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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 88,562 bioRxiv papers from 379,808 authors.

Most downloaded bioRxiv papers, all time

in category neuroscience

15,425 results found. For more information, click each entry to expand.

14741: PI31 expression prevents neuronal degeneration in a mouse Parkinson Disease model
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Posted to bioRxiv 06 May 2020

PI31 expression prevents neuronal degeneration in a mouse Parkinson Disease model
102 downloads neuroscience

Adi Minis, Hermann Steller

Age-related neurodegenerative diseases pose a major unmet health need since no effective treatment strategies are currently available. These disorders are defined by the accumulation of abnormal protein aggregates that impair synaptic function and cause progressive neuronal degeneration. Therefore, stimulating protein clearance mechanisms may be neuro-protective. The proteasome regulator PI31 promotes local protein degradation at synapses by mediating fast proteasome transport in neurites, and loss of PI31 function causes neuronal degeneration. Here we show that transgenic expression of PI31 in a mouse Parkinson's Disease model preserves neuronal function and greatly extends animal health and lifespan. These results indicate that targeting the PI31-pathway may have therapeutic value for treating neurodegenerative disorders. ### Competing Interest Statement The authors have declared no competing interest.

14742: Intermittent hypoxia promotes functional neuroprotection from retinal ischemia in untreated first-generation offspring
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Posted to bioRxiv 27 Feb 2020

Intermittent hypoxia promotes functional neuroprotection from retinal ischemia in untreated first-generation offspring
102 downloads neuroscience

Jarrod C Harman, Jessie J. Guidry, Jeffrey M. Gidday

Environmental stimuli can promote short- or long-lasting changes in phenotype through epigenetics. Under certain circumstances, induced phenotypes can be passed through the germline to subsequent generations, providing a novel mechanistic basis for disease heritability. In the present study, we tested the hypothesis that repetitively exposing parents to a nonharmful epigenetic stimulus can promote disease resilience in offspring. Male and female mice were mated following brief exposures to mild systemic hypoxia every other day for 16 weeks. Electroretinographic determinations of postischemic function in response to transient unilateral retinal ischemia in their 5-month-old F1 progeny revealed significant resilience to injury relative to animals derived from normoxic control parents. Mass spectrometry identified hundreds of differentially expressed proteins between protected and injured retinae; bioinformatic analyses of the pathways and networks these proteins comprise provided specific mechanistic insights into the molecular manifestation of this injury-resilient phenotype. Thus, epigenetics can modify heritability to promote disease resilience.

14743: Altered functional connectivity of cortical networks in semantic variant Primary Progressive Aphasia
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Posted to bioRxiv 14 Apr 2020

Altered functional connectivity of cortical networks in semantic variant Primary Progressive Aphasia
102 downloads neuroscience

Haroon Popal, Megan Quimby, Daisy Hochberg, Bradford C Dickerson, Jessica A. Collins

As their illness progresses, patients with the semantic variant of Primary Progressive Aphasia (svPPA) frequently exhibit peculiar behaviors indicative of altered visual attention or an increased interest in artistic endeavors. In the present study, we examined changes within and between large-scale functional brain networks that may explain this altered visual behavior. We first examined the connectivity of the visual association network, the dorsal attention network, and the default mode network in healthy young adults (n=89) to understand the typical architecture of these networks in the healthy brain. We then compared the large-scale functional connectivity of these networks in a group of svPPA patients (n=12) to a group of age-matched cognitively normal controls (n=30). Our results showed that the between-network connectivity of the dorsal attention and visual association networks was elevated in svPPA patients relative to controls. We further showed that this heightened between-network connectivity was associated with a decrease in the within-network connectivity of the default mode network, possibly due to progressive degeneration of the anterior temporal lobes in svPPA. These results suggest that focal neurodegeneration can lead to the reorganization of large-scale cognitive networks beyond the primarily affected network(s), possibly contributing to cognitive or behavioral changes that are commonly present as part of the clinical phenotype of svPPA. ### Competing Interest Statement The authors have declared no competing interest.

