{"messages":[{"status":"ok","category":"neuroscience","interval":"2024-01-01:2024-01-31","funder":"all","cursor":0,"count":30,"count_new_papers":"599","total":"905"}], "collection":[{"title":"KCNQ2\/3 regulates efferent mediated slow excitation of vestibular afferents in mammals","authors":"Sinha, A. K.; Lee, C.; Holt, J. C.","author_corresponding":"Joseph C Holt","author_corresponding_institution":"Dept. of Pharmacology and Physiology, Univ. of Rochester, Rochester, New York 14642","doi":"10.1101\/2023.12.30.573731","date":"2024-01-01","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.30.573731.source.xml","abstract":"Primary vestibular afferents transmit information from hair cells about head position and movement to the CNS, which is critical for maintaining balance, gaze stability and spatial navigation. The CNS, in turn, modulates hair cells and afferents via the efferent vestibular system (EVS) and its activation of several cholinergic signaling mechanisms. Electrical stimulation of EVS neurons gives rise to three kinetically- and mechanistically-distinct afferent responses including a slow excitation, a fast excitation, and a fast inhibition. EVS-mediated slow excitation is attributed to odd-numbered muscarinic acetylcholine receptors (mAChRs) on the afferent whose activation leads to the closure of a potassium conductance and increased afferent discharge.\n\nLikely effector candidates include low-threshold, voltage-gated potassium channels belonging to the KCNQ (Kv7.X) family, which are involved in neuronal excitability across the nervous system and are subject to mAChR modulation. Specifically, KCNQ2\/3 heteromeric channels may be the molecular correlates for the M-current, a potassium current that is blocked following the activation of odd-numbered mAChRs. To this end, multiple members of the KCNQ channel family, including KCNQ2 and KCNQ3, are localized to several microdomains within vestibular afferent endings, where they influence afferent excitability and could be targeted by EVS neurons. Additionally, the relative expression of KCNQ subunits appears to vary across the sensory epithelia and among different afferent types. However, it is unclear which KCNQ channel subunits are targeted by mAChR activation and whether that also varies among different afferent classes. Here we show that EVS-mediated slow excitation is blocked and enhanced by the non-selective KCNQ channel blocker XE991 and opener retigabine, respectively. Using KCNQ subunit-selective drugs, we observed that a KCNQ2 blocker blocks the slow response in irregular afferents, while a KCNQ2\/3 opener enhances slow responses in regular afferents. The KCNQ2 blockers did not appear to affect resting afferent discharge rates, while KCNQ2\/3 or KCNQ2\/4 openers decreased afferent excitability. Here, we show pharmacological evidence that KCNQ2\/3 subunits are likely targeted by mAChR activation in mammalian vestibular afferents. Additionally, we show that KCNQ3 KO mice have altered resting discharge rate as well as EVS-mediated slow response. These data together suggest that KCNQ channels play a role in slow response and discharge rate of vestibular afferents, which can be modulated by EVS in mammals.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Synaptic connectivity and electrophysiological properties of the nucleus of the lateral olfactory tract","authors":"Penker, S.; Lawabny, N.; Dhamshy, A.; Licht, T.; Rokni, D.","author_corresponding":"Dan Rokni","author_corresponding_institution":"Hebrew University","doi":"10.1101\/2023.12.31.573522","date":"2024-01-01","version":"1","type":"new results","license":"cc_by_nc","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.31.573522.source.xml","abstract":"The sense of smell is tightly linked to emotions, a link that is thought to rely on the direct synaptic connections between the olfactory bulb and nuclei of the amygdala. A small number of amygdaloid nuclei are the recipients of such direct input from the olfactory bulb and their unique functions are not known. Among them, the nucleus of the lateral olfactory tract (NLOT) is unique in its developmental history and gene expression. NLOT has been very little studied and consequentially its function is unknown. Furthermore, formulation of informed hypotheses about NLOT function is at this