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    Ventral subiculum inputs to nucleus accumbens medial shell preferentially innervate D2R medium spiny neurons and contain calcium permeable AMPARs

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.12.511974v1?rss=1 Authors: Boxer, E., Kim, J., Dunn, B., Aoto, J. Abstract: Ventral subiculum (vSUB) is the major output region of ventral hippocampus (vHIPP) and sends major projections to nucleus accumbens medial shell (NAcMS). Hyperactivity of the vSUB-NAcMS circuit is associated with substance use disorders (SUDs) and the modulation of vSUB activity alters drug seeking and drug reinstatement behavior in rodents. However, to the best of our knowledge, the cell-type specific connectivity and synaptic transmission properties of the vSUB-NAcMS circuit have never been directly examined. Instead, previous functional studies have focused on total ventral hippocampal (vHIPP) output to NAcMS without distinguishing vSUB from other subregions of vHIPP, including ventral CA1 (vCA1). Using ex vivo electrophysiology, we systematically characterized the vSUB-NAcMS circuit with cell-type and synapse specific resolution in male and female mice and found that vSUB output to dopamine receptor type-1 (D1R) and type-2 (D2R) expressing medium spiny neurons (MSNs) displays a functional connectivity bias for D2R MSNs. Furthermore, we found that vSUB-D1R and -D2R MSN synapses contain calcium-permeable AMPA receptors in drug-naive mice. Finally, we find that, distinct from other glutamatergic inputs, cocaine exposure selectively induces plasticity at vSUB-D2R synapses. Importantly, we directly compared vSUB and vCA1 output to NAcMS and found that vSUB synapses are functionally distinct and that vCA1 output recapitulated the synaptic properties previously ascribed to vHIPP. Our work highlights the need to consider the contributions of individual subregions of vHIPP to SUDs and represents an important first step toward understanding how the vSUB-NAcMS circuit contributes to the etiologies that underlie SUDs. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Polyphasic circadian neural circuits drive differential activities in multiple downstream rhythmic centers

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.511837v1?rss=1 Authors: Liang, X., Holy, T. E., Taghert, P. Abstract: Circadian clocks align various behaviors such as locomotor activity, sleep/wake, feeding, and mating to times of day that are most adaptive. How rhythmic information in pacemaker circuits is translated to neuronal outputs is not well understood. Here we used brain-wide, 24-hr in vivo calcium imaging in the Drosophila brain and searched for circadian rhythmic activity among identified clusters of dopaminergic (DA) and peptidergic neuroendocrine (PNE) neurons. Such rhythms were widespread and imposed by the PERIOD-dependent clock activity within the ~150 cell circadian pacemaker network. The rhythms displayed either a Morning, an Evening, or Mid-Day phase. Different sub-groups of circadian pacemakers imposed neural activity rhythms onto different downstream non-clock neurons. Outputs from the canonical M and E pacemakers converged to regulate DA-PPM3 and DA-PAL neurons. E pacemakers regulate the Evening-active DA-PPL1 neurons. In addition to these canonical M and E oscillators, we present evidence for a third dedicated phase occurring at Mid-Day (MD): the l-LNv pacemakers present the MD activity peak and they regulate the MD-active DA-PPM1/2 neurons and three distinct PNE cell types. Thus, the Drosophila circadian pacemaker network is a polyphasic rhythm generator. It presents dedicated M, E and MD phases that are functionally transduced as neuronal outputs to organize diverse daily activity patterns in downstream circuits. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    The function of ethanol in olfactory associative behaviors in Drosophila melanogaster larvae

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.13.512092v1?rss=1 Authors: Scholz, H., Berger, M., Yapıcı, B. Abstract: Drosophila melanogaster larvae develop on fermenting fruits with increasing ethanol concentrations. To address the relevance of ethanol in the behavioral response of the larvae, we analyzed the function of ethanol in the context of olfactory associative behavior in Canton S and w1118 larvae. The motivation of larvae to move toward or out of an ethanol-containing substrate depends on the ethanol concentration and the genotype. Ethanol in the substrate reduces the attraction to odorant cues in the environment. Relatively short repetitive exposures to ethanol, which are comparable in their duration to reinforcer representation in olfactory associative learning and memory paradigms, result in positive or negative association with the paired odorant or indifference to it. The outcome depends on the order in which the reinforcer is presented during training, the genotype and the presence of the reinforcer during the test. Independent of the order of odorant presentation during training, Canton S and w1118 larvae do not form a positive or negative association with the odorant when ethanol is not present in the test context. When ethanol is present in the test, w1118 larvae show aversion to an odorant paired with a naturally occurring ethanol concentration of 5%. Our results provide insights into the parameters influencing olfactory associative behaviors using ethanol as a reinforcer in Drosophila larvae and indicate that short exposures to ethanol might not uncover the positive rewarding properties of ethanol for developing larvae. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    A meta-analysis of the effect of protein synthesis inhibitors on rodent fear conditioning

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.509645v1?rss=1 Authors: Carneiro, C. F. D., Amorim, F. E., Amaral, O. B. Abstract: Systematic reviews and meta-analyses have been increasingly recognized for their potential value in pre-clinical research, but their multiple applications have not been extensively explored in behavioral neuroscience. In this work, we studied protein synthesis inhibition, a classic intervention used to disrupt fear learning, reconsolidation, and extinction in rodents, to explore how meta-analyses can identify potential moderators of its effect. We initially performed separate meta-analyses for different injection sites (systemic, hippocampus, amygdala, and cerebral ventricles) and target sessions (training, reconsolidation and extinction) to evaluate the effect of the intervention in various scenarios. Heterogeneity was further investigated by uni- and multivariable meta-regression using models aggregating various sites, with article or research group as additional levels. We detected robust effects of protein synthesis inhibitors on training and reconsolidation, but not on extinction, possibly due to the lower number of studies on the latter. Our analyses identified some well-established moderators, such as injection timing for training interventions and reexposure duration for reactivation interventions. However, other factors proposed as boundary conditions for reconsolidation, such as training strength and memory age, were not associated with effect size across the literature. Additionally, our findings suggest some underexplored associations, such as a larger susceptibility of cued fear conditioning to reconsolidation when compared to the contextual version of the task. While our results point to the value of meta-analyses in consolidating findings from the literature, we believe that associations suggested by data synthesis should ideally be verified by well-powered, rigorous confirmatory experiments. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Physics-based Deep Learning for Imaging Neuronal Activity via Two-photon and Light Field Microscopy

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.511633v1?rss=1 Authors: Verinaz-Jadan, H., Howe, C. L., Song, P., Lesept, F., Kittler, J., Foust, A. J., Dragotti, P. L. Abstract: Light Field Microscopy (LFM) is an imaging technique that offers the opportunity to study fast dynamics in biological systems due to its rapid 3D imaging rate. In particular, it is attractive to analyze neuronal activity in the brain. Unlike scanning-based imaging methods, LFM simultaneously encodes the spatial and angular information of light in a single snapshot. However, LFM is limited by a trade-off between spatial and angular resolution and is affected by scattering at deep layers in the brain tissue. In contrast, two-photon (2P) microscopy is a point-scanning 3D imaging technique that achieves higher spatial resolution, deeper tissue penetration, and reduced scattering effects. However, point-scanning acquisition limits the imaging speed in 2P microscopy and cannot be used to simultaneously monitor the activity of a large population of neurons. This work introduces a physics-driven deep neural network to image neuronal activity in scattering volume tissues using LFM. The architecture of the network is obtained by unfolding the ISTA algorithm and is based on the observation that the neurons in the tissue are sparse. The deep-network architecture is also based on a novel imaging system modeling that uses a linear convolutional neural network and fits the physics of the acquisition process. To achieve the high-quality reconstruction of neuronal activity in 3D brain tissues from temporal sequences of light field (LF) images, we train the network in a semi-supervised manner using generative adversarial networks (GANs). We use the TdTomato indicator to obtain static structural information of the tissue with the microscope operating in 2P scanning modality, representing the target reconstruction quality. We also use additional functional data in LF modality with GCaMP indicators to train the network. Our approach is tested under adverse conditions: limited training data, background noise, and scattering samples. We experimentally show that our method performs better than model-based reconstruction strategies and typical artificial neural networks for imaging neuronal activity in mammalian brain tissue, considering reconstruction quality, generalization to functional imaging, and reconstruction speed. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Single-cell analysis characterizes non-enhancing region of recurrent high-grade glioma