14744: Local sleep during mind-wandering enhances processes of spatial attention allocation
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Posted to bioRxiv 06 Jun 2020

Local sleep during mind-wandering enhances processes of spatial attention allocation
102 downloads neuroscience

Christian Wienke, Mandy V. Bartsch, Lena Vogelgesang, Christoph Reichert, Hermann Hinrichs, Hans-Jochen Heinze, Stefan Dürschmid

Mind wandering (MW) is a subjective, cognitive phenomenon, in which thoughts move away from the task towards an internal train of thoughts, possibly during phases of neuronal sleep-like activity (local sleep, LS). MW decreases cortical processing of external stimuli and is assumed to decouple attention from the external world. Here, we directly tested how indicators of LS, cortical processing and attentional selection change in a pop-out visual search task during phases of MW. Participants brain activity was recorded using magnetoencephalography, MW was assessed via self-report using randomly interspersed probes. As expected, MW worsened performance being accompanied by a decrease in high frequency activity (HFA, 80-150Hz) and an increase in slow wave activity (SWA, 1-6Hz), consistent with the occurrence of LS. In contrast, visual attentional selection as indexed by the N2pc component was enhanced during MW with the N2pc amplitude being directly linked to participants performance. This observation clearly contradicts accounts of attentional decoupling predicting a decrease in attention-related responses to external stimuli during MW. Together our results suggest that MW occurs during phases of LS with processes of attentional target selection being upregulated, potentially to compensate for the mental distraction during MW. ### Competing Interest Statement The authors have declared no competing interest.

14745: Another's pain in my brain: No evidence that placebo analgesia affects the sensory-discriminative component in empathy for pain
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Posted to bioRxiv 20 May 2020

Another's pain in my brain: No evidence that placebo analgesia affects the sensory-discriminative component in empathy for pain
102 downloads neuroscience

Helena Hartmann, Markus Rütgen, Federica Riva, Claus Lamm

The shared representations account of empathy suggests that sharing other people's emotions relies on neural processes similar to those engaged when directly experiencing such emotions. Recent research corroborated this by showing that placebo analgesia resulted in reduced pain empathy and decreased activation in shared neural networks. However, those studies did not report any placebo-related variation of somatosensory engagement during pain empathy. The experimental paradigms used in these studies did not direct attention towards a specific body part in pain, which may explain the absence of effects for somatosensation. The main objective of this preregistered study was to implement a paradigm overcoming this limitation, and to investigate whether placebo analgesia may also modulate the sensory-discriminative component of empathy for pain. We induced a localized, first-hand placebo analgesia effect in the right hand of 45 participants by means of a placebo gel and conditioning techniques, and compared this to the left hand as a control condition. Participants underwent a pain task in the MRI scanner, receiving painful or non-painful electrical stimulation on their left or right hand, or witnessing another person receiving such stimulation. In contrast to a robust localized placebo analgesia effect for self-experienced pain, the empathy condition showed no differences between the two hands, neither for behavioral nor neural responses. We thus report no evidence for somatosensory sharing in empathy, while replicating previous studies showing overlapping brain activity in the affective-motivational component for first-hand and empathy for pain. Hence, in a more rigorous test aiming to overcome limitations of previous work, we again find no causal evidence for the engagement of somatosensory sharing in empathy. Our study refines the understanding of the neural underpinnings of empathy for pain, and the use of placebo analgesia in investigating such models. ### Competing Interest Statement The authors have declared no competing interest.

14746: Effects of emotion and semantic relatedness on recognition memory: Behavioral and electrophysiological evidence
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Posted to bioRxiv 02 Mar 2020

Effects of emotion and semantic relatedness on recognition memory: Behavioral and electrophysiological evidence
101 downloads neuroscience

Meng Han, Bingcan Li, Chunyan Guo, Roni Tibon

Some aspects of our memory are enhanced by emotion, whereas other can be unaffected or even hinder. In particular, previous studies report impaired associative memory of emotional content, an effect termed associative "emotion interference". The current study utilized EEG and an associative recognition paradigm to investigate the cognitive and neural mechanisms associated with this effect. In two experiments, participants studied negative and neutral stimulus-pairs that were either semantically related or unrelated. In Experiment 1 emotions were relevant to the encoding task (valance judgment) whereas in Experiment 2 emotions were irrelevant (familiarity judgment). In a subsequent associative recognition test, EEG was recorded while participants discriminated between intact, rearranged, and new pairs. An associative emotional interference effect was observed in both experiments, but was attenuated for semantically related pairs when emotions were relevant to the study task. Moreover, a modulation of an early associative memory ERP component depended on task relevancy of emotions, and occurred for negative pairs when emotions were relevant, but for semantically related pairs when emotions were irrelevant. A later ERP component depicted a more general pattern, and was observed in all experimental conditions. These results suggest that both emotions and semantic relations can act as organizing principles that promote associative binding. Their ability to contribute to successful retrieval depends on specific task demands.