stage limited by the lack of knowledge about its connectivity and physiological properties. Here, we used pseudo-rabies tracing methods to systematically reveal monosynaptic inputs into NLOT, and adeno-associated viruses to reveal NLOT projection targets. We found that the NLOT is interconnected with several olfactory brain regions and with the basolateral amygdala. Some of these connections were reciprocal, and some showed unique interhemispheric patterns. We tested the excitable properties of NLOT neurons and the properties of each of the major synaptic inputs. We found that the NLOT receives powerful input from piriform cortex, tenia tecta, and the basolateral amygdala, but only very weak input from the olfactory bulb. When input crosses threshold, NLOT neurons respond with calcium-dependent bursts of action potentials. This integration of olfactory and amygdalar inputs suggests that NLOT plays a role in behaviors that combine smell and emotion, possibly assigning emotional value to odors.\n\nSignificance statementDespite the well-known functional links between olfaction and emotions, the physiological properties of these links remain largely understudied. One major pathway by which olfactory and emotional signals interact, is via the nucleus of the lateral olfactory tract (NLOT). NLOT has been little studied and its function is yet unclear. The lack of physiological information hinders informed hypotheses. Here, we characterize the synaptic and intrinsic properties of NLOT neurons. We show that the NLOT receives converging olfactory and amygdalar inputs, and that NLOT neurons respond to input with high-rate bursts of action potentials. This suggests that the NLOT, that harbors [~]2500 cells, encodes a low-dimensional signal that is of high importance. We hypothesize that the NLOT assigns emotional value to odors.","funder":"NA","published":"10.1523\/JNEUROSCI.2420-23.2024","server":"bioRxiv"},{"title":"Transcriptomic Analysis Identifies Candidate Genes for Differential Expression during Xenopus laevis Inner Ear Development","authors":"Virk, S. M.; Trujillo-Provencio, C.; Serrano, E. E.","author_corresponding":"Elba E. Serrano","author_corresponding_institution":"New Mexico State University","doi":"10.1101\/2023.12.29.573599","date":"2024-01-01","version":"1","type":"new results","license":"cc_by","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.29.573599.source.xml","abstract":"BackgroundThe genes involved in inner ear development and maintenance of the adult organ have yet to be fully characterized. Previous genetic analysis has emphasized the early development that gives rise to the otic vesicle. This study aimed to bridge the knowledge gap and identify candidate genes that are expressed as the auditory and vestibular sensory organs continue to grow and develop until the systems reach postmetamorphic maturity.\n\nMethodsAffymetrix microarrays were used to assess inner ear transcriptome profiles from three Xenopus laevis developmental ages where all eight endorgans comprise mechanosensory hair cells: larval stages 50 and 56, and the post-metamorphic juvenile. Pairwise comparisons were made between the three developmental stages and the resulting differentially expressed X. laevis Probe Set IDs (Xl-PSIDs) were assigned to four groups based on differential expression patterns. DAVID analysis was undertaken to impart functional annotation to the differentially regulated Xl-PSIDs.\n\nResultsAnalysis identified 1510 candidate genes for differential gene expression in one or more pairwise comparison. Annotated genes not previously associated with inner ear development emerged from this analysis, as well as annotated genes with established inner ear function, such as oncomodulin, neurod1, and sp7. Notably, 36% of differentially expressed Xl-PSIDs were unannotated.\n\nConclusionsResults draw attention to the complex gene regulatory patterns that characterize Xenopus inner ear development, and underscore the need for improved annotation of the X. laevis genome. Outcomes can be utilized to select candidate inner ear genes for functional analysis, and to promote Xenopus as a model organism for biomedical studies of hearing and balance.