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511639v1?rss=1 Authors: Patel, K. S., Tessema, K. K., Kawaguchi, R., Alvarado, A. G., Muthukrishnan, S. D. D., Hagiwara, A., Swarup, V., Liau, L. M., Wang, A. C., Yong, W., Geschwind, D., Nakano, I., Goldman, S., Everson, R., Ellingson, B., Kornblum, H. Abstract: Both therapy for and molecular investigations into high-grade glioma largely focus on the contrast-enhancing (CE) portion of the tumor. However, given the invasive nature of glioma, residual tumor cells responsible for recurrence exist in the peripheral, non-enhancing (NE) region. Single-cell/single-nucleus RNA-sequencing and subsequent bioinformatics analyses offer a flexible and scalable framework that allows powerful examination of tumor and non-tumor cell subpopulations across various contexts. In this study, we used pre-operative magnetic resonance images to prospectively identify biopsy targets in the CE region and NE sites that lie 0.5-2.0 cm beyond the CE edge from multiple pathologically and molecularly distinct recurrent high-grade gliomas and leveraged single-nucleus RNA-sequencing to generate over 30,000 individual RNA profiles. We analyzed multiple glioma cellular states, non-malignant cell types, and cell-cell interaction patterns, all of which revealed both conserved and patient-specific features. Recurrent gliomas recapitulate the previously reported cellular heterogeneity of primary gliomas. Systematic comparison of the CE and NE regions identified altered composition of malignant and non-malignant cell compartments, as well as cell type- and patient-specific differences in gene expression and pathway activation profiles. We established that NE regions up to 1.5 cm beyond the CE edge contain up to 60% infiltrating malignant cells, of which a significant subset are actively proliferating. These NE glioma cells are preferentially in OPC-like and NPC-like rather than MES-like cellular states. NE cells have altered gene expression patterns, with specific upregulation of certain genes like DGKB and OPHN1 relative to CE regions. We built an integrated atlas of cell-cell communication networks among malignant and non-malignant subpopulations in the two regions of glioma and identified a significantly rewired connectome in the NE regions of all tumors. With respect to tumor-immune interactions, NE regions had decreased numbers of T cells and myeloid cells, along with decreased HLA:CD8 signaling between glioma and immune cells, suggesting decreased immune detection and cell mediated immunity. Furthermore, our findings suggest glioma cells in NE regions maintain interactions with non-malignant neural tissue. Overall, we characterize the NE region in all pathological subtypes of recurrent high-grade glioma and identify possible mechanisms driving progression and recurrence, as well as areas of future therapeutic study. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Electrophysiological population dynamics reveal context dependencies during decision making in human frontal cortex

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.511706v1?rss=1 Authors: Shih, W.-Y., Yu, H.-Y., Lee, C.-C., Chou, C.-C., Chen, C., Glimcher, P. W., Wu, S.-W. Abstract: During economic choice, evidence from monkeys and humans suggest that activity in the orbitofrontal cortex (OFC) encodes the subjective values of options under consideration. Monkey data further suggests that value representations in the OFC are context dependent, representing subjective value in a way influenced by the decision makers recent experience. Using stereo electroencephalography (sEEG) in human subjects, we investigated the neural representations of both past and present subjective values in the OFC, insula, cingulate and parietal cortices, amygdala, hippocampus and striatum. Patients with epilepsy (n=20) reported their willingness to pay, a measure of subjective value, for snack food items in a Becker-DeGroot-Marschack (BDM) auction task. We found that the high frequency power (gamma and high-gamma bands) in the OFC positively correlated with the current subjective value but negatively correlated with the subjective value of the good offered on the last trial, a kind of temporal context dependency not yet observed in humans. These representations were observed at both the group level (across electrode contacts and subjects) and at the level of individual contacts. Noticeably, the majority of significant contacts represented either the present or past subjective value, but not both. A dynamic dimensionality-reduction analysis of OFC population trajectories suggested that the past trial begin to influence activity early in the current trial after the current offer was revealed, and that these two properties, current and past subjective values, dominate the electrophysiological signals. Together, these findings indicate that information about the value of the past and present rewards are simultaneously represented in the human OFC, and offer insights into the algorithmic structure of context-dependent computation during human economic choice. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Seg2Link: an efficient and versatile solution for semi-automatic cell segmentation in 3D image stacks

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511670v1?rss=1 Authors: Wen, C., Matsumoto, M., Sawada, M., Sawamoto, K., Kimura, K. D. Abstract: Recent advances in microscopy techniques, especially in electron microscopy, are transforming biomedical studies by acquiring large quantities of high-precision 3D cell image stacks. However, to study cell morphology and connectivity in organs such as brains, scientists must first perform cell segmentation, which involves extracting individual cell regions of various shapes and sizes from a 3D image. This remains a great challenge because automatic cell segmentation can contain numerous errors, even with advanced deep learning methods. For biomedical research that requires cell segmentation in large 3D image stacks, an efficient semi-automated software solution is still needed. We created Seg2Link, which generates automatic segmentations based on deep learning predictions and allows users to quickly correct errors in the segmentation results. It can perform automatic instance segmentation of 2D cells in each slice, 3D cell linking across slices, and various manual corrections, in order to efficiently transform inaccurate deep learning predictions into accurate segmentation results. Seg2Link's data structure and algorithms were also optimized to process 3D images with billions of voxels on a personal computer quickly. Thus, Seg2Link offers a simple and effective way for scientists to study cell morphology and connectivity in 3D image stacks. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Decoding brain basis of laughter and crying in natural scenes.

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.511708v1?rss=1 Authors: Nummenmaa, L., Malen, T., Nazari-Farsani, S., Seppala, K., Sun, L., Karlsson, H., Hudson, M., Hirvonen, J., Sams, M., Scott, S. K., Putkinen, V. J. Abstract: Laughter and crying are universal signals of prosociality and distress, respectively. Here we investigated the functional brain basis of perceiving laughter and crying using naturalistic functional magnetic resonance imaging (fMRI) approach. We measured haemodynamic brain activity evoked by laughter and crying in three experiments with 100 subjects in each. The subjects i) viewed a 20-minute medley of short video clips, and ii) 30 minutes of a full-length feature film, and iii) listened to 15 minutes of a radio play that all contained bursts of laughter and crying. Intensity of laughing and crying in the videos and radio play was annotated by independent observes, and the resulting time series were used to predict hemodynamic activity to laughter and crying episodes. Multivariate pattern analysis (MVPA) was used to test for regional selectivity in laughter and crying evoked activations. Laughter induced widespread activity in ventral visual cortex and superior and middle temporal and motor cortices. Crying activated thalamus, cingulate cortex along the anterior-posterior axis, insula and orbitofrontal cortex. Both laughter and crying could be decoded accurately (66-77% depending on the experiment) from the BOLD signal, and the voxels contributing most significantly to classification were in superior temporal cortex. These results suggest that perceiving laughter and crying engage distinct neural networks, whose activity suppresses each other to manage appropriate behavioral responses to others bonding and distress signals. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Subcortical circuit dysfunctions delay perceptual decision-making in autism models

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.511691v1?rss=1 Authors: Burnett, L. E., Koppensteiner, P., Symonova, O., Masson, T., Vega-Zuniga, T., Contreras, X., Ruelicke, T., Shigemoto, R., Novarino, G., Joesch, M. Abstract: Autism spectrum disorders (ASD) include a range of neurodevelopmental conditions characterised by social and communication difficulties, often co-occurring with sensory processing abnormalities. The neural origins of these impairments are thought to reside in cortical circuits. Here we demonstrate that a subcortical node required to initiate efficient and timely responses to visual threats is disrupted across genetic models of ASD. Although mutant animals can detect visual threat stimuli, they require longer to evaluate them and respond with less vigour than their wild-type siblings. These delays in perceptual judgement are linked to reduced place-aversion to visual threats. Visual responses and other motor properties remain unaffected, overall indicating cognitive rather than sensory or motor impairments. Focusing on one of the models (Setd5), we show that these behavioural deficits are recapitulated following optogenetic activation of excitatory deep medial collicular neurons, known to initiate threat responses by exciting the dorsal periaqueductal gray (dPAG). Consistently, ex vivo patch-clamp recordings of Setd5 mutant dPAG neurons revealed a stark hypoexcitability phenotype mediated by misregulation of a voltage-gated potassium channel. Our results show that the timing of perceptual decision-making is regulated via intrinsic excitability, mechanistically dissecting a cognitive disorder through an instinctive behaviour. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Characterizing amblyopic perception under naturalistic viewing conditions

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511635v1?rss=1 Authors: Meier, K., Tarczy-Hornoch, K., Boynton, G., Fine, I. Abstract: Current assessments of interocular interactions in amblyopia use rivalrous stimuli, with conflicting stimuli in each eye, which does not reflect vision under typical circumstances. Here we measure interocular interactions in observers with amblyopia, strabismus with equal vision, and controls using a non-rivalrous stimulus. Observers used a joystick to continuously report perceived contrast of dichoptic grating stimuli, identical except that the stimulus was contrast-modulated independently in each eye over time. Consistent with previous studies, a model predicting the time-course of perceived contrast found increased amblyopic eye attenuation, and reduced contrast normalization of the fellow eye by the amblyopic eye, in amblyopic participants compared to controls. However, these suppressive interocular effects were weaker than those found in previous studies, suggesting that rivalrous stimuli may overestimate the effects of amblyopia on interocular interactions during naturalistic viewing conditions. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Spatial memory consolidation during REM sleep requires stabilization of newly formed place cells.