14747: Hierarchical disruption in the cortex of anesthetized monkeys as a new signature of consciousness loss
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Posted to bioRxiv 05 Jun 2020

Hierarchical disruption in the cortex of anesthetized monkeys as a new signature of consciousness loss
101 downloads neuroscience

Camilo Miguel Signorelli, Lynn Uhrig, Morten Kringelbach, Bechir Jarraya, Gustavo Deco

Anesthesia induces a reconfiguration of the repertoire of functional brain states leading to a high function-structure similarity. However, it is unclear how these functional changes lead to loss of consciousness. Here we suggest that the mechanism of conscious access is related to a general dynamical rearrangement of the intrinsic hierarchical organization of the cortex. To measure cortical hierarchy, we applied the Intrinsic Ignition analysis to resting-state fMRI data acquired in awake and anesthetized macaques. Our results reveal the existence of spatial and temporal hierarchical differences of neural activity within the macaque cortex, with a strong modulation by the depth of anesthesia and the employed anesthetic agent. Higher values of Intrinsic Ignition correspond to rich and flexible brain dynamics whereas lower values correspond to poor and rigid, structurally driven brain dynamics. Moreover, spatial and temporal hierarchical dimensions are disrupted in a different manner, involving different hierarchical brain networks. All together suggest that disruption of brain hierarchy is a new signature of consciousness loss. ### Competing Interest Statement The authors have declared no competing interest.

14748: Learning receptive field properties of complex cells in V1
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Posted to bioRxiv 18 May 2020

Learning receptive field properties of complex cells in V1
101 downloads neuroscience

Yanbo Lian, Ali Almasi, David B. Grayden, Tatiana Kameneva, Anthony N. Burkitt, Hamish Meffin

There are two distinct classes of cells in the primary visual cortex (V1): simple cells and complex cells. One defining feature of complex cells is their spatial phase invariance; they respond strongly to oriented grating stimuli with a preferred orientation but with a wide range of spatial phases. A classical model of complete spatial phase invariance in complex cells is the energy model, in which the responses are the sum of the squared outputs of two linear spatially phase-shifted filters. However, recent experimental studies  have shown that complex cells have a diverse range of spatial phase invariance  and only a subset can be characterized by the energy model. While several models have been proposed to explain how complex cells could learn to be selective to orientation but invariant to spatial phase,  most existing models overlook many biologically important details. We propose a biologically plausible model for complex cells  that learns to pool inputs from simple cells based on the presentation of natural scene stimuli. The model is a three-layer network with rate-based neurons that describes the activities of LGN cells (layer 1), V1 simple cells (layer 2), and V1 complex cells (layer 3). The first two layers implement a recently proposed simple cell model that is biologically plausible and accounts for many experimental phenomena. The neural dynamics of the complex cells is modeled as the integration of simple cells inputs along with response normalization. Connections between LGN and simple cells are learned using Hebbian and anti-Hebbian plasticity. Connections between simple and complex cells  are learned using a modified version of the Bienenstock, Cooper, and Munro (BCM) rule. Our results demonstrate that the learning rule can describe a diversity of complex cells, similar to those observed experimentally.

14749: Do Walking Muscle Synergies Influence Propensity of Severe Slipping?
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Posted to bioRxiv 20 Sep 2019

Do Walking Muscle Synergies Influence Propensity of Severe Slipping?
101 downloads neuroscience

Mohammad Moein Nazifi, Kurt Beschorner, Pilwon Hur

Slipping is frequently responsible for falling injuries. Preventing slips, and more importantly severe slips, is of importance in fall prevention. Our previous study characterized mild slipping and severe slipping by the analysis of muscle synergies. Significant discrepancies in motor control of slipping have been observed between mild and severe slippers. We are further interested in whether differences exist in baseline motor control patterns between persons who experience mild and severe slips when exposed to a slippery contaminant. This study investigated walking with a muscle synergy approach to detect if walking muscle synergies differ between groups experiencing different slip severities. Twenty healthy young adults (8 mild slippers and 12 severe slippers) participated in this study and their muscle synergies of walking were extracted. Muscle synergy analysis showed that mild slippers had a higher contribution of hamstring and quadriceps during walking while severe slippers had increased contribution of tibialis group. This study provides novel information that may contribute to identifying diagnostic techniques for identifying persons or populations with a high risk of fall based on their walking patterns.

