Planet Neuroscience

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Editorial: Neuromechanics and Control of Physical Behavior: From Experimental and Computational Formulations to Bio-inspired Technologies
Manish Sreenivasa, Francisco J. Valero-Cuevas, Matthew Tresch, Yoshihiko Nakamura, Alfred C. Schouten, Massimo Sartori
in Frontiers in Computational Neuroscience | New and Recent Articles on March 19, 2019 06:00 PM.
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Correction to Supporting Information for Townsend et al., Dietary sugar silences a colonization factor in a mammalian gut symbiont [SI Correction]
MICROBIOLOGY Correction to Supporting Information for “Dietary sugar silences a colonization factor in a mammalian gut symbiont,” by Guy E. Townsend II, Weiwei Han, Nathan D. Schwalm III, Varsha Raghavan, Natasha A. Barry, Andrew L. Goodman, and Eduardo A. Groisman, which was first published December 17, 2018; 10.1073/pnas.1813780115 (Proc Natl...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Correction for Moore et al., Robust predictions of specialized metabolism genes through machine learning [Correction]
PLANT BIOLOGY Correction for “Robust predictions of specialized metabolism genes through machine learning,” by Bethany M. Moore, Peipei Wang, Pengxiang Fan, Bryan Leong, Craig A. Schenck, John P. Lloyd, Melissa D. Lehti-Shiu, Robert L. Last, Eran Pichersky, and Shin-Han Shiu, which was first published February 5, 2019; 10.1073/pnas.1817074116 (Proc Natl...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Correction for Li et al., Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors [Correction]
MEDICAL SCIENCES Correction for “Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors,” by Charles Li, Elena Bonazzoli, Stefania Bellone, Jungmin Choi, Weilai Dong, Gulden Menderes, Gary Altwerger, Chanhee Han, Aranzazu Manzano, Anna Bianchi, Francesca Pettinella, Paola Manara, Salvatore Lopez, Ghanshyam...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Correction for Shneiderman, Creativity and collaboration: Revisiting cybernetic serendipity [Correction]
COLLOQUIUM Correction for “Creativity and collaboration: Revisiting cybernetic serendipity,” by Ben Shneiderman, which was first published February 5, 2019; 10.1073/pnas.1807200116 (Proc Natl Acad Sci USA 116:1837–1843). The author notes that, on page 1840, left column, second full paragraph, lines 4–5, Jeffrey Heer should have been included in the list of...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Genomic and molecular characterization of preterm birth [Systems Biology]
Preterm birth (PTB) complications are the leading cause of long-term morbidity and mortality in children. By using whole blood samples, we integrated whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and DNA methylation data for 270 PTB and 521 control families. We analyzed this combined dataset to identify genomic variants associated with...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Task-driven visual exploration at the foveal scale [Psychological and Cognitive Sciences]
Humans use saccades to inspect objects of interest with the foveola, the small region of the retina with highest acuity. This process of visual exploration is normally studied over large scenes. However, in everyday tasks, the stimulus within the foveola is complex, and the need for visual exploration may extend...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Symbolic labeling in 5-month-old human infants [Psychological and Cognitive Sciences]
Humans’ ability to create and manipulate symbolic structures far exceeds that of other animals. We hypothesized that this ability rests on an early capacity to use arbitrary signs to represent any mental representation, even as abstract as an algebraic rule. In three experiments, we collected high-density EEG recordings while 150...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Constitutive signaling activity of a receptor-associated protein links fertilization with embryonic patterning in Arabidopsis thaliana [Plant Biology]
In flowering plants, the asymmetrical division of the zygote is the first hallmark of apical-basal polarity of the embryo and is controlled by a MAP kinase pathway that includes the MAPKKK YODA (YDA). In Arabidopsis, YDA is activated by the membrane-associated pseudokinase SHORT SUSPENSOR (SSP) through an unusual parent-of-origin effect:...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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AAV cis-regulatory sequences are correlated with ocular toxicity [Neuroscience]
Adeno-associated viral vectors (AAVs) have become popular for gene therapy, given their many advantages, including their reduced inflammatory profile compared with that of other viruses. However, even in areas of immune privilege such as the eye, AAV vectors are capable of eliciting host-cell responses. To investigate the effects of such...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Lipid transporter TMEM24/C2CD2L is a Ca2+-regulated component of ER-plasma membrane contacts in mammalian neurons [Neuroscience]
Close appositions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are a general feature of all cells and are abundant in neurons. A function of these appositions is lipid transport between the two adjacent bilayers via tethering proteins that also contain lipid transport modules. However, little is known...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration [Neuroscience]
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene represent a cause of late-onset, autosomal dominant familial Parkinson’s disease (PD). A single missense mutation, D620N, is considered pathogenic based upon its segregation with disease in multiple families with PD. At present, the mechanism(s) by which familial VPS35 mutations precipitate...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Control of hearing sensitivity by tectorial membrane calcium [Neuroscience]
When sound stimulates the stereocilia on the sensory cells in the hearing organ, Ca2+ ions flow through mechanically gated ion channels. This Ca2+ influx is thought to be important for ensuring that the mechanically gated channels operate within their most sensitive response region, setting the fraction of channels open at...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Transcranial alternating current stimulation entrains single-neuron activity in the primate brain [Neuroscience]
Spike timing is thought to play a critical role in neural computation and communication. Methods for adjusting spike timing are therefore of great interest to researchers and clinicians alike. Transcranial electrical stimulation (tES) is a noninvasive technique that uses weak electric fields to manipulate brain activity. Early results have suggested...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Long-term population spike-timing-dependent plasticity promotes synaptic tagging but not cross-tagging in rat hippocampal area CA1 [Neuroscience]
In spike-timing-dependent plasticity (STDP), the direction and degree of synaptic modification are determined by the coherence of pre- and postsynaptic activities within a neuron. However, in the adult rat hippocampus, it remains unclear whether STDP-like mechanisms in a neuronal population induce synaptic potentiation of a long duration. Thus, we asked...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons [Neuroscience]
Homeostatic synaptic scaling is a negative feedback response to fluctuations in synaptic strength induced by developmental or learning-related processes, which maintains neuronal activity stable. Although several components of the synaptic scaling apparatus have been characterized, the intrinsic regulatory mechanisms promoting scaling remain largely unknown. MicroRNAs may contribute to posttranscriptional control...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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PERIOD-controlled deadenylation of the timeless transcript in the Drosophila circadian clock [Neuroscience]
The Drosophila circadian oscillator relies on a negative transcriptional feedback loop, in which the PERIOD (PER) and TIMELESS (TIM) proteins repress the expression of their own gene by inhibiting the activity of the CLOCK (CLK) and CYCLE (CYC) transcription factors. A series of posttranslational modifications contribute to the oscillations of...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Activity-dependent visualization and control of neural circuits for courtship behavior in the fly Drosophila melanogaster [Neuroscience]
Males of Drosophila melanogaster exhibit stereotypic courtship behavior through which they assess potential mates by processing multimodal sensory information. Although previous studies revealed important neural circuits involved in this process, the full picture of circuits that participate in male courtship remains elusive. Here, we established a genetic tool to visualize...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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TIM-mediated inhibition of HIV-1 release is antagonized by Nef but potentiated by SERINC proteins [Microbiology]
The T cell Ig and mucin domain (TIM) proteins inhibit release of HIV-1 and other enveloped viruses by interacting with cell- and virion-associated phosphatidylserine (PS). Here, we show that the Nef proteins of HIV-1 and other lentiviruses antagonize TIM-mediated restriction. TIM-1 more potently inhibits the release of Nef-deficient relative to...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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NF-{kappa}B activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-{kappa}B activation [Microbiology]
Vaccinia virus protein A49 inhibits NF-κB activation by molecular mimicry and has a motif near the N terminus that is conserved in IκBα, β-catenin, HIV Vpu, and some other proteins. This motif contains two serines, and for IκBα and β-catenin, phosphorylation of these serines enables recognition by the E3 ubiquitin...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Human cytomegalovirus haplotype reconstruction reveals high diversity due to superinfection and evidence of within-host recombination [Microbiology]
Recent sequencing efforts have led to estimates of human cytomegalovirus (HCMV) genome-wide intrahost diversity that rival those of persistent RNA viruses [Renzette N, Bhattacharjee B, Jensen JD, Gibson L, Kowalik TF (2011) PLoS Pathog 7:e1001344]. Here, we deep sequence HCMV genomes recovered from single and longitudinally collected blood samples from...
in Proceedings of the National Academy of Sciences Recent Issues on March 19, 2019 05:36 PM.
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Neural Processing of Communication Signals: The Extent of Sender-Receiver Matching Varies across Species of Apteronotus
Abstract
As communication signal properties change, through genetic drift or selective pressure, the sensory systems that receive these signals must also adapt to maintain sensitivity and adaptability in an array of contexts. Shedding light on this process helps us to understand how sensory codes are tailored to specific tasks. In a species of weakly electric fish, Apteronotus albifrons, we examined the unique neurophysiological properties that support the encoding of electrosensory communication signals that the animal encounters in social exchanges. We compare our findings to the known coding properties of the closely related species Apteronotus leptorhynchus to establish how these animals differ in their ability to encode their distinctive communication signals. While there are many similarities between these two species, we found notable differences leading to relatively poor coding of the details of chirp structure occurring on high-frequency background beats. As a result, small differences in chirp properties are poorly resolved by the nervous system. We performed behavioral tests to relate A. albifrons chirp coding strategies to its use of chirps during social encounters. Our results suggest that A. albifrons does not exchange frequent chirps in a nonbreeding condition, particularly when the beat frequency is high. These findings parallel the mediocre chirp coding accuracy in that they both point to a reduced reliance on frequent and rich exchange of information through chirps during these social interactions. Therefore, our study suggests that neural coding strategies in the CNS vary across species in a way that parallels the behavioral use of the sensory signals.

in eNeuro current issue on March 19, 2019 04:30 PM.
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Electrophysiological Properties of Medium Spiny Neuron Subtypes in the Caudate-Putamen of Prepubertal Male and Female Drd1a-tdTomato Line 6 BAC Transgenic Mice
Abstract
The caudate-putamen is a striatal brain region essential for sensorimotor behaviors, habit learning, and other cognitive and premotor functions. The output and predominant neuron of the caudate-putamen is the medium spiny neuron (MSN). MSNs present discrete cellular subtypes that show differences in neurochemistry, dopamine receptor expression, efferent targets, gene expression, functional roles, and most importantly for this study, electrophysiological properties. MSN subtypes include the striatonigral and the striatopallidal groups. Most studies identify the striatopallidal MSN subtype as being more excitable than the striatonigral MSN subtype. However, there is some divergence between studies regarding the exact differences in electrophysiological properties. Furthermore, MSN subtype electrophysiological properties have not been reported disaggregated by biological sex. We addressed these questions using prepubertal male and female Drd1a-tdTomato line 6 BAC transgenic mice, an important transgenic line that has not yet received extensive electrophysiological analysis. We made acute caudate-putamen brain slices and assessed a robust battery of 16 relevant electrophysiological properties using whole-cell patch-clamp recording, including intrinsic membrane, action potential, and miniature EPSC (mEPSC) properties. We found that: (1) MSN subtypes exhibited multiple differential electrophysiological properties in both sexes, including rheobase, action potential threshold and width, input resistance in both the linear and rectified ranges, and mEPSC amplitude; (2) select electrophysiological properties showed interactions between MSN subtype and sex. These findings provide a comprehensive evaluation of mouse caudate-putamen MSN subtype electrophysiological properties across females and males, both confirming and extending previous studies.

in eNeuro current issue on March 19, 2019 04:30 PM.
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Rethinking interhemispheric imbalance as a target for stroke neurorehabilitation

Objective

Patients with chronic stroke have been shown to have failure to release interhemispheric inhibition (IHI) from the intact to the damaged hemisphere before movement execution (premovement IHI). This inhibitory imbalance was found to correlate with poor motor performance in the chronic stage after stroke and has since become a target for therapeutic interventions. The logic of this approach, however, implies that abnormal premovement IHI is causal to poor behavioral outcome and should therefore be present early after stroke when motor impairment is at its worst. To test this idea, in a longitudinal study, we investigated interhemispheric interactions by tracking patients’ premovement IHI for one year following stroke.

Methods

We assessed premovement IHI and motor behavior five times over a 1‐year period after ischemic stroke in 22 patients and 11 healthy participants.

Results

We found that premovement IHI was normal during the acute/subacute period and only became abnormal at the chronic stage; specifically, release of IHI in movement preparation worsened as motor behavior improved. In addition, premovement IHI did not correlate with behavioral measures cross‐sectionally, whereas the longitudinal emergence of abnormal premovement IHI from the acute to the chronic stage was inversely correlated with recovery of finger individuation.

Interpretation

These results suggest that interhemispheric imbalance is not a cause of poor motor recovery, but instead might be the consequence of underlying recovery processes. These findings call into question the rehabilitation strategy of attempting to rebalance interhemispheric interactions in order to improve motor recovery after stroke. ANN NEUROL 2019

in Wiley: Annals of Neurology: Table of Contents on March 19, 2019 03:50 PM.
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Cortical Hemodynamic Response and Connectivity Modulated by Sub-threshold High-Frequency Repetitive Transcranial Magnetic Stimulation
Rihui Li, Thomas Potter, Jun Wang, Zhixi Shi, Chushan Wang, Lingling Yang, Rosa Chan, Yingchun Zhang
in Frontiers in Human Neuroscience | New and Recent Articles on March 19, 2019 12:00 PM.
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A Review of Psychophysiological Measures to Assess Cognitive States in Real-World Driving
Monika Lohani, Brennan R. Payne, David L. Strayer
in Frontiers in Human Neuroscience | New and Recent Articles on March 19, 2019 12:00 PM.
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Photobiomodulation and Coenzyme Q10 Treatments Attenuate Cognitive Impairment Associated With Model of Transient Global Brain Ischemia in Artificially Aged Mice
Farzad Salehpour, Fereshteh Farajdokht, Javad Mahmoudi, Marjan Erfani, Mehdi Farhoudi, Pouran Karimi, Seyed Hossein Rasta, Saeed Sadigh-Eteghad, Michael R. Hamblin, Albert Gjedde
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 19, 2019 12:00 PM.
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A case–control–family study of idiopathic rapid eye movement sleep behavior disorder

Objective

To determine the familial aggregation of idiopathic rapid eye movement sleep behavior disorder (iRBD), neurodegenerative diseases, and related biomarkers.

Methods

A total of 404 and 387 first‐degree relatives of 102 patients with iRBD and of 89 controls were recruited, respectively. Among them, 204 and 208 relatives of patients and controls underwent face‐to‐face clinical assessment, whereas 97 and 75 relatives underwent further video‐polysomnographic assessment, respectively.

Results

Compared with relatives of controls, relatives of patients demonstrated higher levels of RBD features, including chin tonic electromyography activity (mean = 1.5 ± 7.5 vs 0.3 ± 1.0, p = 0.04) and behavioral events (n [weighted %] = 12 [11.3] vs 2 [1.9], adjusted hazard ratio [aHR] = 7.69, 95% confidence interval [CI] = 1.54–33.33, p = 0.009) during rapid eye movement sleep, probable diagnosis (n [%] = 57 [14.9] vs 20 [4.9], aHR = 3.45, 95% CI = 1.96–6.25, p < 0.001), and definite diagnosis (n [weighted %] = 10 [8.4] vs 2 [1.4], aHR = 5.56, 95% CI = 1.16–25.00, p = 0.03). They also had higher risks of Parkinson disease (3.1% vs 0.5%, aHR = 5.88, 95% CI = 1.37–25.00, p = 0.02), dementia (6.9% vs 2.6%, aHR = 2.44, 95% CI = 1.15–5.26, p = 0.02), constipation (8.3% vs 2.4%, adjusted odds ratio = 4.21, 95% CI = 1.34–13.17, p = 0.01), and motor dysfunction (Movement Disorders Society Unified Parkinson's Disease Rating Scale part III motor score, mean = 1.9 ± 3.2 vs 0.9 ± 2.3, p = 0.002). The unaffected relatives of patients demonstrated a higher likelihood ratio of prodromal Parkinson disease (median [interquartile range] = 0.27 [1.19] vs 0.22 [0.51], p = 0.03).

Interpretation

iRBD is familially aggregated from isolated features to full‐blown sleep disorder. Relatives of patients carry a higher risk of alpha‐synucleinopathy in terms of neurodegenerative diseases and prodromal markers, suggesting a familial aggregation and staging pathology of alpha‐synucleinopathy. Ann Neurol 2019

in Wiley: Annals of Neurology: Table of Contents on March 19, 2019 08:09 AM.
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Audiovisual Multisensory Integration and Evoked Potentials in Young Adults With and Without Attention-Deficit/Hyperactivity Disorder
Heather S. McCracken, Bernadette A. Murphy, Cheryl M. Glazebrook, James J. Burkitt, Antonia M. Karellas, Paul C. Yielder
in Frontiers in Human Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Convergent Neural Correlates of Empathy and Anxiety During Socioemotional Processing
Lindsay K. Knight, Teodora Stoica, Nicholas D. Fogleman, Brendan E. Depue
in Frontiers in Human Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Antiphospholipid Antibodies Overlapping in Isolated Neurological Syndrome and Multiple Sclerosis: Neurobiological Insights and Diagnostic Challenges
Chiara D’Angelo, Oriol Franch, Lidia Fernández-Paredes, Celia Oreja-Guevara, María Núñez-Beltrán, Alejandra Comins-Boo, Marcella Reale, Silvia Sánchez-Ramón
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Wheel Running Improves Motor Function and Spinal Cord Plasticity in Mice With Genetic Absence of the Corticospinal Tract
Wei Zhang, Bin Yang, Huandi Weng, Tao Liu, Lingling Shi, Panpan Yu, Kwok-Fai So, Yibo Qu, Libing Zhou
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children
Liming Shen, Chengyun Feng, Kaoyuan Zhang, Youjiao Chen, Yan Gao, Junyan Ke, Xinqian Chen, Jing Lin, Cuihua Li, Javed Iqbal, Yuxi Zhao, Weibin Wang
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Mitochondrial Dysfunction in Huntington’s Disease; Interplay Between HSF1, p53 and PGC-1α Transcription Factors
Taylor A. Intihar, Elisa A. Martinez, Rocio Gomez-Pastor
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Systemic Cellular Activation Mapping of an Extinction-Impaired Animal Model
Kwanghoon Park, ChiHye Chung
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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TF-ChIP Method for Tissue-Specific Gene Targets
Amalia Perna, Lavinia Auber Alberi
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Online Quantification of Lactate Concentration in Microdialysate During Cerebral Activation Using 1H-MRS and Sensitive NMR Microcoil
Yannick Crémillieux, Ursule Dumont, Leslie Mazuel, Roberto Salvati, Vanessa Zhendre, Silvia Rizzitelli, Jordy Blanc, Hélène Roumes, Noël Pinaud, Anne-Karine Bouzier-Sore
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Astrocyte Heterogeneity: Impact to Brain Aging and Disease
Isadora Matias, Juliana Morgado, Flávia Carvalho Alcantara Gomes
in Frontiers in Aging Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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The Role of the Right Hemisphere in Emotional and Behavioral Disorders of Patients With Frontotemporal Lobar Degeneration: An Updated Review
Guido Gainotti
in Frontiers in Aging Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Editorial: Towards an Understanding of Tinnitus Heterogeneity
Christopher R. Cederroth, Silvano Gallus, Deborah A. Hall, Tobias Kleinjung, Berthold Langguth, Antonello Maruotti, Martin Meyer, Arnaud Norena, Thomas Probst, Rüdiger Pryss, Grant Searchfield, Giriraj Shekhawat, Myra Spiliopoulou, Sven Vanneste, Winfried Schlee
in Frontiers in Aging Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Impaired Redox Signaling in Huntington’s Disease: Therapeutic Implications
Bindu D. Paul, Solomon H. Snyder
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Editorial: Glia in Health and Disease
Margaret S. Ho, Alexei Verkhratsky, Shumin Duan, Vladimir Parpura
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 19, 2019 06:00 AM.
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Brain Functional Networks in Type 2 Diabetes Mellitus Patients: A Resting-State Functional MRI Study
Jian Xu, Fuqin Chen, Taiyuan Liu, Ting Wang, Junran Zhang, Huijuan Yuan, Meiyun Wang
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on March 19, 2019 06:00 AM.
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Myelin Damage in Diffuse Axonal Injury
Jiao Mu, Meiyu Li, Tingting Wang, Xiujuan Li, Meiling Bai, Guohui Zhang, Jiming Kong
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 19, 2019 06:00 AM.
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Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation
Qurratulain Aftab, Marc Mesnil, Emmanuel Ojefua, Alisha Poole, Jenna Noordenbos, Pierre-Olivier Strale, Chris Sitko, Caitlin Le, Nikolay Stoynov, Leonard J. Foster, Wun-Chey Sin, Christian C. Naus, Vincent C. Chen
in Frontiers in Neuroscience | Systems Biology section | New and Recent Articles on March 19, 2019 06:00 AM.
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Adopting Text Mining on Rehabilitation Therapy Repositioning for Stroke
Guilin Meng, Yong Huang, Qi Yu, Ying Ding, David Wild, Yanxin Zhao, Xueyuan Liu, Min Song
in Frontiers in Neuroinformatics | New and Recent Articles on March 19, 2019 06:00 AM.
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Subjectivity and complexity of facial attractiveness. (arXiv:1903.07526v1 [q-bio.NC])

The origin and meaning of facial beauty represent a longstanding puzzle. Despite the profuse literature devoted to facial attractiveness, its very nature, its determinants and the nature of inter-person differences remain controversial issues. Here we tackle such questions proposing a novel experimental approach in which human subjects, instead of rating natural faces, are allowed to efficiently explore the face-space and "sculpt" their favorite variation of a reference facial image. The results reveal that different subjects prefer distinguishable regions of the face-space, highlighting the essential subjectivity of the phenomenon. The different sculpted facial vectors exhibit strong correlations among pairs of facial distances, characterizing the underlying universality and complexity of the cognitive processes, leading to the observed subjectivity.

in q-bio.NC updates on arXiv.org on March 19, 2019 01:30 AM.
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An intracellular calcium frequency code model extended to the Riemann zeta function. (arXiv:1903.07394v1 [q-bio.NC])

We have used the Nernst chemical potential treatment to couple the time domains of sodium and calcium ion channel opening and closing rates to the spatial domain of the diffusing waves of the travelling calcium ions inside single cells. The model is plausibly evolvable with respect to the origins of the molecular components and the scaling of the system from simple cells to neurons. The mixed chemical potentials are calculated by summing the concentrations or particle numbers of the two constituent ions which are pure numbers and thus dimensionless. Chemical potentials are true thermodynamic free Gibbs/Fermi energies and the forces acting on chemical flows are calculated from the natural logarithms of the particle numbers or their concentrations. The mixed chemical potential is converted to the time domain of an action potential by assuming that the injection of calcium ions accelerates depolarization in direct proportion to the amplitude of the total charge contribution of the calcium pulse. We assert that the natural logarithm of the real component of the imaginary term of any Riemann zeta zero corresponds to an instantaneous calcium potential. In principle, in a physiologically plausible fashion, the first few thousand Riemann zeta-zeros can be encoded on this chemical scale manifested as regulated step-changes in the amplitudes of naturally occurring calcium current transients. We show that pairs of Zn channels can form Dirac fences which encode the logarithmic spacings and summed amplitudes of any pair of Riemann zeros. Remarkably the beat frequencies of the pairings of the early frequency terms overlap the naturally occurring frequency modes in vertebrate brains. The equation for the time domain in the biological model has a similar form to the Riemann zeta function on the half-plane and mimics analytical continuation on the complex plane.

in q-bio.NC updates on arXiv.org on March 19, 2019 01:30 AM.
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Reconstructing neuronal anatomy from whole-brain images. (arXiv:1903.07027v1 [cs.CV])

Reconstructing multiple molecularly defined neurons from individual brains and across multiple brain regions can reveal organizational principles of the nervous system. However, high resolution imaging of the whole brain is a technically challenging and slow process. Recently, oblique light sheet microscopy has emerged as a rapid imaging method that can provide whole brain fluorescence microscopy at a voxel size of 0.4 by 0.4 by 2.5 cubic microns. On the other hand, complex image artifacts due to whole-brain coverage produce apparent discontinuities in neuronal arbors. Here, we present connectivity-preserving methods and data augmentation strategies for supervised learning of neuroanatomy from light microscopy using neural networks. We quantify the merit of our approach by implementing an end-to-end automated tracing pipeline. Lastly, we demonstrate a scalable, distributed implementation that can reconstruct the large datasets that sub-micron whole-brain images produce.

in q-bio.NC updates on arXiv.org on March 19, 2019 01:30 AM.
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Does disease start in the mouth, the gut or both?
Oral bacteria colonize the gut more frequently than previously thought.
in eLife: latest articles on March 19, 2019 12:00 AM.
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Guy1, a Y-linked embryonic signal, regulates dosage compensation in Anopheles stephensi by increasing X gene expression
We previously showed that Guy1, a primary signal expressed from the Y chromosome, is a strong candidate for a male-determining factor that confers female-specific lethality in Anopheles stephensi (Criscione et al., 2016). Here we present evidence that Guy1 increases X gene expression in Guy1-transgenic females from two independent lines, providing a mechanism underlying the Guy1-conferred female lethality. The median level gene expression (MGE) of X-linked genes is significantly higher than autosomal genes in Guy1-transgenic females while there is no significant difference in MGE between X and autosomal genes in wild type females. Furthermore, Guy1 significantly up-regulates at least 40% of the 996 genes across the X chromosome in transgenic females. Guy1-conferred female-specific lethality is remarkably stable and completely penetrant. These findings indicate that Guy1 regulates dosage compensation in An. stephensi and components of dosage compensation may be explored to develop novel strategies to control mosquito-borne diseases.
in eLife: latest articles on March 19, 2019 12:00 AM.
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Dissociation rate compensation mechanism for budding yeast pioneer transcription factors
Nucleosomes restrict the occupancy of most transcription factors (TF) by reducing binding and accelerating dissociation, while a small group of TFs have high affinities to nucleosome-embedded sites and facilitate nucleosome displacement. To mechanistically understand this process, we investigated two S. cerevisiae TFs, Reb1 and Cbf1. We show these factors bind their sites within nucleosomes with similar affinities to naked DNA, trapping a partially unwrapped nucleosome without histone eviction. Both the binding and dissociation rates of Reb1 and Cbf1 are significantly slower at the nucleosomal sites relative to DNA, demonstrating that the high affinities are achieved by increasing the dwell time on nucleosomes to compensate for reduced binding. Reb1 also shows slow migration rate in the yeast nuclei. These properties are similar to human pioneer factors (PFs), suggesting the mechanism of nucleosome targeting is conserved from yeast to human.
in eLife: latest articles on March 19, 2019 12:00 AM.
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External validation of postnatal gestational age estimation using newborn metabolic profiles in Matlab, Bangladesh
This study sought to evaluate the performance of metabolic gestational age estimation models developed in Ontario, Canada in infants born in Bangladesh. Cord and heel prick blood spots were collected in Bangladesh and analyzed at a newborn screening facility in Ottawa, Canada. Algorithm-derived estimates of gestational age and preterm birth were compared to ultrasound-validated estimates. 1036 cord blood and 487 heel prick samples were collected from 1069 unique newborns. The majority of samples (93.2% of heel prick and 89.9% of cord blood) were collected from term infants. When applied to heel prick data, algorithms correctly estimated gestational age to within an average deviation of 1 week overall (root mean square error = 1.07 weeks). Metabolic gestational age estimation provides accurate population-level estimates of gestational age in this data set. Models were effective on data obtained from both heel prick and cord blood, the latter being a more feasible option in low-resource settings.
in eLife: latest articles on March 19, 2019 12:00 AM.
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Plasmodium Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis
Plasmodium parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Niemann-Pick Type C1-Related protein, NCR1). We isolated parasites with resistance-conferring mutations in Plasmodium falciparum NCR1 (PfNCR1) during selections with three diverse small-molecule antimalarial compounds and show that the mutations are causative for compound resistance. PfNCR1 protein knockdown results in severely attenuated growth and confers hypersensitivity to the compounds. Compound treatment or protein knockdown leads to increased sensitivity of the parasite plasma membrane (PPM) to the amphipathic glycoside saponin and engenders digestive vacuoles (DVs) that are small and malformed. Immuno-electron microscopy and split-GFP experiments localize PfNCR1 to the PPM. Our experiments show that PfNCR1 activity is critically important for the composition of the PPM and is required for DV biogenesis, suggesting PfNCR1 as a novel antimalarial drug target.
in eLife: latest articles on March 19, 2019 12:00 AM.
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Step-to-step variations in human running reveal how humans run without falling
Humans can run without falling down, usually despite uneven terrain or occasional pushes. Even without such external perturbations, intrinsic sources like sensorimotor noise perturb the running motion incessantly, making each step variable. Here, using simple and generalizable models, we show that even such small step-to-step variability contains considerable information about strategies used to run stably. Deviations in the center of mass motion predict the corrective strategies during the next stance, well in advance of foot touchdown. Horizontal motion is stabilized by total leg impulse modulations, whereas the vertical motion is stabilized by differentially modulating the impulse within stance. We implement these human-derived control strategies on a simple computational biped, showing that it runs stably for hundreds of steps despite incessant noise-like perturbations or larger discrete perturbations. This running controller derived from natural variability echoes behaviors observed in previous animal and robot studies.
in eLife: latest articles on March 19, 2019 12:00 AM.
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Switching From Fear to No Fear by Different Neural Ensembles in Mouse Retrosplenial Cortex

Abstract
Fear extinction is generally considered a form of new learning that inhibits previously acquired fear memories. Here, by tracking immediate early gene expression in vivo, we found that contextual fear extinction training evoked distinct neural ensembles in mouse retrosplenial cortex (RSC). The optogenetic reactivation of these extinction-activated neurons in the RSC was sufficient to suppress a fear response, while the reactivation of conditioning-activated neurons in the same area promoted a fear response. The generation of such an extinction-memory-related neural ensemble was associated with adult neurogenesis, as abolishing newborn neurons in the adult hippocampus via X-ray irradiation eliminated both the extinction-activated neurons in the RSC and the optogenetic-reactivation-induced suppression of contextual fear memory. Therefore, switching from fear to no fear in response to the same context is modulated by the RSC through an extinction-activated neural ensemble, the generation of which might require adult neurogenesis in the hippocampus.
in Cerebral Cortex Advance Access on March 19, 2019 12:00 AM.
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Neurostimulation Reveals Context-Dependent Arbitration Between Model-Based and Model-Free Reinforcement Learning