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511566v1?rss=1 Authors: Boyce, R., Yong, H. C., Carmichael, J. E., Brandon, M., Williams, S. Abstract: The neural mechanisms behind the role of rapid-eye-movement sleep (REMs) in spatial memory formation are unclear. Here, we performed hippocampal CA1 single-unit recordings in mice expressing archaerhodopsin in GABAergic neurons of the medial septum (MSGABA), an established optogenetic method enabling REMs-selective theta rhythm attenuation resulting in spatial memory deficits. Analysis of CA1 neural assemblies during REMs revealed reduced synchrony of constituent neural activity during MSGABA silencing. Subsequent investigation of recently formed CA1 place cells demonstrated that REMs-selective MSGABA inhibition reduced the place stability of those which participated in prior REMs assembly activity, but not of those which did not. This suggests that CA1 neural assemblies during REMs facilitate spatial memory formation by stabilizing spatial representations in a plastic subpopulation of participating CA1 neurons. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    OPTIMIZED NEURON TRACING USING POST HOC REANALYSIS

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511642v1?rss=1 Authors: Azzouz, S., Walker, L. A., Doerner, A., Geisel, K., Rodriguez-Rivera, A. K., Li, Y., Roossien, D. H., Cai, D. Abstract: Over the last decade, the advances in Brainbow labeling allowed labeling hundreds of neurons with distinct colors in the same field of view of a brain [1, 2]. Reconstruction (or "tracing") of the 3D structures of these images has been enabled by a growing set of software tools for automatic and manual annotation. It is common, however, to have errors introduced by heuristics used by tracing software, namely that they assume the "best" path is the highest intensity one, a more pertinent issue when dealing with multicolor microscope images. Here, we report nCorrect, an algorithm for correcting this error by reanalyzing previously created neuron traces to produce more physiologically-relevant ones. Specifically, we use a four dimensional minimization algorithm to identify a more-optimal reconstruction of the image, allowing us to better take advantage of existing manual tracing results. We define a new metric (hyperspectral cosine similarity) for describing the similarity of different neuron colors to each other. Our code is available in an open source license and forms the basis for future improved neuron tracing software. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Post-saccadic following in the marmoset monkey as a read-out of pre-saccadic attention

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511640v1?rss=1 Authors: Coop, S. H., Bunce, G. W., Abrham, Y. T., Bucklaew, A., Mitchell, J. F. Abstract: During natural visual foraging, primates move their eyes 2-3 times per second to bring objects of interest to central, high-resolution vision at the fovea. For moving objects, they use a combination of rapid saccadic eye movements along with smooth following movements to track targets continuously. It is also known that saccadic eye movements produce perceptual enhancements for the saccade target before the eyes move, called pre-saccadic attention. Recently, in human participants, we found that saccades made to peripheral motion apertures resulted in smooth post-saccadic following that tracked stimulus motion at low gain (Kwon, Rolfs, & Mitchell, 2019). Because this effect persisted even when the stimulus disappeared in saccade flight, we can infer the post-saccadic following was predictive, reflecting the integration of peripheral motion information from the target before the saccade, and provides an automatic perceptual read-out of stimulus motion. Here we examined post-saccadic following in marmoset monkeys to determine if they automatically tracked stimulus motion like humans, and if so, if that following response could be used as a reliable behavioral read-out of motion. Marmosets performed a saccade foraging task in which they initially acquired central fixation and then made a saccade that sampled between three different motion apertures. For each trial, the direction of motion of each aperture was independently sampled from 16 directions. We found that immediately upon saccade offset, the marmosets eye traces followed the pre-saccadic motion with a low (10-20%) gain that was consistent with humans. We also found that the motion from other non-target apertures influenced following responses though with a much weaker gain. The gain was distributed equally across apertures before the saccade, but immediately after the saccade was enhanced for the saccade target relative to other apertures, consistent with a post-saccadic target enhancement found in smooth pursuit (Gardener and Lisberger, 2001). This following response provided an estimate of target motion with a median absolute angular errors ranging from 25 to 50 degrees across sessions, roughly half as accurate as that achieved with an explicit trained perceptual report (Cloherty et. al., 2020). Session by session the relative gain for the target as compared to other apertures also varied, providing an index of attentional selection. These findings support that natural visual foraging with moving targets can provide an automatic behavioral read-out of peripheral motion integration and pre-saccadic attention. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    A Cre-Driver Rat Model for Anatomical and Functional Analysis of Glucagon (Gcg)-Expressing Cells in the Brain and Periphery

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511573v1?rss=1 Authors: Zheng, H., Lopez-Ferreras, L., Krieger, J.-P., Fasul, S., Cea Salazar, V., Valderrama Pena, N., Skibicka, K. P., Rinaman, L. Abstract: Objective: The glucagon gene (Gcg) encodes preproglucagon, which is cleaved to form glucagon-like peptide 1 (GLP1) and other mature signaling molecules implicated in metabolic functions. To date there are no transgenic rat models available for precise manipulation of GLP1-expressing cells in the brain and periphery. Methods: To visualize and manipulate Gcg-expressing cells in rats, CRISPR/Cas9 was used to express iCre under control of the Gcg promoter. Gcg-Cre rats were bred with tdTomato reporter rats to tag Gcg-expressing cells. Cre-dependent AAVs and RNAscope in situ hybridization were used to evaluate the specificity of iCre expression by GLP1 neurons in the caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt), and by intestinal and pancreatic secretory cells. Food intake was assessed in heterozygous (Het) Gcg-Cre rats after chemogenetic stimulation of cNTS GLP1 neurons expressing an excitatory DREADD. Results: While genotype has minimal effect on body weight or composition in chow-fed Gcg-Cre rats, homozygous (Homo) rats have lower plasma glucose levels. In neonatal and adult Gcg-Cre/tdTom rats, reporter-labeled cells are present in the cNTS and IRt, and in additional brain regions (e.g., basolateral amygdala, piriform cortex) that lack detectable Gcg mRNA in adults but display transient developmental or persistently low Gcg expression. Compared to wildtype (WT) rats, hindbrain Gcg mRNA and GLP1 protein in brain and plasma are markedly reduced in Homo Gcg-Cre rats. Chemogenetic stimulation of cNTS GLP1 neurons reduced overnight chow intake in males but not females, the effect in males was blocked by antagonism of central GLP1 receptors, and hypophagia was enhanced when combined with a subthreshold dose of cholecystokinin-8 to stimulate gastrointestinal vagal afferents. Conclusions: Gcg-Cre rats are a novel and valuable experimental tool for analyzing the development, anatomy, and function of Gcg-expressing cells in the brain and periphery. In addition, Homo Gcg-Cre rats are a unique model for assessing the role of Gcg-encoded proteins in glucose homeostasis and energy metabolism. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Recording brain activity with ear-EEG (cEEGrids)

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.07.511290v1?rss=1 Authors: Hoelle, D., Bleichner, M. G. Abstract: The cEEGrid (ear-electroencephalography; ear-EEG) is an unobtrusive and comfortable electrode array affixed around the ear. It is suited to investigate brain activity outside of the laboratory for long durations. Previous research established that cEEGrids can be used to study various cognitive processes in and also beyond the lab, even for a whole day. To record high-quality ear-EEG data, careful preparation is necessary. In this protocol, we explain the steps needed for successful experimenting with cEEGrids: First, we show how to test the functionality of the cEEGrid prior to a recording. Second, we describe how to prepare the participant and to fit the cEEGrid, which is the most important step to record high-quality data. Third, we outline how to connect the cEEGrids to the amplifier and how to check the signal quality. In this protocol, we give best practice recommendations and tips that make cEEGrid recordings easier. If researchers follow this protocol, they are comprehensively equipped for experimenting with the cEEGrid in and beyond the lab. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Timing matters: Sex differences in acute and chronic outcomes following repetitive blast mild traumatic brain injury

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.511013v1?rss=1 Authors: Baskin, B. M., Logsdon, A. F., Lee, J. S., Foresi, B. D., Peskind, E., Banks, W. A., Cook, D. G., Schindler, A. G. Abstract: Background: Repetitive blast-related mild traumatic brain injury (mTBI) caused by exposure to high explosives is increasingly common among warfighters as well as civilians. While women have been serving in military positions with increased risk of blast exposure since 2016, there are few published reports examining sex as a biological variable in models of blast mTBI, greatly limiting diagnosis and treatment capabilities. As such, here we examined acute and chronic outcomes of repetitive blast trauma in female and male mice in relation to potential behavioral, inflammatory, microbiome, and vascular dysfunction. Methods: In this study we utilized a well-established blast overpressure model to induce repetitive (3x) blast-mTBI in both female and male mice. Acutely following repetitive exposure, we measured serum and brain cytokine levels, blood-brain barrier (BBB) disruption, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. Chronically, in female and male mice we assessed behavioral correlates of mTBI and PTSD-related symptoms commonly reported by Veterans with a history of blast-mTBI using the elevated zero maze, acoustic startle, and conditioned odorant aversion paradigms. Results: Repetitive blast exposure resulted in similar and disparate patterns of acute serum and brain cytokine as well as gut microbiome changes in female and male mice. Acute BBB disruption following repetitive blast exposure was apparent in both sexes. While female and male blast mice both exhibited acute locomotor and anxiety-like deficits in the open field assay, only male mice exhibited chronic adverse behavioral outcomes. Discussion: Representing a novel survey of potential sex differences following repetitive blast trauma, our results demonstrate unique similar and divergent patterns of blast-induced dysfunction in female vs. male mice and highlight novel targets for future diagnosis and therapeutic development. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Inability to make facial expressions dampens emotion perception.