14750: Association between proteomic blood biomarkers and DTI/NODDI metrics in adolescent football players
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Posted to bioRxiv 24 Feb 2020

Association between proteomic blood biomarkers and DTI/NODDI metrics in adolescent football players
101 downloads neuroscience

Keisuke Kawata, Jesse A Steinfeldt, Megan E. Huibregtse, Madeleine K Nowak, Jonathan T. Macy, Andrea Shin, Zhongxue Chen, Keisuke Ejima, Kyle Kercher, Sharlene D. Newman, Hu Cheng

The objective of the study was to examine the association between diffusion MRI techniques [diffusion tensor imaging (DTI) and neurite orientation/dispersion density imaging (NODDI)] and brain-injury blood biomarker levels [Tau, neurofilament-light (NfL), glial-fibrillary-acidic-protein (GFAP)] in high-school football and cross-country runners at their baseline, aiming to detect cumulative neuronal damage from prior seasons. Twenty-five football players and 8 cross-country runners underwent MRI and blood biomarker measures during preseason data collection. The whole-brain, tract-based spatial statistics was conducted for six diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), axial/radial diffusivity (AD, RD), neurite density index (NDI), and orientation dispersion index (ODI). Diffusion metrics and blood biomarker levels were compared between groups and associated within each group. The football group showed lower AD and MD than the cross-country group in various axonal tracts of the right hemisphere. Elevated ODI was observed in the football group in the right hemisphere of the corticospinal tract. Blood biomarker levels were consistent between groups except for elevated Tau levels in the cross-country group. Tau level was positively associated with MD and negatively associated with NDI in the corpus callosum of football players, but not in cross-country runners. Our data suggest that football players may develop axonal microstructural abnormality. Levels of MD and NDI in the corpus callosum were associated with serum Tau levels, highlighting the vulnerability of the corpus callosum against cumulative head impacts. Despite observing multimodal associations in some brain areas, neuroimaging and blood biomarkers may not strongly correlate to reflect the severity of brain damage.

14751: Reward-based invigoration of sequential reaching
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Posted to bioRxiv 16 Jun 2020

Reward-based invigoration of sequential reaching
101 downloads neuroscience

Sebastian Sporn, Xiuli Chen, Joseph M Galea

Seeking reward is a powerful tool for shaping human behaviour. While it has been demonstrated that reward invigorates performance of simple movements, its effect on more complex sequential actions is less clear. In addition, it is unknown why reward-based improvements for discrete actions are transient, i.e. performance gains are lost once reward is removed, but appear long lasting for sequential actions. We show across three experiments that reward invigorates sequential reaching performance. Driven by a reward-based increase in speed, movements also exhibited greater coarticulation, smoothness and a closer alignment to a minimum jerk trajectory. Critically, these performance gains were maintained across multiple days even after the removal of reward. We propose that coarticulation, the blending together of sub-movements into a single continuous action, provides a mechanism by which reward can invigorate sequential performance whilst also increasing efficiency. This change in efficiency appears essential for the retention of reward-based improvements in motor behaviour. ### Competing Interest Statement The authors have declared no competing interest.

14752: The adoptive transfer of BCG-induced T lymphocytes contributes to hippocampal cell proliferation and tempers anxiety-like behavior in immune deficient mice
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Posted to bioRxiv 15 Nov 2019

The adoptive transfer of BCG-induced T lymphocytes contributes to hippocampal cell proliferation and tempers anxiety-like behavior in immune deficient mice
101 downloads neuroscience