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Mechanisms of alcohol influence on fear conditioning: a computational model","authors":"Lonnberg, A.; Logrip, M. L.; Kuznetsov, A.","author_corresponding":"Alexey Kuznetsov","author_corresponding_institution":"IUPUI","doi":"10.1101\/2023.12.30.573310","date":"2024-01-01","version":"1","type":"new results","license":"cc_by_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.30.573310.source.xml","abstract":"A connection between stress-related illnesses and alcohol use disorders is extensively documented. Fear conditioning is a standard procedure used to study stress learning and links it to the activation of amygdala circuitry. However, the connection between the changes in amygdala circuit and function induced by alcohol and fear conditioning is not well established. We introduce a computational model to test the mechanistic relationship between amygdala functional and circuit adaptations during fear conditioning and the impact of acute vs. repeated alcohol exposure. In accordance with experiments, both acute and prior repeated alcohol decreases speed and robustness of fear extinction in our simulations. The model predicts that, first, the delay in fear extinction in alcohol is mostly induced by greater activation of the basolateral amygdala (BLA) after fear acquisition due to alcohol-induced modulation of synaptic weights. Second, both acute and prior repeated alcohol shifts the amygdala network away from the robust extinction regime by inhibiting the activity in the central amygdala (CeA). Third, our model predicts that fear memories formed in acute or after chronic alcohol are more connected to the context. Thus, the model suggests how circuit changes induced by alcohol may affect fear behaviors and provides a framework for investigating the involvement of multiple neuromodulators in this neuroadaptive process.","funder":"NA","published":"10.1111\/acer.70071","server":"bioRxiv"},{"title":"The brainstem's red nucleus was evolutionarily upgraded to support goal-directed action","authors":"Krimmel, S. R.; Laumann, T. O.; Chauvin, R.; Hershey, T.; Roland, J. L.; Shimony, J. S.; Willie, J. T.; Norris, S. A.; Marek, S.; Van, A. N.; Monk, J.; Scheidter, K. M.; Whiting, F.; Ramirez-Perez, N.; Metoki, A.; Wang, A.; Kay, B. P.; Nahman-Averbuch, H.; Fair, D. A.; Lynch, C. J.; Raichle, M. E.; Gordon, E. M.; Dosenbach, N. U. F.","author_corresponding":"Samuel R Krimmel","author_corresponding_institution":"Washington University in St. Louis","doi":"10.1101\/2023.12.30.573730","date":"2024-01-01","version":"1","type":"new results","license":"cc_by_nc","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.30.573730.source.xml","abstract":"The red nucleus is a large brainstem structure that coordinates limb movement for locomotion in quadrupedal animals (Basile et al., 2021). The humans red nucleus has a different pattern of anatomical connectivity compared to quadrupeds, suggesting a unique purpose (Hatschek, 1907). Previously the function of the human red nucleus remained unclear at least partly due to methodological limitations with brainstem functional neuroimaging (Sclocco et al., 2018). Here, we used our most advanced resting-state functional connectivity (RSFC) based precision functional mapping (PFM) in highly sampled individuals (n = 5) and large group-averaged datasets (combined N [~] 45,000), to precisely examine red nucleus functional connectivity.\n\nNotably, red nucleus functional connectivity to motor-effector networks (somatomotor hand, foot, and mouth) was minimal. Instead, red nucleus functional connectivity along the central sulcus was specific to regions of the recently discovered somato-cognitive action network (SCAN; (Gordon et al., 2023)). Outside of primary motor cortex, red nucleus connectivity was strongest to the cingulo-opercular (CON) and salience networks, involved in action\/cognitive control (Dosenbach et al., 2007; Newbold et al., 2021) and reward\/motivated behavior (Seeley, 2019), respectively. Functional connectivity to these two networks was organized into discrete dorsal-medial and ventral-lateral zones. Red nucleus functional connectivity to the thalamus recapitulated known structural connectivity of the dento-rubral thalamic tract (DRTT) and could prove clinically useful in functionally targeting the ventral intermediate (VIM) nucleus. In total, our results indicate that far from being a  motor structure, the red nucleus is better understood as a brainstem nucleus for implementing goal-directed behavior, integrating behavioral valence and action plans.