Abstract
While it is established that humans use model-based (MB) and model-free (MF) reinforcement learning in a complementary fashion, much less is known about how the brain determines which of these systems should control behavior at any given moment. Here we provide causal evidence for a neural mechanism that acts as a context-dependent arbitrator between both systems. We applied excitatory and inhibitory transcranial direct current stimulation over a region of the left ventrolateral prefrontal cortex previously found to encode the reliability of both learning systems. The opposing neural interventions resulted in a bidirectional shift of control between MB and MF learning. Stimulation also affected the sensitivity of the arbitration mechanism itself, as it changed how often subjects switched between the dominant system over time. Both of these effects depended on varying task contexts that either favored MB or MF control, indicating that this arbitration mechanism is not context-invariant but flexibly incorporates information about current environmental demands.
in Cerebral Cortex Advance Access on March 19, 2019 12:00 AM.
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p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts
Axon growth requires an enormous signaling matrix as the underlying code for building the nervous system. In a genetic screen, Bonanomi et al. identify p190RhoGAP as a critical regulatory switch that silences contextually inappropriate guidance signals for precise wiring of neuronal connections.
in Neuron on March 19, 2019 12:00 AM.
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An event-related potential study of decision making and feedback utilization in female college students who binge drink
This study investigated the ability to use feedback for decision making in female college students who binge drink (BD) using the Iowa Gambling Task (IGT) and event-related potentials (ERPs). Twenty-seven binge drinkers and 23 non-binge drinkers (non-BD) were identified based on scores on the Korean version of the Alcohol Use Disorder Test and the Alcohol Use Questionnaire. The IGT consists of four cards, including two cards that result in a net loss, with large immediate gains but greater losses in the long term, and two cards that result in a net gain, with small immediate gains but reduced losses in the long term. Participants were required to choose one card at a time to maximize profit until the end of the task while avoiding losses. The BD group showed a significantly lower total net score than the non-BD group, indicating that the BD group chose more disadvantageous cards. The BD group showed significantly smaller {Delta}FRN amplitudes (difference in amplitudes of feedback-related negativity [FRN] between gain and loss feedback) except in P3. Additionally, {Delta}FRN amplitudes in the fronto-central area were positively correlated with the total net score and net scores for sectors 4 and 5. Thus, total net scores and later performance on the IGT increased as {Delta}FRN amplitudes from the fronto-central area increased. FRN is known to reflect early feedback evaluation employing a bottom-up mechanism, whereas P3 is known to reflect late feedback processing and allocation of attentional resources using a top-down mechanism. These results indicate that college students who binge drink have deficits in early evaluation of positive or negative feedback and that this deficit may be related to decision making deficits.
in bioRxiv Subject Collection: Neuroscience on March 19, 2019 12:00 AM.
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Post-transcriptional mechanisms distinguish human and chimp forebrain progenitor cells
The forebrain has expanded in size and complexity during hominoid evolution. The contribution of post-transcriptional control of gene expression to this process is unclear. Using in-depth proteomics in combination with bulk and single-cell RNA sequencing, we analyzed protein and RNA levels of almost 5,000 genes in human and chimpanzee forebrain neural progenitor cells. We found that species differences in protein expression level was often independent of RNA levels, and more frequent than transcriptomic differences. Low-abundant proteins were more likely to show species-specific expression levels, while proteins expressed at a high level appeared to have evolved under stricter constraints. Our study implicates a previously unappreciated broad and important role for post-transcriptional regulatory mechanisms in the evolution of the human forebrain.
in bioRxiv Subject Collection: Neuroscience on March 19, 2019 12:00 AM.
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Corticolimbic circuit structure moderates an association between early life stress and later trait anxiety
Childhood adversity is associated with a wide range of negative behavioral and neurodevelopmental consequences. However, individuals vary substantially in their sensitivity to such adversity. Here, we examined how individual variability in structural features of the corticolimbic circuit, which plays a key role in emotional reactivity, moderates the association between childhood adversity and later trait anxiety in 798 young adult university students. Consistent with prior research, higher self-reported childhood adversity was significantly associated with higher self-reported trait anxiety. However, this association was attenuated in participants with higher microstructural integrity of the uncinate fasciculus and greater thickness of the orbitofrontal cortex. These structural properties of the corticolimbic circuit may capture a neural profile of relative resiliency to early life stress, especially against the negative effects of childhood adversity on later trait anxiety. More generally, our findings highlight the potential utility in the simultaneous consideration of qualitatively different brain structural measures in explaining complex behavioral associations in future research.
in bioRxiv Subject Collection: Neuroscience on March 19, 2019 12:00 AM.
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Transitions in brain-network level information processing dynamics are driven by alterations in neural gain
A key component of the flexibility and complexity of the brain is its ability to dynamically adapt its functional network structure between integrated and segregated brain states depending on the demands of different cognitive tasks. Integrated states are prevalent when performing tasks of high complexity, such as maintaining items in working memory, consistent with models of a global workspace architecture. Recent work has suggested that the balance between integration and segregation is under the control of ascending neuromodulatory systems, such as the noradrenergic system. In a previous large-scale nonlinear oscillator model of neuronal network dynamics, we showed that manipulating neural gain led to a critical transition in phase synchrony that was associated with a shift from segregated to integrated topology, thus confirming our original prediction. In this study, we advance these results by demonstrating that the gain-mediated phase transition is characterized by a shift in the underlying dynamics of neural information processing. Specifically, the dynamics of the subcritical (segregated) regime are dominated by information storage, whereas the supercritical (integrated) regime is associated with increased information transfer (measured via transfer entropy). Operating near to the critical regime with respect to modulating neural gain would thus appear to provide computational advantages, offering flexibility in the information processing that can be performed with only subtle changes in gain control. Our results thus link studies of whole-brain network topology and the ascending arousal system with information processing dynamics, and suggest that the constraints imposed by the ascending arousal system constrain low-dimensional modes of information processing within the brain.
in bioRxiv Subject Collection: Neuroscience on March 19, 2019 12:00 AM.
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Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent vs adult mice
IntroductionTraumatic brain injury (TBI) is a major public health concern affecting 2.8 million people per year, of which about 1 million are children under 19 years old. Animal models of TBI have been developed and used in multiple ages of animals, but direct comparisons of adult and adolescent populations are rare. The current studies were undertaken to directly compare outcomes between adult and adolescent mice, using a closed head, single impact model of TBI.nnMethodsSix-week-old adolescent and 9-week-old adult male mice were subjected to TBI using a closed head weight drop model. Histological measures for neurodegeneration, gliosis, and microglial neuroinflammation, and behavioral tests of locomotion and memory were performed.nnResultsAdolescent TBI mice have increased mortality (X2= 20.72, p < 0.001) compared to adults. There is also evidence of hippocampal neurodegeneration in adolescents, but not adults. Presence of hippocampal neurodegeneration correlates with histologic activation of microglia, but not with increased markers of astrogliosis. Adults and adolescents have similar locomotion deficits after TBI that recover by 16 days post-injury. Adolescents have memory deficits as evidenced by impaired novel object recognition performance 3 and 16 days post injury (F1,26 = 5.23, p = 0.031) while adults do not.nnConclusionsAdults and adolescents within a close age range (6-9 weeks) respond to TBI differently. Adolescents are more severely affected by mortality, neurodegeneration, and inflammation in the hippocampus compared to adults. Adolescents, but not adults, have worse memory performance after TBI that lasts up to 16 days post injury.
in bioRxiv Subject Collection: Neuroscience on March 19, 2019 12:00 AM.
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Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish
Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood, and currently no treatment exists to prevent these negative effects. We previously found that the NO donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish and the ability of SNP to prevent these. We incubated 4 days post fertilisation (dpf) zebrafish embryos in 20mM glucose or mannitol for five days until 9dpf, with or without 0.1mM SNP co-treatment for 24h (8-9dpf), and quantified vascular nitric oxide reactivity, vascular mural cell number, expression of a klf2a reporter, glial fibrillary acidic protein (GFAP) and TRPV4, as well as spontaneous neuronal activation at 9dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies. We find that glucose exposure significantly reduced nitric oxide reactivity, klf2a reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour we found glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure. Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype, and function of the optic tectum and on whole organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.
in bioRxiv Subject Collection: Neuroscience on March 19, 2019 12:00 AM.
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Building a mechanistic mathematical model of hepatitis C virus entry

by Mphatso Kalemera, Dilyana Mincheva, Joe Grove, Christopher J. R. Illingworth
The mechanism by which hepatitis C virus (HCV) gains entry into cells is a complex one, involving a broad range of host proteins. Entry is a critical phase of the viral lifecycle, and a potential target for therapeutic or vaccine-mediated intervention. However, the mechanics of HCV entry remain poorly understood. Here we describe a novel computational model of viral entry, encompassing the relationship between HCV and the key host receptors CD81 and SR-B1. We conduct experiments to thoroughly quantify the influence of an increase or decrease in receptor availability upon the extent of viral entry. We use these data to build and parameterise a mathematical model, which we then validate by further experiments. Our results are consistent with sequential HCV-receptor interactions, whereby initial interaction between the HCV E2 glycoprotein and SR-B1 facilitates the accumulation CD81 receptors, leading to viral entry. However, we also demonstrate that a small minority of virus can achieve entry in the absence of SR-B1. Our model estimates the impact of the different obstacles that viruses must surmount to achieve entry; among virus particles attaching to the cell surface, around one third of viruses accumulate sufficient CD81 receptors, of which 4–8% then complete the subsequent steps to achieve productive infection. Furthermore, we make estimates of receptor stoichiometry; in excess of 10 receptors are likely to be required to achieve viral entry. Our model provides a tool to investigate the entry characteristics of HCV variants and outlines a framework for future quantitative studies of the multi-receptor dynamics of HCV entry.
in PLOS Computational Biology: New Articles on March 18, 2019 09:00 PM.
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Endemicity and prevalence of multipartite viruses under heterogeneous between-host transmission

by Eugenio Valdano, Susanna Manrubia, Sergio Gómez, Alex Arenas
Multipartite viruses replicate through a puzzling evolutionary strategy. Their genome is segmented into two or more parts, and encapsidated in separate particles that appear to propagate independently. Completing the replication cycle, however, requires the full genome, so that a systemic infection of a host requires the concurrent presence of several particles. This represents an apparent evolutionary drawback of multipartitism, while its advantages remain unclear. A transition from monopartite to multipartite viral forms has been described in vitro under conditions of high multiplicity of infection, suggesting that cooperation between defective mutants is a plausible evolutionary pathway towards multipartitism. However, it is unknown how the putative advantages that multipartitism might enjoy at the microscopic level affect its epidemiology, or if an explicit advantange is needed to explain its ecological persistence. In order to disentangle which mechanisms might contribute to the rise and fixation of multipartitism, we here investigate the interaction between viral spreading dynamics and host population structure. We set up a compartmental model of the spread of a virus in its different forms and explore its epidemiology using both analytical and numerical techniques. We uncover that the impact of host contact structure on spreading dynamics entails a rich phenomenology of ecological relationships that includes cooperation, competition, and commensality. Furthermore, we find out that multipartitism might rise to fixation even in the absence of explicit microscopic advantages. Multipartitism allows the virus to colonize environments that could not be invaded by the monopartite form, while homogeneous contacts between hosts facilitate its spread. We conjecture that these features might have led to an increase in the diversity and prevalence of multipartite viral forms concomitantly with the expansion of agricultural practices.
in PLOS Computational Biology: New Articles on March 18, 2019 09:00 PM.
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Modeling second-order boundary perception: A machine learning approach

by Christopher DiMattina, Curtis L. Baker
Visual pattern detection and discrimination are essential first steps for scene analysis. Numerous human psychophysical studies have modeled visual pattern detection and discrimination by estimating linear templates for classifying noisy stimuli defined by spatial variations in pixel intensities. However, such methods are poorly suited to understanding sensory processing mechanisms for complex visual stimuli such as second-order boundaries defined by spatial differences in contrast or texture. We introduce a novel machine learning framework for modeling human perception of second-order visual stimuli, using image-computable hierarchical neural network models fit directly to psychophysical trial data. This framework is applied to modeling visual processing of boundaries defined by differences in the contrast of a carrier texture pattern, in two different psychophysical tasks: (1) boundary orientation identification, and (2) fine orientation discrimination. Cross-validation analysis is employed to optimize model hyper-parameters, and demonstrate that these models are able to accurately predict human performance on novel stimulus sets not used for fitting model parameters. We find that, like the ideal observer, human observers take a region-based approach to the orientation identification task, while taking an edge-based approach to the fine orientation discrimination task. How observers integrate contrast modulation across orientation channels is investigated by fitting psychophysical data with two models representing competing hypotheses, revealing a preference for a model which combines multiple orientations at the earliest possible stage. Our results suggest that this machine learning approach has much potential to advance the study of second-order visual processing, and we outline future steps towards generalizing the method to modeling visual segmentation of natural texture boundaries. This study demonstrates how machine learning methodology can be fruitfully applied to psychophysical studies of second-order visual processing.
in PLOS Computational Biology: New Articles on March 18, 2019 09:00 PM.
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Stochastic neural field model of stimulus-dependent variability in cortical neurons

by Paul C. Bressloff
We use stochastic neural field theory to analyze the stimulus-dependent tuning of neural variability in ring attractor networks. We apply perturbation methods to show how the neural field equations can be reduced to a pair of stochastic nonlinear phase equations describing the stochastic wandering of spontaneously formed tuning curves or bump solutions. These equations are analyzed using a modified version of the bivariate von Mises distribution, which is well-known in the theory of circular statistics. We first consider a single ring network and derive a simple mathematical expression that accounts for the experimentally observed bimodal (or M-shaped) tuning of neural variability. We then explore the effects of inter-network coupling on stimulus-dependent variability in a pair of ring networks. These could represent populations of cells in two different layers of a cortical hypercolumn linked via vertical synaptic connections, or two different cortical hypercolumns linked by horizontal patchy connections within the same layer. We find that neural variability can be suppressed or facilitated, depending on whether the inter-network coupling is excitatory or inhibitory, and on the relative strengths and biases of the external stimuli to the two networks. These results are consistent with the general observation that increasing the mean firing rate via external stimuli or modulating drives tends to reduce neural variability.
in PLOS Computational Biology: New Articles on March 18, 2019 09:00 PM.
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Self-organization of conducting pathways explains electrical wave propagation in cardiac tissues with high fraction of non-conducting cells

by Nina Kudryashova, Aygul Nizamieva, Valeriya Tsvelaya, Alexander V. Panfilov, Konstantin I. Agladze
Cardiac fibrosis occurs in many forms of heart disease and is considered to be one of the main arrhythmogenic factors. Regions with a high density of fibroblasts are likely to cause blocks of wave propagation that give rise to dangerous cardiac arrhythmias. Therefore, studies of the wave propagation through these regions are very important, yet the precise mechanisms leading to arrhythmia formation in fibrotic cardiac tissue remain poorly understood. Particularly, it is not clear how wave propagation is organized at the cellular level, as experiments show that the regions with a high percentage of fibroblasts (65-75%) are still conducting electrical signals, whereas geometric analysis of randomly distributed conducting and non-conducting cells predicts connectivity loss at 40% at the most (percolation threshold). To address this question, we used a joint in vitro-in silico approach, which combined experiments in neonatal rat cardiac monolayers with morphological and electrophysiological computer simulations. We have shown that the main reason for sustainable wave propagation in highly fibrotic samples is the formation of a branching network of cardiomyocytes. We have successfully reproduced the morphology of conductive pathways in computer modelling, assuming that cardiomyocytes align their cytoskeletons to fuse into cardiac syncytium. The electrophysiological properties of the monolayers, such as conduction velocity, conduction blocks and wave fractionation, were reproduced as well. In a virtual cardiac tissue, we have also examined the wave propagation at the subcellular level, detected wavebreaks formation and its relation to the structure of fibrosis and, thus, analysed the processes leading to the onset of arrhythmias.
in PLOS Computational Biology: New Articles on March 18, 2019 09:00 PM.
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High‐Frequency Oscillation Networks and Surgical Outcome in Adult Focal Epilepsy

Objective

To investigate whether high‐frequency oscillations (HFOs) show spatiotemporal propagation and assess the relevance of the earliest oscillations in relation to the seizure onset zone (SOZ) and postsurgical outcome.

Methods

We retrospectively investigated the intracerebral electroencephalography (EEG) of patients who became seizure free after subsequent surgery. We marked HFOs during 1 hour of recordings. We calculated the time delay between pairs of channels as the median delay between their HFOs and constructed a time line of the delay of each channel with respect to the earliest channel (first source channel). A network was defined when a temporal order could be established among the channels based on the existence of statistically significant delays.

Results

Fifteen patients with good surgical outcome were included. We found ripple networks in all patients, and fast ripple networks in 9. For ripples, first source channels were found in a higher proportion in the SOZ than the rest of the network channels (15 of 27 [56%] versus 93 of 262 [35%]; p = 0.04). For both ripples and fast ripples, first source channels were resected more often that the rest of the network channels (ripples: 13 of 27 [48%] versus 65 of 262 [25%]; p = 0.01; fast ripples: 8 of 9 [89%] versus 17 of 40 [43%]; p = 0.002); channels with the highest rates of ripples and fast ripples were resected in a similar proportion.

Interpretation

These results demonstrate that interictal HFOs are organized in networks and indicate a possible need for the resection of first source channels. However, resecting them is not superior to resecting channels with highest rates of HFOs. Ann Neurol, 2019

in Wiley: Annals of Neurology: Table of Contents on March 18, 2019 07:01 PM.
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Slow‐wave sleep and motor progression in Parkinson disease

Abstract

Growing evidence from Alzheimer disease supports a potentially beneficial role of slow‐wave sleep in neurodegeneration. However, the importance of slow‐wave sleep in Parkinson disease is unknown. In 129 patients with Parkinson disease, we retrospectively tested whether sleep slow waves, objectively quantified with polysomnography, relate to longitudinal changes in Unified Parkinson's Disease Rating Scale motor scores. We found that higher accumulated power of sleep slow waves was associated with slower motor progression, particularly of axial motor symptoms, over a mean time of 4.6±2.3 years. This preliminary finding suggests that deeper sleep relates to slower motor progression in Parkinson disease.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on March 18, 2019 06:44 PM.
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Smoking is a cause of ALS. High LDL‐cholesterol levels? Unsure

in Wiley: Annals of Neurology: Table of Contents on March 18, 2019 06:30 PM.
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Attention to Monocular Images Bias Binocular Rivalry
Manuel Moreno-Sánchez, J. Antonio Aznar-Casanova, Fernando Valle-Inclán
in Frontiers in Systems Neuroscience | New and Recent Articles on March 18, 2019 06:00 PM.
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Catalyzing Neurophysiology: Jacques Loeb, the Stazione Zoologica di Napoli, and a Growing Network of Brain Scientists, 1900s–1930s
Frank W. Stahnisch
in Frontiers in Neuroanatomy | New and Recent Articles on March 18, 2019 06:00 PM.
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Transduction of the Geomagnetic Field as Evidenced from Alpha-band Activity in the Human Brain
Abstract
Magnetoreception, the perception of the geomagnetic field, is a sensory modality well-established across all major groups of vertebrates and some invertebrates, but its presence in humans has been tested rarely, yielding inconclusive results. We report here a strong, specific human brain response to ecologically-relevant rotations of Earth-strength magnetic fields. Following geomagnetic stimulation, a drop in amplitude of EEG alpha oscillations (8-13 Hz) occurred in a repeatable manner. Termed alpha event-related desynchronization (alpha-ERD), such a response has been associated previously with sensory and cognitive processing of external stimuli including vision, auditory and somatosensory cues. Alpha-ERD in response to the geomagnetic field was triggered only by horizontal rotations when the static vertical magnetic field was directed downwards, as it is in the Northern Hemisphere; no brain responses were elicited by the same horizontal rotations when the static vertical component was directed upwards. This implicates a biological response tuned to the ecology of the local human population, rather than a generic physical effect.
Biophysical tests showed that the neural response was sensitive to static components of the magnetic field. This rules out all forms of electrical induction (including artifacts from the electrodes) which are determined solely on dynamic components of the field. The neural response was also sensitive to the polarity of the magnetic field. This rules out free-radical 'quantum compass' mechanisms like the cryptochrome hypothesis, which can detect only axial alignment. Ferromagnetism remains a viable biophysical mechanism for sensory transduction and provides a basis to start the behavioral exploration of human magnetoreception.
Significance Statement Although many migrating and homing animals are sensitive to Earth’s magnetic field, most humans are not consciously aware of the geomagnetic stimuli that we encounter in everyday life. Either we have lost a shared, ancestral magnetosensory system, or the system lacks a conscious component with detectable neural activity but no apparent perceptual awareness by us. We found two classes of ecologically-relevant rotations of Earth-strength magnetic fields that produce strong, specific and repeatable effects on human brainwave activity in the EEG alpha band (8-13 Hz); EEG discriminates in response to different geomagnetic field stimuli. Biophysical tests rule out all except the presence of a ferromagnetic transduction element, such as biologically-precipitated crystals of magnetite (Fe₃O₄).

in RSS PAP on March 18, 2019 04:30 PM.
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Vector-Derived Transformation Binding: An Improved Binding Operation for Deep Symbol-Like Processing in Neural Networks
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on March 18, 2019 08:06 AM.
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Information Geometry for Regularized Optimal Transport and Barycenters of Patterns
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on March 18, 2019 08:06 AM.
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Inhibition and Excitation Shape Activity Selection: Effect of Oscillations in a Decision-Making Circuit
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on March 18, 2019 08:06 AM.
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Introducing User-Prescribed Constraints in Markov Chains for Nonlinear Dimensionality Reduction
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on March 18, 2019 08:06 AM.
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Semisupervised Deep Stacking Network with Adaptive Learning Rate Strategy for Motor Imagery EEG Recognition
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on March 18, 2019 08:06 AM.
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Multiple Timescale Online Learning Rules for Information Maximization with Energetic Constraints
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on March 18, 2019 08:05 AM.
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Sparse Associative Memory
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on March 18, 2019 08:05 AM.
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Brain Morphometry Methods for Feature Extraction in Random Subspace Ensemble Neural Network Classification of First-Episode Schizophrenia
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on March 18, 2019 08:05 AM.
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Increased Functional Connectivity of the Angular Gyrus During Imagined Music Performance
Shoji Tanaka, Eiji Kirino
in Frontiers in Human Neuroscience | New and Recent Articles on March 18, 2019 06:00 AM.
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Editorial: Owning a Body + Moving a Body = Me?
Lorenzo Pia, Francesca Garbarini, Andreas Kalckert, Hong Yu Wong
in Frontiers in Human Neuroscience | New and Recent Articles on March 18, 2019 06:00 AM.
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Predicting Known Sentences: Neural Basis of Proverb Reading Using Non-parametric Statistical Testing and Mixed-Effects Models
Bruno Bianchi, Diego E. Shalom, Juan E. Kamienkowski
in Frontiers in Human Neuroscience | New and Recent Articles on March 18, 2019 06:00 AM.
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Neural Correlates of Preference: A Transmodal Validation Study
Henrique T. Akiba, Marcelo F. Costa, July S. Gomes, Eduardo Oda, Paula B. Simurro, Alvaro M. Dias
in Frontiers in Human Neuroscience | New and Recent Articles on March 18, 2019 06:00 AM.
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Electromagnetic Brain Stimulation in Patients With Disorders of Consciousness
Pierre Bourdillon, Bertrand Hermann, Jacobo D. Sitt, Lionel Naccache
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on March 18, 2019 06:00 AM.
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Elevated Plasma microRNA-105-5p Level in Patients With Idiopathic Parkinson’s Disease: A Potential Disease Biomarker
Zhaofei Yang, Tianbai Li, Yanhua Cui, Song Li, Cheng Cheng, Bairong Shen, Weidong Le
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 18, 2019 06:00 AM.
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Phase fMRI Reveals More Sparseness and Balance of Rest Brain Functional Connectivity Than Magnitude fMRI
Zikuan Chen, Zening Fu, Vince Calhoun
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on March 18, 2019 06:00 AM.
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Brain Segmentation From Computed Tomography of Healthy Aging and Geriatric Concussion at Variable Spatial Resolutions
Andrei Irimia, Alexander S. Maher, Kenneth A. Rostowsky, Nahian F. Chowdhury, Darryl H. Hwang, E. Meng Law
in Frontiers in Neuroinformatics | New and Recent Articles on March 18, 2019 06:00 AM.
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Multiplexed peroxidase-based electron microscopy labeling enables simultaneous visualization of multiple cell types

Multiplexed peroxidase-based electron microscopy labeling enables simultaneous visualization of multiple cell types
Multiplexed peroxidase-based electron microscopy labeling enables simultaneous visualization of multiple cell types, Published online: 18 March 2019; doi:10.1038/s41593-019-0358-7
A peroxidase-based labeling method allows simultaneous visualization of multiple cell types using electron microscopy without the need for spectral separation, enabling identification of synapses between genetically defined neuronal populations.
in Nature Neuroscience - Issue - nature.com science feeds on March 18, 2019 12:00 AM.
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A whole-brain atlas of monosynaptic input targeting four different cell types in the medial prefrontal cortex of the mouse

A whole-brain atlas of monosynaptic input targeting four different cell types in the medial prefrontal cortex of the mouse
A whole-brain atlas of monosynaptic input targeting four different cell types in the medial prefrontal cortex of the mouse, Published online: 18 March 2019; doi:10.1038/s41593-019-0354-y
The connectivity of a cortical region is instrumental to its function. The authors generated brain-wide maps of the afferent input to four distinct cell types in the mPFC to reveal the structural architecture that underlies the mPFC’s functions.
in Nature Neuroscience - Issue - nature.com science feeds on March 18, 2019 12:00 AM.
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Cerebral organoids at the air–liquid interface generate diverse nerve tracts with functional output

Cerebral organoids at the air–liquid interface generate diverse nerve tracts with functional output
Cerebral organoids at the air–liquid interface generate diverse nerve tracts with functional output, Published online: 18 March 2019; doi:10.1038/s41593-019-0350-2
A modified brain-organoid culture generates extensive axon outgrowth with specific tract-like patterns. Organoid tracts connect neurons across distant sites and can innervate and stimulate co-cultured mouse spinal cord tissue to elicit muscle contractions.
in Nature Neuroscience - Issue - nature.com science feeds on March 18, 2019 12:00 AM.
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Taking the good with the bad

Taking the good with the bad
Taking the good with the bad, Published online: 18 March 2019; doi:10.1038/s41583-019-0159-8
Neurons expressing corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus of mice show increases and decreases in activity in response to aversive and appetitive stimuli.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 18, 2019 12:00 AM.
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Conversational control in singing mice

Conversational control in singing mice
Conversational control in singing mice, Published online: 18 March 2019; doi:10.1038/s41583-019-0158-9
In ‘singing’ mice, the motor cortex controls the timing of rapid vocal exchanges to enable turn-taking during social interaction.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 18, 2019 12:00 AM.
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Complementary networks of cortical somatostatin interneurons enforce layer specific control
The neocortex is functionally organized into layers. Layer four receives the densest bottom up sensory inputs, while layers 2/3 and 5 receive top down inputs that may convey predictive information. A subset of cortical somatostatin (SST) neurons, the Martinotti cells, gate top down input by inhibiting the apical dendrites of pyramidal cells in layers 2/3 and 5, but it is unknown whether an analogous inhibitory mechanism controls activity in layer 4. Using high precision circuit mapping, in vivo optogenetic perturbations, and single cell transcriptional profiling, we reveal complementary circuits in the mouse barrel cortex involving genetically distinct SST subtypes that specifically and reciprocally interconnect with excitatory cells in different layers: Martinotti cells connect with layers 2/3 and 5, whereas non-Martinotti cells connect with layer 4. By enforcing layer-specific inhibition, these parallel SST subnetworks could independently regulate the balance between bottom up and top down input.
in eLife: latest articles on March 18, 2019 12:00 AM.
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Behavioural and neural signatures of perceptual decision-making are modulated by pupil-linked arousal
The timing and accuracy of perceptual decision-making is exquisitely sensitive to fluctuations in arousal. Although extensive research has highlighted the role of various neural processing stages in forming decisions, our understanding of how arousal impacts these processes remains limited. Here we isolated electrophysiological signatures of decision-making alongside signals reflecting target selection, attentional engagement and motor output and examined their modulation as a function of tonic and phasic arousal, indexed by baseline and task-evoked pupil diameter, respectively. Reaction times were shorter on trials with lower tonic, and higher phasic arousal. Additionally, these two pupil measures were predictive of a unique set of EEG signatures that together represent multiple information processing steps of decision-making. Finally, behavioural variability associated with fluctuations in tonic and phasic arousal, indicative of neuromodulators acting on multiple timescales, was mediated by its effects on the EEG markers of attentional engagement, sensory processing and the variability in decision processing.
in eLife: latest articles on March 18, 2019 12:00 AM.
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The SNAP-25 linker supports fusion intermediates by local lipid interactions
SNAP-25 is an essential component of SNARE complexes driving fast Ca²⁺-dependent exocytosis. Yet, the functional implications of the tandem-like structure of SNAP-25 are unclear. Here, we have investigated the mechanistic role of the acylated “linker” domain that concatenates the two SNARE motifs within SNAP-25. Refuting older concepts of an inert connector, our detailed structure-function analysis in murine chromaffin cells demonstrates that linker motifs play a crucial role in vesicle priming, triggering, and fusion pore expansion. Mechanistically, we identify two synergistic functions of the SNAP-25 linker: First, linker motifs support t-SNARE interactions and accelerate ternary complex assembly. Second, the acylated N-terminal linker segment engages in local lipid interactions that facilitate fusion triggering and pore evolution, putatively establishing a favorable membrane configuration by shielding phospholipid headgroups and affecting curvature. Hence, the linker is a functional part of the fusion complex that promotes secretion by SNARE interactions as well as concerted lipid interplay.
in eLife: latest articles on March 18, 2019 12:00 AM.
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Consolidation alters motor sequence-specific distributed representations
FMRI studies investigating the acquisition of sequential motor skills in humans have revealed learning-related functional reorganizations of the cortico-striatal and cortico-cerebellar motor systems accompanied with an initial hippocampal contribution. Yet, the functional significance of these activity level changes remains ambiguous as they convey the evolution of both sequence-specific knowledge and unspecific task ability. Moreover, these changes do not specifically assess the occurrence of learning-related plasticity. To address these issues, we investigated local circuits tuning to sequence-specific information using multivariate distances between patterns evoked by consolidated or newly acquired motor sequences production. The results reveal that representations in dorsolateral striatum, prefrontal and secondary motor cortices are greater when executing consolidated sequences than untrained ones. By contrast, sequence representations in the hippocampus and dorsomedial striatum becomes less engaged. Our findings show, for the first time in humans, that complementary sequence-specific motor representations evolve distinctively during critical phases of skill acquisition and consolidation.
in eLife: latest articles on March 18, 2019 12:00 AM.
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A Disinhibitory Microcircuit Mediates Conditioned Social Fear in the Prefrontal Cortex
Prefrontal cortex plays an essential role in fear expression. Xu et al. reveal a disinhibitory microcircuit in prefrontal cortex through interactions between interneuron subtypes and suggest that SST INs-mediated disinhibition represents an important circuit mechanism in gating social fear behavior.
in Neuron on March 18, 2019 12:00 AM.
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Pretreatment with a CRF antagonist amplifies feeding inhibition induced by fourth ventricular cocaine- and amphetamine-regulated transcript peptide
Pre-treatment with the corticotropin-releasing factor antagonist α-helical CRF9-41 prevents inhibition of gastric emptying by cocaine-and amphetamine-regulated transcript peptide at a dorsal hindbrain level, b...
in Most Recent Articles: BMC Neuroscience on March 18, 2019 12:00 AM.
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Non-invasive measurement of hemodynamic change during 8 MHz transcranial focused ultrasound stimulation using near-infrared spectroscopy
Transcranial focused ultrasound (tFUS) attracts wide attention in neuroscience as an effective noninvasive approach to modulate brain circuits. In spite of this, the effects of tFUS on the brain is still uncle...
in Most Recent Articles: BMC Neuroscience on March 18, 2019 12:00 AM.
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Effect of lesion proximity on the regenerative response of long descending propriospinal neurons after spinal transection injury
The spinal cord is limited in its capacity to repair after damage caused by injury or disease. However, propriospinal (PS) neurons in the spinal cord have demonstrated a propensity for axonal regeneration afte...
in Most Recent Articles: BMC Neuroscience on March 18, 2019 12:00 AM.
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Dissociable neural circuits underlie the resolution of three discrete sources of competition during task-switching.
Humans perform sub-optimally when juggling more than one task, but are nonetheless required to multitask during many daily activities. Rapidly and effectively switching attentional focus between tasks is fundamental to navigating complex environments. Task-switching paradigms in conjunction with neuroimaging have identified brain networks underpinning flexible reallocation of cognitive resources and a core network of neural regions is repeatedly implicated (i.e., posterior parietal, inferior frontal, anterior cingulate, and middle frontal cortex). Performance costs such as reduced accuracy and slowed responses accompany the first execution of a task following a task-switch. These costs stem from three main sources of competition: 1) the need to reconfigure task-rules, 2) the immediate history of motor responding, and 3) whether inputs to be acted upon provide congruent or incongruent information regarding the appropriate motor response, relative to the recently switched-away-from task. Here, we asked whether both common (domain-general) and non-overlapping (domain-specific) neural circuits were involved in resolving these three distinct sources of competition under high-demand task-switching conditions. Networks of domain-specific regions were active in resolving each of the three sources of competition. No domain-general regions were implicated in all three. Rather, two regions were common across rule-switching and incongruency, and five regions to incongruence and response-switching. Each source of conflict elicited activation from many regions including the posterior cingulate, thalamus, and cerebellum, regions not commonly implicated in the task-switching literature. These results suggest that discrete domain-specific neural networks are principally responsible for resolving different sources of competition, but with partial interaction of some overlapping domain-general circuitry.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Statistical context dictates the relationship between feedback-related EEG signals and learning
Successful decision-making requires learning expectations based on experienced outcomes. This learning should be calibrated according to the surprise associated with an outcome, but also to the statistical context dictating the most likely source of surprise. For example, when occasional changepoints are expected, surprising outcomes should be weighted heavily, demanding increased learning. In contrast, when signal corruption is expected to occur occasionally, surprising outcomes can suggest a corrupt signal that should be ignored by learning systems. Here we dissociate surprising outcomes from the degree to which they demand learning using a predictive inference task and computational modeling. We show that the updating P300, a stimulus-locked electrophysiological response previously associated with adjustments in learning behavior, does so conditionally on the source of surprise. Larger P300 signals predicted greater learning in a changing context, but predicted less learning in a context where surprise was indicative of a one-off outlier (oddball). The conditional predictive relationship between the P300 and learning behavior was persistent even after adjusting for known sources of learning rate variability. Our results suggest that the P300 provides a surprise signal that is interpreted by downstream learning processes differentially according to statistical context in order to appropriately calibrate learning across complex environments.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Transient upregulation of translational efficiency in prodromal Tg2576 mice precipitates AD symptoms
Tg2576 mice overexpressing APPK670/671L exhibit elevated hAPP levels from birth but remain at a prodromal stage until 3 months of age. Whether variations in hAPP mRNA specific and overall translation occur during development and precipitates the transition from an asymptomatic to a symptomatic stage is unknown. By performing polysome profiling and distribution of hAPP, and measuring the levels of eukaryotic initial translation factors in hippocampal extracts from pre- and early symptomatic Tg2576 mice, we found that the presence of mRNA and protein polysomal signals was associated with decreased levels of the phosphorylated form of the initial translation factor eIF2a (p-eIF2a), revealing a transient upregulation of overall translation. Differently, the reduction of hAPP mRNA polysomal signals was associated with increased p-eIF2a levels - repressing translation - when mice were symptomatic, suggesting a compensatory mechanism aimed at downregulating hAPP mRNA. Confirming that prodromal upregulation of translational efficiency contributes to AD pathogenesis, pharmacological restoration of proper translational control in early symptomatic mice blocked the manifestation of neural and cognitive AD-like alterations.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Asymmetric sampling in human auditory cortex reveals spectral processing hierarchy
Speech perception is mediated by both left and right auditory cortices, but with differential sensitivity to specific acoustic information contained in the speech signal. A detailed description of this functional asymmetry is missing, and the underlying models are widely debated. We analyzed cortical responses from 96 epilepsy patients with electrode implantation in left or right primary, secondary, and/or association auditory cortex. We presented short acoustic transients to reveal the stereotyped spectro-spatial oscillatory response profile of the auditory cortical hierarchy. We show remarkably similar bimodal spectral response profiles in left and right primary and secondary regions, with preferred processing modes in the theta (~4-8 Hz) and low gamma (~25-50 Hz) ranges. These results highlight that the human auditory system employs a two-timescale processing mode. Beyond these first cortical levels of auditory processing, a hemispheric asymmetry emerged, with delta and beta band (~3/15 Hz) responsivity prevailing in the right hemisphere and theta and gamma band (~6/40 Hz) activity in the left. These intracranial data provide a more fine-grained and nuanced characterization of cortical auditory processing in the two hemispheres, shedding light on the neural dynamics that potentially shape auditory and speech processing at different levels of the cortical hierarchy.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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The parietal operculum preferentially encodes heat pain and not salience
Substantial controversy exists as to which part of brain activity is genuinely attributable to pain-related percepts, and which activity is due to general aspects of sensory stimulation, such as its salience. The challenge posed by this question rests largely in the fact that pain is per se highly salient, a characteristic which therefore has to be matched by potential control conditions. Here, we used a unique combination of functional magnetic resonance imaging, behavioral and autonomic measures to address this longstanding debate in pain research. Subjects rated perceived intensity in a sequence alternating between heat and sound stimuli. Neuronal activity was monitored using fMRI. Either modality was presented in six different intensities, three of which lay above the pain threshold (for heat) or the unpleasantness threshold (for sound). We performed our analysis on 26 volunteers in which psychophysiological responses (as per skin conductance responses) did not differ between the two stimulus modalities. Having thus ascertained a comparable amount of stimulus salience, we analyzed pain-related stimulus response functions, and contrasted them with those of the salience-matched acoustic control condition. Furthermore, analysis of fMRI data was performed on the brain surface to circumvent blurring issues stemming from the close proximity of several regions of interest located in heavily folded cortical areas. We focused our analyses on insular and periinsular regions which are strongly involved in processing of painful stimuli. We employed an axiomatic approach to determine areas showing higher activation in painful compared to non-painful heat, and at the same time showing a steeper stimulus response function for painful heat as compared to unpleasant acoustic stimuli. Intriguingly, an area in the posterior parietal operculum emerged whose response showed a pain preference, and where we can unequivocally exclude salience as explanation. This result has important implications for the interpretation of functional imaging findings in pain research, as it clearly demonstrates that there are areas whose pain-related activity is not due to general stimulus characteristics such as salience. Conversely, several areas did not conform to the formulated axioms to rule out general factors as explanations.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Predictive Coding beyond simple tone-based oddball designs
As the evidence of predictive processes playing a role in a wide variety of cognitive domains increases, the brain as a predictive machine becomes a central idea in neuroscience. In auditory processing a considerable amount of progress has been made using variations of the Oddball design, but most of the existing work seems restricted to simple stimuli and predictions based on physical features or conditional rules linking successive stimuli. Here we present two experiments that use speech-like stimuli to overcome these limitations and avoid common confounds. Pseudowords were presented in isolation, intermixed with infrequent deviants that contained unexpected phoneme sequences. As hypothesized, the occurrence of unexpected sequences of phonemes reliably elicited an early prediction error signal, compatible with a MMN-like response. These prediction error signals were not modulated by an attentional manipulation induced by different task instructions, suggesting that the predictions are deployed even when the task at hand does not volitionally involve error detection. In contrast, the amount of syllables congruent with a standard pseudoword presented before the point of deviance exerted a strong modulation. Prediction error's amplitude doubled when two congruent syllables were presented instead of one, despite keeping local transitional probabilities constant, this suggest that auditory predictions can be built integrating information beyond the immediate past. In sum, the results presented here attest the predictive capabilities of the human auditory system when facing complex stimuli and abstract rules.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Integrating electric field modelling and neuroimaging to explain variability of low intensity tES effects
Variability of transcranial electrical stimulation (tES) effects is one of the major challenges in the brain stimulation community. Promising candidates to explain this variability are individual anatomy and the resulting differences of electric fields inside the brain. Here, we integrated individual simulations of electric fields during tES with source-localization to predict variability of transcranial alternating current stimulation (tACS) aftereffects on -oscillations. Forty participants received 20 minutes of either -tACS (1 mA) or sham stimulation. Magnetoencephalogram was recorded for 10 minutes before and after stimulation. tACS caused a larger power increase in the -band as compared to sham. The variability of this effect was significantly predicted by measures derived from individual electric field modelling. Our results are the first to directly link electric field variability to variability of tES outcomes, stressing the importance of individualizing stimulation protocols and providing a novel approach to analyze tES effects in terms of dose-response relationships.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Schwann cell demyelination is triggered by a transient mitochondrial calcium release through Voltage Dependent Anion Channel 1
The maintenance of the myelin sheath by Schwann cells around peripheral nerve axons is essential for the rapid propagation of action potentials. A large number of peripheral neuropathies results for the loss of this myelin sheath, a process called demyelination. Demyelination is a program of cell dedifferentiation characterized by reprograming and several catabolic and anabolic events. This process was best characterized in Wallerian demyelination that occurs following nerve injury. In this model, the earliest well characterized steps are MAPK pathways activation and cJun phosphorylation and nuclear localization starting around 4hrs after nerve injury. Here we show, using in vivo imaging of virally-delivered fluorescent probes to mitochondria, that Schwann cell mitochondria pH, motility and calcium are altered as soon as 1hr after nerve injury. Mitochondrial calcium release through VDAC1 mitochondrial channel and mPTP directly induced Schwann cell demyelination via MAPK and c-Jun activation. Decreasing mitochondrial calcium release through VDAC1 silencing or TRO19622 blocking prevented MAPK and cJun activation and demyelination. VDAC1 opening with Methyl Jasmonate induced these cellular mechanisms in absence of nerve injury. Taken together, these data indicate that mitochondria calcium homeostasis through VDAC1 is instrumental in the Schwann cell demyelination process and therefore provide a molecular basis for an anti-demyelinating drug approach.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Increased hippocampal excitability and reduced modulation in relevant neural networks underlying age-related cognitive mapping deficits
Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn novel spatial environments deteriorates substantially but the underlying neural mechanisms are unknown. Here, we report findings from a behavioral and a fMRI experiment where older and younger adults performed a spatial learning task in a photorealistic virtual environment. We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex/parieto-occipital sulcus and anterior hippocampus did not change systematically as a function learning in older compared to younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits are linked to an increase in hippocampal excitability. Together, these results provide important insights into how human aging affects computations in the brain's navigation system, highlighting the critical role of the hippocampus.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Specific oligodendrocyte populations have differential spatial distribution and susceptibility to injury
Oligodendrocytes (OLs), the myelinating cells of the central nervous system, are transcriptionally heterogeneous, the origin and functional consequences of which are unknown. We report that mature OL2 (MOL2) preferentially distribute in the spinal cord white matter, while MOL5/6 are abundant in the brain and spinal cord grey matter. Remarkably, MOL2 and MOL5/6 segregate around sensory and motor tracts in the spinal cord, respectively. Lineage tracing, single-cell RNA-Sequencing and RNAscope ISH indicated that the developmental origin does not specify OL progenitors into MOL populations. Following spinal cord injury, we observed depletion of MOL2, while MOL5/6 abundantly repopulate the injury site. Thus, specific MOL populations, identified by scRNAseq, have spatial preference and differential responses to disease, suggesting that OLs are both transcriptionally and functionally heterogeneous.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Atypical developmental features of cortical thickness trajectories in Autism Spectrum Disorder
Neuroimaging studies have reported numerous region-specific atypicalities in the brains of individuals with Autism Spectrum Disorder (ASD), including alterations in cortical thickness (CT). However, there are many inconsistent findings, and this is probably due to atypical CT developmental trajectories in ASD. To this end, we investigated group differences in terms of shapes of developmental trajectories of CT between ASD and typically developing (TD) populations. Using the Autism Brain Imaging Data Exchange (ABIDE) repository (releases I and II combined), we investigated atypical shapes of developmental trajectories in ASD using a linear, quadratic and cubic models at various scales of spatial coarseness, and their association with symptomatology using the Autism Diagnostic Observation Schedule (ADOS) scores. These parameters were also used to predict ASD and TD CT development. While no overall group differences in CT was observed across the entire age range, ASD and TD populations were different in terms of age-related changes. Developmental trajectories of CT in ASD were mostly characterized by decreased cortical thinning during early adolescence and increased thinning at later stages, involving mostly frontal and parietal areas. Such changes were associated with ADOS scores. The curvature of the trajectories estimated from the quadratic model was the most accurate and sensitive measure for detecting ASD. Our findings suggest that under the context of longitudinal changes in brain morphology, robust detection of ASD would require three time points to estimate the curvature of age-related changes.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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Presynaptic boutons that contain mitochondria are more stable
Addition and removal of presynaptic terminals reconfigures neuronal circuits of the mammalian neocortex, but little is known about how this presynaptic structural plasticity is controlled. Since mitochondria can regulate presynaptic function, we investigated whether the presence of axonal mitochondria relates to structural plasticity of presynaptic boutons in mouse neocortex. We found that the overall density of axonal mitochondria did not appear to influence loss and gain of boutons. However, positioning of mitochondria at individual presynaptic sites did relate to increased stability of those boutons. In line with this, synaptic localisation of mitochondria increased as boutons aged and showed differing patterns of localisation at en passant and terminaux boutons. These results suggest that mitochondria accumulate locally at boutons over time to increase bouton stability.
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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The Fruit Fly Brain Observatory: From Structure to Function
The fruit fly is a key model organism for studying the activity of interconnected brain circuits. A large scattered global research community of neurobiologists and neurogeneticists, computational and theoretical neuroscientists, and computer scientists and engineers has been developing a vast trove of experimental and modeling data that has yet to be distilled into new knowledge and understanding of the functional logic of the brain. Developing open shared models, modelling tools and data repositories that can be accessed from anywhere in the world is the necessary engine for accelerating our understanding of how the brain works. To that end we developed the Fruit Fly Brain Observatory (FFBO), the next generation open-source platform to support open, collaborative Drosophila neuroscience research. FFBO provides a (i) hub for storing and integrating fruit fly brain research data from multiple data sources worldwide, (ii) unified repository of tools and methods to build, emulate and compare fruit fly brain models in health and disease, and (iii) an open framework for fruit fly brain data processing and model execution. FFBO provides access to application tools for visualizing, configuring, simulating and analyzing computational models of brain circuits of the (i) cell type map, (ii) connectome, (iii) synaptome, and (iv) activity map using intuitive queries in plain English. Tools are provided to extract the function inherent in these structural maps. All applications can be accessed with any modern browser
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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The mesoSPIM initiative: open-source light-sheet mesoscopes for imaging in cleared tissue
Over the course of the past decade, tissue clearing methods have reached a high level of sophistication with a wide variety of approaches now available. To image large cleared samples, light-sheet microscopes have proven to be ideal due to their excellent optical sectioning capability in transparent tissue. Such instruments have recently seen extensive technological and commercial development. However, despite this progress, the community is lacking instruments capable of exploring large samples with near-isotropic resolution within minutes. Here, we introduce the mesoscale selective plane-illumination microscopy (mesoSPIM) initiative, an open-hardware project that provides researchers with instructions and software to easily build and operate light-sheet microscopes for centimeter-sized cleared samples (www.mesospim.org).
in bioRxiv Subject Collection: Neuroscience on March 18, 2019 12:00 AM.
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The Role of Redox Dysregulation in the Effects of Prenatal Stress on Embryonic Interneuron Migration