Dan Song, Fangfang Qi, ShuaiShuai Liu, Zhongsheng Tang, Jinhai Duan, Zhibin Yao

Background: We previously have reported that neonatal Bacillus Calmette-Guerin (BCG) vaccination improves neurogenesis and behavior in early life through affecting the neuroimmune milieu in the brain, but it is uncertain whether activation phenotypes and functional changes in T lymphocytes shape brain development. Results: We studied the effects of BCG vaccination via the adoptive transfer of T lymphocytes from the BALB/c wild-type mice into naive mice. Our results show that mice adoptive BCG-induced lymphocytes (BCG->naive mice) showed anxiolytic and antidepressant-like performance when completing an elevated plus maze (EPM) test. Meanwhile, BCG->naive mice possess more cell proliferation and newborn neurons than PBS->naive and nude mice in the hippocampus. IFN-γ and IL-4 levels in the serum of BCG->naive mice also increased, while TNF-α and IL-1β levels were reduced relative to those of PBS->naive and nude mice. We further found that BCG->naive mice showed different repartition of CD4+ and CD8+ T cell to naive (CD62L+CD44low), effector memory (CD62L−CD44hi), central memory (CD62L+CD44hi) and acute/activated effector (CD62L−CD44low) cells in the spleen. Importantly, the adoptive transfer of BCG-induced T lymphocytes infiltrated into the dura mater and brain parenchyma of the nude mice. Conclusions: Activation phenotypes and functional changes in T lymphocytes are very likely to affect the neuroimmune milieu in the brain, and alterations in ratios of splenic CD4+ and CD8+ memory T cells may affect the expression of correlative cytokines in the serum, accounting for our behavioral results. We conclude thus that the adoptive transfer of BCG-induced T lymphocytes contributes to hippocampal cell proliferation and tempers anxiety-like behavior in immune deficient mice. Our work shows that BCG vaccination improves hippocampal cell proliferation outcomes and behaviors, likely as a result of splenic effector/memory T lymphocytes regulating the neuroimmune niche in the brain.

14753: Plis de passage in the Superior Temporal Sulcus: Morphology and local connectivity
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Posted to bioRxiv 28 May 2020

Plis de passage in the Superior Temporal Sulcus: Morphology and local connectivity
101 downloads neuroscience

C. Bodin, A. Pron, M. Le Mao, J Régis, P. Belin, O. Coulon

While there is a profusion of functional investigations involving the superior temporal sulcus (STS), our knowledge of the anatomy of this sulcus is still limited by a large variability across individuals. Several "plis de passage" (PPs), annectant gyri buried inside the fold, can separate the STS into distinct segments and could explain part of the observed variability. However, an accurate characterization is lacking to properly extract and fully understand the nature of PPs. The aim of the present study is twofold: i. to characterize the STS PPs by directly identifying them within individual STS, using the geometry of the surrounding surface and considering both deep and superficial PPs. ii. to test the hypothesis that PPs constitute local increases of the short-range structural connectivity. Performed on 90 subjects from the Human Connectome Project database, our study revealed that PPs constitute surface landmarks that can be identified from the geometry of the STS walls and that they constitute critical pathways of the U-shaped white-matter connecting the two banks of the STS. Specifically, a larger amount of fibers was extracted at the location of PPs compared to other locations in the STS. This quantity was also larger for superficial PPs than for deep buried ones. These findings raise new hypotheses regarding the relation between the cortical surface geometry and structural connectivity, as well as the possible role of PPs in the functional organization of the STS. ### Competing Interest Statement The authors have declared no competing interest.

14754: Multicellular rosettes organize neuropil formation
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Posted to bioRxiv 28 May 2020

Multicellular rosettes organize neuropil formation
101 downloads neuroscience

Christopher Brittin, Anthony Santella, Kristopher Barnes, Mark W. Moyle, Li Fan, Ryan Christensen, Irina Kolotuev, William A. Mohler, Hari Shroff, Daniel A. Colón-Ramos, Zhirong Bao

Neuropils are compartments in the nervous system containing dense networks of neurites and synapses which function as information processing centers. Neuropil formation requires structural and functional organization at and across different scales, achieving single-axon precision for circuits that carry out the core functions while simultaneously accommodating variability among individuals1-4. How these organizational features emerge over development is poorly understood. The nerve ring is the primary neuropil in C. elegans , and its structure is thoroughly mapped 5,6. We show that prior to axon outgrowth, nerve ring neurons form a ring of multicellular rosettes with surrounding cells to organize the stratified nerve ring structure 7,8. Axon bundles which correspond to future nerve ring strata grow from rosette centers, travel along the ring on "bridge" cells that are simultaneously engaged in adjacent rosettes, and assemble into a topographic scaffold of the nerve ring. SAX-3/Robo is required for proper rosette formation and outgrowth from the center. Furthermore, axon contact sites that form early in development are more conserved than the later ones, indicating a temporal component in neuropil structural variability. Our results reveal an unexpected and critical role of collective cell behaviors prior to innervation to pattern a complex neuropil and orchestrate its formation across scales. ### Competing Interest Statement The authors have declared no competing interest.