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Pharmacological inhibition of mTORC1 reduces neural death and damage volume after MCAO by modulating microglial reactivity","authors":"Villa-Gonzalez, M.; Rubio, M.; Martin-Lopez, G.; R. Mallavibarrena, P.; Valles-Saiz, L.; Vivien, D.; Wandosell Jurado, F.; Perez-Alvarez, M. J.","author_corresponding":"Maria Jose Perez-Alvarez","author_corresponding_institution":"Universidad Autonoma de Madrid, Madrid (Spain)","doi":"10.1101\/2023.12.31.571469","date":"2024-01-01","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.31.571469.source.xml","abstract":"Ischemic stroke is a sudden and acute disease characterized by neuronal death, glia activation, and a severe inflammatory process. Neuroinflammation is an early event after cerebral ischemia, with microglia playing a leading role. Microglial activation involves functional and morphological changes that drive a wide variety of phenotypes. In this context, deciphering the molecular mechanisms underlying such microglial activation is essential to devise strategies to protect neurons and maintain certain brain functions affected by early neuroinflammation after ischemia.\n\nHere, we studied the role of mammalian target of rapamycin (mTOR) activity in the microglial response using a murine model of cerebral ischemia in the acute phase. We also determined the therapeutic relevance of the pharmacological administration of rapamycin, a mTOR inhibitor, before and after ischemic injury.\n\nOur data show that rapamycin, administered before or after brain ischemia induction, reduced the volume of brain damage and neuronal loss by attenuating the microglial response. Therefore, our findings indicate that the pharmacological inhibition of mTORC1 in the acute phase of ischemia may provide an alternative strategy to reduce neuronal damage through attenuation of the associated neuroinflammation.","funder":"NA","published":"10.1186\/s13062-024-00470-5","server":"bioRxiv"},{"title":"Transcranial direct current stimulation alters cerebrospinal fluid-interstitial fluid exchange in mouse brain","authors":"Wang, Y.; Monai, H.","author_corresponding":"Hiromu Monai","author_corresponding_institution":"Graduate School of Humanities and Sciences, Ochanomizu University","doi":"10.1101\/2023.12.30.573695","date":"2024-01-01","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.30.573695.source.xml","abstract":"BackgroundTranscranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has gained prominence recently. Clinical studies have explored tDCS as an adjunct to neurologic disease rehabilitation, with evidence suggesting its potential in modulating brain clearance mechanisms. The glymphatic system, a proposed brain waste clearance system, posits that cerebrospinal fluid-interstitial fluid (CSF-ISF) exchange aids in efficient metabolic waste removal. While some studies have linked tDCS to astrocytes inositol trisphosphate (IP3)\/Ca2+ signaling, the impact of tDCS on CSF-ISF exchange dynamics remains unclear.\n\nHypothesistDCS influences the dynamics of CSF-ISF exchange through astrocytic IP3\/Ca2+ signaling.\n\nMethodsIn this study, we administered tDCS (0.1mA for 10 minutes) to C57BL\/6 mice anesthetized with ketamine-xylazine (KX). The anode was positioned on the cranial bone above the cortex, and the cathode was inserted into the neck. Following tDCS, we directly assessed brain fluid dynamics by injecting biotinylated dextran amine (BDA) as a CSF tracer into the cisterna magna (CM). The brain was then extracted after either 30 or 60 minutes and fixed. After 24 hours, the sectioned brain slices were stained with Alexa 594-conjugated streptavidin (SA) to visualize BDA using immunohistochemistry. We conducted Electroencephalography (EEG) recordings and aquaporin 4 (AQP4)\/CD31 immunostaining to investigate the underlying mechanisms of tDCS. Additionally, we monitored the efflux of Evans blue, injected into the cisterna magna, using cervical lymph node imaging. The experiments were subsequently repeated with inositol trisphosphate receptor type 2 (IP3R2)-knockout mice.