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.510399v1?rss=1 Authors: Japee, S., Jordan, J., Licht, J., Lokey, S., Moebius Syndrome Research Consortium,, Chen, G., Snow, J., Jabs, E. W., Webb, B. D., Engle, E. C., Manoli, I., Baker, C., Ungerleider, L. G. Abstract: Humans rely heavily on facial expressions for social communication to convey their thoughts and emotions and to understand them in others. One prominent but controversial view is that humans learn to recognize the significance of facial expressions by mimicking the expressions of others. This view predicts that an inability to make facial expressions (e.g., facial paralysis) would result in reduced perceptual sensitivity to others' facial expressions. To test this hypothesis, we developed a diverse battery of sensitive emotion recognition tasks to characterize emotion perception in individuals with Moebius Syndrome (MBS), a congenital neurological disorder that causes facial palsy. Using computer-based emotion detection tasks we systematically assessed emotion perception thresholds for static and dynamic face and body expressions. We found that while MBS individuals were able to perform challenging perceptual control tasks, they were less efficient at extracting emotion from facial expressions, compared to matched controls. Exploratory analyses of fMRI data from a small group of MBS participants suggested potentially reduced engagement of the amygdala in MBS participants during expression processing relative to matched controls. Collectively, these results support the role of facial mimicry and consequent facial feedback and motor experience in the perception of others' expressions. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    A novel pH-sensitive reporter reveals the cocaine-regulated trafficking of dopamine transporters in neuronal processes

    Play Episode Listen Later Oct 13, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.12.511970v1?rss=1 Authors: Saenz, J., Yao, O., Aggarwal, M., Zhou, X., Barker, D. J., DiCicco-Bloom, E., Pan, P.-Y. Abstract: The dopamine transporter (DAT) mediated DA reuptake is a major molecular mechanism for termination of dopaminergic signaling in the brain. Psychoactive substances such as cocaine act by inhibition of plasma membrane DAT function as well as by altering its expression. The precise manner and mechanism by which cocaine regulates DAT trafficking, especially at neuronal processes, are poorly understood. We have now engineered a novel pH-sensitive reporter for DAT by conjugating pHluorin to the second exofacial loop of human DAT. We show that DAT-pHluorin can be used to study DAT localization and its dynamic trafficking at neuronal processes. Using DAT-pHluorin we show that unlike neuronal soma and dendrites, which contain majority of the DATs in weakly acidic intracellular compartments, axonal DATs at both shafts and boutons are primarily (75%) localized to the plasma membrane, while varicosities contain abundant intracellular DAT within acidic intracellular structures. Using this novel reporter, we show, for the first time, that cocaine exposure leads to a brief DAT internalization followed by membrane reinsertion that lasts for days. We further show that the cocaine-induced DAT trafficking is sensitive to the activities of Synaptojanin1 phosphatase. Thus, our study using the newly engineered DAT optical reporter reveals the previously unknown dynamics and molecular regulation for cocaine-regulated DAT trafficking in neuronal processes. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    The clock gene Per1 expression may exert diurnal control over hippocampal memory consolidation

    Play Episode Listen Later Oct 12, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.511798v1?rss=1 Authors: Bellfy, L., Smies, C. W., Bernhardt, A. R., Bodinayake, K. K., Sebastian, A., Stuart, E. M., Wright, D. S., Lo, C.-Y., Murakami, S., Boyd, H. M., von Abo, M. J., Albert, I., Kwapis, J. L. Abstract: The circadian system influences many different biological processes, including memory performance. While the suprachiasmatic nucleus (SCN) functions as the central pacemaker of the brain, satellite clocks have also been identified in other brain regions, such as the memory-relevant dorsal hippocampus. Although it is unclear how these satellite clocks contribute to brain function, one possibility is that they may serve to exert diurnal control over local processes. Within the hippocampus, for example, the local clock may contribute to time-of-day effects on memory. Here, we used the hippocampus-dependent Object Location Memory task to determine how memory is regulated across the day/night cycle in mice. First, we systematically determined which phase of memory (acquisition, consolidation, or retrieval) is modulated across the 24h day. We found that mice show better long-term memory performance during the day than at night, an effect that was specifically attributed to diurnal changes in memory consolidation, as neither memory acquisition nor memory retrieval fluctuated across the day/night cycle. Using RNA-sequencing we identified the circadian clock gene Period1 (Per1) as a key mechanism capable of supporting this diurnal fluctuation in memory consolidation, as Per1 oscillates in tandem with memory performance. We then show that local knockdown of Per1 within the dorsal hippocampus has no effect on either the circadian rhythm or sleep behavior, although previous work has shown this manipulation impairs memory. Thus, Per1 may independently function within the dorsal hippocampus to regulate memory in addition to its known role in regulating the circadian rhythm within the SCN. Per1 may therefore exert local diurnal control over memory consolidation within the dorsal hippocampus. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Therapeutic trial of anle138b in mouse models of genetic prion disease

    Play Episode Listen Later Oct 12, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.511739v1?rss=1 Authors: Vallabh, S. M., Zou, D., Pitstick, R., O'Moore, J., Peters, J., Silvius, D., Kriz, J., Jackson, W. S., Carlson, G. A., Minikel, E. V., Cabin, D. E. Abstract: Phenotypic screening has yielded small molecule inhibitors of prion replication that are effective in vivo against certain prion strains but not others. Here we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live animal bioluminescence imaging. In knock-in mouse models of the D178N and E200K mutations that cause genetic prion disease, however, we were unable to identify a clear, quantifiable disease endpoint against which to measure therapeutic efficacy. Among untreated animals, the mutations did not impact overall survival, and bioluminescence remained low out to greater than 20 months of age. Vacuolization and PrP deposition were observed in some brain regions in a subset of mutant animals, but appeared unable to carry the weight of a primary endpoint in a therapeutic study. We conclude that not all animal models of prion disease are suited to well-powered therapeutic efficacy studies, and care should be taken in choosing the models that will support drug development programs. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Ritualistic use of ayahuasca enhances a shared functional connectome identity with others.

    Play Episode Listen Later Oct 11, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.07.511268v1?rss=1 Authors: Mallaroni, P., Mason, N. L., Kloft, L., Reckweg, J. T., van Oorsouw, K., Toennes, S. W., Tolle, H. M., Amico, E., Ramaekers, J. G. Abstract: The knowledge that brain functional connectomes are both unique and reliable has enabled The knowledge that brain functional connectomes are both unique and reliable has enabled behaviourally relevant inferences at a subject level. However, it is unknown whether such fingerprints persist under altered states of consciousness. Ayahuasca is a potent serotonergic psychedelic which elicits a widespread dysregulation of functional connectivity. Used communally in religious ceremonies, its shared use may highlight relevant novel interactions between mental state and FC inherency. Using 7T fMRI, we assessed resting-state static and dynamic FCs for 21 Santo Daime members after collective ayahuasca intake in an acute, within-subject study. Here, connectome fingerprinting revealed a shared functional space, accompanied by a spatiotemporal reallocation of keypoint edges. Importantly, we show that interindividual differences in higher-order FCs motifs are relevant to experiential phenotypes, given that they can predict perceptual drug effects. Collectively, our findings offer an example as to how individualised connectivity markers can be used to trace a subjects functional connectome across altered states of consciousness. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    The enzymatic and neurochemical outcomes of a mutation in Mexican cavefish MAO reveal teleost-specific aspects of brain monoamine homeostasis

    Play Episode Listen Later Oct 11, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511577v1?rss=1 Authors: Pierre, C., Callebert, J., Launay, J.-M., Retaux, S. Abstract: Monoamine oxidases (MAO; MAO-A and MAO-B in mammals) are enzymes catalyzing the degradation of biogenic amines, including monoamine neurotransmitters. In humans, coding mutations in MAOs are extremely rare and deleterious. Here, we assessed the structural and biochemical consequences of a point mutation (P106L) in the single mao gene of the blind cavefish Astyanax mexicanus. This mutation decreased mao enzymatic activity by ~3-fold, probably as a result of decreased flexibility in one of the three loops forming the entrance of the active site, thus reducing the access of substrates. HPLC measurements in brains of mutant and non-mutant larvae and adults of the cave and surface morphs of the species showed major disturbances in serotonin, dopamine and noradrenalin (and metabolites) contents in mutants, demonstrating that the P106L mao mutation is fully responsible for monoaminergic disequilibrium in the P106L mao mutant cavefish brain. The outcomes of the mutation were different in the posterior brain (containing the raphe nucleus) and the anterior brain (containing fish-specific hypothalamic serotonergic clusters), revealing contrasting properties in neurotransmitter homeostasis in these different neuronal groups. We also discovered that the effects of the mutation were partially compensated by a decrease in activity of the tph, the serotonin biosynthesis rate-limiting enzyme. Finally, the neurochemical outcomes of the mao P106L mutation differed in many respects from a treatment with deprenyl, an irreversible MAO inhibitor, showing that genetic and pharmacological interference with MAO function are not the same. Our results shade light on our understanding of cavefish evolution, on the specificities of fish monoaminergic systems, and on MAO-dependent homeostasis of brain neurochemistry in general. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Genome-wide RNA binding analysis of C9orf72 poly(PR) dipeptides

    Play Episode Listen Later Oct 11, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511318v1?rss=1 Authors: Balendra, R., Ruiz de los Mozos, I., Glaria, I., Milioto, C., Odeh, H. M., Wilson, K. M., Ule, A. M., Hallegger, M., Masino, L., Martin, S., Patani, R., Shorter, J., Ule, J., Isaacs, A. Abstract: An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed in both sense and antisense directions to generate distinct dipeptide repeat proteins, of which poly(GA), poly(GR) and poly(PR) have been implicated in contributing to neurodegeneration. Poly(PR) binding to RNA may contribute to toxicity, but analysis of poly(PR)-RNA binding on a genome-wide scale has not yet been carried out. We therefore performed crosslinking and immunoprecipitation (CLIP) analysis in human cells to identify the RNA binding sites of poly(PR). We found that poly(PR) binds to nearly 600 RNAs, with the sequence GAAGA enriched at the binding sites. In vitro experiments showed that polyGAAGA RNA binds poly(PR) with higher affinity than control RNA and induces phase-separation of poly(PR) into condensates. These data indicate that poly(PR) preferentially binds to polyGAAGA-containing RNAs, which may have physiological consequences. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Febrile seizure unleashes spreading depolarizations in Scn1a deficient mice