Abstract
Maternal stress during pregnancy is associated with increased risk of psychiatric disorders in offspring, but embryonic brain mechanisms disrupted by prenatal stress are not fully understood. Our lab has shown that prenatal stress delays inhibitory neural progenitor migration. Here, we investigated redox dysregulation as a mechanism for embryonic cortical interneuron migration delay, utilizing direct manipulation of pro- and antioxidants and a mouse model of maternal repetitive restraint stress starting on embryonic day 12. Time-lapse, live-imaging of migrating GAD67GFP+ interneurons showed that normal tangential migration of inhibitory progenitor cells was disrupted by the pro-oxidant, hydrogen peroxide. Interneuron migration was also delayed by in utero intracerebroventricular rotenone. Prenatal stress altered glutathione levels and induced changes in activity of antioxidant enzymes and expression of redox-related genes in the embryonic forebrain. Assessment of dihydroethidium (DHE) fluorescence after prenatal stress in ganglionic eminence (GE), the source of migrating interneurons, showed increased levels of DHE oxidation. Maternal antioxidants (N-acetylcysteine and astaxanthin) normalized DHE oxidation levels in GE and ameliorated the migration delay caused by prenatal stress. Through convergent redox manipula-tions, delayed interneuron migration after prenatal stress was found to critically involve redox dysregulation. Redox biology during prenatal periods may be a target for protecting brain development.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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The Hyperpolarization-Activated HCN4 Channel is Important for Proper Maintenance of Oscillatory Activity in the Thalamocortical System

Abstract
Hyperpolarization-activated cation channels are involved, among other functions, in learning and memory, control of synaptic transmission and epileptogenesis. The importance of the HCN1 and HCN2 isoforms for brain function has been demonstrated, while the role of HCN4, the third major neuronal HCN subunit, is not known. Here we show that HCN4 is essential for oscillatory activity in the thalamocortical (TC) network. HCN4 is selectively expressed in various thalamic nuclei, excluding the thalamic reticular nucleus. HCN4-deficient TC neurons revealed a massive reduction of Ih and strongly reduced intrinsic burst firing, whereas the current was normal in cortical pyramidal neurons. In addition, evoked bursting in a thalamic slice preparation was strongly reduced in the mutant mice probes. HCN4-deficiency also significantly slowed down thalamic and cortical oscillations during active wakefulness. Taken together, these results establish that thalamic HCN4 channels are essential for the production of rhythmic intrathalamic oscillations and determine regular TC oscillatory activity during alert states.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Prefrontal Cortical and Behavioral Adaptations to Surgical Delivery Mediated by Metabolic Principles

Abstract
We previously observed an association between mode of delivery and brain mitochondrial mechanisms in pups. We also showed that mitochondrial processes impact adult behavior. However, no experimental data is available to causally connect mode of delivery with cellular processes of neurons in the cerebral cortex and adult behavior. Here we show that surgical delivery of pups alters mitochondrial dynamics and spine synapses of layer 3 pyramidal neurons of the prefrontal cortex compared to the values of mice delivered vaginally. These alterations in ultrastructure seen in adult mice delivered surgically were associated with the development of behavioral phenotypes resembling those characteristic of animal models of psychiatric illness. This included impaired performance in prepulse inhibition as well as hyperlocomotion in the open field and elevated plus maze tests. Knocking out a mitochondria-related gene, UCP-2, blocked cellular and behavioral adaptations induced by surgical delivery. These results highlight a crucial role for brain mitochondrial adaptations in the process of birth to affect neuronal circuitry in support of normal and altered adult behaviors. Further, these findings were supported with neuroimaging data from human neonates delivered vaginally and surgically, suggesting that the murine findings have human clinical relevance.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Corticostriatal Circuits Encode the Subjective Value of Perceived Control

Abstract
The ability to perceive and exercise control over an outcome is both desirable and beneficial to our well-being. It has been shown that animals and humans alike exhibit behavioral bias towards seeking control and that such bias recruits the ventromedial prefrontal cortex (vmPFC) and striatum. Yet, this bias remains to be quantitatively captured and studied neurally. Here, we employed a behavioral task to measure the preference for control and characterize its neural underpinnings. Participants made a series of binary choices between having control and no-control over a game for monetary reward. The mere presence of the control option evoked activity in the ventral striatum. Importantly, we manipulated the expected value (EV) of each choice pair to extract the pairing where participants were equally likely to choose either option. The difference in EV between the options at this point of equivalence was inferred as the subjective value of control. Strikingly, perceiving control inflated the reward value of the associated option by 30% and this value inflation was tracked by the vmPFC. Altogether, these results capture the subjective value of perceived control inherent in decision making and highlight the role of corticostriatal circuitry in the perception of control.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Dynamic Causal Modeling of the Relationship between Cognition and Theta–alpha Oscillations in Adults with Down Syndrome

Abstract
Individuals with Down syndrome (DS) show high inter-subject variability in cognitive ability and have an ultra-high risk of developing dementia (90% lifetime prevalence). Elucidating factors underlying variability in cognitive function can inform us about intellectual disability (ID) and may improve our understanding of factors associated with later cognitive decline. Increased neuronal inhibition has been posited to contribute to ID in DS. Combining electroencephalography (EEG) with dynamic causal modeling (DCM) provides a non-invasive method for investigating excitatory/inhibitory mechanisms. Resting-state EEG recordings were obtained from 36 adults with DS with no evidence of cognitive decline. Theta–alpha activity (4–13 Hz) was characterized in relation to general cognitive ability (raw Kaufmann’s Brief Intelligence Test second Edition (KBIT-2) score). Higher KBIT-2 was associated with higher frontal alpha peak amplitude and higher theta–alpha band power across distributed regions. Modeling this association with DCM revealed intrinsic self-inhibition was the key network parameter underlying observed differences in 4–13 Hz power in relation to KBIT-2 and age. In particular, intrinsic self-inhibition in right V1 was negatively correlated with KBIT-2. Results suggest intrinsic self-inhibition within the alpha network is associated with individual differences in cognitive ability in adults with DS, and may provide a potential therapeutic target for cognitive enhancement.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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When Conflict Cannot be Avoided: Relative Contributions of Early Selection and Frontal Executive Control in Mitigating Stroop Conflict

Abstract
When viewing familiar stimuli (e.g., common words), processing is highly automatized such that it can interfere with the processing of incompatible sensory information. At least two mechanisms may help mitigate this interference. Early selection accounts posit that attentional processes filter out distracting sensory information to avoid conflict. Alternatively, late selection accounts hold that all sensory inputs receive full semantic analysis and that frontal executive mechanisms are recruited to resolve conflict. To test how these mechanisms operate to overcome conflict induced by highly automatized processing, we developed a novel version of the color-word Stroop task, where targets and distractors were simultaneously flickered at different frequencies. We measured the quality of early sensory processing by assessing the amplitude of steady-state visually evoked potentials (SSVEPs) elicited by targets and distractors. We also indexed frontal executive processes by assessing changes in frontal theta oscillations induced by color-word incongruency. We found that target- and distractor-related SSVEPs were not modulated by changes in the level of conflict whereas frontal theta activity increased on high compared to low conflict trials. These results suggest that frontal executive processes play a more dominant role in mitigating cognitive interference driven by the automatic tendency to process highly familiar stimuli.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Phosphodiesterase 1 Bridges Glutamate Inputs with NO- and Dopamine-Induced Cyclic Nucleotide Signals in the Striatum

Abstract
The calcium-regulated phosphodiesterase 1 (PDE1) family is highly expressed in the brain, but its functional role in neurones is poorly understood. Using the selective PDE1 inhibitor Lu AF64196 and biosensors for cyclic nucleotides including a novel biosensor for cGMP, we analyzed the effect of PDE1 on cAMP and cGMP in individual neurones in brain slices from male newborn mice. Release of caged NMDA triggered a transient increase of intracellular calcium, which was associated with a decrease in cAMP and cGMP in medium spiny neurones in the striatum. Lu AF64196 alone did not increase neuronal cyclic nucleotide levels, but blocked the NMDA-induced reduction in cyclic nucleotides indicating that this was mediated by calcium-activated PDE1. Similar effects were observed in the prefrontal cortex and the hippocampus. Upon corelease of dopamine and NMDA, PDE1 was shown to down-regulate the D₁-receptor mediated increase in cAMP. PDE1 inhibition increased long-term potentiation in rat ventral striatum, showing that PDE1 is implicated in the regulation of synaptic plasticity. Overall, our results show that PDE1 reduces cyclic nucleotide signaling in the context of glutamate and dopamine coincidence. This effect could have a therapeutic value for treating brain disorders related to dysfunctions in dopamine neuromodulation.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Premotor Cortex Provides a Substrate for the Temporal Transformation of Information During the Planning of Gait Modifications

Abstract
We tested the hypothesis that the premotor cortex (PMC) in the cat contributes to the planning and execution of visually guided gait modifications. We analyzed single unit activity from 136 cells localized within layer V of cytoarchitectonic areas 6iffu and that part of 4δ within the ventral bank of the cruciate sulcus while cats walked on a treadmill and stepped over an obstacle that advanced toward them. We found a rich variety of discharge patterns, ranging from limb-independent cells that discharged several steps in front of the obstacle to step-related cells that discharged either during steps over the obstacle or in the steps leading up to that step. We propose that this population of task-related cells within this region of the PMC contributes to the temporal evolution of a planning process that transforms global information of the presence of an obstacle into the precise spatio-temporal limb adjustment required to negotiate that obstacle.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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No Evidence that Predictions and Attention Modulate the First Feedforward Sweep of Cortical Information Processing

Abstract
Predictive coding models propose that predictions (stimulus likelihood) reduce sensory signals as early as primary visual cortex (V1), and that attention (stimulus relevance) can modulate these effects. Indeed, both prediction and attention have been shown to modulate V1 activity, albeit with fMRI, which has low temporal resolution. This leaves it unclear whether these effects reflect a modulation of the first feedforward sweep of visual information processing and/or later, feedback-related activity. In two experiments, we used electroencephalography and orthogonally manipulated spatial predictions and attention to address this issue. Although clear top-down biases were found, as reflected in pre-stimulus alpha-band activity, we found no evidence for top-down effects on the earliest visual cortical processing stage (<80 ms post-stimulus), as indexed by the amplitude of the C1 event-related potential component and multivariate pattern analyses. These findings indicate that initial visual afferent activity may be impenetrable to top-down influences by spatial prediction and attention.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Acute Inescapable Stress Rapidly Increases Synaptic Energy Metabolism in Prefrontal Cortex and Alters Working Memory Performance

Abstract
Brain energy metabolism actively regulates synaptic transmission and activity. We have previously shown that acute footshock (FS)-stress induces fast and long-lasting functional and morphological changes at excitatory synapses in prefrontal cortex (PFC). Here, we asked whether FS-stress increased energy metabolism in PFC, and modified related cognitive functions. Using positron emission tomography (PET), we found that FS-stress induced a redistribution of glucose metabolism in the brain, with relative decrease of [¹⁸F]FDG uptake in ventro-caudal regions and increase in dorso-rostral ones. Absolute [¹⁸F]FDG uptake was inversely correlated with serum corticosterone. Increased specific hexokinase activity was also measured in purified PFC synaptosomes (but not in total extract) of FS-stressed rats, which positively correlated with 2-Deoxy [³H] glucose uptake by synaptosomes. In line with increased synaptic energy demand, using an electron microscopy-based stereological approach, we found that acute stress induced a redistribution of mitochondria at excitatory synapses, together with an increase in their volume. The fast functional and metabolic activation of PFC induced by acute stress, was accompanied by rapid and sustained alterations of working memory performance in delayed response to T-maze test. Taken together, the present data suggest that acute stress increases energy consumption at PFC synaptic terminals and alters working memory.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Reduced Hippocampal Dendrite Branching, Spine Density and Neurocognitive Function in Premature Rabbits, and Reversal with Estrogen or TrkB Agonist Treatment

Abstract
Preterm-born children suffer from neurological and behavioral disorders. Herein, we hypothesized that premature birth and non-maternal care of preterm newborns might disrupt neurobehavioral function, hippocampal dendritic arborization, and dendritic spine density. Additionally, we assessed whether 17β-estradiol (E2) replacement or the TrkB receptor agonist, 7,8-dihydroxyflavone (DHF), would reverse compromised dendritic development and cognitive function in preterm newborns. These hypotheses were tested by comparing preterm (E28.5) rabbit kits cared and gavage-fed by laboratory personnel and term-kits reared and breast-fed by their mother doe at an equivalent postconceptional age. Neurobehavioral tests showed that both premature-birth and formula-feeding with non-maternal care led to increased anxiety behavior, poor social interaction, and lack of novelty preference compared with term-kits. Dendritic branching and number of total or mushroom dendritic spines were reduced in the CA1 field of preterm-kits compared with term controls. While CDC42 and Rac1/2/3 expression levels were lower, RhoA-activity was higher in preterm-kits compared with term controls. Both E2 and DHF treatment reversed prematurity-induced reduction in spine density, reduced total RhoA-GTPase levels, and enhanced cognitive function. Hence, prematurity and non-maternal care result in cognitive deficits, and reduced dendritic arbors and spines in CA1. E2 replacement or DHF treatment might reverse changes in dendritic spines and improve neurodevelopment in premature infants.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Deletion of the KH1 Domain of Fmr1 Leads to Transcriptional Alterations and Attentional Deficits in Rats

Abstract
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. It is a leading monogenic cause of autism spectrum disorder and inherited intellectual disability and is often comorbid with attention deficits. Most FXS cases are due to an expansion of CGG repeats leading to suppressed expression of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in mRNA metabolism. We found that the previously published Fmr1 knockout rat model of FXS expresses an Fmr1 transcript with an in-frame deletion of exon 8, which encodes for the K-homology (KH) RNA-binding domain, KH1. Notably, 3 pathogenic missense mutations associated with FXS lie in the KH domains. We observed that the deletion of exon 8 in rats leads to attention deficits and to alterations in transcriptional profiles within the medial prefrontal cortex (mPFC), which map to 2 weighted gene coexpression network modules. These modules are conserved in human frontal cortex and enriched for known FMRP targets. Hub genes in these modules represent potential therapeutic targets for FXS. Taken together, these findings indicate that attentional testing might be a reliable cross-species tool for investigating FXS and identify dysregulated conserved gene networks in a relevant brain region.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Association Between Earliest Amyloid Uptake and Functional Connectivity in Cognitively Unimpaired Elderly

Abstract
Alterations in cognitive performance have been noted in nondemented subjects with elevated accumulation of amyloid-β (Aβ) fibrils. However, it is not yet understood whether brain function is already influenced by Aβ deposition during the very earliest stages of the disease. We therefore investigated associations between [¹⁸F]Flutemetamol PET, resting-state functional connectivity, gray and white matter structure and cognitive performance in 133 cognitively normal elderly that exhibited normal global Aβ PET levels. [¹⁸F]Flutemetamol uptake in regions known to accumulate Aβ fibrils early in preclinical AD (i.e., mainly certain parts of the default-mode network) was positively associated with dynamic but not static functional connectivity (r = 0.77). Dynamic functional connectivity was further related to better cognitive performance (r = 0.21–0.72). No significant associations were found for Aβ uptake with gray matter volume or white matter diffusivity. The findings demonstrate that the earliest accumulation of Aβ fibrils is associated with increased functional connectivity, which occurs before any structural alterations. The enhanced functional connectivity may reflect a compensatory mechanism to maintain high cognitive performance in the presence of increasing amyloid accumulation during the earliest phases of AD.
in Cerebral Cortex Advance Access on March 16, 2019 12:00 AM.
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Neuro-Immune Mechanisms Regulating Social Behavior: Dopamine as Mediator?
Social interactions are fundamental to survival and overall health. The mechanisms underlying social behavior are complex, but we now know that immune signaling plays a fundamental role in the regulation of social interactions. Prolonged or exaggerated alterations in social behavior often accompany altered immune signaling and function in pathological states. Thus, unraveling the link between social behavior and immune signaling is a fundamental challenge, not only to advance our understanding of human health and development, but for the design of comprehensive therapeutic approaches for neural disorders.
in Trends in Neurosciences on March 16, 2019 12:00 AM.
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Boolean model of growth signaling, cell cycle and apoptosis predicts the molecular mechanism of aberrant cell cycle progression driven by hyperactive PI3K

by Herbert Sizek, Andrew Hamel, Dávid Deritei, Sarah Campbell, Erzsébet Ravasz Regan
The PI3K/AKT signaling pathway plays a role in most cellular functions linked to cancer progression, including cell growth, proliferation, cell survival, tissue invasion and angiogenesis. It is generally recognized that hyperactive PI3K/AKT are oncogenic due to their boost to cell survival, cell cycle entry and growth-promoting metabolism. That said, the dynamics of PI3K and AKT1 during cell cycle progression are highly nonlinear. In addition to negative feedback that curtails their activity, protein expression of PI3K subunits has been shown to oscillate in dividing cells. The low-PI3K/low-AKT1 phase of these oscillations is required for cytokinesis, indicating that oncogenic PI3K may directly contribute to genome duplication. To explore this, we construct a Boolean model of growth factor signaling that can reproduce PI3K oscillations and link them to cell cycle progression and apoptosis. The resulting modular model reproduces hyperactive PI3K-driven cytokinesis failure and genome duplication and predicts the molecular drivers responsible for these failures by linking hyperactive PI3K to mis-regulation of Polo-like kinase 1 (Plk1) expression late in G2. To do this, our model captures the role of Plk1 in cell cycle progression and accurately reproduces multiple effects of its loss: G2 arrest, mitotic catastrophe, chromosome mis-segregation / aneuploidy due to premature anaphase, and cytokinesis failure leading to genome duplication, depending on the timing of Plk1 inhibition along the cell cycle. Finally, we offer testable predictions on the molecular drivers of PI3K oscillations, the timing of these oscillations with respect to division, and the role of altered Plk1 and FoxO activity in genome-level defects caused by hyperactive PI3K. Our model is an important starting point for the predictive modeling of cell fate decisions that include AKT1-driven senescence, as well as the non-intuitive effects of drugs that interfere with mitosis.
in PLOS Computational Biology: New Articles on March 15, 2019 09:00 PM.
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Inverted encoding models reconstruct an arbitrary model response, not the stimulus
Abstract
Probing how large populations of neurons represent stimuli is key to understanding sensory representations as many stimulus characteristics can only be discerned from population activity and not from individual single-units. Recently, inverted encoding models have been used to produce channel response functions from large spatial-scale measurements of human brain activity that are reminiscent of single-unit tuning functions and have been proposed to assay "population-level stimulus representations" (Sprague et al., 2018a). However, these channel response functions do not assay population tuning. We show by derivation that the channel response function is only determined up to an invertible linear transform. Thus these channel response functions are arbitrary, one of an infinite family and therefore not a unique description of population representation. Indeed, simulations demonstrate that bimodal, even random, channel basis functions can account perfectly well for population responses without any underlying neural response units that are so tuned. However, the approach can be salvaged by extending it to reconstruct the stimulus, not the assumed model. We show that when this is done, even using bimodal and random channel basis functions, a unimodal function peaking at the appropriate value of the stimulus is recovered which can be interpreted as a measure of population selectivity. More precisely, the recovered function signifies how likely any value of the stimulus is, given the observed population response. Whether an analysis is recovering the hypothetical responses of an arbitrary model rather than assessing the selectivity of population representations is not an issue unique to the inverted encoding model and human neuroscience, but a general problem that must be confronted as more complex analyses intervene between measurement of population activity and presentation of data.
Significance Statement We recently showed that inverted encoding models conflate signal to noise ratio with neural tuning width. Sprague and colleagues argued that despite this short falling, inverted encoding models "assay population-level stimulus representations". However, we show that inverted encoding models reconstruct the model responses, not the stimulus. This is problematic because the model, as we derive here, is only determined up to a linear transform and thus the recovered model responses are only one of an infinite family of equivalent solutions. The approach thus fails to provide a unique assay of population representation. This problem can be circumvented by extending the approach to estimate the probability of different values of the stimulus, thus resulting in an interpretable assay of population representation.

in RSS PAP on March 15, 2019 05:00 PM.
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Smoking is a cause of ALS. High LDL‐cholesterol levels? Unsure

in Wiley: Annals of Neurology: Table of Contents on March 15, 2019 04:04 PM.
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Sign Tracking and Goal Tracking Are Characterized by Distinct Patterns of Nucleus Accumbens Activity
Abstract
During Pavlovian conditioning, if a cue (e.g., lever extension) predicts reward delivery in a different location (e.g., a food magazine), some individuals will come to approach and interact with the cue, a behavior known as sign tracking (ST), and others will approach the site of reward, a behavior known as goal tracking (GT). In rats, the acquisition of ST versus GT behavior is associated with distinct profiles of dopamine release in the nucleus accumbens (NAc), but it is unknown whether it is associated with different patterns of accumbens neural activity. Therefore, we recorded from individual neurons in the NAc core during the acquisition, maintenance, and extinction of ST and GT behavior. Even though NAc dopamine is specifically important for the acquisition and expression of ST, we found that cue-evoked excitatory responses encode the vigor of both ST and GT behavior. In contrast, among sign trackers only, there was a prominent decrease in reward-related activity over the course of training, which may reflect the decreasing reward prediction error encoded by phasic dopamine. Finally, both behavior and cue-evoked activity were relatively resistant to extinction in sign trackers, as compared with goal trackers, although a subset of neurons in both groups retained their cue-evoked responses. Overall, the results point to the convergence of multiple forms of reward learning in the NAc.

in eNeuro current issue on March 15, 2019 03:52 PM.
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Histone demethylases in neuronal differentiation, plasticity, and disease

Publication date: December 2019
Source: Current Opinion in Neurobiology, Volume 59
Author(s): Vijay Swahari, Anne E West
For more than 40 years after its discovery, histone methylation was thought to be largely irreversible. However, the first histone demethylase (HDM) was identified in 2004, challenging this notion. Since that time, more than 20 HDMs have been identified and characterized, and many have been shown to have critical roles in organismal development, cell fate, and disease. Here, we highlight some of the recent advances in our understanding of the function of HDMs in the context of neuronal development, plasticity, and disease. We focus, in particular, on molecular genetic studies of LSD1, Kdm6b, and Kdm5c that have elucidated both enzymatic and non-enzymatic gene regulatory functions of these HDMs in neurons.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 15, 2019 12:00 PM.
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The Susceptibility of Retinal Ganglion Cells to Glutamatergic Excitotoxicity Is Type-Specific
Ian Christensen, Bo Lu, Ning Yang, Kevin Huang, Ping Wang, Ning Tian
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 15, 2019 12:00 PM.
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Decreasing the Size of the Restricted Boltzmann Machine
Neural Computation, Volume 31, Issue 4, Page 784-805, April 2019.

in MIT Press: Neural Computation: Table of Contents on March 15, 2019 08:13 AM.
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Deconstructing Odorant Identity via Primacy in Dual Networks
Neural Computation, Volume 31, Issue 4, Page 710-737, April 2019.

in MIT Press: Neural Computation: Table of Contents on March 15, 2019 08:13 AM.
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Gated Orthogonal Recurrent Units: On Learning to Forget
Neural Computation, Volume 31, Issue 4, Page 765-783, April 2019.

in MIT Press: Neural Computation: Table of Contents on March 15, 2019 08:12 AM.
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Biologically Realistic Mean-Field Models of Conductance-Based Networks of Spiking Neurons with Adaptation
Neural Computation, Volume 31, Issue 4, Page 653-680, April 2019.

in MIT Press: Neural Computation: Table of Contents on March 15, 2019 08:12 AM.
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A Distributed Framework for the Construction of Transport Maps
Neural Computation, Volume 31, Issue 4, Page 613-652, April 2019.

in MIT Press: Neural Computation: Table of Contents on March 15, 2019 08:12 AM.
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Estimating Scale-Invariant Future in Continuous Time
Neural Computation, Volume 31, Issue 4, Page 681-709, April 2019.

in MIT Press: Neural Computation: Table of Contents on March 15, 2019 08:12 AM.
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Filtering Compensation for Delays and Prediction Errors during Sensorimotor Control
Neural Computation, Volume 31, Issue 4, Page 738-764, April 2019.

in MIT Press: Neural Computation: Table of Contents on March 15, 2019 08:12 AM.
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Multiclass Alpha Integration of Scores from Multiple Classifiers
Neural Computation, Volume 31, Issue 4, Page 806-825, April 2019.

in MIT Press: Neural Computation: Table of Contents on March 15, 2019 08:12 AM.
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Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway
Jialiang Wei, Xiuquan Wu, Peng Luo, Kangyi Yue, Yang Yu, Jingnan Pu, Lei Zhang, Shuhui Dai, Donghui Han, Zhou Fei
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 15, 2019 06:00 AM.
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Calcium Dynamics in Dendrites of Hippocampal CA1 Interneurons in Awake Mice
Ruggiero Francavilla, Vincent Villette, Olivier Martel, Lisa Topolnik
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 15, 2019 06:00 AM.
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Zika Virus Impairs Neurogenesis and Synaptogenesis Pathways in Human Neural Stem Cells and Neurons
Livia Rosa-Fernandes, Fernanda Rodrigues Cugola, Fabiele Baldino Russo, Rebeca Kawahara, Caio Cesar de Melo Freire, Paulo Emílio Corrêa Leite, Ana Carolina Bassi Stern, Claudia Blanes Angeli, Danielle Bruna Leal de Oliveira, Stella Rezende Melo, Paolo Marinho de Andrade Zanotto, Edison Luiz Durigon, Martin Røssel Larsen, Patricia Cristina Baleeiro Beltrão-Braga, Giuseppe Palmisano
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 15, 2019 06:00 AM.
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The Combination of DAT-SPECT, Structural and Diffusion MRI Predicts Clinical Progression in Parkinson’s Disease
Sara Lorio, Fabio Sambataro, Alessandro Bertolino, Bogdan Draganski, Juergen Dukart
in Frontiers in Aging Neuroscience | New and Recent Articles on March 15, 2019 06:00 AM.
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Effects of in-Scanner Bilateral Frontal tDCS on Functional Connectivity of the Working Memory Network in Older Adults
Nicole R. Nissim, Andrew O’Shea, Aprinda Indahlastari, Rachel Telles, Lindsey Richards, Eric Porges, Ronald Cohen, Adam J. Woods
in Frontiers in Aging Neuroscience | New and Recent Articles on March 15, 2019 06:00 AM.
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GABAA Receptor Subunit α3 in Network Dynamics in the Medial Entorhinal Cortex
Nina Berggaard, Menno P. Witter, Johannes J. L. van der Want
in Frontiers in Systems Neuroscience | New and Recent Articles on March 15, 2019 06:00 AM.
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Iron Metabolism of the Skeletal Muscle and Neurodegeneration
Malgorzata Halon-Golabek, Andzelika Borkowska, Anna Herman-Antosiewicz, Jedrzej Antosiewicz
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 15, 2019 06:00 AM.
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Spiny Projection Neuron Dynamics in Toxin and Transgenic Models of Parkinson’s Disease
Yijuan Du, Steven M. Graves
in Frontiers in Neural Circuits | New and Recent Articles on March 15, 2019 06:00 AM.
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The Frequent Complete Subgraphs in the Human Connectome. (arXiv:1903.05979v1 [q-bio.NC])