\n\nResultsPost-tDCS, we observed an increased CSF tracer influx, indicating a modulation of CSF-ISF exchange by tDCS. Additionally, tDCS appeared to enhance the brains metabolic waste efflux. EEG recordings showed an increase in delta wave post-tDCS. But no significant change in AQP4 expression was detected 30 minutes post-tDCS.\n\nConclusionOur findings suggest that tDCS augments the glymphatic systems influx and efflux. Through astrocyte IP3\/Ca2+ signaling, tDCS was found to modify the delta wave, which correlates positively with brain clearance. This study underscores the potential of tDCS in modulating brain metabolic waste clearance.","funder":"NA","published":"10.1016\/j.brs.2024.04.009","server":"bioRxiv"},{"title":"Extinction Training Suppresses Activity of Fear Memory Ensembles Across the Hippocampus and Alters Transcriptomes of Fear-Encoding Cells","authors":"Zuniga, A.; Han, J.; Miller-Crews, I.; Agee, L. A.; Hofmann, H. A.; Drew, M. R.","author_corresponding":"Michael R Drew","author_corresponding_institution":"University of Texas at Austin","doi":"10.1101\/2023.12.31.573787","date":"2024-01-01","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.31.573787.source.xml","abstract":"Contextual fear conditioning has been shown to activate a set of \"fear ensemble\" cells in the hippocampal dentate gyrus (DG) whose reactivation is necessary and sufficient for expression of contextual fear. We previously demonstrated that extinction learning suppresses reactivation of these fear ensemble cells and activates a competing set of DG cells - the \"extinction ensemble.\" Here, we tested whether extinction was sufficient to suppress reactivation in other regions and used single nucleus RNA sequencing (snRNA-seq) of cells in the dorsal dentate gyrus to examine how extinction affects the transcriptomic activity of fear ensemble and fear recall-activated cells. Our results confirm the suppressive effects of extinction in the dorsal and ventral dentate gyrus and demonstrate that this same effect extends to fear ensemble cells located in the dorsal CA1. Interestingly, the extinction-induced suppression of fear ensemble activity was not detected in ventral CA1. Our snRNA-seq analysis demonstrates that extinction training markedly changes transcription patterns in fear ensemble cells and that cells activated during recall of fear and recall of extinction have distinct transcriptomic profiles. Together, our results indicate that extinction training suppresses a broad portion of the fear ensemble in the hippocampus, and this suppression is accompanied by changes in the transcriptomes of fear ensemble cells and the emergence of a transcriptionally unique extinction ensemble.","funder":"NA","published":"10.1038\/s41386-024-01897-0","server":"bioRxiv"},{"title":"Neurotransmitter Genes in the Nucleus Accumbens that Are Involved in the Development of Behavioral Pathology After Positive Fighting Experiences and Their Deprivation. A Conceptual Paradigm for Neurogenomic Data Analysis","authors":"Kudryavtseva, N. N.; Smagin, D. A.; Redina, O. E.; Kovalenko, I. L.; Galyamina, A. G.; Babenko, V. N.","author_corresponding":"Natalia N Kudryavtseva","author_corresponding_institution":"FRC Institute of Cytology and Genetics, SB RAS","doi":"10.1101\/2023.12.30.573683","date":"2024-01-01","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.30.573683.source.xml","abstract":"It has been shown earlier that repeated positive fighting experience in daily agonistic interactions is accompanied by the development of psychosis-like behavior with signs of an addiction-like state associated with changes in the expression of genes encoding the proteins involved in the main neurotransmitter events in some brain regions of aggressive male mice. Fighting deprivation (a no-fight period of 2 weeks) causes a significant increase in their aggressiveness. This paper is aimed at studying--after a period of fighting deprivation--the involvement of genes (associated with neurotransmitter systems within the nucleus accumbens) in the above phenomena. The nucleus accumbens is known to participate in reward-related mechanisms of aggression. We found the following differentially expressed genes (DEGs), whose expression significantly differed from that in controls and\/or mice with positive fighting experience in daily agonistic interactions followed by fighting deprivation: catecholaminergic