    Play Episode Listen Later Oct 11, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511466v1?rss=1 Authors: Aiba, I., Ning, Y., Noebels, J. L. Abstract: Objective: Spreading depolarization (SD) is a massive wave of cellular depolarization that slowly migrates across brain gray matter. SD is frequently generated following brain injury and is associated with various acute and chronic neurological deficits. Here we report that spontaneous cortical SD waves are a common EEG abnormality in the Scn1a deficient mouse model (Scn1a+/R1407X). Method: Chronic DC-band EEG recording detected SDs, seizures, and seizure-SD complexes during prolonged monitoring in awake adult Scn1a+/R1407X mice. The effect of hyperthermic seizure and memantine was tested. Results: The spontaneous incidence of events is low and varied among animals, but SDs outnumber seizures. SD waves almost always spread unilaterally from parietal to frontal cortex. On average, spontaneous SD frequency robustly increased by 4.2-fold following a single hyperthermia-evoked seizure, persisting for days to a week without altering the kinetics of individual events. Combined video image and electromyogram analyses revealed that a single interictal SD is associated with prodromal motor activation followed by minutes-lasting immobility upon invasion of frontal cortex. Similar behavioral sequelae also appeared during postictal SD. Memantine treatment was effective in preventing SD exacerbation when given before and after the hyperthermic seizure, suggesting chronic activation of NMDA-receptor contributed to the prolonged SD aftermath. Interpretation: Our results reveal that cortical SD is a prominent electro-behavioral phenotype in this Scn1a deficient mouse model, and SD frequency is robustly sensitive to hyperthermic seizure induced mechanisms likely involving excess NMDAR signaling. The high susceptibility to SD may contribute to co-morbid pathophysiology in developmental epileptic encephalopathy. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Prior information improves tactile representation in primary somatosensory cortex

    Play Episode Listen Later Oct 11, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511201v1?rss=1 Authors: Kassraian, P., Wenderoth, N., Maathuis, M., Rabe, F. Abstract: Successful navigation through the world requires the integration of sensory input with prior information about the environment. Although it has been shown that stimuli which match prior expectations can be detected faster and more accurately, little is known about the integration of prior information with incoming tactile stimulation in human somatosensory areas. It is also unknown if prior information can induce somatotopic activity in the primary somatosensory cortex (S1) in the absence of tactile stimuli. Based on a vibrotactile detection paradigm we assess how prior information impacts the behavioral performance of participants and how it concurrently modulates BOLD activity and multivariate representations of tactile stimuli in somatosensory areas within a human neuroimaging study. The supra-voxel somatotopic organization of S1 allows us to dissociate representations of tactile stimuli and the modulation thereof by prior information with the resolution permitted by fMRI. We find that vibrotactile stimuli that match the expectations of participants enhance stimulus perception, and that this behavioral enhancement is associated with higher decoding accuracies of stimulus representations in the S1 and a concurrent decrease in BOLD levels in the area. Additionally, we show that prior cues are capable of inducing somatotopic BOLD activity even prior to the onset of tactile stimulation, that tactile stimuli can be decoded from this preparatory activity and that the precision of the decoding is related to the upcoming behavioral performance of participants. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Engaging in word recognition elicits highly specific modulations in visual cortex

    Play Episode Listen Later Oct 11, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511419v1?rss=1 Authors: White, A. L., Kay, K., Tang, K. A., Yeatman, J. D. Abstract: The ability to read depends on a region in ventral occipito-temporal cortex known as the "visual word form area" (VWFA). The VWFA, which has several sub-regions, lies amidst a collection of areas involved in visual recognition. Although it responds best to written words, its selectivity is not absolute, and it exhibits top-down modulations that are not well understood. Here, we used fMRI to investigate the interaction of bottom-up visual factors and top-down cognitive factors in the VWFA and neighboring regions. We presented participants with strings of letters and non-letter shapes at a range of visual field locations. For each stimulus type, participants performed a task in which the stimuli were task-relevant (lexical decision and gap localization, respectively), and a task in which the stimuli were irrelevant (detecting fixation dot color changes). Standard models of attention predict that all stimuli would evoke larger responses when task-relevant than irrelevant, throughout visual cortex. To the contrary, the data showed surprising patterns specific to the VWFA. Letter strings did evoke much larger responses when they were task-relevant than irrelevant, even when presented too far in the periphery to be recognized. In contrast, non-letter shapes evoked smaller responses when they were task-relevant. Connectivity analyses suggest that these task effects are due to flexible communication between the VWFA and Broca's area. We conclude that top-down modulations in visual cortex do not merely enhance representations of attended stimuli, but can boost processing in specific brain regions, contingent on engagement in specific tasks. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    A machine learning based approach towards high-dimensional mediation analysis

    Play Episode Listen Later Oct 11, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511329v1?rss=1 Authors: Nath, T., Caffo, B., Wager, T., Lindquist, M. Abstract: Mediation analysis is used to investigate the role of intermediate variables (mediators) that lie in the path between an exposure and an outcome variable. While significant research has focused on developing methods for assessing the influence of mediators on the exposure-outcome relationship, current approaches do not easily extend to settings where the mediator is high-dimensional. These situations are becoming increasingly common with the rapid increase of new applications measuring massive numbers of variables, including brain imaging, genomics, and metabolomics. In this work, we introduce a novel machine learning based method for identifying high dimensional mediators. The proposed algorithm iterates between using a machine learning model to map the high-dimensional mediators onto a lower-dimensional space, and using the predicted values as input in a standard three-variable mediation model. Hence, the machine learning model is trained to maximize the likelihood of the mediation model. Importantly, the proposed algorithm is agnostic to the machine learning model that is used, providing significant flexibility in the types of situations where it can be used. We illustrate the proposed methodology using data from two functional Magnetic Resonance Imaging (fMRI) studies. First, using data from a task-based fMRI study of thermal pain, we combine the proposed algorithm with a deep learning model to detect distributed, network-level brain patterns mediating the relationship between stimulus intensity (temperature) and reported pain at the single trial level. Second, using resting-state fMRI data from the Human Connectome Project, we combine the proposed algorithm with a connectome-based predictive modeling approach to determine brain functional connectivity measures that mediate the relationship between fluid intelligence and working memory accuracy. In both cases, our multivariate mediation model links exposure variables (thermal pain or fluid intelligence), high dimensional brain measures (single-trial brain activation maps or resting-state brain connectivity) and behavioral outcomes (pain report or working memory accuracy) into a single unified model. Using the proposed approach, we are able to identify brain-based measures that simultaneously encode the exposure variable and correlate with the behavioral outcome. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Sex differences in social synchronization of conditioned fear.

    Play Episode Listen Later Oct 11, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511569v1?rss=1 Authors: Ito, W., Morozov, A. Abstract: Coordinated behaviors are prevalent in the animal kingdom as they promote the survival of social specie. Meanwhile, the distinct social roles of males and females predict sex differences in behavioral coordination. Because of its complexity, behavioral coordination and the underlying circuits have not been studied extensively in laboratory animals. Recently, we established a mouse model of social synchronization of conditioned fear, which revealed a sex difference and identified the ventral hippocampus to the amygdala pathway as the integrator of the affective and social information. Here, we investigated the sex differences further by manipulating the social cues or emotional state. Familiarity with social cues increased fear synchrony in male but not female dyads. The emotional distress from brief immobilization disrupted fear synchrony in males but enhanced it in females. Finally, inactivation of the ventral hippocampus abolished fear synchrony in both sexes but elicited negative synchrony in females only. These findings reveal that conspecific identity and emotional state are sex-specific modulators of social synchrony, suggesting sex-specific functions within the socio-emotional integrator, which includes the ventral hippocampus and yet unknown circuits. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Neural dynamics and geometry for transitive inference

    Play Episode Listen Later Oct 11, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511448v1?rss=1 Authors: Kay, K., Wei, X.-X., Khajeh, R., Beiran, M., Cueva, C. J., Jensen, G., Ferrera, V. P., Abbott, L. F. Abstract: The ability to make inferences using abstract rules and relations has long been understood to be a hallmark of human intelligence, as evidenced in logic, mathematics, and language. Intriguingly, modern work in animal cognition has established that this ability is evolutionarily widespread, indicating an ancient and possibly foundational role in natural intelligence. Despite this importance, it remains an open question how inference using abstract rules is implemented in the brain - possibly due to a lack of competing hypotheses at the level of collective neural activity and of behavior. Here we report the generation and analysis of a collection of neural networks (NNs) that perform transitive inference (TI), a classical cognitive task that requires inference of a single abstract relation between novel combinations of inputs (if A greater than B and B greater than C, then A greater than C). We found that NNs generated using standard training methods (i) generalize fully (i.e. to all novel combinations of inputs), (ii) generalize when inference requires working memory (WM), a capacity thought to be essential for inference in living subjects, (iii) express multiple emergent behaviors long documented in humans and animals, in addition to novel behaviors not previously studied, and (iv) adopt different solutions that yield alternative predictions for both behavior and collective neural activity. Further, a subset of NNs expressed a "subtractive" solution that was characterized in neural activity space by a simple dynamical pattern (an oscillation) and geometric arrangement (ordered collinearity). Together, these findings show how collective neural activity can accomplish generalization according to an abstract rule, and provide a series of testable hypotheses not previously established in the study of TI. More broadly, these findings suggest new ways to understand how neural systems realize abstract rules and relations. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Restricted effects of the sole C. elegans Daughterless/E homolog, HLH-2, on nervous system development