While it is still not possible to describe the neural-level connections of the human brain, we can map the human connectome with several hundred vertices, by the application of diffusion-MRI based techniques. In these graphs, the nodes correspond to anatomically identified gray matter areas of the brain, while the edges correspond to the axonal fibers, connecting these areas. In our previous contributions, we have described numerous graph-theoretical phenomena of the human connectomes. Here we map the frequent complete subgraphs of the human brain networks: in these subgraphs, every pair of vertices is connected by an edge. We also examine sex differences in the results. The mapping of the frequent subgraphs gives robust substructures in the graph: if a subgraph is present in the 80\% of the graphs, then, most probably, it could not be an artifact of the measurement or the data processing workflow. We list here the frequent complete subgraphs of the female and the male braingraphs of 414 subjects, each with 463 nodes, with a frequency threshold of 80\%, and identify complete subgraphs, which are more frequent in male and female connectomes, respectively.

in q-bio.NC updates on arXiv.org on March 15, 2019 01:30 AM.
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Recurrence required to capture the dynamic computations of the human ventral visual stream. (arXiv:1903.05946v1 [q-bio.NC])

The visual system is an intricate network of brain regions that enables us to recognize the world around us. Despite its abundant lateral and feedback connections, human object processing is commonly viewed and studied as a feedforward process. Here, we measure and model the rapid representational dynamics across multiple stages of the human ventral stream using time-resolved brain imaging and deep learning. We observe substantial representational transformations during the first 300 ms of processing within and across ventral-stream regions. Categorical divisions emerge in sequence, cascading forward and in reverse across regions, and Granger causality analysis suggests bidirectional information flow between regions. Finally, recurrent deep neural network models clearly outperform feedforward models in terms of their ability to jointly capture the multi-region cortical dynamics. These results establish that recurrent models are required to understand information processing in the human ventral stream.

in q-bio.NC updates on arXiv.org on March 15, 2019 01:30 AM.
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The Neural Basis and Evolution of Divergent and Convergent Thought. (arXiv:1611.03609v2 [q-bio.NC] UPDATED)

This chapter takes as its departure point a neural level theory of insight that arose from studies of the sparse, distributed, content-addressable architecture of associative memory. It is argued that convergent thought is most fruitfully characterized in terms of, not the generation of a single correct solution (as it is conventionally construed), but using concepts in their most compact form by activating neural cell assemblies that respond to their most typical properties. This allows them to be deployed in a conventional manner such that effort is reserved for exploring causal relationships. Conversely, it is argued that divergent thought is most fruitfully characterized in terms of, not the generation of multiple solutions (as it is conventionally construed), but using concepts in a form that is, albeit expanded, constrained by the situation, by activating neural cell assemblies that respond to context-specific atypical properties. This allows them to be deployed in a manner that is conducive to exploring unconventional yet potentially relevant associations, and unearthing potentially useful relationships of correlation. Thus, divergent thought can involve as few as one idea. This proposal is compatible with widespread beliefs that (1) most creative tasks require not many solutions but one, yet entail both divergent and convergent thinking, and (2) not all problems with multiple solutions require creative thinking, and conversely, some problems with single solution do require creative thought. The chapter discusses how the ability to shift between convergent and divergent modes of thought may have evolved, and it concludes with educational and vocational implications.

in q-bio.NC updates on arXiv.org on March 15, 2019 01:30 AM.
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Clinical and Educational Applications of LIVEIA: An Immersive Visualization Environment. (arXiv:1610.03542v2 [cs.CY] UPDATED)

The association between light and psychological states has a long history and permeates our language. LIVEIA (Light-based Immersive Visualization Environment for Imaginative Actualization) is a new immersive, interactive technology that uses physical light as a metaphor for visualizing peoples' inner lives and relationships. This paper outlines its educational value, as a tool for understanding and explaining aspects of how people think and interact, and its potential therapeutic value as a form of art therapy in which the artwork has straightforwardly interpretable symbolic meanings.

in q-bio.NC updates on arXiv.org on March 15, 2019 01:30 AM.
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Cell migration promotes dynamic cellular interactions to control cerebral cortex morphogenesis

Cell migration promotes dynamic cellular interactions to control cerebral cortex morphogenesis
Cell migration promotes dynamic cellular interactions to control cerebral cortex morphogenesis, Published online: 15 March 2019; doi:10.1038/s41583-019-0148-y
The cerebral cortex is made of cells originating in distinct brain regions. In this Review, Silva and colleagues discuss the dual role played by cell migration to bring cells in and to provide crosstalk that shapes cortical morphogenesis.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 15, 2019 12:00 AM.
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Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response
In the unfolded protein response (UPR), stress in the endoplasmic reticulum (ER) activates a large transcriptional program to increase ER folding capacity. During the budding yeast UPR, Ire1 excises an intron from the HAC1 mRNA and the exon products of cleavage are ligated, and the translated protein induces hundreds of stress-response genes. Using cells with mutations in RNA repair and decay enzymes, we show that phosphorylation of two different HAC1 splicing intermediates is required for their degradation by the 5′→3′ exonuclease Xrn1 to enact opposing effects on the UPR. We also found that ligated but 2′-phosphorylated HAC1 mRNA is cleaved, yielding a decay intermediate with both 5′- and 2′-phosphates at its 5′-end that inhibit 5′→3′ decay and suggesting that Ire1 degrades incompletely processed HAC1. These decay events expand the scope of RNA-based regulation in the budding yeast UPR and have implications for the control of the metazoan UPR.
in eLife: latest articles on March 15, 2019 12:00 AM.
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Across-species differences in pitch perception are consistent with differences in cochlear filtering
Pitch perception is critical for recognizing speech, music and animal vocalizations, but its neurobiological basis remains unsettled, in part because of divergent results across species. We investigated whether species-specific differences exist in the cues used to perceive pitch and whether these can be accounted for by differences in the auditory periphery. Ferrets accurately generalized pitch discriminations to untrained stimuli whenever temporal envelope cues were robust in the probe sounds, but not when resolved harmonics were the main available cue. By contrast, human listeners exhibited the opposite pattern of results on an analogous task, consistent with previous studies. Simulated cochlear responses in the two species suggest that differences in the relative salience of the two pitch cues can be attributed to differences in cochlear filter bandwidths. The results support the view that cross-species variation in pitch perception reflects the constraints of estimating a sound’s fundamental frequency given species-specific cochlear tuning.
in eLife: latest articles on March 15, 2019 12:00 AM.
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Environmentally-induced epigenetic conversion of a piRNA cluster
Transposable element (TE) activity is repressed in animal gonads by PIWI-interacting RNAs (piRNAs) produced by piRNA clusters. Current models in flies propose that germinal piRNA clusters are functionally defined by the maternal inheritance of piRNAs produced during the previous generation. Taking advantage of an inactive, but ready to go, cluster of P-element derived transgene insertions in Drosophila melanogaster, we show here that raising flies at high temperature (29°C) instead of 25°C triggers the stable conversion of this locus from inactive into actively producing functional piRNAs. The increase of antisense transcripts from the cluster at 29°C combined with the requirement of transcription of euchromatic homologous sequences, suggests a role of double stranded RNA in the production of de novo piRNAs. This report describes the first case of the establishment of an active piRNA cluster by environmental changes in the absence of maternal inheritance of homologous piRNAs.
in eLife: latest articles on March 15, 2019 12:00 AM.
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Time for What? Breaking Down Temporal Anticipation
A variety of environmental regularities enable us to anticipate the timing of upcoming sensations and actions. A recent article (Breska and Ivry, Proc. Natl. Acad. Sci. U. S. A. 2018;115:12283–12288) reports a striking neural double dissociation between two distinct varieties of temporal anticipation. Looking forward, we consider further dissociations according to the goals for which temporal anticipation is used.
in Trends in Neurosciences on March 15, 2019 12:00 AM.
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The logic of ionic homeostasis: Cations are for voltage, but not for volume

by Andrey V. Dmitriev, Alexander A. Dmitriev, Robert A. Linsenmeier
Neuronal activity is associated with transmembrane ionic redistribution, which can lead to an osmotic imbalance. Accordingly, activity-dependent changes of the membrane potential are sometimes accompanied by changes in intracellular or extracellular volume. Experimental data that include distributions of ions and volume during neuronal activity are rare and rather inconsistent partly due to the technical difficulty of performing such measurements. However, progress in understanding the interrelations among ions, voltage and volume has been achieved recently by computational modelling, particularly “charge-difference” modelling. In this work a charge-difference computational model was used for further understanding of the specific roles for cations and anions. Our simulations show that without anion conductances the transmembrane movements of cations are always osmotically balanced, regardless of the stoichiometry of the pump or the ratio of Na⁺ and K⁺ conductances. Yet any changes in cation conductance or pump activity are associated with changes of the membrane potential, even when a hypothetically electroneutral pump is used in calculations and K⁺ and Na⁺ conductances are equal. On the other hand, when a Cl^- conductance is present, the only way to keep the Cl^-equilibrium potential in accordance with the changed membrane potential is to adjust cell volume. Importantly, this voltage-evoked Cl^—dependent volume change does not affect intracellular cation concentrations or the amount of energy that is necessary to support the system. Taking other factors into consideration (i.e. the presence of internal impermeant poly-anions, the activity of cation-Cl^- cotransporters, and the buildup of intra- and extracellular osmolytes, both charged and electroneutral) adds complexity, but does not change the main principles.
in PLOS Computational Biology: New Articles on March 14, 2019 09:00 PM.
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Understanding narwhal diving behaviour using Hidden Markov Models with dependent state distributions and long range dependence

by Manh Cuong Ngô, Mads Peter Heide-Jørgensen, Susanne Ditlevsen
Diving behaviour of narwhals is still largely unknown. We use Hidden Markov models (HMMs) to describe the diving behaviour of a narwhal and fit the models to a three-dimensional response vector of maximum dive depth, duration of dives and post-dive surface time of 8,609 dives measured in East Greenland over 83 days, an extraordinarily long and rich data set. Narwhal diving patterns have not been analysed like this before, but in studies of other whale species, response variables have been assumed independent. We extend the existing models to allow for dependence between state distributions, and show that the dependence has an impact on the conclusions drawn about the diving behaviour. We try several HMMs with 2, 3 or 4 states, and with independent and dependent log-normal and gamma distributions, respectively, and different covariates to characterize dive patterns. In particular, diurnal patterns in diving behaviour is inferred, by using periodic B-splines with boundary knots in 0 and 24 hours.
in PLOS Computational Biology: New Articles on March 14, 2019 09:00 PM.
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Structural Magnetic Resonance Imaging Demonstrates Abnormal Regionally-Differential Cortical Thickness Variability in Autism: From Newborns to Adults
Jacob Levman, Patrick MacDonald, Sean Rowley, Natalie Stewart, Ashley Lim, Bryan Ewenson, Albert Galaburda, Emi Takahashi
in Frontiers in Human Neuroscience | New and Recent Articles on March 14, 2019 06:00 PM.
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Lmx1b Influences Correct Post-mitotic Coding of Mesodiencephalic Dopaminergic Neurons
Iris Wever, Pablo Largo-Barrientos, Elisa J. Hoekstra, Marten P. Smidt
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 14, 2019 06:00 PM.
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Mental Rotation of Digitally-Rendered Haptic Objects
Ruxandra I. Tivadar, Tom Rouillard, Cédrick Chappaz, Jean-François Knebel, Nora Turoman, Fatima Anaflous, Jean Roche, Pawel J. Matusz, Micah M. Murray
in Frontiers in Integrative Neuroscience | New and Recent Articles on March 14, 2019 06:00 PM.
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Brain Connectivity and Information-Flow Breakdown Revealed by a Minimum Spanning Tree-Based Analysis of MRI Data in Behavioral Variant Frontotemporal Dementia
Valentina Saba, Enrico Premi, Viviana Cristillo, Stefano Gazzina, Fernando Palluzzi, Orazio Zanetti, Roberto Gasparotti, Alessandro Padovani, Barbara Borroni, Mario Grassi
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on March 14, 2019 06:00 PM.
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Supervised Brain Tumor Segmentation Based on Gradient and Context-Sensitive Features
Junting Zhao, Zhaopeng Meng, Leyi Wei, Changming Sun, Quan Zou, Ran Su
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on March 14, 2019 06:00 PM.
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Toward a Biologically Plausible Model of LGN-V1 Pathways Based on Efficient Coding
Yanbo Lian, David B. Grayden, Tatiana Kameneva, Hamish Meffin, Anthony N. Burkitt
in Frontiers in Neural Circuits | New and Recent Articles on March 14, 2019 06:00 PM.
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Plasticity of NMDA Receptors at Ventral Hippocampal Synapses in the Infralimbic Cortex Regulates Cued Fear
Abstract
The medial prefrontal cortex (mPFC) processes contextual information from the hippocampus to generate appropriate fear responses. In rodents, one path for sending contextual information to the mPFC is via the direct projections from the ventral hippocampus (vHC) to the infralimbic cortex (IL). Plasticity in the synaptic communication from the vHC to the IL could contribute to the behavioral changes produced by the acquisition and extinction of conditioned fear. To examine this possibility, we used optogenetic stimulation of vHC synapses in brain slices from trained rats. We found that fear acquisition reduced NMDA receptor (NMDAR) currents at vHC synapses onto IL pyramidal neurons. The depression of NMDAR currents reversed more efficiently after extinction in the conditioning context than extinction in a novel context. Moreover, a cohort of animals that exhibited poor extinction retrieval failed to reverse the plasticity induced by fear conditioning. In addition, ex vivo application of brain-derived neurotrophic factor, which is known to simulate extinction in IL, reversed this conditioning-induced plasticity mimicking extinction. Therefore, we have identified a novel mechanism that modulates conditioned fear via changes in NMDAR current at vHC synapses onto IL pyramidal neurons. Disruption of this mechanism could contribute to the abnormal contextual modulation of fear seen in posttraumatic stress disorder (PTSD).
Significance Statement Contextual information processing by the medial prefrontal cortex is critical for appropriate behavioral responses. Using optogenetics in brain slices, we found that acquisition of conditioned fear depressed NMDA receptor currents at ventral hippocampal synapses in the infralimbic cortex (IL) and extinction reversed the depression. BDNF could also reverse the conditioning-induced depression mimicking extinction. In contrast, animals with impaired fear extinction recall, a PTSD-like phenotype, failed to reverse the conditioning-induced changes. Our findings suggest that conditioned fear responses are modulated by changes in NMDAR current at ventral hippocampal synapses in IL and suggest a novel mechanism that could contribute to impaired contextual modulation of fear seen in patients with PTSD.

in RSS PAP on March 14, 2019 04:26 PM.
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AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2‐CDG

Abstract

Objective

Phosphomannomutase deficiency (PMM2‐CDG) causes cerebellar syndrome and stroke‐like episodes (SLEs). SLEs are also described in patients with gain‐of‐function mutations in the CaV2.1 channel, for which acetazolamide therapy is suggested. Impairment in N‐glycosylation of CaV2.1 promotes gain‐of‐function effects and may participate in cerebellar syndrome in PMM2‐CDG. AZATAX was designed to establish whether acetazolamide is safe and improves cerebellar syndrome in PMM2‐CDG.

Methods

A clinical trial included PMM2‐CDG patients with a 6‐month first‐phase single acetazolamide therapy group, followed by a randomized 5‐week withdrawal phase. Safety was assessed. The primary outcome measure was improvement in the International Cooperative Ataxia Rating Scale (ICARS). Other measures were the Nijmegen Pediatric CDG Rating Scale (NPCRS), a syllable repetition test (PATA test), and cognitive scores.

Results

Twenty‐four patients (mean age 12.3±4.5 years) were included, showing no serious adverse events. Thirteen patients required dose adjustment due to low bicarbonate or asthenia. There were improvements in ICARS (34.9±23.2 vs 40.7±24.8, effect size 1.48, [95%CI 4.0‐7.6]; P<0.001), detected at 6 weeks in 18 patients among the 20 responders, in NPCRS ([95%CI 0.3‐1.6]; P=0.013) and in PATA test ([95%CI 0.5‐3.0]; P=0.006). Acetazolamide improved prothrombin time, factor X, and antithrombin. Clinical severity, epilepsy, and lipodystrophy predicted greater response. The randomized withdrawal phase showed an ICARS worsening in the withdrawal group (effect size 1.46, [95%CI 2.65‐7.52]; P=0.001).

Interpretation

AZATAX is the first clinical trial of PMM2‐CDG. Acetazolamide is well tolerated and effective for motor cerebellar syndrome. Its ability to prevent SLEs and its long‐term effects on kidney function should be addressed in future studies.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on March 14, 2019 04:01 PM.
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The Disease-Associated Chaperone FKBP51 Impairs Cognitive Function by Accelerating AMPA Receptor Recycling
Abstract
Increased expression of the FK506-binding protein 5 (FKBP5) gene has been associated with a number of diseases, but most prominently in connection to psychiatric illnesses. Many of these psychiatric disorders present with dementia and other cognitive deficits, but a direct connection between these issues and alterations in FKBP5 remains unclear. We generated a novel transgenic mouse to selectively overexpress FKBP5, which encodes the FKBP51 protein, in the corticolimbic system, which had no overt effects on gross body weight, motor ability, or general anxiety. Instead, we found that overexpression of FKBP51 impaired long-term depression (LTD) as well as spatial reversal learning and memory, suggesting a role in glutamate receptor regulation. Indeed, FKBP51 altered the association of heat-shock protein 90 (Hsp90) with AMPA receptors, which was accompanied by an accelerated rate of AMPA recycling. In this way, the chaperone system is critical in triage decisions for AMPA receptor trafficking. Imbalance in the chaperone system may manifest in impairments in both inhibitory learning and cognitive function. These findings uncover an unexpected and essential mechanism for learning and memory that is controlled by the psychiatric risk factor FKBP5.

in eNeuro current issue on March 14, 2019 04:01 PM.
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Network Properties Revealed during Multi-Scale Calcium Imaging of Seizure Activity in Zebrafish
Abstract
Seizures are characterized by hypersynchronization of neuronal networks. Understanding these networks could provide a critical window for therapeutic control of recurrent seizure activity, i.e., epilepsy. However, imaging seizure networks has largely been limited to microcircuits in vitro or small "windows" in vivo. Here, we combine fast confocal imaging of genetically encoded calcium indicator (GCaMP)-expressing larval zebrafish with local field potential (LFP) recordings to study epileptiform events at whole-brain and single-neuron levels in vivo. Using an acute seizure model (pentylenetetrazole, PTZ), we reliably observed recurrent electrographic ictal-like events associated with generalized activation of all major brain regions and uncovered a well-preserved anterior-to-posterior seizure propagation pattern. We also examined brain-wide network synchronization and spatiotemporal patterns of neuronal activity in the optic tectum microcircuit. Brain-wide and single-neuronal level analysis of PTZ-exposed and 4-aminopyridine (4-AP)-exposed zebrafish revealed distinct network dynamics associated with seizure and non-seizure hyperexcitable states, respectively. Neuronal ensembles, comprised of coactive neurons, were also uncovered during interictal-like periods. Taken together, these results demonstrate that macro- and micro-network calcium motifs in zebrafish may provide a greater understanding of epilepsy.

in eNeuro current issue on March 14, 2019 04:01 PM.
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Editorial: Multimodal and Longitudinal Bioimaging Methods for Characterizing the Progressive Course of Dementia
Javier Ramírez, Juan M. Górriz, Stefan Teipel
in Frontiers in Aging Neuroscience | New and Recent Articles on March 14, 2019 12:00 PM.
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Divergent Mechanisms for PPARγ Agonism in Ameliorating Aging-Related Versus Cranial Irradiation-Induced Context Discrimination Deficits
Ibdanelo Cortez, Larry Denner, Kelly T. Dineley
in Frontiers in Aging Neuroscience | New and Recent Articles on March 14, 2019 12:00 PM.
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Editorial: Neuroscientific Research for Management of Dementia
Mohammad A. Kamal, Fatima A. Nasrallah
in Frontiers in Aging Neuroscience | New and Recent Articles on March 14, 2019 12:00 PM.
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NCOA4-Mediated Ferritinophagy: A Potential Link to Neurodegeneration
Maria Quiles del Rey, Joseph D. Mancias
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 14, 2019 12:00 PM.
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Diagnosis of Brain Diseases via Multi-Scale Time-Series Model
Zehua Zhang, Junhai Xu, Jijun Tang, Quan Zou, Fei Guo
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on March 14, 2019 12:00 PM.
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Galectin-3 (MAC-2) Controls Microglia Phenotype Whether Amoeboid and Phagocytic or Branched and Non-phagocytic by Regulating the Cytoskeleton
Fanny Reichert, Shlomo Rotshenker
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 14, 2019 12:00 PM.
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Distribution, Morphological Characterization, and Resiniferatoxin-Susceptibility of Sensory Neurons That Innervate Rat Perirenal Adipose Tissue
Bo-Xun Liu, Ming Qiu, Peng-Yu Zong, Xu-Guan Chen, Kun Zhao, Yong Li, Peng Li, Wei Sun, Xiang-Qing Kong
in Frontiers in Neuroanatomy | New and Recent Articles on March 14, 2019 12:00 PM.
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On the Role of Calcium-Permeable AMPARs in Long-Term Potentiation and Synaptic Tagging in the Rodent Hippocampus
Pojeong Park, Heather Kang, Thomas M. Sanderson, Zuner A. Bortolotto, John Georgiou, Min Zhuo, Bong-Kiun Kaang, Graham L. Collingridge
in Frontiers in Synaptic Neuroscience | New and Recent Articles on March 14, 2019 06:00 AM.
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How Can Memories Last for Days, Years, or a Lifetime? Proposed Mechanisms for Maintaining Synaptic Potentiation and Memory. (arXiv:1903.05610v1 [q-bio.NC])

With memory encoding reliant on persistent changes in the properties of synapses, a key question is how can memories be maintained from days to months or a lifetime given molecular turnover? It is likely that positive feedback loops are necessary to persistently maintain the strength of synapses that participate in encoding. Such feedback may occur within signal-transduction cascades and/or the regulation of translation, and it may occur within specific subcellular compartments or within neuronal networks. Not surprisingly, numerous positive feedback loops have been proposed. Some posited loops operate at the level of biochemical signal transduction cascades, such as persistent activation of Ca2+/calmodulin kinase II or protein kinase M zeta. Another level consists of feedback loops involving transcriptional, epigenetic and translational pathways, and autocrine actions of growth factors such as BDNF. Finally, at the neuronal network level, recurrent reactivation of cell assemblies encoding memories is likely to be essential for late maintenance of memory. These levels are not isolated, but linked by shared components of feedback loops. Here, we review characteristics of some commonly discussed feedback loops proposed to underlie the maintenance of memory and long-term synaptic plasticity, assess evidence for and against their necessity, and suggest experiments that could further delineate the dynamics of these feedback loops. We also discuss crosstalk between proposed loops, and ways in which such interaction can facilitate the rapidity and robustness of memory formation and storage.

in q-bio.NC updates on arXiv.org on March 14, 2019 01:30 AM.
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Noisy network attractor models for transitions between EEG microstates. (arXiv:1903.05590v1 [q-bio.NC])

The brain is intrinsically organized into large-scale networks that constantly re-organize on multiple timescales, even when the brain is at rest. The timing of these dynamics is crucial for sensation, perception, cognition and ultimately consciousness, but the underlying dynamics governing the constant reorganization and switching between networks are not yet well understood. Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) provide anatomical and temporal information about the resting-state networks (RSNs), respectively. EEG microstates are brief periods of stable scalp topography, and four distinct configurations with characteristic switching patterns between them are reliably identified at rest. Microstates have been identified as the electrophysiological correlate of fMRI-defined RSNs, this link could be established because EEG microstate sequences are scale-free and have long-range temporal correlations. This property is crucial for any approach to model EEG microstates. This paper proposes a novel modeling approach for microstates: we consider nonlinear stochastic differential equations (SDEs) that exhibit a noisy network attractor between nodes that represent the microstates. Using a single layer network between four states, we can reproduce the transition probabilities between microstates but not the heavy tailed residence time distributions. Introducing a two layer network with a hidden layer gives the flexibility to capture these heavy tails and their long-range temporal correlations. We fit these models to capture the statistical properties of microstate sequences from EEG data recorded inside and outside the MRI scanner and show that the processing required to separate the EEG signal from the fMRI machine noise results in a loss of information which is reflected in differences in the long tail of the dwell-time distributions.

in q-bio.NC updates on arXiv.org on March 14, 2019 01:30 AM.
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Effect of Interpopulation Spike-Timing-Dependent Plasticity on Synchronized Rhythms in Neuronal Networks with Inhibitory and Excitatory Populations. (arXiv:1903.05288v1 [q-bio.NC])

We consider clustered small-world networks (SWNs) with two inhibitory (I) and excitatory (E) populations. This I-E neuronal network has adaptive dynamic I to E and E to I interpopulation synaptic strengths, governed by interpopulation spike-timing-dependent plasticity (STDP). In previous works without STDPs, fast sparsely synchronized rhythms were found to appear in a range of noise intensity $D$. Here, by varying $D$, we investigate the effect of interpopulation STDPs on population states in the I- and the E-populations. Depending on values of $D$, long-term potentiation (LTP) and long-term depression (LTD) for population-averaged values of saturated interpopulation synaptic strengths are found to occur, and they make effects on the degree of population synchronization. In a broad region of intermediate $D$, the degree of good synchronization (with higher spiking measure) becomes decreased, while in a region of large $D$, the degree of bad synchronization (with lower spiking measure) gets increased. Consequently, in each I- or E-population, the synchronization degree becomes nearly the same in a wide range of $D$. This kind of "equalization effect" is found to occur via cooperative interplay between the average occupation and pacing degrees of synchronized rhythms. Such equalization effect is much more enhanced in the presence of combined I to E and E to I STDPs when compared with the case of individual I to E or E to I STDP. We note that the equalization effect in interpopulation synaptic plasticity is in contrast to the Matthew (bipolarization) effect in intrapopulation (I to I and E to E) synaptic plasticity where good (bad) synchronization gets better (worse). Moreover, emergences of LTP and LTD of interpopulation synaptic strengths are intensively investigated via a microscopic method based on the distributions of time delays between the pre- and the post-synaptic spike times.

in q-bio.NC updates on arXiv.org on March 14, 2019 01:30 AM.
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25 years of criticality in neuroscience -- established results, open controversies, novel concepts. (arXiv:1903.05129v1 [q-bio.NC])

Twenty-five years ago, Dunkelmann and Radons (1994) proposed that neural networks should self-organize to a critical state. In models, criticality offers a number of computational advantages. Thus this hypothesis, and in particular the experimental work by Beggs and Plenz (2003), has triggered an avalanche of research, with thousands of studies referring to it. Nonetheless, experimental results are still contradictory. How is it possible, that a hypothesis has attracted active research for decades, but nonetheless remains controversial? We discuss the experimental and conceptual controversy, and then present a parsimonious solution that (i) unifies the contradictory experimental results, (ii) avoids disadvantages of a critical state, and (iii) enables rapid, adaptive tuning of network properties to task requirements.

in q-bio.NC updates on arXiv.org on March 14, 2019 01:30 AM.
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Quantitative regulation of the dynamic steady state of actin networks
Principles of regulation of actin network dimensions are fundamentally important for cell functions, yet remain unclear. Using both in vitro and in silico approaches, we studied the effect of key parameters, such as actin density, ADF/Cofilin concentration and network width on the network length. In the presence of ADF/Cofilin, networks reached equilibrium and became treadmilling. At the trailing edge, the network disintegrated into large fragments. A mathematical model predicts the network length as a function of width, actin and ADF/Cofilin concentrations. Local depletion of ADF/Cofilin by binding to actin is significant, leading to wider networks growing longer. A single rate of breaking network nodes, proportional to ADF/Cofilin density and inversely proportional to the square of the actin density, can account for the disassembly dynamics. Selective disassembly of heterogeneous networks by ADF/Cofilin controls steering during motility. Our results establish general principles on how the dynamic steady state of actin network emerges from biochemical and structural feedbacks.
in eLife: latest articles on March 14, 2019 12:00 AM.
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Inadequate BiP availability defines endoplasmic reticulum stress
How endoplasmic reticulum (ER) stress leads to cytotoxicity is ill-defined. Previously we showed that HeLa cells readjust homeostasis upon proteostatically driven ER stress, triggered by inducible bulk expression of secretory immunoglobulin M heavy chain (μ_s) thanks to the unfolded protein response (UPR; Bakunts et al., 2017). Here we show that conditions that prevent that an excess of the ER resident chaperone (and UPR target gene) BiP over µ_s is restored lead to µ_s-driven proteotoxicity, i.e. abrogation of HRD1-mediated ER-associated degradation (ERAD), or of the UPR, in particular the ATF6α branch. Such conditions are tolerated instead upon removal of the BiP-sequestering first constant domain (C_H1) from µ_s. Thus, our data define proteostatic ER stress to be a specific consequence of inadequate BiP availability, which both the UPR and ERAD redeem.
in eLife: latest articles on March 14, 2019 12:00 AM.
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H3K9me3 is required for inheritance of small RNAs that target a unique subset of newly evolved genes
In Caenorhabditis elegans, RNA interference (RNAi) responses can transmit across generations via small RNAs. RNAi inheritance is associated with Histone-3-Lysine-9 tri-methylation (H3K9me3) of the targeted genes. In other organisms, maintenance of silencing requires a feed-forward loop between H3K9me3 and small RNAs. Here, we show that in C. elegans not only is H3K9me3 unnecessary for inheritance, the modification’s function depends on the identity of the RNAi-targeted gene. We found an asymmetry in the requirement for H3K9me3 and the main worm H3K9me3 methyltransferases, SET-25 and SET-32. Both methyltransferases promote heritable silencing of the foreign gene gfp, but are dispensable for silencing of the endogenous gene oma-1. Genome-wide examination of heritable endogenous small interfering RNAs (endo-siRNAs) revealed that endo-siRNAs that depend on SET-25 and SET-32 target newly acquired and highly H3K9me3 marked genes. Thus, ‘repressive’ chromatin marks could be important specifically for heritable silencing of genes which are flagged as ‘foreign’, such as gfp.
in eLife: latest articles on March 14, 2019 12:00 AM.
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Sparse Labeling and Neural Tracing in Brain Circuits by STARS Strategy: Revealing Morphological Development of Type II Spiral Ganglion Neurons

in Cerebral Cortex Current Issue on March 14, 2019 12:00 AM.
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The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits
Li et al. discover that PVHPDYN neurons, additively with PVHMC4R neurons, are responsible for PVH-mediated satiety. Both PVH neurons are distinct, are equipotent, and use parallel projections to different aspects of the parabrachial complex to cause satiety and prevent obesity.
in Neuron on March 14, 2019 12:00 AM.
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The short-term recovery of corticomotor responses in elbow flexors
The recovery of neurophysiological parameters at various time intervals following fatiguing exercise has been investigated previously. However, the repetition of neuromuscular assessments during the recovery p...
in Most Recent Articles: BMC Neuroscience on March 14, 2019 12:00 AM.
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A spatio-temporal individual-based network framework for West Nile virus in the USA: Spreading pattern of West Nile virus

by Sifat A. Moon, Lee W. Cohnstaedt, D. Scott McVey, Caterina M. Scoglio
West Nile virus (WNV)—a mosquito-borne arbovirus—entered the USA through New York City in 1999 and spread to the contiguous USA within three years while transitioning from epidemic outbreaks to endemic transmission. The virus is transmitted by vector competent mosquitoes and maintained in the avian populations. WNV spatial distribution is mainly determined by the movement of residential and migratory avian populations. We developed an individual-level heterogeneous network framework across the USA with the goal of understanding the long-range spatial distribution of WNV. To this end, we proposed three distance dispersal kernels model: 1) exponential—short-range dispersal, 2) power-law—long-range dispersal in all directions, and 3) power-law biased by flyway direction —long-range dispersal only along established migratory routes. To select the appropriate dispersal kernel we used the human case data and adopted a model selection framework based on approximate Bayesian computation with sequential Monte Carlo sampling (ABC-SMC). From estimated parameters, we find that the power-law biased by flyway direction kernel is the best kernel to fit WNV human case data, supporting the hypothesis of long-range WNV transmission is mainly along the migratory bird flyways. Through extensive simulation from 2014 to 2016, we proposed and tested hypothetical mitigation strategies and found that mosquito population reduction in the infected states and neighboring states is potentially cost-effective.
in PLOS Computational Biology: New Articles on March 13, 2019 09:00 PM.
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Cholinergic system changes of falls and freezing of gait in Parkinson's disease

Objective

Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls.

Methods

Ninety‐four PD subjects underwent clinical assessment and VAChT ([¹⁸F]FEOBV) PET.

Results

Thirty‐five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume‐of‐interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole‐brain voxel‐based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions.