genes Th, Drd1, Drd2, Adra2c, Ppp1r1b, and Maoa; serotonergic genes Maoa, Htr1a, Htr1f, and Htr3a; opioidergic genes Oprk1, Pdyn, and Penk; and glutamatergic genes Grid1, Grik4, Grik5, Grin3a, Grm2, Grm5, Grm7, and Gad1. The expression of DEGs encoding proteins of the GABAergic system in experienced aggressive male mice mostly returned to control levels after fighting deprivation except for Gabra5. In light of the conceptual paradigm for analyzing data that was chosen in our study, the aforementioned DEGs associated with the behavioral pathology can be considered responsible for consequences of aggression followed by fighting deprivation, including mechanisms of an aggression relapse.","funder":"NA","published":"10.3390\/ijms26178580","server":"bioRxiv"},{"title":"Decoding of resting-state using task-based multivariate pattern analysis supports the Incentive-Sensitization Theory in nicotine use disorder","authors":"Lor, C. S.; Steyrl, D.; Zhang, M.; Zhou, F.; Becker, B.; Herdener, M.; Quednow, B. B.; Haugg, A.; Scharnowski, F.","author_corresponding":"Cindy Sumaly Lor","author_corresponding_institution":"University of Vienna","doi":"10.1101\/2023.12.31.573585","date":"2024-01-01","version":"1","type":"new results","license":"cc_by_nc","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.31.573585.source.xml","abstract":"BackgroundThe Incentive-Sensitization Theory postulates that addiction is primarily driven by the sensitization of the brains reward system to addictive substances, such as nicotine. According to this theory, exposure to such substances leads to an increase in  wanting, while  liking the experience remains relatively unchanged. Although this candidate mechanism has been well substantiated through animal brain research, its translational validity for humans has only been partially demonstrated so far, with evidence from human neuroscience data being very limited.\n\nMethodsFrom fMRI data of N=31 individuals with Nicotine Use Disorder, we created multivoxel patterns capable of capturing wanting and liking-related dimensions from a smoking cue-reactivity task. Using these patterns, we then designed a novel resting-state  reading method to evaluate how much wanting or liking still persist as a neural trace after watching the cues.\n\nResultsWe found that the persistence of wanting-related brain patterns at rest increases with longer smoking history but this was not the case for liking-related patterns. Interestingly, such behavior has not been observed for non-temporal measures of smoking intensity.\n\nConclusionThis study provides basic human neuroscience evidence that the dissociation between liking and wanting escalates over time, further substantiating the Incentive-Sensitization Theory, at least for Nicotine Use Disorder. These results suggest that treatment approaches could be personalized to account for the variability in individuals neural adaptation to addiction by considering how individuals differ in the extent to which their incentive salience system is sensitized.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Spatially Resolved Transcriptomic Signatures of Hippocampal Subregions and Arc-Expressing Ensembles in Active Place Avoidance Memory","authors":"Vingan, I. P.; Tung, V. S. K.; Phatarpekar, S.; Hernandez, A. I.; Evgrafov, O. V.; Alarcon, J. M.","author_corresponding":"Juan Marcos Alarcon","author_corresponding_institution":"SUNY Downstate Health Sciences University, Department of Pathology","doi":"10.1101\/2023.12.30.573225","date":"2024-01-01","version":"1","type":"new results","license":"cc_by","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.30.573225.source.xml","abstract":"The rodent hippocampus is a spatially organized neuronal network that supports the formation of spatial and episodic memories. We conducted bulk RNA sequencing and spatial transcriptomics experiments to measure gene expression changes in the dorsal hippocampus following the recall of active place avoidance (APA) memory. Through bulk RNA sequencing, we examined the gene expression changes following memory recall across the functionally distinct subregions of the dorsal hippocampus. We found that recall induced differentially expressed genes (DEGs) in the CA1 and CA3 hippocampal subregions were enriched with genes involved in synaptic transmission