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511552v1?rss=1 Authors: Masoudi, N., Schnabel, R., Yemini, E., Leyva-Diaz, E., Hobert, O. Abstract: Are there common mechanisms of neurogenesis used throughout an entire nervous system? Making use of the well-defined and relatively small size of the nervous system of the nematode C. elegans, we explored to what extent canonical proneural class I/II bHLH complexes are responsible for neurogenesis throughout the entire C. elegans nervous system. Distinct, lineage-specific proneural class II bHLH factors are generally thought to operate via interaction with a common, class I bHLH subunit, encoded by Daugtherless in flies, the E (E2A, E2-2, HEB) proteins in vertebrates, and hlh-2 in C. elegans. To eliminate function of all proneuronal class I/II bHLH complexes, we therefore genetically removed maternal and zygotic hlh-2 gene activity. We observed broad effects on neurogenesis, but still detected normal neurogenesis in many distinct neuron-producing lineages of the central and peripheral nervous system. Moreover, we find that hlh-2 selectively affects some aspects of neuron differentiation while leaving others unaffected. While our studies confirm the function of proneuronal class I/II bHLH complexes in many different lineages throughout a nervous system, we conclude that their function is not universal, but rather restricted by lineage, cell type and components of differentiation programs affected. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Fast prediction in marmoset reach-to-grasp movements for dynamic prey

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.08.511417v1?rss=1 Authors: Shaw, L. H., Wang, K. H., Mitchell, J. Abstract: Primates have evolved sophisticated visually guided reaching behaviors for interacting with dynamic objects, such as insects during foraging. Reaching control in dynamic natural conditions requires active prediction of the target's future position in order to compensate for visuo-motor processing delays and enhance online movement adjustments. Past reaching research in non-human primates mainly focused on seated subjects engaged in repeated ballistic arm movements to either stationary targets, or targets that step once during the movement. However, those highly constrained approaches also impose task constraints that limit the natural dynamics of reaching. A recent field study in marmoset monkeys highlights predictive aspects of visually-guided reaching during insect prey capture among wild marmoset monkeys (Ngo et. al. 2022). To examine the complementary dynamics for similar natural behavior within a laboratory context we developed an ecologically motivated unrestrained reach-to-grasp task involving live crickets. We used multiple high-speed video cameras to capture the movements of marmosets and crickets stereoscopically and applied machine vision algorithms for marker-free object and hand tracking. Contrary to estimates under traditional constrained reaching paradigms, we find that prediction for dynamic targets can operate at incredibly short visuo-motor delays, rivaling the speeds that are typical of the oculomotor systems during closed-loop visual pursuit. Multivariate linear regression modeling of the kinematic relationships between the hand and cricket velocity revealed a visuo-motor delay below 100ms. Predictive corrections for moving crickets were incorporated into hand motion especially during the latter stage of the reach-to-grasp trajectory. This approach reveals that the marmoset motor system for reaching can operate at short visuo-motor delays comparable to the oculomotor system under natural dynamic conditions. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Dysconnection and cognition in schizophrenia: a spectral dynamic causal modeling study

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.09.511459v1?rss=1 Authors: Zarghami, T. S., Zeidman, P., Razi, A., Bahrami, F., Hossein-Zadeh, G.-A. Abstract: Schizophrenia (SZ) is a severe mental disorder characterized by failure of functional integration (aka dysconnection) across the brain. Recent functional connectivity (FC) studies have adopted functional parcellations to define subnetworks of large-scale networks, and to characterize the (dys)connection between them, in normal and clinical populations. While FC examines statistical dependencies between observations, model-based effective connectivity (EC) can disclose the causal influences that underwrite the observed dependencies. In this study, we investigated resting state EC between the subnetworks of seven large-scale networks, in 66 SZ and 74 healthy subjects from a public dataset. The results showed that a remarkable 33% of the effective connections (among subnetworks) of the cognitive control network had been pathologically modulated in SZ. Further dysconnection was identified within the visual, default mode and sensorimotor networks of SZ subjects, with 24%, 20% and 11% aberrant couplings. Overall, the proportion of diagnostic connections was remarkably larger in EC (24%) than FC (1%) analysis. Subsequently, to study the neural correlates of impaired cognition in SZ, we conducted a canonical correlation analysis between the EC parameters and the cognitive scores of the patients. As such, the self-inhibitions of supplementary motor area and paracentral lobule (in the sensorimotor network) and the excitatory connection from parahippocampal gyrus to inferior temporal gyrus (in the cognitive control network) were significantly correlated with the social cognition, reasoning/problem solving and working memory capabilities of the patients. Future research can investigate the potential of whole-brain EC as a biomarker for diagnosis of brain disorders and for cognitive assessment. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Drosophila epidermal cells are intrinsically mechanosensitive and drive nociceptive behavioral outputs

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.07.511265v1?rss=1 Authors: Yoshino, J., Mali, S., Williams, C., Morita, T., Emerson, C., Arp, C., Sophie, M., Yin, C., The, L., Chikaya, H., Motoyoshi, M., Ishii, K., Emoto, K., Bautista, D. M., Parrish, J. Z. Abstract: Somatosensory neurons (SSNs) that detect and transduce mechanical, thermal, and chemical stimuli densely innervate an animal's skin. However, despite the fact that epidermal cells provide the first point of contact for sensory stimuli. our understanding of roles that epidermal cells play in SSN function, particularly nociception, remains limited. Here, we show that stimulating Drosophila epidermal cells elicits activation of SSNs including nociceptors and triggers a variety of behavior outputs, including avoidance and escape. Further, we find that epidermal cells are intrinsically mechanosensitive and that epidermal mechanically evoked calcium responses require the store-operated calcium channel Orai. Epidermal cell stimulation augments larval responses to acute nociceptive stimuli and promotes prolonged hypersensitivity to subsequent mechanical stimuli. Hence, epidermal cells are key determinants of nociceptive sensitivity and sensitization, acting as primary sensors of noxious stimuli that tune nociceptor output and drive protective behaviors. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Unattended visual stimuli do not produce prediction error responses despite being initially encoded

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.04.510779v1?rss=1 Authors: Male, A. G., O'Shea, R. P. Abstract: Prediction error is a basic component of predictive-coding theory of brain processing. According to the theory, each stage of brain processing of sensory information generates a model of the current sensory input; subsequent input is compared against the model and only if there is a mismatch, a prediction error, is further processing performed. Recently, Smout et al. found that a signature of prediction error, the visual (v) mismatch negativity (MMN), for a fundamental property of visual input--its orientation--was absent without attention on the stimuli. This is remarkable because the weight of evidence for MMNs from audition and vision is that they occur without attention. To resolve this discrepancy, we conducted an experiment addressing two alternative explanations for Smout et al.'s finding: that it was from a lack of reproducibility or that participants' visual systems did not encode the stimuli when attention was on something else. We conducted a similar experiment to Smout et al.'s. We showed 21 participants sequences of identically oriented Gabor patches, standards, and, unpredictably, otherwise identical, Gabor patches differing in orientation by {+/-}15{degrees}, {+/-}30{degrees}, and {+/-}60{degrees}, deviants. To test whether participants encoded the orientation of the standards, we varied the numbers of standards preceding a deviant, allowing us to search for a decrease in activity with the number of repetitions of standards--repetition suppression. We diverted participants' attention from the oriented stimuli with a central, letter-detection task. We reproduced Smout et al.'s finding of no vMMN without attention, strengthening their finding. We also found that our participants showed repetition suppression: they did encode the stimuli pre-attentively. We also found early processing of deviants. We discuss whether this earlier processing of deviants may be why no further processing, in the vMMN time window, occurs. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Computational constraints on the associative recall of spatial scenes

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.08.511429v1?rss=1 Authors: Ryom, K. I., Stendardi, D., Ciaramelli, E., Treves, A. Abstract: We consider a model of associative storage and retrieval of compositional memories in an extended cortical network. Our model network is comprised of Potts units, which represent patches of cortex, interacting through long-range connections. The critical assumption is that a memory is composed of a limited number of items, each of which has a pre-established representation: storing a new memory only involves acquiring the connections, if novel, among the participating items. The model is shown to have a much lower storage capacity than when it stores simple unitary representations. It is also shown that an input from the hippocampus facilitates associative retrieval. When it is absent, it is advantageous to cue rare rather than frequent items. The implications of these results for emerging trends in empirical research are discussed. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Generalized habitual tendencies in alcohol dependent rats

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.04.510642v1?rss=1 Authors: Giannone, F., Hach, A., Chroszcz, M., Friske, M. M., Meinhardt, M. W., Spanagel, R., Sommer, W. H., Hansson, A. C. Abstract: Habitual responses and ultimately compulsive behavior are thought to be at the core of addiction including alcohol use disorder (AUD). Little is known whether the habitization concerns exclusively the response towards alcohol or generalizes to other daily activities. Here, we address this question in a well-established animal model of AUD - the post-dependent rat model - by testing habitual responses towards a sweet palatable reward in two striatal learning paradigms: spatial navigation and reward conditioning. For the spatial navigation task, alcohol-dependent and control rats were tested on a sequential decision-making test after short and prolonged T-Maze training; for the reward conditioning task, rats were trained under a random interval schedule for a short and prolonged period and tested in a satiety devaluation test at each time point. Another cohort of alcohol-naive rats was trained and tested on both paradigms under DREADD (designer receptors exclusively activated by designer drugs)-mediated inactivation of the dorsomedial striatum (DMS) which controls goal-directed behavior. Our results show that alcohol-dependent rats displayed increased habitual behavior to obtain saccharin reward on both paradigms, with overall more habitual choices after prolonged training on the spatial navigation task, and increased habitual responses already after short training on the reward conditioning task. Finally, DREADD-mediated inactivation of the DMS increased habitual behavior in non-dependent rats on both paradigms. Our results provide evidence that a history of alcohol dependence produces a bias towards habitual responding that generalizes to a natural reward in rats. Similarly, a habitual bias was induced in non-dependent rats after inactivation of the DMS, thus confirming the critical role of this region in maintaining goal-directed behavior and suggesting its diminished control in AUD. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Multifunctional fibers enable modulation of cortical and deep brain activity during cognitive behavior in macaques