Interpretation

Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol, 2019

in Wiley: Annals of Neurology: Table of Contents on March 13, 2019 06:49 PM.
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Inflammasome Activation Induces Pyroptosis in the Retina Exposed to Ocular Hypertension Injury
Alexey Pronin, Dien Pham, Weijun An, Galina Dvoriantchikova, Galina Reshetnikova, Jianzhong Qiao, Zhanna Kozhekbaeva, Ashlyn E. Reiser, Vladlen Z. Slepak, Valery I. Shestopalov
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 13, 2019 06:00 PM.
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Overexpression of Calretinin Enhances Short-Term Synaptic Depression
Alexey P. Bolshakov, Alexander Kolleker, Evgenia P. Volkova, Fliza Valiullina-Rakhmatullina, Peter M. Kolosov, Andrei Rozov
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 13, 2019 06:00 PM.
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Corrigendum: 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 March 13, 2019 06:00 PM.
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Perceived target range shapes human sound-localization behavior
Abstract
The auditory system relies on binaural differences and spectral pinna cues to localize sounds in azimuth and elevation. However, the acoustic input can be unreliable, due to uncertainty about the environment, and neural noise. A possible strategy to reduce sound-location uncertainty is to integrate the sensory observations with sensorimotor information from previous experience, to infer where sounds are more likely to occur. We investigated whether and how human sound localization performance is affected by the spatial distribution of target sounds, and changes thereof. We tested three different open-loop paradigms, in which we varied the spatial range of sounds in different ways. For the narrowest ranges, target-response gains were highly idiosyncratic and deviated from an optimal gain predicted by error-minimization; in the horizontal plane the deviation typically consisted of a response overshoot. Moreover, participants adjusted their behavior by rapidly adapting their gain to the target range, both in elevation and in azimuth, yielding behavior closer to optimal for larger target ranges. Notably, gain changes occurred without any exogenous feedback about performance. We discuss how the findings can be explained by a sub-optimal model in which the motor-control system reduces its response error across trials to within an acceptable range – rather than strictly minimizing the error.
Significance statement Sensory observations can be noisy, leading to uncertainty in perceptual inferences and variable estimation errors. Theoretically, to reduce uncertainty, sensory information could be integrated with knowledge from prior experience, and with feedback about one’s own response behavior. Here we show, that for a basic and accurate sensorimotor task such as sound localization, humans indeed rely on perceived experience in the absence of exogenous feedback, as they rapidly changed their response sensitivity to experimental variations in the spatial distribution of targets. We argue that the auditory system reduces its estimated localization error close to its expected minimum across trials, allowing for idiosyncratic sub-optimal target response gains.

in RSS PAP on March 13, 2019 04:35 PM.
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LDB1 Is Required for the Early Development of the Dorsal Telencephalon and the Thalamus
Abstract
LIM domain binding protein 1 (LDB1) is a protein cofactor that participates in several multiprotein complexes with transcription factors that regulate mouse forebrain development. Since Ldb1 null mutants display early embryonic lethality, we used a conditional knockout strategy to examine the role of LDB1 in early forebrain development using multiple Cre lines. Loss of Ldb1 from E8.75 using Foxg1Cre caused a disruption of midline boundary structures in the dorsal telencephalon. While this Cre line gave the expected pattern of recombination of the floxed Ldb1 locus, unexpectedly, standard Cre lines that act from embryonic day (E)10.5 (Emx1Cre) and E11.5 (NesCre) did not show efficient or complete recombination in the dorsal telencephalon by E12.5. Intriguingly, this effect was specific to the Ldb1 floxed allele, since three other lines including floxed Ai9 and mTmG reporters, and a floxed Lhx2 line, each displayed the expected spatial patterns of recombination. Furthermore, the incomplete recombination of the floxed Ldb1 locus using NesCre was limited to the dorsal telencephalon, while the ventral telencephalon and the diencephalon displayed the expected loss of Ldb1. This permitted us to examine the requirement for LDB1 in the development of the thalamus in a context wherein the cortex continued to express Ldb1. We report that the somatosensory VB nucleus is profoundly shrunken upon loss of LDB1. Our findings highlight the unusual nature of the Ldb1 locus in terms of recombination efficiency, and also report a novel role for LDB1 during the development of the thalamus.

in eNeuro current issue on March 13, 2019 04:30 PM.
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Erratum: Takata et al., "Sleep and Wakefulness Are Controlled by Ventral Medial Midbrain/Pons GABAergic Neurons in Mice"

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Erratum: Graupner et al., "Natural Firing Patterns Imply Low Sensitivity of Synaptic Plasticity to Spike Timing Compared with Firing Rate"

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy

Neurotrophic factors are candidates for treating epilepsy, but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the desired brain region. We have developed an encapsulated cell technology that overcomes these obstacles by providing a targeted, continuous, de novo synthesized source of high levels of neurotrophic molecules from human clonal ARPE-19 cells encapsulated into hollow fiber membranes. Here we illustrate the potential of this approach for delivering glial cell line-derived neurotrophic factor (GDNF) directly to the hippocampus of epileptic rats. In vivo studies demonstrated that bilateral intrahippocampal implants continued to secrete GDNF that produced high hippocampal GDNF tissue levels in a long-term manner. Identical implants robustly reduced seizure frequency in the pilocarpine model. Seizures were reduced rapidly, and this effect increased in magnitude over 3 months, ultimately leading to a reduction of seizures by 93%. This effect persisted even after device removal, suggesting potential disease-modifying benefits. Importantly, seizure reduction was associated with normalized changes in anxiety and improved cognitive performance. Immunohistochemical analyses revealed that the neurological benefits of GDNF were associated with the normalization of anatomical alterations accompanying chronic epilepsy, including hippocampal atrophy, cell degeneration, loss of parvalbumin-positive interneurons, and abnormal neurogenesis. These effects were associated with the activation of GDNF receptors. All in all, these results support the concept that the implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner, paving the way for continuing preclinical evaluation and eventual clinical translation of this approach for epilepsy.

SIGNIFICANCE STATEMENT Epilepsy is one of the most common neurological conditions, affecting millions of individuals of all ages. These patients experience debilitating seizures that frequently increase over time and can associate with significant cognitive decline and psychiatric disorders that are generally poorly controlled by pharmacotherapy. We have developed a clinically validated, implantable cell encapsulation system that delivers high and consistent levels of GDNF directly to the brain. In epileptic animals, this system produced a progressive and permanent reduction (>90%) in seizure frequency. These benefits were accompanied by improvements in cognitive and anxiolytic behavior and the normalization of changes in CNS anatomy that underlie chronic epilepsy. Together, these data suggest a novel means of tackling the frequently intractable neurological consequences of this devastating disorder.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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MicroRNA-1224 Splicing CircularRNA-Filip1l in an Ago2-Dependent Manner Regulates Chronic Inflammatory Pain via Targeting Ubr5

Dysfunctions of gene transcription and translation in the nociceptive pathways play the critical role in development and maintenance of chronic pain. Circular RNAs (circRNAs) are emerging as new players in regulation of gene expression, but whether and how circRNAs are involved in chronic pain remain elusive. We showed here that complete Freund's adjuvant-induced chronic inflammation pain significantly increased circRNA-Filip1l (filamin A interacting protein 1-like) expression in spinal neurons of mice. Blockage of this increase attenuated complete Freund's adjuvant-induced nociceptive behaviors, and overexpression of spinal circRNA-Filip1l in naive mice mimicked the nociceptive behaviors as evidenced by decreased thermal and mechanical nociceptive threshold. Furthermore, we found that mature circRNA-Filip1l expression was negatively regulated by miRNA-1224 via binding and splicing of precursor of circRNA-Filip1l (pre-circRNA-Filip1l) in the Argonaute-2 (Ago2)-dependent manner. Increase of spinal circRNA-Filip1l expression resulted from the decrease of miRNA-1224 expression under chronic inflammation pain state. miRNA-1224 knockdown or Ago2 overexpression induced nociceptive behaviors in naive mice, which was prevented by the knockdown of spinal circRNA-Filip1l. Finally, we demonstrated that a ubiquitin protein ligase E3 component n-recognin 5 (Ubr5), validated as a target of circRNA-Filip1l, plays a pivotal role in regulation of nociception by spinal circRNA-Filip1l. These data suggest that miRNA-1224-mediated and Ago2-dependent modulation of spinal circRNA-Filip1l expression regulates nociception via targeting Ubr5, revealing a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.

SIGNIFICANCE STATEMENT circRNAs are emerging as new players in regulation of gene expression. Here, we found that the increase of circRNA-Filip1l mediated by miRNA-1224 in an Ago2-dependent way in the spinal cord is involved in regulation of nociception via targeting Ubr5. Our study reveals a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Neurons in FEF Keep Track of Items That Have Been Previously Fixated in Free Viewing Visual Search

When searching a visual scene for a target, we tend not to look at items or locations we have already searched. It is thought that this behavior is driven by an inhibitory tagging mechanism that inhibits responses on priority maps to the relevant items. We hypothesized that this inhibitory tagging signal should be represented as an elevated response in neurons that keep track of stimuli that have been fixated. We recorded from 231 neurons in the frontal eye field (FEF) of 2 male animals performing a visual foraging task, in which they had to find a reward linked to one of five identical targets (Ts) among five distractors. We identified 38 neurons with activity that was significantly greater when the stimulus in the receptive field had been fixated previously in the trial than when it had not been fixated. The response to a fixated object began before the saccade ended, suggesting that this information is remapped. Unlike most FEF neurons, the activity in these cells was not suppressed during active fixation, had minimal motor responses, and did not change through the trial. Yet using traditional classifications from a memory-guided saccade, they were indistinguishable from the rest of the FEF population. We propose that these neurons keep track of any items that have been fixated within the trial and this signal is propagated by remapping. These neurons could be the source of the inhibitory tagging signal to parietal cortex, where a neuronal instantiation of inhibitory tagging is seen.

SIGNIFICANCE STATEMENT When we search a scene for an item, we rarely examine the same location twice. It is thought that this is due to a neural mechanism that keeps track of the items at which we have looked. Here we identified a subset of neurons in the frontal eye field that preferentially responded to items that had been fixated earlier in the trial. These responses were remapped, appearing before the saccade even ended, and were not suppressed during maintained fixation. We propose that these neurons keep track of which items have been examined in search and could be the source of feedback that creates the inhibitory tagging seen in parietal cortex.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Structural Thalamofrontal Hypoconnectivity Is Related to Oculomotor Corollary Discharge Dysfunction in Schizophrenia

By predicting sensory consequences of actions, humans can distinguish self-generated sensory inputs from those that are elicited externally. This is one mechanism by which we achieve a subjective sense of agency over our actions. Corollary discharge (CD) signals—"copies" of motor signals sent to sensory areas—permit such predictions, and CD abnormalities are a hypothesized mechanism for the agency disruptions in schizophrenia that characterize a subset of symptoms. Indeed, behavioral evidence of altered CD, including in the oculomotor system, has been observed in schizophrenia patients. A pathway projecting from the superior colliculus to the frontal eye fields (FEFs) via the mediodorsal thalamus (MD) conveys oculomotor CD associated with saccadic eye movements in nonhuman primates. This animal work provides a promising translational framework in which to investigate CD abnormalities in clinical populations. In the current study, we examined whether structural connectivity of this MD–FEF pathway relates to oculomotor CD functioning in schizophrenia. Twenty-two schizophrenia patients and 24 healthy control participants of both sexes underwent diffusion tensor imaging, and a large subset performed a trans-saccadic perceptual task that yields measures of CD. Using probabilistic tractography, we identified anatomical connections between FEF and MD and extracted indices of microstructural integrity. Patients exhibited compromised microstructural integrity in the MD–FEF pathway, which was correlated with greater oculomotor CD abnormalities and more severe psychotic symptoms. These data reinforce the role of the MD–FEF pathway in transmitting oculomotor CD signals and suggest that disturbances in this pathway may relate to psychotic symptom manifestation in patients.

SIGNIFICANCE STATEMENT People with schizophrenia sometimes experience abnormalities in a sense of agency, which may stem from abnormal sensory predictions about their own actions. Consistent with this notion, the current study found reduced structural connectivity in patients with schizophrenia in a specific brain pathway found to transmit such sensorimotor prediction signals in nonhuman primates. Reduced structural connectivity was correlated with behavioral evidence for impaired sensorimotor predictions and psychotic symptoms.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Changes in Both Neuron Intrinsic Properties and Neurotransmission Are Needed to Drive the Increase in GnRH Neuron Firing Rate during Estradiol-Positive Feedback

Central output of gonadotropin-releasing hormone (GnRH) neurons controls fertility and is sculpted by sex-steroid feedback. A switch of estradiol action from negative to positive feedback initiates a surge of GnRH release, culminating in ovulation. In ovariectomized mice bearing constant-release estradiol implants (OVX+E), GnRH neuron firing is suppressed in the morning (AM) by negative feedback and activated in the afternoon (PM) by positive feedback; no time-of-day-dependent changes occur in OVX mice. In this daily surge model, GnRH neuron intrinsic properties are shifted to favor increased firing during positive feedback. It is unclear whether this shift and the observed concomitant increase in GABAergic transmission, which typically excites GnRH neurons, are independently sufficient for increasing GnRH neuron firing rate during positive feedback or whether both are needed. To test this, we used dynamic clamp to inject selected previously recorded trains of GABAergic postsynaptic conductances (PSgs) collected during the different feedback states of the daily surge model into GnRH neurons from OVX, OVX+E AM, and OVX+E PM mice. PSg trains mimicking positive feedback initiated more action potentials in cells from OVX+E PM mice than negative feedback or OVX (open feedback loop) trains in all three animal models, but the positive-feedback train was most effective when applied to cells during positive feedback. In silico studies of model GnRH neurons in which >1000 PSg trains were tested exhibited the same results. These observations support the hypothesis that GnRH neurons integrate fast-synaptic and intrinsic changes to increase firing rates during positive feedback.

SIGNIFICANCE STATEMENT Infertility affects 15%–20% of couples; failure to ovulate is a common cause. Understanding how the brain controls ovulation is critical for new developments in both infertility treatment and contraception. Ovarian estradiol alters both the intrinsic properties of gonadotropin-releasing hormone (GnRH) neurons and synaptic inputs to these cells coincident with production of sustained GnRH release that ultimately triggers ovulation. We demonstrate here using dynamic clamp and mathematical modeling that estradiol-induced shifts in synaptic transmission alone can increase firing output, but that the intrinsic properties of GnRH neurons during positive feedback further poise these cells for increased response to higher frequency synaptic transmission. These data suggest that GnRH neurons integrate fast-synaptic and intrinsic changes to increase firing rates during the preovulatory GnRH surge.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Prefrontal Corticotropin-Releasing Factor (CRF) Neurons Act Locally to Modulate Frontostriatal Cognition and Circuit Function

The PFC and extended frontostriatal circuitry support higher cognitive processes that guide goal-directed behavior. PFC-dependent cognitive dysfunction is a core feature of multiple psychiatric disorders. Unfortunately, a major limiting factor in the development of treatments for PFC cognitive dysfunction is our limited understanding of the neural mechanisms underlying PFC-dependent cognition. We recently demonstrated that activation of corticotropin-releasing factor (CRF) receptors in the caudal dorsomedial PFC (dmPFC) impairs higher cognitive function, as measured in a working memory task. Currently, there remains much unknown about CRF-dependent regulation of cognition, including the source of CRF for cognition-modulating receptors and the output pathways modulated by these receptors. To address these issues, the current studies used a viral vector-based approach to chemogenetically activate or inhibit PFC CRF neurons in working memory-tested male rats. Chemogenetic activation of caudal, but not rostral, dmPFC CRF neurons potently impaired working memory, whereas inhibition of these neurons improved working memory. Importantly, the cognition-impairing actions of PFC CRF neurons were dependent on local CRF receptors coupled to protein kinase A. Additional electrophysiological recordings demonstrated that chemogenetic activation of caudal dmPFC CRF neurons elicits a robust degradation of task-related coding properties of dmPFC pyramidal neurons and, to a lesser extent, medium spiny neurons in the dorsomedial striatum. Collectively, these results demonstrate that local CRF release within the caudal dmPFC impairs frontostriatal cognitive and circuit function and suggest that CRF may represent a potential target for treating frontostriatal cognitive dysfunction.

SIGNIFICANCE STATEMENT The dorsomedial PFC and its striatal targets play a critical role in higher cognitive function. PFC-dependent cognitive dysfunction is associated with many psychiatric disorders. Although it has long-been known that corticotropin-releasing factor (CRF) neurons are prominent within the PFC, their role in cognition has remained unclear. Using a novel chemogenetic viral vector system, the present studies demonstrate that PFC CRF neurons impair working memory via activation of local PKA-coupled CRF receptors, an action associated with robust degradation in task-related frontostriatal neuronal coding. Conversely, suppression of constitutive PFC CRF activity improved working memory. Collectively, these studies provide novel insight into the neurobiology of cognition and suggest that CRF may represent a novel target for the treatment of cognitive dysfunction.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Plasticity in the Link between Pain-Transmitting and Pain-Modulating Systems in Acute and Persistent Inflammation

There is strong evidence that spinoparabrachial neurons in the superficial dorsal horn contribute to persistent pain states, and that the lateral parabrachial complex (PB) conveys relevant nociceptive information to higher structures. The role of PB itself in hyperalgesia and how it recruits descending facilitation has nevertheless received significantly less attention. The current study is a first step toward delineating the functional dynamics of PB and its link to descending control in acute and persistent inflammatory pain. In lightly anesthetized rats, we recorded behavioral withdrawal evoked by mechanical stimulation of the hindpaw and, simultaneously, the activity of identified pain-modulating neurons, "ON-cells" and "OFF-cells," in the rostral ventromedial medulla (RVM). This was done before and after the inactivation of PB, contralateral or ipsilateral to an inflamed paw [1 h, 1 d, or 5–6 d after intraplantar injection of Complete Freund's Adjuvant (CFA)]. The inactivation of contralateral, but not ipsilateral, PB interfered with nociceptive input to RVM under basal conditions, as well as in acute inflammation. By contrast, blocking ipsilateral, but not contralateral, PB in established inflammation interfered with behavioral hyperalgesia and ON-cell and OFF-cell responses. The lesioning of contralateral PB before CFA injection prevented this recruitment of ipsilateral PB in persistent inflammation. These experiments show that contralateral PB is required to initiate hyperalgesia, which is then maintained by ipsilateral PB, most likely in both cases via the engagement of pain-modulating neurons of the RVM.

SIGNIFICANCE STATEMENT The lateral parabrachial complex (PB) relays nociceptive information to brain circuits that are important for the transmission and modulation of pain, but its specific role in persistent pain and engagement of descending control mechanisms has received relatively little attention. We show here that PB contralateral and ipsilateral to an inflammatory insult demonstrate different functions as inflammation persists, likely by engaging pain-facilitating neurons of the rostral ventromedial medulla. While the contralateral PB, the target of the major spinoparabrachial pathway, relays acute nociceptive information, the ipsilateral PB is recruited or unmasked in persistent inflammation to maintain hyperalgesia. These data point to plasticity in the PB itself or its direct and indirect connections with pain-modulating systems as central to the development and maintenance of persistent pain.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Superficial Layers Suppress the Deep Layers to Fine-tune Cortical Coding

The descending microcircuit from layer 2/3 (L2/3) to layer 5 (L5) is one of the strongest excitatory pathways in the cortex, presumably forming a core component of its feedforward hierarchy. To date, however, no experiments have selectively tested the impact of L2/3 activity on L5 during active sensation. We used optogenetic, cell-type-specific manipulation of L2/3 neurons in the barrel cortex of actively sensing mice (of either sex) to elucidate the significance of this pathway to sensory coding in L5. Contrary to standard models, activating L2/3 predominantly suppressed spontaneous activity in L5, whereas deactivating L2/3 mainly facilitated touch responses in L5. Somatostatin interneurons are likely important to this suppression because their optogenetic deactivation significantly altered the functional impact of L2/3 onto L5. The net effect of L2/3 was to enhance the stimulus selectivity and expand the range of L5 output. These data imply that the core cortical pathway increases the selectivity and expands the range of cortical output through feedforward inhibition.

SIGNIFICANCE STATEMENT The primary sensory cortex contains six distinct layers that interact to form the basis of our perception. While rudimentary patterns of connectivity between the layers have been outlined quite extensively in vitro, functional relationships in vivo, particularly during active sensation, remain poorly understood. We used cell-type-specific optogenetics to test the functional relationship between layer 2/3 and layer 5. Surprisingly, we discovered that L2/3 primarily suppresses cortical output from L5. The recruitment of somatostatin-positive interneurons is likely fundamental to this relationship. The net effect of this translaminar suppression is to enhance the selectivity and expand the range of receptive fields, therefore potentially sharpening the perception of space.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Ventral Pallidum Is the Primary Target for Accumbens D1 Projections Driving Cocaine Seeking

Outputs from the nucleus accumbens (NAc) include projections to the ventral pallidum and the ventral tegmental area and subtantia nigra in the ventral mesencephalon. The medium spiny neurons (MSN) that give rise to these pathways are GABAergic and consist of two populations of equal number that are segregated by differentially expressed proteins, including D1- and D2-dopamine receptors. Afferents to the ventral pallidum arise from both D1- and D2-MSNs, whereas the ventral mesencephalon is selectively innervated by D1-MSN. To determine the extent of collateralization of D1-MSN to these axon terminal fields we used retrograde labeling in transgenic mice expressing tdTomato selectively in D1-MSN, and found that a large majority of D1-MSN in either the shell or core subcompartments of the accumbens collateralized to both output structures. Approximately 70% of D1-MSNs projecting to the ventral pallidum collateralized to the ventral mesencephalon, whereas >90% of mesencephalic D1-MSN afferents collateralized to the ventral pallidum. In contrast, <10% of dorsal striatal D1-MSNs collateralized to both the globus pallidus and ventral mesencephalon. D1-MSN activation is required for conditioned cues to induce cocaine seeking. To determine which D1-MSN projection mediates cued cocaine seeking, we selectively transfected D1-MSNs in transgenic rats with an inhibitory Gi-coupled DREADD. Activation of the transfected Gi-DREADD with clozapine-N-oxide administered into the ventral pallidum, but not into the ventral mesencephalon, blocked cue-induced cocaine seeking. These data show that, although accumbens D1-MSNs largely collateralize to both the ventral pallidum and ventral mesencephalon, only D1-MSN innervation of the ventral pallidum is necessary for cue-induced cocaine seeking.

SIGNIFICANCE STATEMENT Activity in D1 dopamine receptor-expressing neurons in the NAc is required for rodents to respond to cocaine-conditioned cues and relapse to drug seeking behaviors. The D1-expressing neurons project to both the ventral pallidum and ventral mesencephalon, and we found that a majority of the neurons that innervate the ventral pallidum also collateralize to the ventral mesencephalon. However, despite innervating both structures, only D1 innervation of the ventral pallidum mediates cue-induced cocaine seeking.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia

Microglia play important roles in shaping the developing CNS, and at early stages they have been proposed to regulate progenitor proliferation, differentiation, and neuronal survival. However, these studies reveal contradictory outcomes, highlighting the complexity of these cell–cell interactions. Here, we investigate microglia function during embryonic mouse retina development, where only microglia, progenitors, and neurons are present. In both sexes, we determine that microglia primarily interact with retinal neurons and find that depletion of microglia via conditional KO of the Csf1 receptor results in increased density of retinal ganglion cells (RGCs). Pharmacological inhibition of microglia also results in an increase in RGCs, with no effect on retinal progenitor proliferation, RGC genesis, or apoptosis. We show that microglia in the embryonic retina are enriched for phagocytic markers and observe engulfment of nonapoptotic Brn3-labeled RGCs. We investigate the molecular pathways that can mediate cell engulfment by microglia and find selective downregulation of complement pathway components with microglia inhibition, and further show that C1q protein marks a subset of RGCs in the embryonic retina. KO of complement receptor 3 (CR3; Itgam), which is only expressed by microglia, results in increased RGC density, similar to what we observed after depletion or inhibition of microglia. Thus, our data suggest that microglia regulate neuron elimination in the embryonic mouse retina by complement-mediated phagocytosis of non-apoptotic newborn RGCs.

SIGNIFICANCE STATEMENT Microglia are emerging as active and important participants in regulating neuron number in development, during adult neurogenesis, and following stem cell therapies. However, their role in these contexts and the mechanisms involved are not fully defined. Using a well-characterized in vivo system, we provide evidence that microglia regulate neuronal elimination by complement-mediated engulfment of nonapoptotic neurons. This work provides a significant advancement of the field by defining in vivo molecular mechanisms for microglia-mediated cell elimination. Our data add to a growing body of evidence that microglia are essential for proper nervous system development. In addition, we elucidate microglia function in the developing retina, which may shed light on microglia involvement in the context of retinal injury and disease.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Knockdown of Fidgetin Improves Regeneration of Injured Axons by a Microtubule-Based Mechanism

Fidgetin is a microtubule-severing protein that pares back the labile domains of microtubules in the axon. Experimental depletion of fidgetin results in elongation of the labile domains of microtubules and faster axonal growth. To test whether fidgetin knockdown assists axonal regeneration, we plated dissociated adult rat DRGs transduced using AAV5-shRNA-fidgetin on a laminin substrate with spots of aggrecan, a growth-inhibitory chondroitin sulfate proteoglycan. This cell culture assay mimics the glial scar formed after CNS injury. Aggrecan is more concentrated at the edge of the spot, such that axons growing from within the spot toward the edge encounter a concentration gradient that causes growth cones to become dystrophic and axons to retract or curve back on themselves. Fidgetin knockdown resulted in faster-growing axons on both laminin and aggrecan and enhanced crossing of axons from laminin onto aggrecan. Strikingly, axons from within the spot grew more avidly against the inhibitory aggrecan concentration gradient to cross onto laminin, without retracting or curving back. We also tested whether depleting fidgetin improves axonal regeneration in vivo after a dorsal root crush in adult female rats. Whereas control DRG neurons failed to extend axons across the dorsal root entry zone after injury, DRG neurons in which fidgetin was knocked down displayed enhanced regeneration of axons across the dorsal root entry zone into the spinal cord. Collectively, these results establish fidgetin as a novel therapeutic target to augment nerve regeneration and provide a workflow template by which microtubule-related targets can be compared in the future.

SIGNIFICANCE STATEMENT Here we establish a workflow template from cell culture to animals in which microtubule-based treatments can be tested and compared with one another for their effectiveness in augmenting regeneration of injured axons relevant to spinal cord injury. The present work uses a viral transduction approach to knock down fidgetin from rat neurons, which coaxes nerve regeneration by elevating microtubule mass in their axons. Unlike previous strategies using microtubule-stabilizing drugs, fidgetin knockdown adds microtubule mass that is labile (rather than stable), thereby better recapitulating the growth status of a developing axon.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Cenpj Regulates Cilia Disassembly and Neurogenesis in the Developing Mouse Cortex

Primary cilia are microtubule-based protuberances that project from the eukaryotic cell body to sense the extracellular environment. Ciliogenesis is closely correlated to the cell cycle and defects of cilia are related to human systemic diseases such as primary ciliary dyskinesia. However, the role of ciliogenesis in cortical development remains unclear. Here, we demonstrate that Cenpj, a protein that is required for centriole biogenesis, plays a role in regulating cilium disassembly in vivo. Depletion of Cenpj in neural progenitor cells results in long cilia and abnormal cilia disassembly. Radial glial cells Cenpj depletion exhibit uncompleted cell division, reduced cell proliferation, and increased cell apoptosis in the developing mouse cerebrum cortex, leading to microcephaly. In addition, Cenpj depletion causes long and thin primary cilia and motile cilia in adult neural stem cells and reduced cell proliferation in the subventricular zone. Furthermore, we show that Cenpj regulates cilia disassembly and neurogenesis through Kif2a, a plus-end-directed motor protein. These data collected from mice of both sexes provide insights into how ciliogenesis plays roles in cortical development and how primary microcephaly is induced by Cenpj mutations in humans.

SIGNIFICANCE STATEMENT Autosomal recessive primary microcephaly is a neurodevelopmental disorder with the major symptoms of reduction of circumference of the head, brain volume, and cortex thickness with normal brain architecture in birth. We used conditional Cenpj deletion mice and found that neural progenitor cells (NPCs) exhibited long primary cilia and abnormal cilium appendages. The defective cilium disassembly caused by Cenpj depletion might correlate to reduced cell proliferation, uncompleted cell division, cell apoptosis, and microcephaly in mice. Cenpj also regulates the cilium structure of adult neural stem cells and adult neurogenesis in mice. Additionally, our results illustrate that Cenpj regulates cilia disassembly and neurogenesis through Kif2a, indicating that primary cilia dynamics play a crucial role in NPC mitosis and adult neurogenesis.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Activation of Dopamine Receptor 2 Prompts Transcriptomic and Metabolic Plasticity in Glioblastoma

Glioblastoma (GBM) is one of the most aggressive and lethal tumor types. Evidence continues to accrue indicating that the complex relationship between GBM and the brain microenvironment contributes to this malignant phenotype. However, the interaction between GBM and neurotransmitters, signaling molecules involved in neuronal communication, remains incompletely understood. Here we examined, using human patient-derived xenograft lines, how the monoamine dopamine influences GBM cells. We demonstrate that GBM cells express dopamine receptor 2 (DRD2), with elevated expression in the glioma-initiating cell (GIC) population. Stimulation of DRD2 caused a neuron-like hyperpolarization exclusively in GICs. In addition, long-term activation of DRD2 heightened the sphere-forming capacity of GBM cells, as well as tumor engraftment efficiency in both male and female mice. Mechanistic investigation revealed that DRD2 signaling activates the hypoxia response and functionally alters metabolism. Finally, we found that GBM cells synthesize and secrete dopamine themselves, suggesting a potential autocrine mechanism. These results identify dopamine signaling as a potential therapeutic target in GBM and further highlight neurotransmitters as a key feature of the pro-tumor microenvironment.

SIGNIFICANCE STATEMENT This work offers critical insight into the role of the neurotransmitter dopamine in the progression of GBM. We show that dopamine induces specific changes in the state of tumor cells, augmenting their growth and shifting them to a more stem-cell like state. Further, our data illustrate that dopamine can alter the metabolic behavior of GBM cells, increasing glycolysis. Finally, this work demonstrates that GBM cells, including tumor samples from patients, can synthesize and secrete dopamine, suggesting an autocrine signaling process underlying these results. These results describe a novel connection between neurotransmitters and brain cancer, further highlighting the critical influence of the brain milieu on GBM.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Two Distinct Sets of Ca2+ and K+ Channels Are Activated at Different Membrane Potentials by the Climbing Fiber Synaptic Potential in Purkinje Neuron Dendrites

In cerebellar Purkinje neuron dendrites, the transient depolarization associated with a climbing fiber (CF) EPSP activates voltage-gated Ca²⁺ channels (VGCCs), voltage-gated K⁺ channels (VGKCs), and Ca²⁺-activated SK and BK K⁺ channels. The resulting membrane potential (V_m) and Ca²⁺ transients play a fundamental role in dendritic integration and synaptic plasticity of parallel fiber inputs. Here we report a detailed investigation of the kinetics of dendritic Ca²⁺ and K⁺ channels activated by CF-EPSPs, based on optical measurements of V_m and Ca²⁺ transients and on a single-compartment NEURON model reproducing experimental data. We first measured V_m and Ca²⁺ transients associated with CF-EPSPs at different initial V_m, and we analyzed the changes in the Ca²⁺ transients produced by the block of each individual VGCCs, of A-type VGKCs and of SK and BK channels. Then, we constructed a model that includes six active ion channels to accurately match experimental signals and extract the physiological kinetics of each channel. We found that two different sets of channels are selectively activated. When the dendrite is hyperpolarized, CF-EPSPs mainly activate T-type VGCCs, SK channels, and A-type VGKCs that limit the transient V_m ~ <0 mV. In contrast, when the dendrite is depolarized, T-type VGCCs and A-type VGKCs are inactivated and CF-EPSPs activate P/Q-type VGCCs, high-voltage activated VGKCs, and BK channels, leading to Ca²⁺ spikes. Thus, the potentially activity-dependent regulation of A-type VGKCs, controlling the activation of this second set of channels, is likely to play a crucial role in signal integration and plasticity in Purkinje neuron dendrites.

SIGNIFICANCE STATEMENT The climbing fiber synaptic input transiently depolarizes the dendrite of cerebellar Purkinje neurons generating a signal that plays a fundamental role in dendritic integration. This signal is mediated by two types of Ca²⁺ channels and four types of K⁺ channels. Thus, understanding the kinetics of all of these channels is crucial for understanding PN function. To obtain this information, we used an innovative strategy that merges ultrafast optical membrane potential and Ca²⁺ measurements, pharmacological analysis, and computational modeling. We found that, according to the initial membrane potential, the climbing fiber depolarizing transient activates two distinct sets of channels. Moreover, A-type K⁺ channels limit the activation of P/Q-type Ca²⁺ channels and associated K⁺ channels, thus preventing the generation of Ca²⁺ spikes.

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Updating Internal Cognitive Models during Sleep

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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This Week in The Journal

in Journal of Neuroscience current issue on March 13, 2019 04:30 PM.
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Powerhouse of the mind: mitochondrial plasticity at the synapse

Publication date: August 2019
Source: Current Opinion in Neurobiology, Volume 57
Author(s): Meghan J Rossi, Gulcin Pekkurnaz
Neurons are highly polarized cells with extraordinary energy demands, which are mainly fulfilled by mitochondria. In response to altered neuronal energy state, mitochondria adapt to enable energy homeostasis and nervous system function. This adaptation, also called mitochondrial plasticity, can be observed as alterations in the form, function and position. The primary site of energy consumption in neurons is localized at the synapse, where mitochondria are critical for both pre- and postsynaptic functions. In this review, we will discuss molecular mechanisms regulating mitochondrial plasticity at the synapse and how they contribute to information processing within neurons.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 13, 2019 12:00 PM.
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Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes
Ole Kristian Drange, Olav Bjerkehagen Smeland, Alexey A. Shadrin, Per Ivar Finseth, Aree Witoelar, Oleksandr Frei, Psychiatric Genomics Consortium Bipolar Disorder Working Group , Yunpeng Wang, Sahar Hassani, Srdjan Djurovic, Anders M. Dale, Ole A. Andreassen, Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Yunpeng Wang, Jonathan R I Coleman, Heìleìna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Srdjan Djurovic, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Friseìn, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Melissa J Green, Tiffany A Greenwood, Jakob Grove, Weihua Guan, Joseì Guzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Steìphane Jamain, Jessica S Johnson, Anders Jureìus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, Anna C Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B Lawson, Markus Leber, Phil H Lee, Shawn E Levy, Jun Z Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M Nievergelt, Annelie Nordin Adolfsson, Evaristus A Nwulia, Claire O’Donovan, Loes M Olde Loohuis, Anil P S Ori, Lilijana Oruc, Urban Ösby, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Ceìline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Saìnchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, ToÞnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, Reneì S Kahn, George Kirov, Mikael Landeìn, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribaseìs, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, Pamela Sklar
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 13, 2019 12:00 PM.
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Neural Interactome: Interactive Simulation of a Neuronal System
Jimin Kim, William Leahy, Eli Shlizerman
in Frontiers in Computational Neuroscience | New and Recent Articles on March 13, 2019 12:00 PM.
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Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

Objective

To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS).

Methods

Linkage disequilibrium score regression and Mendelian randomization were applied in a large‐scale, data‐driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome‐wide association studies (GWASes) summary statistics from MR Base and LD‐hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed.

Results

We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest.