and synaptic plasticity, while DEGs in the dentate gyrus (DG) were enriched with genes involved in energy balance and ribosomal function. Through spatial transcriptomics, we examined gene expression changes following memory recall across an array of spots encompassing putative memory-associated neuronal ensembles marked by the expression of the IEGs Arc, Egr1, and c-Jun. Within samples from both trained and untrained mice, the subpopulations of spatial transcriptomic spots marked by these IEGs were transcriptomically and spatially distinct from one another. DEGs detected between Arc+ and Arc-spots exclusively in the trained mouse were enriched in several memory-related gene ontology terms, including \"regulation of synaptic plasticity\" and \"memory.\" Our results suggest that APA memory recall is supported by regionalized transcriptomic profiles separating the CA1 and CA3 from the DG, transcriptionally and spatially distinct IEG expressing spatial transcriptomic spots, and biological processes related to synaptic plasticity as a defining the difference between Arc+ and Arc-spatial transcriptomic spots.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Human DDIT4L intron retention contributes to cognitive impairment and amyloid plaque formation.","authors":"Li, k. c.; shi, h. x.; li, z.; you, p.; pan, j.; cai, y. c.; li, j. w.; ma, x. f.; zhang, s.; diao, l.; cai, b.; lu, y.; wang, h. b.; zhong, y. q.; chen, l.; mao, y.; zhang, x.","author_corresponding":"kai cheng Li","author_corresponding_institution":"QuietD Biotech","doi":"10.1101\/2023.12.30.573740","date":"2024-01-01","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.30.573740.source.xml","abstract":"Cognitive impairment and amyloid plaques are the most important clinical and neuropathological feature for dementia, especially in Alzheimers disease (AD). However, the etiology of dementia is complicated. The present study reveals that an aberrant splicing of DDIT4L, the isoform DDIT4L intron retention (DIR), occurs in AD patients. Homozygous DIR-knock-in (KI) mice showed DIR expression in hippocampal neurons, marked cognitive impairment, augmented A{beta} deposition and enhanced Tau phosphorylation. The DIR colocalized with thioflavin S-positive plaques and gelsolin in AD patients. The DIR induced A{beta} deposition and cognitive impairment by interacting with gelsolin. Moreover, DIR interacted with GluA1, the subunit of the AMPA receptor, contributing to synaptic deficiency and cognitive impairment. Furthermore, an anti-DIR monoclonal antibody (mAb) alleviated cognitive impairment and reduced A{beta} deposition and Tau phosphorylation. Thus, DIR contributes to cognitive impairment and amyloid plaques, and could be a potential therapeutic target for dementia.","funder":"NA","published":"10.1038\/s41421-024-00759-9","server":"bioRxiv"},{"title":"Basolateral amygdala population coding of a cued reward seeking state depends on orbitofrontal cortex","authors":"Ottenheimer, D. J.; Vitale, K. R.; Ambroggi, F.; Janak, P. H.; Saunders, B. T.","author_corresponding":"Benjamin T Saunders","author_corresponding_institution":"University of Minnesota","doi":"10.1101\/2023.12.31.573789","date":"2024-01-01","version":"1","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.31.573789.source.xml","abstract":"Basolateral amygdala (BLA) neuronal responses to conditioned stimuli are closely linked to the expression of conditioned behavior. An area of increasing interest is how the dynamics of BLA neurons relate to evolving behavior. Here, we recorded the activity of individual BLA neurons across the acquisition and extinction of conditioned reward seeking and employed population-level analyses to assess ongoing neural dynamics. We found that, with training, sustained cue-evoked activity emerged that discriminated between the CS+ and CS-and correlated with conditioned responding. This sustained population activity continued until reward receipt and rapidly extinguished along with conditioned behavior during extinction. To assess the contribution of orbitofrontal cortex (OFC), a major reciprocal partner to BLA, to this component of BLA neural activity, we inactivated OFC while recording in BLA and found blunted sustained cue-evoked activity in BLA that accompanied reduced reward seeking. Optogenetic disruption of BLA activity and OFC terminals in BLA also reduced reward seeking. Our data suggest that sustained cue-driven activity in BLA, which in part depends on OFC input, underlies conditioned reward-seek-ing states.