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.09.511302v1?rss=1 Authors: Garwood, I. C., Major, A. J., Antonini, M.-J., Correa, J., Lee, Y., Sahasrabudhe, A., Mahnke, M. K., Miller, E. K., Brown, E. N., Anikeeva, P. Abstract: Recording and modulating neural activity in vivo enables investigations of neural circuits during behavior. However, there is a dearth of tools for simultaneous recording and localized receptor modulation in large animal models. We address this limitation by translating multifunctional fiber-based neurotechnology previously only available for rodent studies to enable cortical and subcortical neural modulation in macaques. We record single unit and local field potential activity before, during, and after intracranial GABA infusions in the premotor cortex and putamen. We apply state-space models to characterize changes in neural activity and investigate how neural activity evoked by a working memory task varies in the presence of local inhibition. The recordings provide detailed insight into the electrophysiological effect of neurotransmitter receptor modulation in both cortical and subcortical structures in an awake, behaving macaque. Our results demonstrate a first-time translation of multifunctional fibers for causal studies in behaving non-human primates. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Evidence for a Spoken Word Lexicon in the Auditory Ventral Stream

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.09.511436v1?rss=1 Authors: Damera, S. R., Chang, L., Nikolov, P. P., Mattei, J. A., Banerjee, S., Glezer, L. S., Cox, P. H., Jiang, X., Rauschecker, J. P., Riesenhuber, M., Riesenhuber, M. Abstract: The existence of a neural representation for whole words(i.e.,a lexicon) is a common feature of many models of speech processing. Prior studies have provided evidence for a visual lexicon containing representations of whole written words in an area of the ventral visual stream known as the "Visual Word Form Area" (VWFA). Similar experimental support for an auditory lexicon containing representations of spoken words has yet to be shown. Using fMRI rapid adaptation techniques, we provide evidence for an auditory lexicon in the "Auditory Word Form Area" (AWFA) in the human left anterior superior temporal gyrus that contains representations highly selective for individual spoken words. Furthermore, we show that familiarization with novel auditory words sharpens their selectivity in the AWFA. These findings reveal strong parallels in how the brain represents written and spoken words, showing convergent processing strategies across speech modalities in the visual and auditory ventral streams. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511483v1?rss=1 Authors: Mihailovich, M., Germain, P.-L., Shyti, R., Pozzi, D., Noberini, R., Liu, Y., Aprile, D., Tenderini, E., Troglio, F., Trattaro, S., Fabris, S., Ciptasari, U., Rigoli, M. T., Caporale, N., D Agostino, G., Vitriolo, A., Capocefalo, D., Skaros, A., Franchini, A., Ricciardi, S., Biunno, I., Neri, A., Kasri, N. N., Bonaldi, T., Aebersold, R., Matteoli, M., Testa, G. Abstract: Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and excitability. Genes related to neuronal transmission chiefly followed 7q11.23 dosage and appeared transcriptionally controlled, while translation and ribosomal protein genes followed the opposite trend and were post-transcriptionally buffered. Mechanistically, we uncovered REST regulon as a key mediator of observed phenotypes and rescued transcriptional and excitability alterations through REST inhibition. We identified downregulation of global protein synthesis, mGLUR5 and ERK-mTOR pathways activity in steady-state in both WBS and 7Dup, whereas BDNF stimulation rescued them specifically in 7Dup. Overall, we show that 7q11.23 CNVs alter protein synthesis and neuronal firing-established molecular and cellular phenotypes of neurodevelopmental disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Autophagy in parvalbumin interneurons is required for inhibitory transmission and memory via regulation of synaptic proteostasis

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511533v1?rss=1 Authors: Chalatsi, T., Fernandez, L. M. J., Scholler, J., Batti, L., Kolaxi, A., Restivo, L., Luthi, A., Mameli, M., Nikoletopoulou, V. Abstract: With the emerging role of the autophagic machinery in healthy brain development and aging, there is a pressing need to better characterize its functions in different neuronal populations, providing cellular insight into autophagy-related brain diseases. Here, we generated and characterized mice with conditional ablation of atg5 in GABAergic neurons expressing parvalbumin (PV-atg5KO), mostly comprising fast-spiking interneurons, as well as Purkinje cells in the cerebellum. Using light-sheet microscopy to image PV neurons throughout the brain, we reveal that autophagy is required for the sustenance of Purkinje cells but not of PV-interneurons. Yet, proteomic analysis showed that autophagy deficiency in cortical and hippocampal PV-interneurons alters the proteostasis of key synaptic proteins, as well as the surface expression of glutamate receptor subunits. Consistently, hippocampal autophagy-deficient PV-interneurons exhibit reduced inhibitory neurotransmission and PV-atg5KO mice display excitation-inhibition imbalance in the hippocampus and memory deficits. Our findings demonstrate a neuronal type-specific vulnerability to autophagy deficiency, while also identifying PV-interneurons as cellular substrates where autophagy is required for memory. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Dopamine depletion leads to pathological synchronization of distinct basal ganglia loops in the beta band

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511532v1?rss=1 Authors: Ortone, A., Vergani, A. A., Mannella, R., Mazzoni, A. Abstract: Motor symptoms of Parkinson's Disease (PD) are associated with dopamine deficits and pathological oscillation of basal ganglia (BG) neurons in the beta range ([12-30] Hz). However, how the dopamine depletion affects the oscillation dynamics of BG nuclei is still unclear. With a spiking neurons model, we here captured the features of BG nuclei interactions leading to oscillations in dopamine-depleted condition. We found that both the loop between subthalamic nucleus and Globus Pallidus pars externa (GPe) and the loop between striatal fast spiking and medium spiny neurons and GPe displayed resonances in the beta range, and synchronized to a common beta frequency through interaction. Crucially, the synchronization depends on dopamine depletion: the two loops were largely independent for high levels of dopamine, but progressively synchronized as dopamine was depleted due to the increased strength of the striatal loop. Our results highlight the role of the interplay between the GPe-STN and the GPe-striatum loop in generating sustained beta oscillations in PD subjects, and explain how this interplay depends on the level of dopamine. This paves the way to the design of therapies specifically addressing the onset of pathological beta oscillations. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders

    Play Episode Listen Later Oct 10, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511434v1?rss=1 Authors: Lopez-Tobon, A., Shyti, R., Villa, C. E., Cheroni, C., Fuentes-Bravo, P., Trattaro, S., Caporale, N., Troglio, F., Tenderini, E., Mihailovich, M., Skaros, A., Gibson, W. T., Cuomo, A., Bonaldi, T., Mercurio, C., Varasi, M., Osborne, L. R., Testa, G. Abstract: Copy number variations at 7q11.23 cause neurodevelopmental disorders with shared and opposite manifestations. Deletion causes Williams-Beuren syndrome (WBS), while duplication causes 7q11.23 microduplication syndrome (7Dup). Converging evidence indicates GTF2I, from the 7q11.23 locus, is a key mediator of the cognitive-behavioral phenotypes associated with WBS and 7Dup. Here we integrate molecular profiling of patient-derived cortical organoids (COs) and transgenic mouse models to dissect 7q11.23 disease mechanisms. Proteomic and transcriptomic profiling of COs revealed opposite dynamics of neural progenitor proliferation and transcriptional imbalances, leading to precocious excitatory neuron production in 7Dup. The accelerated excitatory neuron production in 7Dup COs could be rescued by GTF2I knockdown. Transgenic mice with Gtf2i duplication recapitulated early neuronal differentiation defects and ASD-like behaviors. Remarkably, inhibition of LSD1, a downstream effector of GTF2I, was sufficient to rescue ASD-like phenotypes. We propose that the GTF2I-LSD1 axis constitutes a molecular pathway amenable to therapeutic intervention. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Proteomics of resilience to Alzheimer's disease identifies brain regional soluble Aβ levels, actin filament processes, and response to injury

    Play Episode Listen Later Oct 9, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.09.511430v1?rss=1 Authors: Huang, Z., Merrihew, G. E., Larson, E. B., Park, J., Plubell, D., Fox, E. J., Montine, K. S., Keene, C. D., Zou, J., MacCoss, M. J., Montine, T. J. Abstract: Resilience to Alzheimers disease (RAD) is an uncommon combination of high disease burden without dementia that may provide critical insights into limiting the clinical impact of this incurable disease. In this study, we used mass spectrometry-based proteomics to quantify regional protein differences that characterize RAD. Starting with over 700 brain donations, we identified 43 extensively annotated research participants who met stringent inclusion exclusion criteria and analyzed matched isocortical regions, hippocampus, and caudate nucleus. Differential expression analysis of 7,115 soluble proteins identified lower isocortical and hippocampal soluble A{beta} peptide levels as a significant feature of RAD. Protein co-expression analysis revealed a group of 181 densely-interacting proteins significantly associated with RAD that were enriched for actin filament-based process, cellular detoxification, and wound healing in isocortex and hippocampus. We further support our findings using data from 689 human isocortical samples from four independent external cohorts that were the closest approximations of our clinico-pathologic groups. The molecular basis of RAD, a widely replicated state in older adults for which there is no experimental model, likely holds important insights into therapeutic interventions for Alzheimers disease. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Longitudinal investigation of changes in resting-state co-activation patterns and their predictive ability in the zQ175 DN mouse model of Huntington's disease