Interpretation

Here, we have developed a public resource (https://lng-nia.shinyapps.io/mrshiny) which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low‐desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;00:1–12

in Wiley: Annals of Neurology: Table of Contents on March 13, 2019 09:56 AM.
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Smoking and amyotrophic lateral sclerosis: A mendelian randomization study

In this study, we examined the potential causal effect of smoking on amyotrophic lateral sclerosis (ALS) using the Project MinE data involving 12,577 patients with ALS and 23,475 controls in a Mendelian randomization (MR) framework. The MR approach has the potential to investigate a causal relationship between a risk factor and a disease, avoiding confounding and information bias that often present in conventional epidemiological studies. We found that smokers had a higher risk of ALS compared to never smokers. Our study thus provides evidence for a causal relationship between smoking and ALS. Ann Neurol, 2019

in Wiley: Annals of Neurology: Table of Contents on March 13, 2019 09:53 AM.
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Finger Temperature: A Psychophysiological Assessment of the Attentional State
Rodrigo C. Vergara, Cristóbal Moënne-Loccoz, Camila Ávalos, José Egaña, Pedro E. Maldonado
in Frontiers in Human Neuroscience | New and Recent Articles on March 13, 2019 06:00 AM.
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The Interactome of Palmitoyl-Protein Thioesterase 1 (PPT1) Affects Neuronal Morphology and Function
Tamar Sapir, Michal Segal, Gayane Grigoryan, Karin M. Hansson, Peter James, Menahem Segal, Orly Reiner
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 13, 2019 06:00 AM.
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A Review and Hypothesized Model of the Mechanisms That Underpin the Relationship Between Inflammation and Cognition in the Elderly
Masoumeh Tangestani Fard, Con Stough
in Frontiers in Aging Neuroscience | New and Recent Articles on March 13, 2019 06:00 AM.
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Single-Cell Electrical Stimulation Using CMOS-Based High-Density Microelectrode Arrays
Silvia Ronchi, Michele Fiscella, Camilla Marchetti, Vijay Viswam, Jan Müller, Urs Frey, Andreas Hierlemann
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on March 13, 2019 06:00 AM.
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Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons
Guanqun Huang, Shuting Chen, Xiaoxia Chen, Jiajun Zheng, Zhuoran Xu, Abolfazl Doostparast Torshizi, Siyi Gong, Qingpei Chen, Xiaokuang Ma, Jiandong Yu, Libing Zhou, Shenfeng Qiu, Kai Wang, Lingling Shi
in Frontiers in Neuroanatomy | New and Recent Articles on March 13, 2019 06:00 AM.
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Emergence of Brain Rhythms: Model Interpretation of EEG Data. (arXiv:1903.04576v1 [q-bio.NC])

Electroencephalography (EEG) monitors ---by either intrusive or noninvasive electrodes--- time and frequency variations and spectral content of voltage fluctuations or waves, known as brain rhythms, which in some way uncover activity during both rest periods and specific events in which the subject is under stimulus. This is a useful tool to explore brain behavior, as it complements imaging techniques that have a poorer temporal resolution. We here approach the understanding of EEG data from first principles by studying a networked model of excitatory and inhibitory neurons which generates a variety of comparable waves. In fact, we thus reproduce $\alpha$, $\beta,$ $\gamma$ and other rhythms as observed by EEG, and identify the details of the respectively involved complex phenomena, including a precise relationship between an input and the collective response to it. It ensues the potentiality of our model to better understand actual mind mechanisms and its possible disorders, and we also describe kind of stochastic resonance phenomena which locate main qualitative changes of mental behavior in (e.g.) humans. We also discuss the plausible use of these findings to design deep learning algorithms to detect the occurence of phase transitions in the brain and to analyse its consequences.

in q-bio.NC updates on arXiv.org on March 13, 2019 01:30 AM.
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Understanding regeneration at different scales
Regeneration occurs at many different levels in nature, from individual organisms (notably earthworms and hydra), through communities of microbes, to ecosystems such as forests. Researchers in the life sciences and the history and philosophy of science are collaborating to explore how the processes of repair and recovery observed at these different scales are related.
in eLife: latest articles on March 13, 2019 12:00 AM.
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Towards a classification of stem cells
The characteristic properties of stem cells – notably their ability to self-renew and to differentiate – have meant that they have traditionally been viewed as distinct from most other types of cells. However, recent research has blurred the line between stem cells and other cells by showing that the former display a range of behaviors in different tissues and at different stages of development. Here, we use the tools of metaphysics to describe a classification scheme for stem cells, and to highlight what their inherent diversity means for cancer treatment.
in eLife: latest articles on March 13, 2019 12:00 AM.
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From primal scenes to synthetic cells
Synthetic cells spark intriguing questions about the nature of life. Projects such as BaSyC (Building a Synthetic Cell) aim to build an entity that mimics how living cells work. But what kind of entity would a synthetic cell really be? I assess this question from a philosophical perspective, and show how early fictional narratives of artificial life – such as the laboratory scene in Goethe’s Faust – can help us to understand the challenges faced by synthetic biology researchers.
in eLife: latest articles on March 13, 2019 12:00 AM.
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Impaired ABCA1/ABCG1-mediated lipid efflux in the mouse retinal pigment epithelium (RPE) leads to retinal degeneration
Age-related macular degeneration (AMD) is a progressive disease of the retinal pigment epithelium (RPE) and the retina leading to loss of central vision. Polymorphisms in genes involved in lipid metabolism, including the ATP-binding cassette transporter A1 (ABCA1), have been associated with AMD risk. However, the significance of retinal lipid handling for AMD pathogenesis remains elusive. Here, we study the contribution of lipid efflux in the RPE by generating a mouse model lacking ABCA1 and its partner ABCG1 specifically in this layer. Mutant mice show lipid accumulation in the RPE, reduced RPE and retinal function, retinal inflammation and RPE/photoreceptor degeneration. Data from human cell lines indicate that the ABCA1 AMD risk-conferring allele decreases ABCA1 expression, identifying the potential molecular cause that underlies the genetic risk for AMD. Our results highlight the essential homeostatic role for lipid efflux in the RPE and suggest a pathogenic contribution of reduced ABCA1 function to AMD.
in eLife: latest articles on March 13, 2019 12:00 AM.
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Movement Vigor as a Reflection of Subjective Economic Utility
To understand subjective evaluation of an option, various disciplines have quantified the interaction between reward and effort during decision making, producing an estimate of economic utility, namely the subjective ‘goodness’ of an option. However, variables that affect utility of an option also influence the vigor of movements toward that option. For example, expectation of reward increases speed of saccadic eye movements, whereas expectation of effort decreases this speed. These results imply that vigor may serve as a new, real-time metric with which to quantify subjective utility, and that the control of movements may be an implicit reflection of the brain’s economic evaluation of the expected outcome.
in Trends in Neurosciences on March 13, 2019 12:00 AM.
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Pain-Induced Negative Affect Is Mediated via Recruitment of The Nucleus Accumbens Kappa Opioid System
Massaly et al. identify a pain-induced enhancement in the kappa opioid system within nucleus accumbens, which drives pain-associated negative emotional states. These results provide a functional substrate for therapies that would circumvent pain-induced affective disorders.
in Neuron on March 13, 2019 12:00 AM.
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Reversible Inactivation of Different Millimeter-Scale Regions of Primate IT Results in Different Patterns of Core Object Recognition Deficits
Rajalingham and DiCarlo show that inactivating millimeter-scale IT subregions results in selective object recognition deficits, providing direct evidence for a causal role of IT in this behavior. Inactivating different subregions resulted in different deficit patterns, revealing an underlying topographical organization.
in Neuron on March 13, 2019 12:00 AM.
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Synaptic plasticity onto inhibitory neurons as a mechanism for ocular dominance plasticity

by Jacopo Bono, Claudia Clopath
Ocular dominance plasticity is a well-documented phenomenon allowing us to study properties of cortical maturation. Understanding this maturation might be an important step towards unravelling how cortical circuits function. However, it is still not fully understood which mechanisms are responsible for the opening and closing of the critical period for ocular dominance and how changes in cortical responsiveness arise after visual deprivation. In this article, we present a theory of ocular dominance plasticity. Following recent experimental work, we propose a framework where a reduction in inhibition is necessary for ocular dominance plasticity in both juvenile and adult animals. In this framework, two ingredients are crucial to observe ocular dominance shifts: a sufficient level of inhibition as well as excitatory-to-inhibitory synaptic plasticity. In our model, the former is responsible for the opening of the critical period, while the latter limits the plasticity in adult animals. Finally, we also provide a possible explanation for the variability in ocular dominance shifts observed in individual neurons and for the counter-intuitive shifts towards the closed eye.
in PLOS Computational Biology: New Articles on March 12, 2019 09:00 PM.
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Optimizing the depth and the direction of prospective planning using information values

by Can Eren Sezener, Amir Dezfouli, Mehdi Keramati
Evaluating the future consequences of actions is achievable by simulating a mental search tree into the future. Expanding deep trees, however, is computationally taxing. Therefore, machines and humans use a plan-until-habit scheme that simulates the environment up to a limited depth and then exploits habitual values as proxies for consequences that may arise in the future. Two outstanding questions in this scheme are “in which directions the search tree should be expanded?”, and “when should the expansion stop?”. Here we propose a principled solution to these questions based on a speed/accuracy tradeoff: deeper expansion in the appropriate directions leads to more accurate planning, but at the cost of slower decision-making. Our simulation results show how this algorithm expands the search tree effectively and efficiently in a grid-world environment. We further show that our algorithm can explain several behavioral patterns in animals and humans, namely the effect of time-pressure on the depth of planning, the effect of reward magnitudes on the direction of planning, and the gradual shift from goal-directed to habitual behavior over the course of training. The algorithm also provides several predictions testable in animal/human experiments.
in PLOS Computational Biology: New Articles on March 12, 2019 09:00 PM.
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Spike burst-pause dynamics of Purkinje cells regulate sensorimotor adaptation

by Niceto R. Luque, Francisco Naveros, Richard R. Carrillo, Eduardo Ros, Angelo Arleo
Cerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of targeted medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation.
in PLOS Computational Biology: New Articles on March 12, 2019 09:00 PM.
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The Effect of ASIC3 Knockout on Corticostriatal Circuit and Mouse Self-grooming Behavior
Wei-Li Wu, Sin-Jhong Cheng, Shing-Hong Lin, Yu-Chia Chuang, Eagle Yi-Kung Huang, Chih-Cheng Chen
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 12, 2019 06:00 PM.
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Cholinergic Deficit Induced by Central Administration of 192IgG-Saporin Is Associated With Activation of Microglia and Cell Loss in the Dorsal Hippocampus of Rats
Yulia V. Dobryakova, Maria N. Volobueva, Anna O. Manolova, Tatiana M. Medvedeva, Alexey A. Kvichansky, Natalia V. Gulyaeva, Vlamidir A. Markevich, Mikhail Yu. Stepanichev, Alexey P. Bolshakov
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 12, 2019 06:00 PM.
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Editorial: Brain Protein Aging and Dementia Control
Gen Sobue
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 12, 2019 06:00 PM.
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How the Brain Represents Language and Answers Questions? Using an AI System to Understand the Underlying Neurobiological Mechanisms
Marco A. P. Idiart, Aline Villavicencio, Boris Katz, César Rennó-Costa, John Lisman
in Frontiers in Computational Neuroscience | New and Recent Articles on March 12, 2019 06:00 PM.
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Different Inhibitory Interneuron Cell Classes Make Distinct Contributions to Visual Contrast Perception
Abstract
While recent work has revealed how different inhibitory interneurons influence responses of cortical neurons to sensory stimuli, little is known about their distinct contributions to sensory perception. Here, we optogenetically activated different genetically defined interneurons [parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP)] in visual cortex (V1) of mice working at threshold in a contrast increment detection task. The visual stimulus was paired with optogenetic stimulation to assess how enhancing V1 inhibitory neuron activity during visual processing altered task performance. PV or SST activation impaired, while VIP stimulation improved, contrast increment detection. The impairment produced by PV or SST activation persisted over several weeks of testing. In contrast, mice learned to reliably detect VIP activation in the absence of any natural visual stimulus. Thus, different inhibitory signals make distinct contributions to visual contrast perception.

in eNeuro current issue on March 12, 2019 04:30 PM.
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The Thalamus Regulates Retinoic Acid Signaling and Development of Parvalbumin Interneurons in Postnatal Mouse Prefrontal Cortex
Abstract
GABAergic inhibitory neurons in the prefrontal cortex (PFC) play crucial roles in higher cognitive functions. Despite the link between aberrant development of PFC interneurons and a number of psychiatric disorders, mechanisms underlying the development of these neurons are poorly understood. Here we show that the retinoic acid (RA)-degrading enzyme CYP26B1 (cytochrome P450 family 26, subfamily B, member 1) is transiently expressed in the mouse frontal cortex during postnatal development, and that medial ganglionic eminence (MGE)-derived interneurons, particularly in parvalbumin (PV)-expressing neurons, are the main cell type that has active RA signaling during this period. We found that frontal cortex-specific Cyp26b1 knock-out mice had an increased density of PV-expressing, but not somatostatin-expressing, interneurons in medial PFC, indicating a novel role of RA signaling in controlling PV neuron development. The initiation of Cyp26b1 expression in neonatal PFC coincides with the establishment of connections between the thalamus and the PFC. We found that these connections are required for the postnatal expression of Cyp26b1 in medial PFC. In addition to this region-specific role in postnatal PFC that regulates RA signaling and PV neuron development, the thalamocortical connectivity had an earlier role in controlling radial dispersion of MGE-derived interneurons throughout embryonic neocortex. In summary, our results suggest that the thalamus plays multiple, temporally separate roles in interneuron development in the PFC.

in eNeuro current issue on March 12, 2019 04:30 PM.
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Retraction

in Wiley: Annals of Neurology: Table of Contents on March 12, 2019 03:04 PM.
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Gene therapy improves brain white matter in aromatic l‐amino acid decarboxylase deficiency

Abstract

Objective

Children with aromatic l‐amino acid decarboxylase (AADC) deficiency suffer from severe motor dysfunction. Restoration of dopamine levels in the putamen by gene therapy has led to significant improvement in motor function. This study explored brain structure changes in patients.

Methods

Brain diffusion tensor imaging (DTI) were performed before and 12 months after gene therapy. Whole‐brain tract‐specific analysis was performed to assess white matter microstructural integrity.

Results

In the eight patients (1.67 to 8.42 years of age) enrolled in the study, gene therapy did not affect macroscopic structure. DTI prior to gene therapy revealed lower total mean fractional anisotropy (FA) values in the patients than in the age‐matched pretreatment controls (p = 0.017, median difference = −0.0136, 95% confidence interval [CI] [−0.0319, −0.0126]). After gene therapy, total mean FA increased (p = 0.012, median difference = 0.0211, 95% CI [0.0094, 0.0456]) and the values in the patients were not different from the age‐matched posttreatment controls. The increase in total mean FA after gene therapy in the patients was correlated with their increase in motor score (R = 0.846; p = 0.008), but was inversely correlated with their ages at the time of gene therapy (R = −0.754; p = 0.031). The corticospinal tracts, and the thalamic radiation and callosal fibers involving motor function, improved after gene therapy.

Interpretation

Improvement in the microstructural integrity of white matter tracts is associated with the improvement in motor function following gene therapy.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on March 12, 2019 02:23 PM.
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Association between Perihematomal Cerebral Blood Volume and Intracerebral Hemorrhage Expansion: a CT Perfusion Study

ABSTRACT

We investigated whether CT perfusion can identify intracerebral hemorrhage patients at high risk of hematoma growth (HG). A total of 155 subjects underwent CT perfusion on admission. Variables associated with log‐transformed absolute HG were explored with multivariable linear regression. Perihematomal cerebral blood volume (CBV) was inversely associated with HG (B=‐0.20,p<0.001), independently from blood pressure, ICH volume and other confounders. This association was not dose‐dependent and only very low CBV (<1.4 mL/100g) was significantly associated with HG (B=0.25,p<0.001).

In conclusion, reduced perihematomal CBV is associated with HG, suggesting a potential role of the perihematomal region in the pathophysiology of hematoma enlargement.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on March 12, 2019 02:19 PM.
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The Historical Roots of Visual Analog Scale in Psychology as Revealed by Reference Publication Year Spectroscopy
Andy Wai Kan Yeung, Natalie Sui Miu Wong
in Frontiers in Human Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Balance Training With a Vibrotactile Biofeedback System Affects the Dynamical Structure of the Center of Pressure Trajectories in Chronic Stroke Patients
Kentaro Kodama, Kazuhiro Yasuda, Nikita A. Kuznetsov, Yuki Hayashi, Hiroyasu Iwata
in Frontiers in Human Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Electrophysiology of Inhibitory Control in the Context of Emotion Processing in Children With Autism Spectrum Disorder
Justine R. Magnuson, Nicholas A. Peatfield, Shaun D. Fickling, Adonay S. Nunes, Greg Christie, Vasily Vakorin, Ryan C. N. D’Arcy, Urs Ribary, Grace Iarocci, Sylvain Moreno, Sam M. Doesburg
in Frontiers in Human Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Automatic Analysis of EEGs Using Big Data and Hybrid Deep Learning Architectures
Meysam Golmohammadi, Amir Hossein Harati Nejad Torbati, Silvia Lopez de Diego, Iyad Obeid, Joseph Picone
in Frontiers in Human Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Probing for Intentions: Why Clocks Do Not Provide the Only Measurement of Time
Ceci Verbaarschot, Pim Haselager, Jason Farquhar
in Frontiers in Human Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Responses of Neurons in Lateral Intraparietal Area Depend on Stimulus-Associated Reward During Binocular Flash Suppression
Hamed Bahmani, Qinglin Li, Nikos K. Logothetis, Georgios A. Keliris
in Frontiers in Systems Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Mutation p.R356Q in the Collybistin Phosphoinositide Binding Site Is Associated With Mild Intellectual Disability
Tzu-Ting Chiou, Philip Long, Alexandra Schumann-Gillett, Venkateswarlu Kanamarlapudi, Stefan A. Haas, Kirsten Harvey, Megan L. O’Mara, Angel L. De Blas, Vera M. Kalscheuer, Robert J. Harvey
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Homogenizing Estimates of Heritability Among SOLAR-Eclipse, OpenMx, APACE, and FPHI Software Packages in Neuroimaging Data
Peter Kochunov, Binish Patel, Habib Ganjgahi, Brian Donohue, Meghann Ryan, Elliot L. Hong, Xu Chen, Bhim Adhikari, Neda Jahanshad, Paul M. Thompson, Dennis Van’t Ent, Anouk den Braber, Eco J. C. de Geus, Rachel M. Brouwer, Dorret I. Boomsma, Hilleke E. Hulshoff Pol, Greig I. de Zubicaray, Katie L. McMahon, Nicholas G. Martin, Margaret J. Wright, Thomas E. Nichols
in Frontiers in Neuroinformatics | New and Recent Articles on March 12, 2019 06:00 AM.
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Quantitative Determination of Cellular-and Neurite Motility Speed in Dense Cell Cultures
Andreas W. Henkel, Lulwa A. A. D. Al-Abdullah, Mohammed S. Al-Qallaf, Zoran B. Redzic
in Frontiers in Neuroinformatics | New and Recent Articles on March 12, 2019 06:00 AM.
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RTHybrid: A Standardized and Open-Source Real-Time Software Model Library for Experimental Neuroscience
Rodrigo Amaducci, Manuel Reyes-Sanchez, Irene Elices, Francisco B. Rodriguez, Pablo Varona
in Frontiers in Neuroinformatics | New and Recent Articles on March 12, 2019 06:00 AM.
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Prediction of Forelimb Reach Results From Motor Cortex Activities Based on Calcium Imaging and Deep Learning
Chunyue Li, Danny C. W. Chan, Xiaofeng Yang, Ya Ke, Wing-Ho Yung
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions
Manoela V. Fogaça, Ronald S. Duman
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Remembering to Forget: A Dual Role for Sleep Oscillations in Memory Consolidation and Forgetting
Jesse J. Langille
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Moderating Effect of Cortical Thickness on BOLD Signal Variability Age-Related Changes
Daiana R. Pur, Roy A. Eagleson, Anik de Ribaupierre, Nathalie Mella, Sandrine de Ribaupierre
in Frontiers in Aging Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Ca2+/Calmodulin Binding to PSD-95 Downregulates Its Palmitoylation and AMPARs in Long-Term Depression
Dhrubajyoti Chowdhury, Johannes W. Hell
in Frontiers in Synaptic Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Neural Correlates of Abnormal Temporal Discrimination in Unaffected Relatives of Cervical Dystonia Patients
Shruti Narasimham, Eavan M. McGovern, Brendan Quinlivan, Owen Killian, Rebecca Beck, Sean O’Riordan, Michael Hutchinson, Richard B. Reilly
in Frontiers in Integrative Neuroscience | New and Recent Articles on March 12, 2019 06:00 AM.
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Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain
Shu-Yin Xu, Qi-Lei Zhang, Qi Zhang, Lily Wan, Juan Jiang, Tian Tu, Jim Manavis, Aihua Pan, Yan Cai, Xiao-Xin Yan
in Frontiers in Neuroanatomy | New and Recent Articles on March 12, 2019 06:00 AM.
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Continual Learning via Neural Pruning. (arXiv:1903.04476v1 [cs.LG])

We introduce Continual Learning via Neural Pruning (CLNP), a new method aimed at lifelong learning in fixed capacity models based on neuronal model sparsification. In this method, subsequent tasks are trained using the inactive neurons and filters of the sparsified network and cause zero deterioration to the performance of previous tasks. In order to deal with the possible compromise between model sparsity and performance, we formalize and incorporate the concept of graceful forgetting: the idea that it is preferable to suffer a small amount of forgetting in a controlled manner if it helps regain network capacity and prevents uncontrolled loss of performance during the training of future tasks. CLNP also provides simple continual learning diagnostic tools in terms of the number of free neurons left for the training of future tasks as well as the number of neurons that are being reused. In particular, we see in experiments that CLNP verifies and automatically takes advantage of the fact that the features of earlier layers are more transferable. We show empirically that CLNP leads to significantly improved results over current weight elasticity based methods.

in q-bio.NC updates on arXiv.org on March 12, 2019 01:30 AM.
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Labeler-hot Detection of EEG Epileptic Transients. (arXiv:1903.04337v1 [cs.LG])

Preventing early progression of epilepsy and so the severity of seizures requires effective diagnosis. Epileptic transients indicate the ability to develop seizures but humans easily overlook such brief events in an electroencephalogram (EEG) what compromises patient treatment. Traditionally, training of the EEG event detection algorithms has relied on ground truth labels, obtained from the consensus of the majority of labelers. In this work, we go beyond labeler consensus on EEG data. Our event descriptor integrates EEG signal features with one-hot encoded labeler category that is a key to improved generalization performance. Notably, boosted decision trees take advantage of singly-labeled but more varied training sets. Our quantitative experiments show the proposed labeler-hot epileptic event detector consistently outperforms a consensus-trained detector and maintains confidence bounds of the detection. The results on our infant EEG recordings suggest datasets can gain higher event variety faster and thus better performance by shifting available human effort from consensus-oriented to separate labeling when labels include both, the event and the labeler category.

in q-bio.NC updates on arXiv.org on March 12, 2019 01:30 AM.
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A causal role of sensory cortices in behavioral benefits of 'learning by doing'. (arXiv:1903.04201v1 [q-bio.NC])

Despite a rise in the use of "learning by doing" pedagogical methods in praxis, little is known as to why these methods may improve learning outcomes. This is surprising given that an increased mechanistic knowledge of learning by doing-based improvements has the potential to speed up the development of evidence-based teaching practices. Here we use neuroscience methods and a gesture-enriched foreign language (L2) vocabulary learning paradigm to adjudicate between opposing predictions of two neuroscientific learning theories. We demonstrate that sensory brain regions associated with the processing of gesture-related stimulus information causally contribute to performance benefits following gesture-enriched L2 vocabulary learning. Sensory brain responses benefitted both short- and long-term learning outcomes, as well as the learning of both concrete and abstract words. These findings suggest that responses within specialized visual sensory cortices precipitate sensorimotor-based learning benefits. Such a mechanism could play a role in comparatively effortless native language learning and may be key for accelerating L2 proficiency in adults.

in q-bio.NC updates on arXiv.org on March 12, 2019 01:30 AM.
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Identical ideal individuals. (arXiv:1903.03964v1 [q-bio.NC])

Based on the behavior coordinate system, ideal individual model and quantum probability, the state of an ideal individual is assumed to be described by the behavior state function. Then we present a conjecture that the ideal individuals can be identical. A consequence of the identical individual conjecture is that the existence of the personal space and the behavior differentiation under high population density condition receive a possible theoretical explanation.

in q-bio.NC updates on arXiv.org on March 12, 2019 01:30 AM.
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A contextual binding theory of episodic memory: systems consolidation reconsidered

A contextual binding theory of episodic memory: systems consolidation reconsidered
A contextual binding theory of episodic memory: systems consolidation reconsidered, Published online: 12 March 2019; doi:10.1038/s41583-019-0150-4
In this Opinion, Yonelinas et al. propose that the hippocampus binds together item-related and content-related information to form memories. They compare the evidence for this contextual binding theory with that for another theory of memory, standard systems consolidation theory.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 12, 2019 12:00 AM.
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Nucleoporin Seh1 Interacts with Olig2/Brd7 to Promote Oligodendrocyte Differentiation and Myelination
Liu et al. demonstrate that the nucleoporin Seh1 functions in oligodendrocyte differentiation, myelination, and post-injury remyelination by assembling a Seh1/Olig2/Brd7 transcription complex at nuclear periphery.
in Neuron on March 12, 2019 12:00 AM.
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Retinoic Acid Induces Hyperactivity, and Blocking Its Receptor Unmasks Light Responses and Augments Vision in Retinal Degeneration
Photoreceptor degeneration causes blindness, but hyperactivity of downstream neurons may obscure retinal signaling to the brain before all photoreceptors die. Here we identify the chemical trigger of hyperactivity and show that blocking its receptor augments light responses in vision-impaired mice.
in Neuron on March 12, 2019 12:00 AM.
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Latent goal models for dynamic strategic interaction

by Shariq N. Iqbal, Lun Yin, Caroline B. Drucker, Qian Kuang, Jean-François Gariépy, Michael L. Platt, John M. Pearson
Understanding the principles by which agents interact with both complex environments and each other is a key goal of decision neuroscience. However, most previous studies have used experimental paradigms in which choices are discrete (and few), play is static, and optimal solutions are known. Yet in natural environments, interactions between agents typically involve continuous action spaces, ongoing dynamics, and no known optimal solution. Here, we seek to bridge this divide by using a “penalty shot” task in which pairs of monkeys competed against each other in a competitive, real-time video game. We modeled monkeys’ strategies as driven by stochastically evolving goals, onscreen positions that served as set points for a control model that produced observed joystick movements. We fit this goal-based dynamical system model using approximate Bayesian inference methods, using neural networks to parameterize players’ goals as a dynamic mixture of Gaussian components. Our model is conceptually simple, constructed of interpretable components, and capable of generating synthetic data that capture the complexity of real player dynamics. We further characterized players’ strategies using the number of change points on each trial. We found that this complexity varied more across sessions than within sessions, and that more complex strategies benefited offensive players but not defensive players. Together, our experimental paradigm and model offer a powerful combination of tools for the study of realistic social dynamics in the laboratory setting.
in PLOS Computational Biology: New Articles on March 11, 2019 09:00 PM.
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The number of active metabolic pathways is bounded by the number of cellular constraints at maximal metabolic rates

by Daan H. de Groot, Coco van Boxtel, Robert Planqué, Frank J. Bruggeman, Bas Teusink
Growth rate is a near-universal selective pressure across microbial species. High growth rates require hundreds of metabolic enzymes, each with different nonlinear kinetics, to be precisely tuned within the bounds set by physicochemical constraints. Yet, the metabolic behaviour of many species is characterized by simple relations between growth rate, enzyme expression levels and metabolic rates. We asked if this simplicity could be the outcome of optimisation by evolution. Indeed, when the growth rate is maximized—in a static environment under mass-conservation and enzyme expression constraints—we prove mathematically that the resulting optimal metabolic flux distribution is described by a limited number of subnetworks, known as Elementary Flux Modes (EFMs). We show that, because EFMs are the minimal subnetworks leading to growth, a small active number automatically leads to the simple relations that are measured. We find that the maximal number of flux-carrying EFMs is determined only by the number of imposed constraints on enzyme expression, not by the size, kinetics or topology of the network. This minimal-EFM extremum principle is illustrated in a graphical framework, which explains qualitative changes in microbial behaviours, such as overflow metabolism and co-consumption, and provides a method for identification of the enzyme expression constraints that limit growth under the prevalent conditions. The extremum principle applies to all microorganisms that are selected for maximal growth rates under protein concentration constraints, for example the solvent capacities of cytosol, membrane or periplasmic space.
in PLOS Computational Biology: New Articles on March 11, 2019 09:00 PM.
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Myopic control of neural dynamics

by David Hocker, Il Memming Park
Manipulating the dynamics of neural systems through targeted stimulation is a frontier of research and clinical neuroscience; however, the control schemes considered for neural systems are mismatched for the unique needs of manipulating neural dynamics. An appropriate control method should respect the variability in neural systems, incorporating moment to moment “input” to the neural dynamics and behaving based on the current neural state, irrespective of the past trajectory. We propose such a controller under a nonlinear state-space feedback framework that steers one dynamical system to function as through it were another dynamical system entirely. This “myopic” controller is formulated through a novel variant of a model reference control cost that manipulates dynamics in a short-sighted manner that only sets a target trajectory of a single time step into the future (hence its myopic nature), which omits the need to pre-calculate a rigid and computationally costly neural feedback control solution. To demonstrate the breadth of this control’s utility, two examples with distinctly different applications in neuroscience are studied. First, we show the myopic control’s utility to probe the causal link between dynamics and behavior for cognitive processes by transforming a winner-take-all decision-making system to operate as a robust neural integrator of evidence. Second, an unhealthy motor-like system containing an unwanted beta-oscillation spiral attractor is controlled to function as a healthy motor system, a relevant clinical example for neurological disorders.
in PLOS Computational Biology: New Articles on March 11, 2019 09:00 PM.
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Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer

by Margaret P. Chapman, Tyler Risom, Anil J. Aswani, Ellen M. Langer, Rosalie C. Sears, Claire J. Tomlin
Drug resistance in breast cancer cell populations has been shown to arise through phenotypic transition of cancer cells to a drug-tolerant state, for example through epithelial-to-mesenchymal transition or transition to a cancer stem cell state. However, many breast tumors are a heterogeneous mixture of cell types with numerous epigenetic states in addition to stem-like and mesenchymal phenotypes, and the dynamic behavior of this heterogeneous mixture in response to drug treatment is not well-understood. Recently, we showed that plasticity between differentiation states, as identified with intracellular markers such as cytokeratins, is linked to resistance to specific targeted therapeutics. Understanding the dynamics of differentiation-state transitions in this context could facilitate the development of more effective treatments for cancers that exhibit phenotypic heterogeneity and plasticity. In this work, we develop computational models of a drug-treated, phenotypically heterogeneous triple-negative breast cancer (TNBC) cell line to elucidate the feasibility of differentiation-state transition as a mechanism for therapeutic escape in this tumor subtype. Specifically, we use modeling to predict the changes in differentiation-state transitions that underlie specific therapy-induced changes in differentiation-state marker expression that we recently observed in the HCC1143 cell line. We report several statistically significant therapy-induced changes in transition rates between basal, luminal, mesenchymal, and non-basal/non-luminal/non-mesenchymal differentiation states in HCC1143 cell populations. Moreover, we validate model predictions on cell division and cell death empirically, and we test our models on an independent data set. Overall, we demonstrate that changes in differentiation-state transition rates induced by targeted therapy can provoke distinct differentiation-state aggregations of drug-resistant cells, which may be fundamental to the design of improved therapeutic regimens for cancers with phenotypic heterogeneity.
in PLOS Computational Biology: New Articles on March 11, 2019 09:00 PM.
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Pan-cancer association of a centrosome amplification gene expression signature with genomic alterations and clinical outcome

by Bernardo P. de Almeida, André F. Vieira, Joana Paredes, Mónica Bettencourt-Dias, Nuno L. Barbosa-Morais
Centrosome amplification (CA) is a common feature of human tumours and a promising target for cancer therapy. However, CA’s pan-cancer prevalence, molecular role in tumourigenesis and therapeutic value in the clinical setting are still largely unexplored. Here, we used a transcriptomic signature (CA20) to characterise the landscape of CA-associated gene expression in 9,721 tumours from The Cancer Genome Atlas (TCGA). CA20 is upregulated in cancer and associated with distinct clinical and molecular features of breast cancer, consistently with our experimental CA quantification in patient samples. Moreover, we show that CA20 upregulation is positively associated with genomic instability, alteration of specific chromosomal arms and C>T mutations, and we propose novel molecular players associated with CA in cancer. Finally, high CA20 is associated with poor prognosis and, by integrating drug sensitivity with drug perturbation profiles in cell lines, we identify candidate compounds for selectively targeting cancer cells exhibiting transcriptomic evidence for CA.
in PLOS Computational Biology: New Articles on March 11, 2019 09:00 PM.
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A complete statistical model for calibration of RNA-seq counts using external spike-ins and maximum likelihood theory

by Rodoniki Athanasiadou, Benjamin Neymotin, Nathan Brandt, Wei Wang, Lionel Christiaen, David Gresham, Daniel Tranchina
A fundamental assumption, common to the vast majority of high-throughput transcriptome analyses, is that the expression of most genes is unchanged among samples and that total cellular RNA remains constant. As the number of analyzed experimental systems increases however, different independent studies demonstrate that this assumption is often violated. We present a calibration method using RNA spike-ins that allows for the measurement of absolute cellular abundance of RNA molecules. We apply the method to pooled RNA from cell populations of known sizes. For each transcript, we compute a nominal abundance that can be converted to absolute by dividing by a scale factor determined in separate experiments: the yield coefficient of the transcript relative to that of a reference spike-in measured with the same protocol. The method is derived by maximum likelihood theory in the context is a complete statistical model for sequencing counts contributed by cellular RNA and spike-ins. The counts are based on a sample from a fixed number of cells to which a fixed population of spike-in molecules has been added. We illustrate and evaluate the method with applications to two global expression data sets, one from the model eukaryote Saccharomyces cerevisiae, proliferating at different growth rates, and differentiating cardiopharyngeal cell lineages in the chordate Ciona robusta. We tested the method in a technical replicate dilution study, and in a k-fold validation study.
in PLOS Computational Biology: New Articles on March 11, 2019 09:00 PM.
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Role of Thalamus in Sleep–Wake Cycle Regulation

in Wiley: Annals of Neurology: Table of Contents on March 11, 2019 06:51 PM.
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Accumulation of prion protein in the vagus nerve in creutzfeldt–jakob disease

Disease‐associated proteins are thought to propagate along neuronal processes in neurodegenerative diseases. To detect disease‐associated prion protein (PrP^Sc) in the vagus nerve in different forms and molecular subtypes of Creutzfeldt–Jakob disease (CJD), we applied 3 different anti‐PrP antibodies. We screened the vagus nerve in 162 sporadic and 30 genetic CJD cases. Four of 31 VV‐2 type sporadic CJD and 7 of 30 genetic CJD cases showed vagal PrP^Sc immunodeposits with distinct morphology. Thus, PrP^Sc in CJD affects the vagus nerve analogously to α‐synuclein in Parkinson disease. The morphologically diverse deposition of PrP^Sc in genetic and sporadic CJD argues against uniform mechanisms of propagation of PrP^Sc. Ann Neurol, 2019

in Wiley: Annals of Neurology: Table of Contents on March 11, 2019 06:50 PM.
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Concordance for Parkinson's disease in twins: A 20‐year update

During the 1990s, we estimated the genetic contribution to Parkinson's disease risk in a large, population‐based twin registry. Because many unaffected twins were still alive, previous concordance estimates were based on incomplete information. Ninety‐five percent of twins are now deceased. Here, we update concordance and heritability through 2015 using National Death Index data. In total, we identified 30 concordant and 193 discordant pairs. Proband‐wise concordance was 0.20 in monozygotic and 0.13 in dizygotic pairs. Heritability was 0.27 overall, 0.83 in pairs diagnosed ≤50, and 0.19 in pairs diagnosed >50. High concordance in dizygotic twins suggests shared effects of early childhood environment. Ann Neurol, 2019

in Wiley: Annals of Neurology: Table of Contents on March 11, 2019 06:50 PM.
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Homocysteine and small vessel stroke: A mendelian randomization analysis

Objective

Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization.