14755: Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson's disease
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Posted to bioRxiv 31 Jan 2020

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson's disease
101 downloads neuroscience

Valerie Joers, Gunasingh Masilamoni, Doty Kempf, Alison R Weiss, Travis Rotterman, Benjamin Murray, Gul Yalcin-Cakmakli, Ronald J Voll, Mark M Goodman, Leonard Howell, Jocelyne Bachevalier, Stefan Green, Ankur Naqib, Maliha Shaikh, Phillip Engen, Ali Keshavarzian, Christopher J Barnum, Jonathon A Nye, Yoland Smith, MG Tansey

Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

14756: Cerebellar Golgi cell models predict dendritic processing and mechanisms of synaptic plasticity
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Posted to bioRxiv 13 May 2020

Cerebellar Golgi cell models predict dendritic processing and mechanisms of synaptic plasticity
101 downloads neuroscience

Stefano Masoli, Alessandra Ottaviani, Egidio D’Angelo

The Golgi cells are the main inhibitory interneurons of the cerebellar granular layer. Although recent works have highlighted the complexity of their dendritic organization and synaptic inputs, the mechanisms through which these neurons integrate complex input patterns remained unknown. Here we have used 8 detailed morphological reconstructions to develop multicompartmental models of Golgi cells, in which Na, Ca, and K channels were distributed along dendrites, soma, axonal initial segment and axon. The models faithfully reproduced a rich pattern of electrophysiological and pharmacological properties and predicted the operating mechanisms of these neurons. Basal dendrites turned out to be more tightly electrically coupled to the axon initial segment than apical dendrites. During synaptic transmission, parallel fibers caused slow Ca-dependent depolarizations in apical dendrites that boosted the axon initial segment encoder and Na-spike backpropagation into basal dendrites, while inhibitory synapses effectively shunted backpropagating currents. This oriented dendritic processing set up a coincidence detector controlling voltage-dependent NMDA receptor unblock in basal dendrites, which, by regulating local calcium influx, may provide the basis for spike-timing dependent plasticity anticipated by theory.

14757: Diminished ventral oligodendrocyte precursor generation results in the subsequent over-production of dorsal oligodendrocyte precursors of aberrant morphology and function.
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Posted to bioRxiv 09 Mar 2020

Diminished ventral oligodendrocyte precursor generation results in the subsequent over-production of dorsal oligodendrocyte precursors of aberrant morphology and function.
101 downloads neuroscience

Lev Starikov, Andreas H. Kottmann

Oligodendrocyte precursor cells (OPCs) arise sequentially first from a ventral and then from a dorsal precursor domain at the end of neurogenesis during spinal cord development. Whether the sequential production of OPCs is of physiological significance has not been examined. Here we show that ablating Shh signaling from nascent ventricular zone derivatives and partially from the floor plate results in a severe diminishment of ventral derived OPCs but normal numbers of motor neurons in the postnatal spinal cord. In the absence of ventral vOPCs, dorsal dOPCs populate the entire spinal cord resulting in an increased OPC density in the ventral horns. These OPCs take on an altered morphology, do not participate in the removal of excitatory vGlut1 synapses from injured motor neurons, and exhibit morphological features similar to those found in the vicinity of motor neurons in the SOD1 mouse model of Amyotrophic Lateral Sclerosis (ALS). Our data indicates that vOPCs prevent dOPCs from invading ventral spinal cord laminae and suggests that vOPCs have a unique ability to communicate with injured motor neurons.

14758: Mosaic expression of X-linked PCDH19 Protein by in Utero Electroporation in Rats Replicates Human Cortical and Hippocampal Developmental Abnormalities, Associated Core Behaviors Related to Autism, and Cognitive Impairment.
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Posted to bioRxiv 12 Jun 2020

Mosaic expression of X-linked PCDH19 Protein by in Utero Electroporation in Rats Replicates Human Cortical and Hippocampal Developmental Abnormalities, Associated Core Behaviors Related to Autism, and Cognitive Impairment.
101 downloads neuroscience

Andrzej W Cwetsch, Roberto Narducci, Maria Bolla, Bruno Pinto, Laura Perlini, Silvia Bassani, Maria Passafaro, Laura Cancedda