    Play Episode Listen Later Oct 9, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.09.511485v1?rss=1 Authors: Adhikari, M. H., Vasilkovska, T., Cachope, R., Tang, H., Liu, L., Keliris, G. A., Munoz-Sanjuan, I., Pustina, D., Van Der Linden, A., Verhoye, M. Abstract: Huntingtons disease (HD) is a neurodegenerative disorder caused by expanded ( greater than or equal to 40) glutamine-encoding CAG repeats in the huntingtin gene, which leads to dysfunction and death of predominantly striatal and cortical neurons. While the genetic profile and behavioural signs of the disease are better known, changes in the functional architecture of the brain, especially before the behavioural symptoms become apparent, are not fully and consistently characterized. In this study, we sought markers at pre, early and late manifest states of phenotypic progression in the heterozygous (HET) zQ175 delta-neo (DN) mouse model, using resting-state functional magnetic resonance imaging (RS-fMRI). This mouse model shows molecular, cellular and circuitry alterations that resemble those seen in HD in humans. Specifically, we investigated, longitudinally, changes in co-activation patterns (CAPs) that are the transient states of brain activity constituting the resting-state networks (RSNs). Most robust changes in the temporal properties of CAPs occurred at the late manifest state; the durations of two anti-correlated CAPs, characterized by simultaneous co-activation of default-mode like network (DMLN) and co-deactivation of lateral-cortical network (LCN) and vice-versa, were reduced in the zQ175 DN HET animals compared to the wild-type mice. Changes in the spatial properties, measured in terms of activation levels of different brain regions, during CAPs were found at all three states and became progressively more pronounced at the manifest states. We then assessed the cross-validated predictive power of CAP metrics to distinguish HET animals from controls. Spatial properties of CAPs performed significantly better than the chance level at all three states with 80% classification accuracy at the early and late manifest states. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Domino-like Effect of C112R Mutation on APOE4 Aggregation and Its Suppression by Alzheimer's Disease Drug Candidate

    Play Episode Listen Later Oct 9, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.09.511473v1?rss=1 Authors: Nemergut, M., Marques, S. M., Uhrik, L., Vanova, T., Nezvedova, M., Gadara, D. C., Jha, D., Tulis, J., Novakova, V., Iglesias-Planas, J., Kunka, A., Legrand, A., Hribkova, H., Pospisilova, V., Sedmik, J., Raska, J., Prokop, Z., Damborsky, J., Bohaciakova, D., Spacil, Z., Hernychova, L., Bednar, D., Marek, M. Abstract: Apolipoprotein E (APOE) {varepsilon}4 genotype is the most prevalent risk factor for late-onset Alzheimers Disease (AD). Although APOE4 differs from its non-pathological APOE3 isoform only by the C112R mutation, the mechanism of its proteinopathy is poorly understood. Here, we combine experimental and computational techniques to uncover a "domino-like" effect of C112R mutation on APOE4 behavior. We found that C112R substitution in APOE4 induces long-distance ( greater than 15 [A]) conformational changes leading to the formation of a T-shaped dimeric unit that is geometrically different and more aggregation-prone than the APOE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce APOE3-like conformational behavior in APOE4 and suppress its aggregation propensity. Analysis of APOE {varepsilon}4/{varepsilon}4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol. Overall, our results connect the APOE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Speech and music recruit frequency-specific distributed and overlapping cortical networks

    Play Episode Listen Later Oct 9, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.08.511398v1?rss=1 Authors: te Rietmolen, N. A. G., Mercier, M., Trebuchon, A., Morillon, B., Schon, D. Abstract: To what extent do speech and music processing rely on domain-specific and domain-general neural networks? Adopting a dynamical system framework, we investigate the presence of frequency-specific and network-level selectivity and combine it with a statistical approach in which a clear distinction is made between shared, preferred, and category-selective neural responses. Using intracranial EEG recordings in 18 epilepsy patients listening to natural and continuous speech and music, we show that the majority of focal and network-level neural activity is shared between speech and music processing. Our data also reveal an absence of regional selectivity. Instead, neural selectivity is restricted to distributed and frequency-specific coherent oscillations, typical of spectral fingerprints. Our work addresses a longstanding debate and redefines an epistemological posture on how to map cognitive and brain functions. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    GABA decrease is associated with degraded neural specificity in the visual cortex of glaucoma patients

    Play Episode Listen Later Oct 9, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.09.508561v1?rss=1 Authors: Bang, J. W., Parra, C., Yu, K., Wollstein, G., Schuman, J., Chan, K. Abstract: Glaucoma is an age-related neurodegenerative disease of the visual system, affecting both the eye and the brain. Yet its underlying metabolic mechanisms and neurobehavioral relevance remain largely unclear. Here, using proton magnetic resonance spectroscopy and functional magnetic resonance imaging, we investigated the GABAergic and glutamatergic systems in the visual cortex of glaucoma patients, as well as neural specificity, which is shaped by GABA and glutamate signals and underlies efficient sensory and cognitive functions. Our study showed that among the older adults, both GABA and glutamate levels decrease with increasing glaucoma severity regardless of age. Further, the reduction of GABA but not glutamate predicted the neural specificity. This association was independent of the impairments on the retina structure and age. Our results suggest that glaucoma-specific decline of GABA undermines neural specificity in the visual cortex and that targeting GABA could improve the neural specificity in glaucoma. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Controlling Neocortical Epileptic Seizures using Forced TemporalSpike-Time Stimulation: An In Silico Computational Study

    Play Episode Listen Later Oct 9, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.09.511502v1?rss=1 Authors: Schmalz, J., Quinarez, R. V., Kothare, M. V., Kumar, G. Abstract: Epileptic seizure is typically characterized by highly synchronized episodes of neural activity. Existing stimulation therapies focus purely on suppressing the pathologically synchronized neuronal firing patterns during the ictal (seizure) period. While these strategies are effective in suppressing seizures when they occur, they fail to prevent the re-emergence of seizures once the stimulation is turned off. Previously, we developed a novel neurostimulation motif, which we refer to as "Forced Temporal Spike-Time Stimulation" (FTSTS) [1] that has shown remarkable promise in long-lasting desynchronization of excessively synchronized neuronal firing patterns by harnessing synaptic plasticity. In this paper, we build upon this prior work [1] by optimizing the parameters of the FTSTS protocol in order to efficiently desynchronize the pathologically synchronous neuronal firing patterns that occur during epileptic seizures using a recently published computational model of neocortical-onset seizures [2]. We show that the FTSTS protocol applied during the ictal period can modify the excitatory-to inhibitory synaptic weight in order to effectively desynchronize the pathological neuronal firing patterns even after the ictal period. Our investigation opens the door to a possible new neurostimulation therapy for epilepsy. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    The effects of biological sex on estimates of persistent inward currents in the human lower limb

    Play Episode Listen Later Oct 9, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.09.511486v1?rss=1 Authors: Jenz, S. T., Beauchamp, J. A., Gomes, M. M., Negro, F., Heckman, C., Pearcey, G. Abstract: Non-invasive recordings of motor unit (MU) spike trains help us understand how neural drive is modulated by various motor commands and/or physiological conditions. The majority of study participants in human and non-human animal physiology studies are male, and it is assumed mechanisms uncovered in these studies are shared between males and females. However, sex differences in neurological impairment and physical performance warrant the study of sex as a biological variable in human physiology and performance. To begin addressing this gap in the study of biophysical properties of human motoneurons, we quantified MU discharge rates and estimates of persistent inward current (PIC) magnitude in both sexes by quantifying {Delta}F. We decomposed MU spike trains from the tibialis anterior (TA), medial gastrocnemius (MG), and soleus (SOL) using high-density surface electromyography and blind source separation algorithms. Ten participants of each sex performed slow triangular (10s up and down) isometric contractions to a peak of 30% of their maximum voluntary contraction. We then used linear mixed effects models to determine if peak discharge rate and {Delta}F were predicted by the fixed effects of sex, muscle, and their interaction. Despite similar peak discharge rates across all muscles, {Delta}F was larger ({chi}2(1) = 6.26, p = 0.012) in females (4.73 [0.242 pps]) than males (3.81 [0.240 pps]). These findings suggest that neuromodulatory drive and/or biophysical properties of motoneurons differ between the sexes and may contribute to differences in MU discharge patterns. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

    Entorhinal grid-like codes and time-locked network dynamics track others navigating through space

    Play Episode Listen Later Oct 9, 2022


    Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.08.511403v1?rss=1 Authors: Wagner, I. C., Graichen, L., Todorova, B., Luettig, A., Omer, D., Stangl, M., Lamm, C. Abstract: Navigating through crowded, dynamically changing social environments requires the ability to keep track of other individuals. Grid cells in the entorhinal cortex are a central component of self-related navigation but whether they also track others' movement is unclear. Here, we propose that entorhinal grid-like codes make an essential contribution to socio-spatial navigation. Sixty human participants underwent functional magnetic resonance imaging (fMRI) while observing and re-tracing different paths of a demonstrator that navigated a virtual reality environment. Results revealed that grid-like codes in the entorhinal cortex tracked the other individual navigating through space. Further, the activity of grid-like codes was time-locked to increases in co-activation and entorhinal-cortical connectivity that included the striatum, the hippocampus, parahippocampal and right posterior parietal cortices, altogether modulated by accuracy when subsequently re-tracing the paths. This suggests that network dynamics time-locked to entorhinal grid-cell-related activity might serve to distribute information about the "socio-spatial map" throughout the brain. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

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