Methods

We used summary statistics data for single‐nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B₆ (n = 1), and vitamin B₁₂ (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases).

Results

Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13–1.58; p = 6.7 × 10^–4) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B₆ levels were 0.49 (95% CI, 0.34–0.71; p = 1.3 × 10^–4) and 0.70 (95% CI, 0.52–0.94; p = 0.02), respectively. Genetically higher vitamin B₁₂ levels were not associated with any stroke subtype.

Interpretation

These findings suggest that any effect of homocysteine‐lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol, 2019

in Wiley: Annals of Neurology: Table of Contents on March 11, 2019 06:49 PM.
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Reply to “Role of Thalamus in Sleep–Wake Cycle Regulation”

in Wiley: Annals of Neurology: Table of Contents on March 11, 2019 06:49 PM.
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Oxytocin Enhances the Neural Efficiency of Social Perception
Rachael Tillman, Ilanit Gordon, Adam Naples, Max Rolison, James F. Leckman, Ruth Feldman, Kevin A. Pelphrey, James C. McPartland
in Frontiers in Human Neuroscience | New and Recent Articles on March 11, 2019 06:00 PM.
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InTool Explorer: An Interactive Exploratory Analysis Tool for Versatile Visualizations of Neuroscientific Data
Diana Furcila, Marcos García, Cosmin Toader, Juan Morales, Antonio LaTorre, Ángel Rodríguez, Luis Pastor, Javier DeFelipe, Lidia Alonso-Nanclares
in Frontiers in Neuroanatomy | New and Recent Articles on March 11, 2019 06:00 PM.
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Corrigendum: The Effects of Money on Fake Rating Behavior in E-Commerce: Electrophysiological Time Course Evidence From Consumers
Cuicui Wang, Yun Li, Xuan Luo, Qingguo Ma, Weizhong Fu, Huijian Fu
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on March 11, 2019 12:00 PM.
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A Non-cognitive Behavioral Model for Interpreting Functional Neuroimaging Studies
Robert G. Shulman, Douglas L. Rothman
in Frontiers in Human Neuroscience | New and Recent Articles on March 11, 2019 12:00 PM.
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L-Cysteine-Derived H2S Promotes Microglia M2 Polarization via Activation of the AMPK Pathway in Hypoxia-Ischemic Neonatal Mice
Xin Zhou, Xili Chu, Danqing Xin, Tingting Li, Xuemei Bai, Jie Qiu, Hongtao Yuan, Dexiang Liu, Dachuan Wang, Zhen Wang
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 11, 2019 06:00 AM.
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The Ventral Intermediate Nucleus Differently Modulates Subtype-Related Networks in Parkinson’s Disease
Qiaoling Zeng, Xiaojun Guan, Tao Guo, Jason C. F. Law Yan Lun, Cheng Zhou, Xiao Luo, Zhujing Shen, Peiyu Huang, Minming Zhang, Guanxun Cheng
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 11, 2019 06:00 AM.
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Psychiatric Symptoms in Amyotrophic Lateral Sclerosis: Beyond a Motor Neuron Disorder
Elisabetta Zucchi, Nicola Ticozzi, Jessica Mandrioli
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 11, 2019 06:00 AM.
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Mixed Spatial and Movement Representations in the Primate Posterior Parietal Cortex
Kostas Hadjidimitrakis, Sophia Bakola, Yan T. Wong, Maureen A. Hagan
in Frontiers in Neural Circuits | New and Recent Articles on March 11, 2019 06:00 AM.
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Serum miRNAs Expression and SNAP-25 Genotype in Alzheimer’s Disease
Simone Agostini, Roberta Mancuso, Gaia Liuzzo, Elisabetta Bolognesi, Andrea Saul Costa, Anna Bianchi, Mario Clerici
in Frontiers in Aging Neuroscience | New and Recent Articles on March 11, 2019 06:00 AM.
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Influence of Normal Aging on Brain Autophagy: A Complex Scenario
David A. Loeffler
in Frontiers in Aging Neuroscience | New and Recent Articles on March 11, 2019 06:00 AM.
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The meta-problem and the transfer of knowledge between theories of consciousness: a software engineer's take. (arXiv:1903.03418v1 [q-bio.NC])

This contribution examines two radically different explanations of our phenomenal intuitions, one reductive and one strongly non-reductive, and identifies two germane ideas that could benefit many other theories of consciousness. Firstly, the ability of sophisticated agent architectures with a purely physical implementation to support certain functional forms of qualia or proto-qualia appears to entail the possibility of machine consciousness with qualia, not only for reductive theories but also for the nonreductive ones that regard consciousness as ubiquitous in Nature. Secondly, analysis of introspective psychological material seems to hint that, under the threshold of our ordinary waking awareness, there exist further 'submerged' or 'subliminal' layers of consciousness which constitute a hidden foundation and support and another source of our phenomenal intuitions. These 'submerged' layers might help explain certain puzzling phenomena concerning subliminal perception, such as the apparently 'unconscious' multisensory integration and learning of subliminal stimuli.

in q-bio.NC updates on arXiv.org on March 11, 2019 01:30 AM.
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SeizureNet: A Deep Convolutional Neural Network for Accurate Seizure Type Classification and Seizure Detection. (arXiv:1903.03232v1 [cs.LG])

Automatic epileptic seizure analysis is important because the differentiation of neural patterns among different patients can be used to classify people with specific types of epilepsy. This could enable more efficient management of the disease. Automatic seizure type classification using clinical electroencephalograms (EEGs) is challenging due to factors such as low signal to noise ratios, signal artefacts, high variance in the seizure semiology among individual epileptic patients, and limited clinical data constraints. To overcome these challenges, in this paper, we present a deep learning based framework which uses a Convolutional Neural Network (CNN) with dense connections and learns highly robust features at different spatial and temporal resolutions of the EEG data spectrum for accurate cross-patient seizure type classification. We evaluate our framework for seizure type classification and seizure detection on the recently released TUH EEG Seizure Corpus, where our framework achieves overall weighted f 1 scores of up to 0.90 and 0.88, thereby setting new benchmarks on the dataset.

in q-bio.NC updates on arXiv.org on March 11, 2019 01:30 AM.
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Astrocytes usurp neurons as a disease focus

Astrocytes usurp neurons as a disease focus
Astrocytes usurp neurons as a disease focus, Published online: 11 March 2019; doi:10.1038/s41593-019-0367-6
Astrocytes are emerging as causal or modulating factors in diverse neurological disorders. Two papers published in Nature Neuroscience in 2007 revealed astrocytes as causally contributing to motor neuron loss in amyotrophic lateral sclerosis, thereby challenging the longstanding neuron-centric view of neurodegenerative disease.
in Nature Neuroscience - Issue - nature.com science feeds on March 11, 2019 12:00 AM.
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Locomotion-dependent remapping of distributed cortical networks

Locomotion-dependent remapping of distributed cortical networks
Locomotion-dependent remapping of distributed cortical networks, Published online: 11 March 2019; doi:10.1038/s41593-019-0357-8
Clancy et al. investigated the relationship between individual neuron activity and cortex-wide dynamics. Neurons were diversely coupled to distal areas, and locomotion affected how neurons in different areas coupled with distal activity.
in Nature Neuroscience - Issue - nature.com science feeds on March 11, 2019 12:00 AM.
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Long-range inhibitory intersection of a retrosplenial thalamocortical circuit by apical tuft-targeting CA1 neurons

Long-range inhibitory intersection of a retrosplenial thalamocortical circuit by apical tuft-targeting CA1 neurons
Long-range inhibitory intersection of a retrosplenial thalamocortical circuit by apical tuft-targeting CA1 neurons, Published online: 11 March 2019; doi:10.1038/s41593-019-0355-x
Apical tuft dendrites of pyramidal neurons in retrosplenial cortex receive inhibition from a class of CA1 GABAergic neurons with long-range layer 1-targeting axons; this inhibition opposes matrix-type thalamocortical excitation from anterior thalamus.
in Nature Neuroscience - Issue - nature.com science feeds on March 11, 2019 12:00 AM.
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In vivo neuronal gene editing via CRISPR–Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer’s disease

In vivo neuronal gene editing via CRISPR–Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer’s disease
In vivo neuronal gene editing via CRISPR–Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer’s disease, Published online: 11 March 2019; doi:10.1038/s41593-019-0352-0
Park et al. demonstrate in vivo the efficacy of Cas9 nanocomplexes as therapeutic agents in mouse models of Alzheimer’s disease. This strategy may be applicable to the treatment of a broad range of neurological diseases.
in Nature Neuroscience - Issue - nature.com science feeds on March 11, 2019 12:00 AM.
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Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons

Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons
Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons, Published online: 11 March 2019; doi:10.1038/s41593-019-0349-8
The lateral hypothalamic area (LHA) regulates fundamental aspects of innate behavior. However, the circuit-level underpinnings of LHA function are poorly understood given its cellular heterogeneity. Here, Mickelsen et al. employ a single-cell RNA-sequencing approach to classify molecularly distinct cell types in the mouse LHA.
in Nature Neuroscience - Issue - nature.com science feeds on March 11, 2019 12:00 AM.
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Be Prepared: Tune to FM-Theta for Cognitive Control
Rhythmical brain activity around 5Hz can be observed in the prefrontal cortex under conditions requiring high levels of cognitive control. However, its temporal dynamics are still elusive. A recent research paper (Cooper et al. Neuroimage 2019;189:130–140) provides evidence that the temporal evolution of this frontal-midline theta activity reflects the style of cognitive control being implemented.
in Trends in Neurosciences on March 11, 2019 12:00 AM.
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Hippocampal Contributions to Model-Based Planning and Spatial Memory
Testing patients with hippocampal damage, Vikbladh et al. demonstrate that model-based planning and place memory rely on a common hippocampal substrate. The study bridges the reinforcement learning and spatial memory literatures to clarify the scope of hippocampal contributions to behavior.
in Neuron on March 11, 2019 12:00 AM.
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Neuroligin-1 Signaling Controls LTP and NMDA Receptors by Distinct Molecular Pathways
At excitatory synapses on CA1 pyramidal neurons lacking neuroligins, Nlgn1 rescues impairments in functional and structural LTP and in NMDA receptor-mediated synaptic transmission. Structure-function rescue experiments reveal that Nlgn1 plays mechanistically distinct roles in LTP and basal NMDA receptor-mediated transmission.
in Neuron on March 11, 2019 12:00 AM.
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Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat

Abstract

Objective

Degenerative cerebellar ataxias (DCAs) affect up to 1 in 5,000 people worldwide, leading to incoordination, tremor, and falls. Loss of Purkinje cells, nearly universal across DCAs, dysregulates the dentatothalamocortical network. To address the paucity of treatment strategies, we developed an electrical stimulation‐based therapy for DCAs targeting the dorsal dentate nucleus.

Methods

We tested this therapeutic strategy in the Wistar Furth shaker rat model of Purkinje cell loss resulting in tremor and ataxia. We implanted shaker rats with stimulating electrodes targeted to the dorsal dentate nucleus and tested a spectrum of frequencies ranging from 4 to 180 Hz.

Results

Stimulation at 30 Hz most effectively reduced motor symptoms. Stimulation frequencies over 100 Hz, commonly used for Parkinsonism and essential tremor, worsened incoordination, while frequencies within the tremor physiologic range may worsen tremor.

Interpretations

Low‐frequency deep cerebellar stimulation may provide a novel strategy for treating motor symptoms of degenerative cerebellar ataxias.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on March 10, 2019 06:49 PM.
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Local translation in neuronal processes

Publication date: August 2019
Source: Current Opinion in Neurobiology, Volume 57
Author(s): Anne Biever, Paul G Donlin-Asp, Erin M Schuman
Neurons exhibit a unique degree of spatial compartmentalization and are able to maintain and remodel their proteomes independently from the cell body. While much effort has been devoted to understanding the capacity and role for local protein synthesis in dendrites and spines, local mRNA translation in mature axons, projecting over distances up to a meter, has received much less attention. Also, little is known about the spatio-temporal dynamics of axonal and dendritic gene expression as function of mRNA abundance, protein synthesis and degradation. Here, we summarize key recent findings that have shaped our knowledge of the precise location of local protein production and discuss unique strategies used by neurons to shape presynaptic and postsynaptic proteomes.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 10, 2019 12:00 PM.
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CBP/p300 in brain development and plasticity: disentangling the KAT’s cradle

Publication date: December 2019
Source: Current Opinion in Neurobiology, Volume 59
Author(s): Michal Lipinski, Beatriz del Blanco, Angel Barco
The paralogous transcriptional co-activators CBP and p300 (aka KAT3A and KAT3B, respectively) contain a characteristic and promiscuous lysine acetyltransferase (KAT) domain and multiple independent protein-binding domains that enable them to interact with hundreds of proteins, possibly promoting the acetylation of thousands of target lysine residues. Both proteins play critical roles during the development of the nervous system and may also regulate stimuli-driven transcription and plasticity in postmitotic neurons. The multiplicity of functions, substrates, and molecular partners, together with the redundancy and singularity of the two KAT3 paralogs, define a complex cat’s cradle of relationships. In this review, we discuss the role of the KAT3 proteins in neurons and integrate recent information regarding their function and mode of action.
Graphical abstract
The multiplicity of functions, substrates, and molecular partners of the two KAT3 proteins defines a complex cat’s cradle of relationships.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 10, 2019 12:00 PM.
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Divergent Patterns of TDP‐43 and Tau Pathologies in Primary Progressive Aphasia

Abstract

Objective

To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP‐43 (FTLD‐TDP) or tau (FTLD‐Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology, and identify clinicopathological correlates of these distinct proteinopathies.

Methods

In an autopsy cohort of PPA (FTLD‐TDP=13, FTLD‐Tau=14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to eight cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features.

Results

Postmortem cortical pathology was left‐lateralized in both FTLD‐TDP (beta=‐0.15,SE=0.05,p=0.007) and FTLD‐Tau (beta=‐0.09,SE=0.04,p=0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta=‐8.18,SE=3.22,p=0.015). Among five core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD‐TDP, which was greater than in FTLD‐Tau (F=47.07,df=1,17,p<0.001), and in left mid‐frontal cortex (MFC) in FTLD‐Tau, which was greater than in FTLD‐TDP (F=19.34,df=1,16,p<0.001). Postmortem pathology was inversely associated with antemortem MRI cortical thickness (beta=‐0.04,SE=0.01,p=0.007) in regions matching autopsy sampling. Irrespective of PPA syndromic variant, single‐word comprehension impairment was associated with greater left OFC pathology (t=‐3.72,df=10.72,p=0.004), while nonfluent speech with greater left MFC pathology (t=‐3.62,df=12.00,p=0.004) among the five core pathology regions.

Interpretation

In PPA, FTLD‐TDP and FTLD‐Tau have divergent anatomic distributions of left‐lateralized postmortem pathology that relate to antemortem structural imaging and distinct language deficits. While other brain regions may be implicated in neural networks supporting these complex language measures, our observations may eventually help to improve antemortem diagnosis of neuropathology in PPA.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on March 09, 2019 02:12 PM.
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A demonstration of modularity, reuse, reproducibility, portability and scalability for modeling and simulation of cardiac electrophysiology using Kepler Workflows

by Pei-Chi Yang, Shweta Purawat, Pek U. Ieong, Mao-Tsuen Jeng, Kevin R. DeMarco, Igor Vorobyov, Andrew D. McCulloch, Ilkay Altinas, Rommie E. Amaro, Colleen E. Clancy
Multi-scale computational modeling is a major branch of computational biology as evidenced by the US federal interagency Multi-Scale Modeling Consortium and major international projects. It invariably involves specific and detailed sequences of data analysis and simulation, often with multiple tools and datasets, and the community recognizes improved modularity, reuse, reproducibility, portability and scalability as critical unmet needs in this area. Scientific workflows are a well-recognized strategy for addressing these needs in scientific computing. While there are good examples if the use of scientific workflows in bioinformatics, medical informatics, biomedical imaging and data analysis, there are fewer examples in multi-scale computational modeling in general and cardiac electrophysiology in particular. Cardiac electrophysiology simulation is a mature area of multi-scale computational biology that serves as an excellent use case for developing and testing new scientific workflows. In this article, we develop, describe and test a computational workflow that serves as a proof of concept of a platform for the robust integration and implementation of a reusable and reproducible multi-scale cardiac cell and tissue model that is expandable, modular and portable. The workflow described leverages Python and Kepler-Python actor for plotting and pre/post-processing. During all stages of the workflow design, we rely on freely available open-source tools, to make our workflow freely usable by scientists.
in PLOS Computational Biology: New Articles on March 08, 2019 10:00 PM.
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OptRAM: In-silico strain design via integrative regulatory-metabolic network modeling

by Fangzhou Shen, Renliang Sun, Jie Yao, Jian Li, Qian Liu, Nathan D. Price, Chenguang Liu, Zhuo Wang
The ultimate goal of metabolic engineering is to produce desired compounds on an industrial scale in a cost effective manner. To address challenges in metabolic engineering, computational strain optimization algorithms based on genome-scale metabolic models have increasingly been used to aid in overproducing products of interest. However, most of these strain optimization algorithms utilize a metabolic network alone, with few approaches providing strategies that also include transcriptional regulation. Moreover previous integrated approaches generally require a pre-existing regulatory network. In this study, we developed a novel strain design algorithm, named OptRAM (Optimization of Regulatory And Metabolic Networks), which can identify combinatorial optimization strategies including overexpression, knockdown or knockout of both metabolic genes and transcription factors. OptRAM is based on our previous IDREAM integrated network framework, which makes it able to deduce a regulatory network from data. OptRAM uses simulated annealing with a novel objective function, which can ensure a favorable coupling between desired chemical and cell growth. The other advance we propose is a systematic evaluation metric of multiple solutions, by considering the essential genes, flux variation, and engineering manipulation cost. We applied OptRAM to generate strain designs for succinate, 2,3-butanediol, and ethanol overproduction in yeast, which predicted high minimum predicted target production rate compared with other methods and previous literature values. Moreover, most of the genes and TFs proposed to be altered by OptRAM in these scenarios have been validated by modification of the exact genes or the target genes regulated by the TFs, for overproduction of these desired compounds by in vivo experiments cataloged in the LASER database. Particularly, we successfully validated the predicted strain optimization strategy for ethanol production by fermentation experiment. In conclusion, OptRAM can provide a useful approach that leverages an integrated transcriptional regulatory network and metabolic network to guide metabolic engineering applications.
in PLOS Computational Biology: New Articles on March 08, 2019 10:00 PM.
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Low Cerebrospinal Fluid Levels of Melanotransferrin Are Associated With Conversion of Mild Cognitively Impaired Subjects to Alzheimer’s Disease
Azhaar Ashraf, Jose Andres Alepuz Guillen, Manal Aljuhani, Chantal Hubens, Po-Wah So
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 08, 2019 06:00 PM.
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Septal GABA and Glutamate Neurons Express RXFP3 mRNA and Depletion of Septal RXFP3 Impaired Spatial Search Strategy and Long-Term Reference Memory in Adult Mice
Mouna Haidar, Kimberly Tin, Cary Zhang, Mohsen Nategh, João Covita, Alexander D. Wykes, Jake Rogers, Andrew L. Gundlach
in Frontiers in Neuroanatomy | New and Recent Articles on March 08, 2019 06:00 PM.
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A Neuron-Optimized CRISPR/dCas9 Activation System for Robust and Specific Gene Regulation
Abstract
CRISPR-based technology has provided new avenues to interrogate gene function, but difficulties in transgene expression in post-mitotic neurons has delayed incorporation of these tools in the central nervous system (CNS). Here, we demonstrate a highly efficient, neuron-optimized dual lentiviral CRISPR-based transcriptional activation (CRISPRa) system capable of robust, modular, and tunable gene induction and multiplexed gene regulation across several primary rodent neuron culture systems. CRISPRa targeting unique promoters in the complex multi-transcript gene brain-derived neurotrophic factor (Bdnf) revealed both transcript- and genome-level selectivity of this approach, in addition to highlighting downstream transcriptional and physiological consequences of Bdnf regulation. Finally, we illustrate that CRISPRa is highly efficient in vivo, resulting in increased protein levels of a target gene in diverse brain structures. Taken together, these results demonstrate that CRISPRa is an efficient and selective method to study gene expression programs in brain health and disease.

in eNeuro current issue on March 08, 2019 05:30 PM.
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Effects of Acute Aerobic Exercise on Cognition and Constructs of Decision-Making in Adults With and Without Hypertension
Wesley K. Lefferts, Jacob P. DeBlois, Corey N. White, Kevin S. Heffernan
in Frontiers in Aging Neuroscience | New and Recent Articles on March 08, 2019 12:00 PM.
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Time Perception of an Artwork’s Manipulation Is Distorted by Patients With Parkinson’s Disease
Márcia Regina Motta, Vitor Tumas, José Lino Oliveira Bueno
in Frontiers in Integrative Neuroscience | New and Recent Articles on March 08, 2019 12:00 PM.
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Brain Differences Between Men and Women: Evidence From Deep Learning
Jiang Xin, Yaoxue Zhang, Yan Tang, Yuan Yang
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on March 08, 2019 12:00 PM.
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Neuroactive Steroids and GABAergic Involvement in the Neuroendocrine Dysfunction Associated With Major Depressive Disorder and Postpartum Depression
Jamie Maguire
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 08, 2019 12:00 PM.
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The Dietary Flavonoid, Luteolin, Negatively Affects Neuronal Differentiation
Amrutha Swaminathan, Moumita Basu, Abdelhamid Bekri, Pierre Drapeau, Tapas K. Kundu
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 08, 2019 12:00 PM.
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Development of Sample-Adaptable Holders for Lightsheet Microscopy
Thierry Laroche, Olivier Burri, Lalit Kumar Dubey, Arne Seitz
in Frontiers in Neuroanatomy | New and Recent Articles on March 08, 2019 12:00 PM.
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Cell Autonomous Neuroprotection by the Mitochondrial Uncoupling Protein 2 in a Mouse Model of Glaucoma
Daniel T. Hass, Colin J. Barnstable
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 08, 2019 06:00 AM.
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Editorial: Deep Learning in Biological, Computer, and Neuromorphic Systems
Evgeniy Bart, Jay Hegdé
in Frontiers in Computational Neuroscience | New and Recent Articles on March 08, 2019 06:00 AM.
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CT-Guided Stellate Ganglion Pulsed Radiofrequency Stimulation for Facial and Upper Limb Postherpetic Neuralgia
Yuanyuan Ding, Peng Yao, Hongxi Li, Zhenkai Han, Shimeng Wang, Tao Hong, Guangyi Zhao
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on March 08, 2019 06:00 AM.
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A toy quantum model of psychology. (arXiv:1903.02633v1 [q-bio.NC])

We propose the ideal individual model and the behavior coordinate system. Based on the ideal individual model, the behavior coordinate system and the quantum probability, a toy quantum model of human psychology is presented here in a different way. It can give some enlightening viewpoints through which some phenomena can be discussed from a different perspective.

in q-bio.NC updates on arXiv.org on March 08, 2019 01:30 AM.
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Systems of Oscillators Designed for a Specific Conscious Percept. (arXiv:1903.02594v1 [q-bio.NC])

As put forward by neuroscientists, the mechanisms of consciousness can be elucidated by revealing correlations between neural dynamics and specific conscious percepts. Recently, I have elaborated on the mathematical formulation for a system of processes that are mutually connected to be isomorphic to a conscious percept of a point in space. Importantly, in such a system, any process can be derived through all other processes that form its complement, or interpretation. To generate such a solution, I am proposing a dynamical system of oscillators coupled in a manner to preserve the properties of a percept. Specifically, I crafted a dynamical system that retains the mutual relationships among processes, forming an operational map isomorphic to a distance matrix that mimics a percept of space-like properties. The study and results pave a novel way to analyze the dynamics of neural-like (oscillatory) processes with a purpose of extracting the information relevant to specific conscious percepts, which will facilitate the search for neural correlates of consciousness.

in q-bio.NC updates on arXiv.org on March 08, 2019 01:30 AM.
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A Missing Connection: A Review of the Macrostructural Anatomy and Tractography of the Acoustic Radiation
Chiara Maffei, Silvio Sarubbo, Jorge Jovicich
in Frontiers in Neuroanatomy | New and Recent Articles on March 07, 2019 06:00 PM.
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Molecular Mechanisms of Synaptic Dysregulation in Fragile X Syndrome and Autism Spectrum Disorders
Michael Telias
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 07, 2019 06:00 PM.
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Evolutionary-Conserved Allosteric Properties of Three Neuronal Calcium Sensor Proteins
Valerio Marino, Daniele Dell'Orco
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 07, 2019 06:00 PM.
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Selectively inhibiting the median preoptic nucleus attenuates angiotensin II and hyperosmotic-induced drinking behavior and vasopressin release in adult male rats
Abstract
The median preoptic nucleus (MnPO) is a putative integrative region that contributes to body fluid balance. Activation of the MnPO can influence thirst but it is not clear how these responses are linked to body fluid homeostasis. We used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to determine the role of the MnPO in drinking behavior and vasopressin release in response to peripheral angiotensin II (ANG II) or 3% hypertonic saline in adult male Sprague-Dawley rats (250-300g). Rats were anesthetized with isoflurane and stereotaxically injected with an inhibitory DREADD (rAAV5-CaMKIIa-hM4D(G_i)-mCherry) or control (rAAV5-CaMKIIa-mCherry) virus in the MnPO. After 2 weeks’ recovery, a subset of rats were used for extracellular recordings to verify functional effects of ANG II or hyperosmotic challenges in MnPO slice preparations. Remaining rats were used in drinking behavior studies. Each rat was administered either 10mg/kg of exogenous clozapine-N-oxide (CNO) to inhibit DREADD-expressing cells or vehicle ip followed by a test treatment with either 2mg/kg ANG II or 3% hypertonic saline (1mL/100g bw) sc, twice per week for two separate treatment weeks. CNO-induced inhibition during either test treatment significantly attenuated drinking responses compared to vehicle treatments and controls. Brain tissue processed for cFos immunohistochemistry showed decreased expression with CNO-induced inhibition during either test treatment in the MnPO and downstream nuclei compared to controls. CNO-mediated inhibition significantly attenuated treatment-induced increases in plasma vasopressin compared to controls. The results indicate inhibition of CaMKIIa-expressing MnPO neurons significantly reduces drinking and vasopressin release in response to ANG II or hyperosmotic challenge.
Significance Statement The MnPO is an important regulatory center that influences thirst, cardiovascular and neuroendocrine function. Activation of different MnPO neuronal populations can inhibit or stimulate water intake. However, the role of the MnPO and its pathway-specific projections during ANG II and hyperosmotic challenges still have not yet been fully elucidated. These studies directly address this by using DREADDs to acutely and selectively inhibit pathway-specific MnPO neurons, and uses techniques that measure changes at the protein, neuronal, and overall physiological and behavioral level. More importantly, we have been able to demonstrate that physiological challenges related to extracellular (ANG II) or cellular (hypertonic saline) dehydration activate MnPO neurons that may project to different parts of the hypothalamus.

in RSS PAP on March 07, 2019 05:52 PM.
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FGF-23-deficiency impairs hippocampal-dependent cognitive function
Abstract
Fibroblast growth factor receptor and α-Klotho transduce fibroblast growth factor 23 (FGF-23) signaling in renal tubules to maintain systemic phosphate/Vitamin D homeostasis. Mice deficient for either the ligand, FGF-23, or the co-receptor, Klotho, are phenocopies with both showing rapid and premature development of multiple aging-like abnormalities. Such similarity in phenotype, suggests that FGF-23 and Klotho have co-dependent systemic functions. Recent reports revealed inverse central nervous system effects of Klotho deficiency or Klotho overexpression on hippocampal synaptic, neurogenic, and cognitive functions. However, it is unknown whether FGF-23 deficiency effects function of the hippocampus. We report that, similar to Klotho-deficient mice, FGF-23-deficient mice develop dose-dependent, hippocampal-dependent cognitive impairment. However, FGF-23-deficient brains had no gross structural or developmental defects, no change in hippocampal synaptic plasticity, and only minor impairment to postnatal hippocampal neurogenesis. Together these data provide evidence that FGF-23 deficiency impairs hippocampal-dependent cognition but otherwise results in a brain phenotype that is distinct from the KL-deficient mouse.
Significance Statement Although FGF-23 is reportedly expressed by the brain, it has no known brain function. In the periphery, kidney transduction of FGF-23 signaling is required for proper phosphate, calcium and Vitamin D homeostasis. Recent reports show that Klotho, the obligate FGF-23 co-receptor, is required for multiple hippocampal activities. If Klotho-deficient brain effects are the result of disrupted FGF-23 signaling, similar phenotypes may occur under conditions of FGF-23 deficiency. Herein, studies were undertaken to determine whether FGF-23-deficient mice show impairment of the same hippocampal functions, as a first step toward investigating whether FGF-23 is the mechanism by which Klotho effects brain function. Our data show that FGF-23 is only required for normal hippocampal-dependent cognition suggesting that FGF-23 may effect the brain uniquely.

in RSS PAP on March 07, 2019 05:52 PM.
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Phase Coherent Currents underlying neocortical seizure-like state transitions
Abstract
In the epileptic brain, phase amplitude cross frequency coupling (CFC) features have been used to objectively classify seizure-related states, and the inter-seizure state has been demonstrated as being random, in contrast to the seizure state being predictable; however, the excitatory and inhibitory networks underlying their dynamics remain unclear. Therefore, the objectives of this study are to classify the dynamics of seizure sub-states labeling seizure-like event (SLE) onset and termination intervals using CFC features and to obtain their underlying excitatory/inhibitory cellular correlates. SLEs were induced in mouse neocortical brain slices using a low-magnesium perfusate, and were recorded in layer II/III using simultaneous local field potential and whole cell voltage clamp electrodes. Classification of onset and termination of SLE transitions was investigated using CFC features in conjunction with an unsupervised 2-state hidden Markov model (HMM). Gamma distributions of their durations indicated that both are predictable. Furthermore, omitting 4Hz from the HMM classifier switched both SLE sub-states from statistically deterministic to random without changing the dynamics of the SLE state. These results were generalized to 4-AP induced SLEs and human seizure traces. Only during these sub-states, both excitatory and inhibitory currents coupled with the field. Where excitatory currents phase locked to a broad range of frequencies between 1 and 12Hz, inhibitory currents dominantly phase locked at 4Hz. We conclude that inhibition underlies the predictability of neocortical CFC-defined SLE transition sub-states.
Significance Statement To date, the underlying excitatory and inhibitory bases of objectively identified seizure sub-states have not been determined. Here we identify these sub-states using phase amplitude cross frequency coupling features. This is tested in both human and rodent seizure models. Then, using simultaneous field and whole cell recordings in a mouse model, we investigate the potential for explaining seizure sub-state dynamics from interactions of the excitatory and inhibitory currents with local field network activity. We found that the frequency ranges at which these currents are coherent with field oscillations have a dramatic effect on the predictability of seizure state sub-states. Such information is critical for identifying the mechanisms underlying the dynamics of epileptic seizures.

in RSS PAP on March 07, 2019 05:52 PM.
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Development of local circuit connections to hilar mossy cells in the mouse dentate gyrus
Abstract
Hilar mossy cells in the dentate gyrus (DG) shape the firing and function of the hippocampal circuit. However, the neural circuitry providing afferent input to mossy cells is incompletely understood, and little is known about the development of these inputs. Thus, we used whole-cell recording and laser scanning photostimulation (LSPS) to characterize the developmental trajectory of local excitatory and inhibitory synaptic inputs to mossy cells in the mouse hippocampus. Hilar mossy cells were targeted by visualizing non-red fluorescent cells in the dentate hilus of GAD2-Cre; Ai9 mice, which expressed tdTomato in GAD+ neurons, and were confirmed by post hoc morphological characterization. Our results show that at postnatal days 6-7 (P6-7), mossy cells received more excitatory input from neurons in the proximal CA3 versus those in the DG. In contrast, at P13-14 and P21-28, the largest source of excitatory input originated in DG cells, while the strength of CA3 and hilar inputs declined. A developmental trend was also evident for inhibitory inputs. Overall inhibitory input at P6-7 was weak, while inhibitory inputs from the DG cell layer and the hilus predominated at P13-14 and P21-28. The strength of local DG excitation and inhibition to mossy cells peaked at P13-14 and decreased slightly in older P21-28 mice. Together, these data provide new detailed information on the development of local synaptic connectivity of mossy cells, and suggests mechanisms through which developmental changes in local circuit inputs to hilar mossy cells shape their physiology and vulnerability to injury during postnatal periods.
Significance statement Mossy cells of the dentate gyrus (DG) have been implicated in hippocampal circuits regulating pattern separation, an important function attributed to the DG. However, physiological inputs regulating mossy cell activity are incompletely understood. Here, we show that sources of both excitatory and inhibitory inputs arise developmentally. Our results suggest that excitatory inputs from the DG and local inhibitory inputs are well-positioned to powerfully sculpt receptive fields in mature mossy cells.