PCDH19 gene-related epilepsy or epileptic encephalopathy, early infantile, 9 (EIEE9) is an infantile onset epilepsy syndrome characterized by psychiatric (including autistic) sensory and cognitive impairment of varying degrees. EIEE9 is caused by X-linked PCDH19 protein loss of function. Due to random X-chromosome inactivation, EIEE9-affected females present a mosaic population of healthy and Pcdh19-mutant cells. Unfortunately, no mouse models recapitulate to date both the brain histological and behavioural deficits present in people with EIEE9. Thus, the search for a proper understanding of the disease, and possible future treatment is hampered. By inducing a focal mosaicism of Pdch19 expression using in utero electroporation in rat, we found here that Pcdh19 signaling in specific brain areas is implicated in neuronal migration, as well as in core behaviors related to autism and cognitive function. ### Competing Interest Statement The authors have declared no competing interest.

14759: Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes
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Posted to bioRxiv 05 Jun 2020

Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes
101 downloads neuroscience

Juliane Schiweck, Kai Murk, Julia Ledderose, Agnieszka Münster-Wandowski, Imre Vida, Britta J Eickholt

The brain of mammals lacks a significant ability to regenerate neurons and is thus particularly vulnerable. To protect the brain from injury and disease, damage control by astrocytes through astrogliosis and scar formation is vital. Here, we show that brain injury triggers an ad hoc upregulation of the actin-binding protein Drebrin (DBN) in astrocytes, which is essential for the formation and maintenance of glial scars in vivo. In turn, DBN loss leads to defective glial scar formation and excessive neurodegeneration following mild brain injuries. At the cellular level, DBN switches actin homeostasis from ARP2/3-dependent arrays to microtubule-compatible scaffolds and facilitates the formation of RAB8-positive membrane tubules. This injury-specific RAB8 membrane compartment serves as hub for the trafficking of surface proteins involved in astrogliosis and adhesive responses, such as β1-integrin. Our work identifies DBN as pathology-specific actin regulator, and establishes DBN-dependent membrane trafficking as crucial mechanism in protecting the brain from escalating damage following traumatic injuries. ### Competing Interest Statement The authors have declared no competing interest.

14760: Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Expression of Abnormal Involuntary Movements
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Posted to bioRxiv 10 Mar 2020

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Expression of Abnormal Involuntary Movements
101 downloads neuroscience

Lauren Malave, Dustin R Zuelke, Lev Starikov, Heike Rebholz, Eitan Friedman, Chuan Qin, Qin Li, Erwan Bezard, Andreas H. Kottmann

Our limited understanding of neuronal co-transmission complicates predicting the effects of pharmacological interventions from neuronal wiring diagrams [1, 2]. For example, dopamine neurons (DAN), whose degeneration causes the motor and cognitive deficits of Parkinson Disease (PD) [3], communicate with all their targets by dopamine (DA) and in addition use the neurotransmitters GABA, Glutamate and secreted peptides including the morphogen Sonic Hedgehog (Shh) to signal to select subsets of neurons [4-8]. It is unknown whether Levodopa (L-Dopa) induced dyskinesia (LID), a debilitating side effect of DA supplementation therapy in PD [9], might appear because DAN targets become exposed to high levels of DA but diminished levels of other DAN produced signaling factors. Here we show that restoring the balance of DA and Shh signaling by agonists of the Shh signaling effector G-protein coupled receptor Smoothened (Smo [10, 11]) attenuates LID in mouse- and macaque- models of PD. Using conditional genetic loss of function approaches of pre- and post-synaptic Shh signaling we found that reducing the activity of Smo selectively in cholinergic neurons facilitates LID. Conversely, the expression of a constitutive active form of Smo (SmoM2 [12]) in cholinergic neurons is sufficient to render the sensitized aphakia model of PD resistant to LID. Furthermore, the acute diminishment of Shh emanating from DAN by optogenetic means in the otherwise intact brain and in the absence of L-Dopa results in LID-like abnormal involuntary movements. We reveal that Shh co-transmission counteracts DA action in a DAN target- and striatal domain- specific manner. Our results suggest an un-anticipated mechanism - reduced Shh signaling - by which DAN degeneration sensitizes PD patients to LID. We anticipate that our models provide a starting point for assessing the contributions of Shh to the teaching signal that emanates from DAN and testing the hypothesis that LID are caused by aberrant learning [13-15].

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