are stable between perception and retrieval, hippocampal representations are much stronger during retrieval, implying some form of reorganization of the representations between perception and retrieval.
in Cerebral Cortex Advance Access on December 22, 2018 12:00 AM.
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Aging-Related Changes in Cognition and Cortical Integrity are Associated With Serum Expression of Candidate MicroRNAs for Alzheimer Disease

Abstract
Evidence has shown that microRNAs (miRNAs) are involved in molecular pathways responsible for aging and prevalent aging-related chronic diseases. However, the lack of research linking circulating levels of miRNAs to changes in the aging brain hampers clinical translation. Here, we have investigated if serum expression of brain-enriched miRNAs that have been proposed as potential biomarkers in Alzheimer’s disease (AD) (miR-9, miR-29b, miR-34a, miR-125b, and miR-146a) are also associated with cognitive functioning and changes of the cerebral cortex in normal elderly subjects. Results revealed that candidate miRNAs were linked to changes in cortical thickness (miR-9, miR-29b, miR-34a, and miR-125b), cortical glucose metabolism (miR-29b, miR-125b, and miR-146a), and cognitive performance (miR-9, miR-34a, and miR-125b). While both miR-29b and miR-125b were related to aging-related structural and metabolic cortical changes, only expression levels of miR-125b were associated with patterns of glucose consumption shown by cortical regions that correlated with executive function. Together, these findings suggest that serum expression of AD-related miRNAs are biologically meaningful in aging and may play a role as biomarkers of cerebral vulnerability in late life.
in Cerebral Cortex Advance Access on December 22, 2018 12:00 AM.
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EphA4 Regulates Hippocampal Neural Precursor Proliferation in the Adult Mouse Brain by d-Serine Modulation of N-Methyl-d-Aspartate Receptor Signaling

Abstract
The hippocampal dentate gyrus (DG) is a major region of the adult rodent brain in which neurogenesis occurs throughout life. The EphA4 receptor, which regulates neurogenesis and boundary formation in the developing brain, is also expressed in the adult DG, but whether it regulates adult hippocampal neurogenesis is not known. Here, we show that, in the adult mouse brain, EphA4 inhibits hippocampal precursor cell proliferation but does not affect precursor differentiation or survival. Genetic deletion or pharmacological inhibition of EphA4 significantly increased hippocampal precursor proliferation in vivo and in vitro, by blocking EphA4 forward signaling. EphA4 was expressed by mature hippocampal DG neurons but not neural precursor cells, and an EphA4 antagonist, EphA4-Fc, did not activate clonal cultures of precursors until they were co-cultured with non-precursor cells, indicating an indirect effect of EphA4 on the regulation of precursor activity. Supplementation with d-serine blocked the increased precursor proliferation induced by EphA4 inhibition, whereas blocking the interaction between d-serine and N-methyl-d-aspartate receptors (NMDARs) promoted precursor activity, even at the clonal level. Collectively, these findings demonstrate that EphA4 indirectly regulates adult hippocampal precursor proliferation and thus plays a role in neurogenesis via d-serine-regulated NMDAR signaling.
in Cerebral Cortex Advance Access on December 22, 2018 12:00 AM.
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Temporal Metacognition as the Decoding of Self-Generated Brain Dynamics

Abstract
Metacognition, the ability to know about one’s thought process, is self-referential. Here, we combined psychophysics and time-resolved neuroimaging to explore metacognitive inference on the accuracy of a self-generated behavior. Human participants generated a time interval and evaluated the signed magnitude of their temporal production. We show that both self-generation and self-evaluation relied on the power of beta oscillations (β; 15–40 Hz) with increases in early β power predictive of increases in duration. We characterized the dynamics of β power in a low-dimensional space (β state-space trajectories) as a function of timing and found that the more distinct trajectories, the more accurate metacognitive inferences were. These results suggest that β states instantiate an internal variable determining the fate of the timing network’s trajectory, possibly as release from inhibition. Altogether, our study describes oscillatory mechanisms for timing, suggesting that temporal metacognition relies on inferential processes of self-generated dynamics.
in Cerebral Cortex Advance Access on December 22, 2018 12:00 AM.
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Reorganization of Higher-Order Somatosensory Cortex After Sensory Loss from Hand in Squirrel Monkeys

Abstract
Unilateral dorsal column lesions (DCL) at the cervical spinal cord deprive the hand regions of somatosensory cortex of tactile activation. However, considerable cortical reactivation occurs over weeks to months of recovery. While most studies focused on the reactivation of primary somatosensory area 3b, here, for the first time, we address how the higher-order somatosensory cortex reactivates in the same monkeys after DCL that vary across cases in completeness, post-lesion recovery times, and types of treatments. We recorded neural responses to tactile stimulation in areas 3a, 3b, 1, secondary somatosensory cortex (S2), parietal ventral (PV), and occasionally areas 2/5. Our analysis emphasized comparisons of the responsiveness, somatotopy, and receptive field size between areas 3b, 1, and S2/PV across DCL conditions and recovery times. The results indicate that the extents of the reactivation in higher-order somatosensory areas 1 and S2/PV closely reflect the reactivation in primary somatosensory cortex. Responses in higher-order areas S2 and PV can be stronger than those in area 3b, thus suggesting converging or alternative sources of inputs. The results also provide evidence that both primary and higher-order fields are effectively activated after long recovery times as well as after behavioral and electrocutaneous stimulation interventions.
in Cerebral Cortex Advance Access on December 22, 2018 12:00 AM.
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erbb4 Deficits in Chandelier Cells of the Medial Prefrontal Cortex Confer Cognitive Dysfunctions: Implications for Schizophrenia

Abstract
erbb4 is a known susceptibility gene for schizophrenia. Chandelier cells (ChCs, also known as axo-axonic cells) are a distinct GABAergic interneuron subtype that exclusively target the axonal initial segment, which is the site of pyramidal neuron action potential initiation. ChCs are a source of ErbB4 expression and alterations in ChC-pyramidal neuron connectivity occur in the medial prefrontal cortex (mPFC) of schizophrenic patients and animal models of schizophrenia. However, the contribution of ErbB4 in mPFC ChCs to the pathogenesis of schizophrenia remains unknown. By conditional deletion or knockdown of ErbB4 from mPFC ChCs, we demonstrated that ErbB4 deficits led to impaired ChC-pyramidal neuron connections and cognitive dysfunctions. Furthermore, the cognitive dysfunctions were normalized by L-838417, an agonist of GABA_Aα2 receptors enriched in the axonal initial segment. Given that cognitive dysfunctions are a core symptom of schizophrenia, our results may provide a new perspective for understanding the etiology of schizophrenia and suggest that GABA_Aα2 receptors may be potential pharmacological targets for its treatment.
in Cerebral Cortex Advance Access on December 22, 2018 12:00 AM.

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