in RSS PAP on March 07, 2019 05:52 PM.
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Brain region-specific gene signatures revealed by distinct astrocyte subpopulations unveil links to glioma and neurodegenerative diseases
Abstract
Currently, there are no effective treatments for glioma or for neurodegenerative diseases due, in part, to our limited understanding of the pathophysiology and cellular heterogeneity of these diseases. Mounting evidence suggests that astrocytes play an active role in the pathogenesis of these diseases by contributing to a diverse range of pathophysiological states. In a previous study, five molecularly distinct astrocyte subpopulations from three different brain regions were identified. To further delineate the underlying diversity of these populations, we obtained mouse brain region-specific gene signatures for both protein-coding and long non-coding RNA (lncRNA) and found that these astrocyte subpopulations are endowed with unique molecular signatures across diverse brain regions. Additional gene set and single-sample enrichment analyses revealed that gene signatures of different subpopulations are differentially correlated with glioma tumors that harbor distinct genomic alterations. To the best of our knowledge, this is the first study that links transcriptional profiles of astrocyte subpopulations with glioma genomic mutations. Furthermore, our results demonstrated that subpopulations of astrocytes in select brain regions are associated with specific neurodegenerative diseases. Overall, the present study provides a new perspective for understanding the pathophysiology of glioma and neurodegenerative diseases and highlights the potential contributions of diverse astrocyte populations to normal, malignant, and degenerative brain functions.
Significance Statement Mounting evidence suggests that astrocytes play an active role in disease pathogenesis by contributing to a diverse range of pathophysiological states. The present study identifies new layers of astrocyte diversity and new correlations between distinct astrocyte subpopulations and disease states. Understanding the heterogeneity of astrocytes in different physiological conditions and diseases will provide new avenues for improved diagnostics and therapeutics targeting specific astrocyte subpopulations.

in RSS PAP on March 07, 2019 05:52 PM.
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Choice-Related Activity during Visual Slant Discrimination in Macaque CIP but Not V3A
Abstract
Creating three-dimensional (3D) representations of the world from two-dimensional retinal images is fundamental to visually guided behaviors including reaching and grasping. A critical component of this process is determining the 3D orientation of objects. Previous studies have shown that neurons in the caudal intraparietal area (CIP) of the macaque monkey represent 3D planar surface orientation (i.e., slant and tilt). Here we compare the responses of neurons in areas V3A (which is implicated in 3D visual processing and which precedes CIP in the visual hierarchy) and CIP to 3D oriented planar surfaces. We then examine whether activity in these areas correlates with perception during a fine slant discrimination task in which monkeys report if the top of a surface is slanted towards or away from them. Although we find that V3A and CIP neurons show similar sensitivity to planar surface orientation, significant choice-related activity during the slant discrimination task is rare in V3A but prominent in CIP. These results implicate both V3A and CIP in the representation of 3D surface orientation, and suggest a functional dissociation between the areas based on slant-related choice signals.
Significance Statement Surface orientation perception is fundamental to visually guided behaviors such as reaching, grasping, and navigation. Previous studies implicate the caudal intraparietal area (CIP) in the representation of 3D surface orientation. Here we show that responses to 3D oriented planar surfaces are similar in CIP and V3A, which precedes CIP in the cortical hierarchy. However, we also find a qualitative distinction between the two areas: only CIP neurons show robust choice-related activity during a fine visual orientation discrimination task.

in RSS PAP on March 07, 2019 05:52 PM.
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Electrophysiological properties of medium spiny neuron subtypes in the caudate-putamen of prepubertal male and female Drd1a-tdTomato line 6 BAC transgenic mice
Abstract
The caudate-putamen is a striatal brain region essential for sensorimotor behaviors, habit learning, and other cognitive and premotor functions. The output and predominant neuron of the caudate-putamen is the medium spiny neuron (MSN). MSNs present discrete cellular subtypes that show differences in neurochemistry, dopamine receptor expression, efferent targets, gene expression, functional roles, and most importantly for this study, electrophysiological properties. MSN subtypes include the striatonigral and the striatopallidal groups. Most studies identify the striatopallidal MSN subtype as being more excitable than the striatonigral MSN subtype. However, there is some divergence between studies regarding the exact differences in electrophysiological properties. Furthermore, MSN subtype electrophysiological properties have not been reported disaggregated by biological sex. We addressed these questions using prepubertal male and female Drd1a-tdTomato line 6 BAC transgenic mice, an important transgenic line that has not yet received extensive electrophysiological analysis. We made acute caudate-putamen brain slices and assessed a robust battery of 16 relevant electrophysiological properties using whole-cell patch clamp recording, including intrinsic membrane, action potential, and miniature excitatory postsynaptic current (mEPSC) properties. We found that: (1) MSN subtypes exhibited multiple differential electrophysiological properties in both sexes, including rheobase, action potential threshold and width, input resistance in both the linear and rectified ranges, and mEPSC amplitude; (2) select electrophysiological properties showed interactions between MSN subtype and sex. These findings provide a comprehensive evaluation of mouse caudate-putamen MSN subtype electrophysiological properties across females and males, both confirming and extending previous studies.
Significance Statement The findings presented here provide the most comprehensive evaluation of the electrophysiological properties of caudate-putamen medium spiny neuron (MSN) subtypes ever performed in a single study, both in terms of electrophysiological metrics and animal sex. These data selectively confirm, diverge from, and extend the findings of previous studies, providing a firm foundation upon which to pursue future studies of caudate-putamen MSNs.

in RSS PAP on March 07, 2019 05:52 PM.
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The Small and Dynamic Pre-primed Pool at the Release Site; A Useful Concept to Understand Release Probability and Short-Term Synaptic Plasticity?
Bengt Gustafsson, Rong Ma, Eric Hanse
in Frontiers in Synaptic Neuroscience | New and Recent Articles on March 07, 2019 12:00 PM.
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Alterations in GABAA-Receptor Trafficking and Synaptic Dysfunction in Brain Disorders
Miranda Mele, Rui O. Costa, Carlos B. Duarte
in Frontiers in Cellular Neuroscience | New and Recent Articles on March 07, 2019 06:00 AM.
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Granulovacuolar Degeneration in Brains of Senile Cynomolgus Monkeys
Huda S. Darusman, Dewi Ratih Agungpriyono, Vinka A. Kusumaputri, Dondin Sajuthi, Steven J. Schapiro, Jann Hau
in Frontiers in Aging Neuroscience | New and Recent Articles on March 07, 2019 06:00 AM.
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Structural Associations of Cortical Contrast and Thickness in First Episode Psychosis

Abstract
There is growing evidence that psychosis is characterized by brain network abnormalities. Analyzing morphological abnormalities with T1-weighted structural MRI may be limited in discovering the extent of deviations in cortical associations. We assess whether structural associations of either cortical white–gray contrast (WGC) or cortical thickness (CT) allow for a better understanding of brain structural relationships in first episode of psychosis (FEP) patients. Principal component and structural covariance analyses were applied to WGC and CT derived from T1-weighted MRI for 116 patients and 88 controls, to explore sets of brain regions that showed group differences, and associations with symptom severity and cognitive ability in patients. We focused on 2 principal components: one encompassed primary somatomotor regions, which showed trend-like group differences in WGC, and the second included heteromodal cortices. Patients’ component scores were related to general psychopathology for WGC, but not CT. Structural covariance analyses with WGC revealed group differences in pairwise correlations across widespread brain regions, mirroring areas derived from PCA. More group differences were uncovered with WGC compared with CT. WGC holds potential as a proxy measure of myelin from commonly acquired T1-weighted MRI and may be sensitive in detecting systems-level aberrations in early psychosis, and relationships with clinical/cognitive profiles.
in Cerebral Cortex Advance Access on March 07, 2019 12:00 AM.
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Spatial Patterns of Brain Activity Preferentially Reflecting Transient Pain and Stimulus Intensity

Abstract
How pain emerges in the human brain remains an unresolved question. Neuroimaging studies have suggested that several brain areas subserve pain perception because their activation correlates with perceived pain intensity. However, painful stimuli are often intense and highly salient; therefore, using both intensity- and saliency-matched control stimuli is crucial to isolate pain-selective brain responses. Here, we used these intensity/saliency-matched painful and non-painful stimuli to test whether pain-selective information can be isolated in the functional magnetic resonance imaging responses elicited by painful stimuli. Using two independent datasets, multivariate pattern analysis was able to isolate features distinguishing the responses triggered by (1) intensity/saliency-matched painful versus non-painful stimuli, and (2) high versus low-intensity/saliency stimuli regardless of whether they elicit pain. This indicates that neural activity in the so-called “pain matrix” is functionally heterogeneous, and part of it carries information related to both painfulness and intensity/saliency. The response features distinguishing these aspects are spatially distributed and cannot be ascribed to specific brain structures.
in Cerebral Cortex Advance Access on March 07, 2019 12:00 AM.
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Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death
TDP-43 aggregation is the major hallmark of multiple neurodegenerative diseases, including ALS and FTD. Gasset-Rosa et al. demonstrate that transient stress induces long-lasting cytoplasmic TDP-43 de-mixing independent of stress granules, driving nuclear import defects, nuclear TDP-43 clearance, and cell death.
in Neuron on March 07, 2019 12:00 AM.
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Intrinsic Variable Learning for Brain-Machine Interface Control by Human Anterior Intraparietal Cortex
Sakellaridi, Christopoulos, et al. studied the learning mechanism in human AIP using brain-machine interface paradigms. They found that changes in neural activity during learning reflect cognitive re-adaptation mechanisms. When cognitive strategies were not adequate for compensation, AIP failed to learn.
in Neuron on March 07, 2019 12:00 AM.
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Regulation of NGF Signaling by an Axonal Untranslated mRNA
Crerar et al. report that Tp53inp2, an mRNA transcript abundantly localized in axons of sympathetic neurons, interacts with the NGF receptor TrkA. The Tp53inp2 transcript is not translated but acts in a coding-independent manner to regulate axon growth and neuronal survival in vivo.
in Neuron on March 07, 2019 12:00 AM.
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Corrigendum: Who Deserves My Trust? Cue-Elicited Feedback Negativity Tracks Reputation Learning in Repeated Social Interactions
Diandian Li, Liang Meng, Qingguo Ma
in Frontiers in Human Neuroscience | New and Recent Articles on March 06, 2019 06:00 PM.
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Corrigendum: The Importance of the Validation of M/EEG With Current Biomarkers in Alzheimer's Disease
Fernando Maestú, Pablo Cuesta, Omar Hasan, Alberto Fernandéz, Michael Funke, Paul E. Schulz
in Frontiers in Human Neuroscience | New and Recent Articles on March 06, 2019 06:00 PM.
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The Influence of Hierarchical Masks on Masked Repetition Priming: Evidence From Event-Related Potential Investigation
Ying Mei, Yuqian Dai, Yi Lei
in Frontiers in Human Neuroscience | New and Recent Articles on March 06, 2019 06:00 PM.
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Coordination of neural patterning in the Drosophila visual system

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Maximilien Courgeon, Claude Desplan
Precise formation of neuronal circuits requires the coordinated development of the different components of the circuit. Here, we review examples of coordination at multiples scales of development in one of the best-studied systems for neural patterning and circuit assembly, the Drosophila visual system, from coordination of gene expression in photoreceptors to the coordinated patterning of the different neuropiles of the optic lobe.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 06, 2019 06:00 PM.
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Ipsilesional Mu Rhythm Desynchronization and Changes in Motor Behavior Following Post Stroke BCI Intervention for Motor Rehabilitation
Alexander B. Remsik, Leroy Williams, Klevest Gjini, Keith Dodd, Jaclyn Thoma, Tyler Jacobson, Matt Walczak, Matthew McMillan, Shruti Rajan, Brittany M. Young, Zack Nigogosyan, Hemali Advani, Rosaleena Mohanty, Neelima Tellapragada, Janerra Allen, Mohsen Mazrooyisebdani, Leo M. Walton, Peter L. E. van Kan, Theresa J. Kang, Justin A. Sattin, Veena A. Nair, Dorothy Farrar Edwards, Justin C. Williams, Vivek Prabhakaran
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on March 06, 2019 06:00 PM.
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Adult Hippocampal Neurogenesis Is a Developmental Process Involved in Cognitive Development
Mikhail V. Semënov
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on March 06, 2019 06:00 PM.
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The Metalloproteinase adam19b Is Required for Sensory Axon Guidance in the Hindbrain
Jane A. Cox, Mark M. Voigt
in Frontiers in Neural Circuits | New and Recent Articles on March 06, 2019 06:00 PM.
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Erratum: Liu et al., "p130CAS Is Required for Netrin Signaling and Commissural Axon Guidance"

in Journal of Neuroscience current issue on March 06, 2019 05:45 PM.
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Repetitive Diffuse Mild Traumatic Brain Injury Causes an Atypical Astrocyte Response and Spontaneous Recurrent Seizures

Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial fibrillary acidic protein was limited. Surprisingly, an unrelated population of atypical reactive astrocytes was characterized by the lack of glial fibrillary acidic protein expression, rapid and sustained downregulation of homeostatic proteins and impaired astrocyte coupling. After a latency period, a subset of mice developed spontaneous recurrent seizures reminiscent of PTE in human TBI patients. Seizing mice had larger areas of atypical astrocytes compared with nonseizing mice, suggesting that these atypical astrocytes might contribute to epileptogenesis after diffuse TBI.

SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is a leading cause of acquired epilepsies. Reactive astrocytes have long been associated with seizures and epilepsy in patients, particularly after focal/lesional brain injury. However, most TBIs also include nonfocal, diffuse injuries. Here, we showed that repetitive diffuse TBI is sufficient for the development of spontaneous recurrent seizures in a subset of mice. We identified an atypical response of astrocytes induced by diffuse TBI characterized by the rapid loss of homeostatic proteins and lack of astrocyte coupling while reactive astrocyte markers or glial scar formation was absent. Areas with atypical astrocytes were larger in animals that later developed seizures suggesting that this response may be one root cause of epileptogenesis after diffuse TBI.

in Journal of Neuroscience current issue on March 06, 2019 05:45 PM.
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Immunity Against Bacterial Infection of the Central Nervous System: An Astrocyte Perspective
Sohair Geyer, Muazzam Jacobs, Nai-Jen Hsu
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 06, 2019 12:00 PM.
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The Influence of Genetic Factors and Cognitive Reserve on Structural and Functional Resting-State Brain Networks in Aging and Alzheimer’s Disease
Manuela Pietzuch, Anna E. King, David D. Ward, James C. Vickers
in Frontiers in Aging Neuroscience | New and Recent Articles on March 06, 2019 06:00 AM.
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Support Vector Machine for Analyzing Contributions of Brain Regions During Task-State fMRI
Mengyue Wang, Chunlin Li, Wenjing Zhang, Yonghao Wang, Yuan Feng, Ying Liang, Jing Wei, Xu Zhang, Xia Li, Renji Chen
in Frontiers in Neuroinformatics | New and Recent Articles on March 06, 2019 06:00 AM.
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Arterial Spin Labeling Reveals Disrupted Brain Networks and Functional Connectivity in Drug-Resistant Temporal Epilepsy
Ilaria Boscolo Galazzo, Silvia Francesca Storti, Anna Barnes, Bianca De Blasi, Enrico De Vita, Matthias Koepp, John Sidney Duncan, Ashley Groves, Francesca Benedetta Pizzini, Gloria Menegaz, Francesco Fraioli
in Frontiers in Neuroinformatics | New and Recent Articles on March 06, 2019 06:00 AM.
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TaDa! Analysing cell type-specific chromatin in vivo with Targeted DamID

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Jelle van den Ameele, Robert Krautz, Andrea H Brand
The emergence of neuronal diversity during development of the nervous system relies on dynamic changes in the epigenetic landscape of neural stem cells and their progeny. Targeted DamID (TaDa) is proving invaluable in identifying the genome-wide binding sites of chromatin-associated proteins in vivo, without fixation, cell isolation, or immunoprecipitation. The simplicity and efficiency of the technique have led to an ever-expanding TaDa toolbox. These tools enable profiling of gene expression and chromatin accessibility, as well as the identification of the genome-wide binding sites of chromatin complexes, transcription factors and RNAs. Here, we review these new developments, with particular emphasis on the use of TaDa in studying neuronal specification.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 06, 2019 12:00 AM.
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The High Energy Cost of Theta–Gamma Activity during REM Sleep
The occurrence of wake-like electroencephalography (EEG) traces during rapid-eye movement sleep (REM) has intrigued scientists for decades. A recent study by Bergel et al. (Nat. Commun. 2018;9;5364) imaged brain-wide hemodynamics in rats during wakefulness and sleep. The findings suggest that brain energy expenditure is highest during REM because of heightened theta and gamma activity.
in Trends in Neurosciences on March 06, 2019 12:00 AM.
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Looking into the Brain of Buridan’s Ass
To survive, animals must maximize the minimum—take care of the least satisfied among their basic needs. In this issue of Neuron, a study by Juechems et al. (2019) illustrates that this core principle might shape the way medial prefrontal regions of the human brain drive and valuate sequential choices between different types of reward.
in Neuron on March 06, 2019 12:00 AM.
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Advancing Translational Research Using NIMH Research Domain Criteria and Computational Methods
NIMH’s Research Domain Criteria is a framework for dimensional, trans-diagnostic research on mental disorders. Sanislow et al. discuss ways in which research leveraging computational methods can identify intermediary treatment targets and accelerate translational progress.
in Neuron on March 06, 2019 12:00 AM.
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Order in Odors: A Power Law Structures the Encoding of Stimulus Identity and Intensity
Odorant molecules are detected through the combinatorial activation of ensembles of olfactory sensory neurons. By capitalizing on the numerical simplicity of the Drosophila larval brain, Si et al. (2019) uncover principles constraining the representation of the quality and intensity of olfactory stimuli.
in Neuron on March 06, 2019 12:00 AM.
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The Excitatory, the Inhibitory, and the Modulatory: Mapping Chemical Neurotransmission in the Brain
In this issue of Neuron, Deng et al. (2019) report the generation of a new set of tools to manipulate the entire set of neurotransmitters, neuromodulators, neuropeptides, and their receptors—the “chemoconnectome”—in Drosophila.
in Neuron on March 06, 2019 12:00 AM.
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Special Issue on Disease: Translational Approaches
In this issue of Neuron, we are proud to present the first in a series of special issues on neurological and neuropsychiatric disease. The three consecutively published issues will each center around a specific disease-related topic and feature a mixture of Reviews, Perspectives, and NeuroViews.
in Neuron on March 06, 2019 12:00 AM.
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Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment
This Perspective highlights the significance of chronic pain, its underpinning biology, and the need for composite biomarker signatures alongside self-report. Combining evidence from animal and human research spanning genetics through to neuroimaging, Tracey et al. highlight a few key areas of promise.
in Neuron on March 06, 2019 12:00 AM.
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Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality
Conceptually intuitive, however complex in execution, gene therapy is emerging as a therapeutic modality that can have a transformative impact on patients’ lives. Hudry and Vandenberghe review the clinical progress in gene therapy for nervous system disorders using AAV.
in Neuron on March 06, 2019 12:00 AM.
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The Two Sides of NaV1.7: Painful and Painless Channelopathies
Sodium channel NaV1.7 is a major target in pain research, largely because of genetic validation. In this issue of Neuron, McDermott et al. (2019) now present a comprehensive assessment of congenital pain insensitivity due to NaV1.7 loss of function. This work and studies on NaV1.7 gain of function raise important questions about how channelopathies produce disease.
in Neuron on March 06, 2019 12:00 AM.
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The Superoanterior Fasciculus (SAF): A Novel White Matter Pathway in the Human Brain?
Szabolcs David, Anneriet M. Heemskerk, Francesco Corrivetti, Michel Thiebaut de Schotten, Silvio Sarubbo, Francesco Corsini, Alessandro De Benedictis, Laurent Petit, Max A. Viergever, Derek K. Jones, Emmanuel Mandonnet, Hubertus Axer, John Evans, Tomáš Paus, Alexander Leemans
in Frontiers in Neuroanatomy | New and Recent Articles on March 05, 2019 12:00 PM.
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Corrigendum: They Are What You Hear in Media Reports: The Racial Stereotypes toward Uyghurs Activated by Media
Jia Jin, Guanxiong Pei, Qingguo Ma
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on March 05, 2019 12:00 PM.
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Corrigendum: “You Win, You Buy”—How Continuous Win Effect Influence Consumers' Price Perception: An ERP Study
Qingguo Ma, Linanzi Zhang, Manlin Wang
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on March 05, 2019 12:00 PM.
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Corrigendum: Neural Features of Processing the Enforcement Phrases Used during Occupational Health and Safety Inspections: An ERP Study
Qingguo Ma, Liping Shi, Linfeng Hu, Qiang Liu, Zheng Yang, Qiuzhen Wang
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on March 05, 2019 12:00 PM.
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Transcriptome Analysis of the Human Tibial Nerve Identifies Sexually Dimorphic Expression of Genes Involved in Pain, Inflammation, and Neuro-Immunity
Pradipta R. Ray, Jawad Khan, Andi Wangzhou, Diana Tavares-Ferreira, Armen N. Akopian, Gregory Dussor, Theodore J. Price
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 05, 2019 06:00 AM.
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A Serverless Tool for Platform Agnostic Computational Experiment Management
Gregory Kiar, Shawn T. Brown, Tristan Glatard, Alan C. Evans
in Frontiers in Neuroinformatics | New and Recent Articles on March 05, 2019 06:00 AM.
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IGF1 Gene Therapy Modifies Microglia in the Striatum of Senile Rats
Eugenia Falomir-Lockhart, Franco Juan Cruz Dolcetti, Luis Miguel García-Segura, Claudia Beatriz Hereñú, Maria Jose Bellini
in Frontiers in Aging Neuroscience | New and Recent Articles on March 05, 2019 06:00 AM.
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Pathological Tau From Alzheimer’s Brain Induces Site-Specific Hyperphosphorylation and SDS- and Reducing Agent-Resistant Aggregation of Tau in vivo
Jin Miao, Ruirui Shi, Longfei Li, Feng Chen, Yan Zhou, Yunn Chyn Tung, Wen Hu, Cheng-Xin Gong, Khalid Iqbal, Fei Liu
in Frontiers in Aging Neuroscience | New and Recent Articles on March 05, 2019 06:00 AM.
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Therapeutic Potential of Extracellular Vesicles for the Treatment of Nerve Disorders
Luisa R. Galieva, Victoria James, Yana O. Mukhamedshina, Albert A. Rizvanov
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 05, 2019 06:00 AM.
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Experimental and Computational Methods for the Study of Cerebral Organoids: A Review
Daniele Poli, Chiara Magliaro, Arti Ahluwalia
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on March 05, 2019 06:00 AM.
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Common miRNA Patterns of Alzheimer’s Disease and Parkinson’s Disease and Their Putative Impact on Commensal Gut Microbiota
Charlotte Hewel, Julia Kaiser, Anna Wierczeiko, Jan Linke, Christoph Reinhardt, Kristina Endres, Susanne Gerber
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 05, 2019 06:00 AM.
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Adult Hippocampal Neurogenesis Can Be Enhanced by Cold Challenge Independently From Beigeing Effects
Jong Whi Kim, Kyu Ri Han, Woosuk Kim, Hyo Young Jung, Sung Min Nam, Dae Young Yoo, In Koo Hwang, Je Kyung Seong, Yeo Sung Yoon
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on March 05, 2019 06:00 AM.
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Carnosic Acid Mitigates Early Brain Injury After Subarachnoid Hemorrhage: Possible Involvement of the SIRT1/p66shc Signaling Pathway
Lingfang Teng, Linfeng Fan, Yujiang Peng, Xijun He, Huihui Chen, Hongyu Duan, Fan Yang, Da Lin, Zheng Lin, Huiyong Li, Bo Shao
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 05, 2019 06:00 AM.
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Preserving the balance: diverse forms of long-term GABAergic synaptic plasticity

Preserving the balance: diverse forms of long-term GABAergic synaptic plasticity
Preserving the balance: diverse forms of long-term GABAergic synaptic plasticity, Published online: 05 March 2019; doi:10.1038/s41583-019-0141-5
There is growing evidence for activity-dependent plasticity at inhibitory GABAergic synapses. In this Review, Chiu and colleagues propose that an array of molecular mechanisms promotes the parallel regulation of synapses formed by distinct presynaptic interneurons innervating perisomatic or dendritic targets.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 05, 2019 12:00 AM.
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The Relationship Between Plasma DPP4 Activity to BDNF Ratio and Mild Cognitive Impairment in Elderly Population With Normal Glucose Tolerance
Liuping Xiao, Bo Ge, Xu Chen, Bo Chen, Linyuan Qin, Xueping Hu, Haidong Pan, Yujie Chen, Li Tian, Yun Gao, Tianpeng Zheng
in Frontiers in Aging Neuroscience | New and Recent Articles on March 04, 2019 06:00 AM.
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Optical Quantal Analysis Using Ca2+ Indicators: A Robust Method for Assessing Transmitter Release Probability at Excitatory Synapses by Imaging Single Glutamate Release Events
Zahid Padamsey, Rudi Tong, Nigel Emptage
in Frontiers in Synaptic Neuroscience | New and Recent Articles on March 04, 2019 06:00 AM.
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Molecular Mechanisms Underlying Sensory-Motor Circuit Dysfunction in SMA
Hannah K. Shorrock, Thomas H. Gillingwater, Ewout J. N. Groen
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 04, 2019 06:00 AM.
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Emerging Roles of Neuronal Ca2+ Sensor-1 in Cardiac and Neuronal Tissues: A Mini Review
Tomoe Y. Nakamura, Shu Nakao, Shigeo Wakabayashi
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 04, 2019 06:00 AM.
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Structure-Based Peptide Inhibitor Design of Amyloid-β Aggregation
Jinxia Lu, Qin Cao, Chuchu Wang, Jing Zheng, Feng Luo, Jingfei Xie, Yichen Li, Xiaojuan Ma, Lin He, David Eisenberg, James Nowick, Lin Jiang, Dan Li
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 04, 2019 06:00 AM.
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The two faces of PVN CRF neurons

The two faces of PVN CRF neurons
The two faces of PVN CRF neurons, Published online: 04 March 2019; doi:10.1038/s41593-019-0363-x
In this issue of Nature Neuroscience, Kim and colleagues report that corticotropin-releasing factor neurons in the paraventricular nucleus, known essential regulators of the neuroendocrine axis, encode the valence of environmental stimuli through a bidirectional strategy and modulate animals’ immediate behavioral responses.
in Nature Neuroscience - Issue - nature.com science feeds on March 04, 2019 12:00 AM.
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Spontaneous synchronization to speech reveals neural mechanisms facilitating language learning

Spontaneous synchronization to speech reveals neural mechanisms facilitating language learning
Spontaneous synchronization to speech reveals neural mechanisms facilitating language learning, Published online: 04 March 2019; doi:10.1038/s41593-019-0353-z
A simple behavioral task identifies two qualitatively different groups within the general population, according to their speech-to-speech synchronization abilities. Group pertinence predicts brain function and anatomy, as well as word-learning performance.
in Nature Neuroscience - Issue - nature.com science feeds on March 04, 2019 12:00 AM.
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Rapid, biphasic CRF neuronal responses encode positive and negative valence

Rapid, biphasic CRF neuronal responses encode positive and negative valence
Rapid, biphasic CRF neuronal responses encode positive and negative valence, Published online: 04 March 2019; doi:10.1038/s41593-019-0342-2
Animals must determine quickly whether any given environmental stimuli are beneficial or detrimental. This work reveals a novel strategy to encode opposing valences by a single population of CRF neurons in the hypothalamus.
in Nature Neuroscience - Issue - nature.com science feeds on March 04, 2019 12:00 AM.
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Making waves with ultrasound

Making waves with ultrasound
Making waves with ultrasound, Published online: 04 March 2019; doi:10.1038/s41583-019-0149-x
Targeted ultrasound stimulation can specifically modulate the functional connectivity profiles of targeted structures — including deep structures — in the macaque brain, with effects lasting for up to 2 hours following stimulation.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 04, 2019 12:00 AM.
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Novel electrode technologies for neural recordings

Novel electrode technologies for neural recordings
Novel electrode technologies for neural recordings, Published online: 04 March 2019; doi:10.1038/s41583-019-0140-6
Here, Hong and Lieber review recent developments in electrode technologies for the recording of single-unit spiking activity. They focus on advances in electrodes with high spatial integration, long-term stability and multifunctional capacities.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 04, 2019 12:00 AM.
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Foxg1 Directly Represses Dbx1 to Confine the POA and Subsequently Regulate Ventral Telencephalic Patterning

Abstract
During early development, signaling centers, such as the cortical hem and the preoptic area (POA), are critical for telencephalic patterning. However, the mechanisms underlying the maintenance of signal centers are poorly understood. Here, we report that the transcription factor Foxg1 is required to confine the POA, a resource of Sonic Hedgehog (Shh) that is pivotal for ventral telencephalic development. Cell-specific deletion of Foxg1 achieved by crossing Foxg1^fl/fl with Dbx1-cre or Nestin-CreER combined with tamoxifen induction results in a dramatic expansion of the POA accompanied by the significantly increased activity of the Shh signaling pathway. Ventral pattern formation was severely impaired. Moreover, we demonstrated that Foxg1 directly represses Dbx1 to restrict the POA. Furthermore, we found that the ventral pallium was expanded, which might also contribute to the observed patterning defects. These findings will improve our understanding of the maintenance of signal centers and help to elucidate the mechanisms underlying ventral telencephalic patterning.
in Cerebral Cortex Advance Access on March 04, 2019 12:00 AM.
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HuR in the Medial Prefrontal Cortex is Critical for Stress-Induced Synaptic Dysfunction and Depressive-Like Symptoms in Mice

Abstract
Chronic stress has been observed to increase the risk of developing depression and induce neuronal alterations of synaptic plasticity, yet the underlying molecular mechanisms remain unclear. Here, we found that the ubiquitously expressed RNA-binding protein HuR was up-regulated in the medial prefrontal cortex (mPFC) of mice following chronic stress. In adult mice, AAV-Cre-mediated knockout of HuR in the mPFC prevented anxiety-like and depression-like behaviors induced by chronic stress. HuR was also required for the stress-induced dendritic spine loss and synaptic transmission deficits. Moreover, HuR^flox/flox;Nex-Cre mice, which induce HuR loss of function from embryonic development, exhibited enhanced synaptic functions. Notably, we ascertained RhoA signaling to be regulated by HuR and involved in the modulation of structural synaptic plasticity in response to chronic stress. Our results demonstrate HuR is a critical modulator for the regulation of stress-induced synaptic plasticity alterations and depression, providing a potential therapeutic target for the treatment of depressive disorders.
in Cerebral Cortex Advance Access on March 04, 2019 12:00 AM.
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Enhanced setup for wired continuous long-term EEG monitoring in juvenile and adult rats: application for epilepsy and other disorders
The electroencephalogram (EEG) is a widely used laboratory technique in rodent models of epilepsy, traumatic brain injury (TBI), and other neurological diseases accompanied by seizures. Obtaining prolonged con...
in Most Recent Articles: BMC Neuroscience on March 04, 2019 12:00 AM.
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Neural populations for maintaining body fluid balance

Publication date: August 2019
Source: Current Opinion in Neurobiology, Volume 57
Author(s): Takako Ichiki, Vineet Augustine, Yuki Oka
Fine balance between loss-of water and gain-of water is essential for maintaining body fluid homeostasis. The development of neural manipulation and mapping tools has opened up new avenues to dissect the neural circuits underlying body fluid regulation. Recent studies have identified several nodes in the brain that positively and negatively regulate thirst. The next step forward would be to elucidate how neural populations interact with each other to control drinking behavior.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 03, 2019 06:00 PM.
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Evolution of neuronal types and families

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Detlev Arendt, Paola Yanina Bertucci, Kaia Achim, Jacob M Musser
Major questions in the evolution of neurons and nervous systems remain unsolved, such as the origin of the first neuron, the possible convergent evolution of neuronal phenotypes, and the transition from a relatively simple decentralized nerve net to the complex, centralized nervous systems found in modern bilaterian animals. In recent years, comparative single-cell transcriptomics has opened up new research avenues addressing these issues. Here, we review recent conceptual progress toward an evolutionary definition of cell types, and how it facilitates the identification and large-scale comparison of neuronal types and neuron type families from single-cell data — with the family of GABAergic neurons in distinct parts of the vertebrate forebrain as prime example. We also highlight strategies to infer cell type-specific innovation, so-called apomeres, from single-cell data.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 02, 2019 12:00 PM.
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Compartmentalized distributions of neuronal and glial cell-surface proteins pattern the synaptic network

Publication date: August 2019
Source: Current Opinion in Neurobiology, Volume 57
Author(s): Nuno Apóstolo, Joris de Wit
Neuronal identity and connectivity are closely linked. Single-cell sequencing studies show that different neuronal cell types express distinct combinations of cell-surface proteins important for synaptic connectivity and function. Emerging evidence indicates that glia-derived cell-surface proteins play critical roles in shaping connectivity as well. These studies begin to suggest that the proteins present on presynaptic and postsynaptic membranes, glial processes, and secreted into the synaptic cleft and extracellular matrix together confer unique surface identities to different types of synaptic connections. Here, we summarize recent findings demonstrating that cell-surface proteins derived from both neurons and glia interact and cooperate to control the connectivity, architecture and function of specific synapses.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 02, 2019 12:00 PM.
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Computational Model for Human 3D Shape Perception From a Single Specular Image
Takeaki Shimokawa, Akiko Nishio, Masa-aki Sato, Mitsuo Kawato, Hidehiko Komatsu
in Frontiers in Computational Neuroscience | New and Recent Articles on March 01, 2019 06:00 PM.
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The development and assembly of the Drosophila adult ventral nerve cord

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Lalanti Venkatasubramanian, Richard S Mann
In order to generate complex motor outputs, the nervous system integrates multiple sources of sensory information that ultimately controls motor neurons to generate coordinated movements. The neural circuits that integrate higher order commands from the brain and generate motor outputs are located in the nerve cord of the central nervous system. Recently, genetic access to distinct functional subtypes that make up the Drosophila adult ventral nerve cord has significantly begun to advance our understanding of the structural organization and functions of the neural circuits coordinating motor outputs. Moreover, lineage-tracing and genetic intersection tools have been instrumental in deciphering the developmental mechanisms that generate and assemble the functional units of the adult nerve cord. Together, the Drosophila adult ventral nerve cord is emerging as a powerful system to understand the development and function of neural circuits that are responsible for coordinating complex motor outputs.

in ScienceDirect Publication: Current Opinion in Neurobiology on March 01, 2019 12:00 PM.
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Alzheimer’s Disease and Cancer: When Two Monsters Cannot Be Together
Shohreh Majd, John Power, Zohreh Majd
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 01, 2019 12:00 PM.
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Hijacking of Embryonic Programs by Neural Crest-Derived Neuroblastoma: From Physiological Migration to Metastatic Dissemination
Céline Delloye-Bourgeois, Valérie Castellani
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 01, 2019 06:00 AM.
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27-Hydroxycholesterol Contributes to Lysosomal Membrane Permeabilization-Mediated Pyroptosis in Co-cultured SH-SY5Y Cells and C6 Cells
Si Chen, Cui Zhou, Huiyan Yu, Lingwei Tao, Yu An, Xiaona Zhang, Ying Wang, Yushan Wang, Rong Xiao
in Frontiers in Molecular Neuroscience | New and Recent Articles on March 01, 2019 06:00 AM.
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Iron in Neurodegeneration – Cause or Consequence?
Alain Ndayisaba, Christine Kaindlstorfer, Gregor K. Wenning
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on March 01, 2019 06:00 AM.

Planet Neuroscience

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