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Single-Nuclei RNA Sequencing Identifies Type C Low-Threshold Mechanoreceptors as Key Players in Paclitaxel-Induced Peripheral Neuropathy","authors":"Sun, W.; Li, R.; Zhang, X.; Wu, S.; Jiang, Y.; Li, Q.; Cao, D.; Xiong, D.; Xiao, L.; Liu, X.","author_corresponding":"Xiaodong Liu","author_corresponding_institution":"2 Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, China 3 Peter Hung Pain Research Institute, The Chinese Univ","doi":"10.1101\/2023.12.31.573703","date":"2024-01-01","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.31.573703.source.xml","abstract":"Neuropathic pain triggered by chemotherapy poses a significant clinical challenge. Investigating cell type-specific alterations through single-cell transcriptome analysis holds promise in understanding symptom development and pathogenesis. In this study, we performed single nuclei RNA (snRNA) sequencing of dorsal root ganglions (DRG) to explore the molecular mechanism underlying paclitaxel-induced neuropathic pain. Mouse exposed to repeated paclitaxel doses developed persistent pain hypersensitivity lasting at least 21 days. The snRNA sequencing unveiled seven major cell types within DRGs, with neurons further subdivided into 12 distinct subclusters using known markers. Notably, type C low-threshold mechanoreceptors (C_LTMR) exhibited the most pronounced transcriptomic changes post-paclitaxel administration. Differential gene expression and Gene Ontology (GO) analysis highlighted suppressed potassium-related currents, microtubule transport, and mitochondrial functions in C_LTMR following paclitaxel treatment. Meanwhile, Gene Set Enrichment Analysis (GSEA) suggested increased Interleukin 17 production in C_LTMR after paclitaxel exposure. Pseudo-time analysis uncovered nine distinct states (state 1 to 9) of C_LTMR. State 1 exhibits higher prevalence in paclitaxel-treated mice and altered neurotransmission properties, likely contributing to paclitaxel-induced pain hypersensitivity. This comprehensive exploration sheds light on the molecular mechanisms driving paclitaxel-induced neuropathic pain, offering potential avenues for therapeutic intervention.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Spindle Oscillation Emerges at the Critical State of the Electrically Coupled Network in Thalamic Reticular Nucleus","authors":"Li, S.; Wang, C.; Wu, S.","author_corresponding":"Si Wu","author_corresponding_institution":"Peking University","doi":"10.1101\/2023.12.31.573769","date":"2024-01-01","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.31.573769.source.xml","abstract":"Spindle oscillation is a waxing-and-waning neural oscillation observed in the brain, initiated at the thalamic reticular nucleus (TRN) and typically occurring at 7-15 Hz. Experiments have shown that in the adult brain, electrical synapses, rather than chemical synapses, dominate between TRN neurons, suggesting that the traditional view of spindle generation via chemical synapses may need reconsideration. Based on known experimental data, we develop a computational model of the TRN network, where heterogeneous neurons are connected by electrical synapses. The model shows that the interplay between synchronizing electrical synapses and desynchro-nizing heterogeneity leads to multiple synchronized clusters with slightly different oscillation frequencies, whose summed activity produces spindle oscillation as seen in local field potentials. Our results suggest that during spindle oscillation, the network operates at the critical state, which is known for facilitating efficient information processing. This study provides insights into the underlying mechanism of spindle oscillation and its functional significance.","funder":"NA","published":"10.1016\/j.celrep.2024.114790","server":"bioRxiv"},{"title":"Saturated fatty acid-Coenzyme A supplementation restores neuronal energy levels and protein homeostasis in hereditary spastic paraplegia","authors":"Saber, S. H.; Yak, N.; Yong, X. L. H.; Lu, S.; Binder, T.; Purushothaman, R.; Gaudin, A.; Harmer, J.; Talbo, G.; van Waardenberg, A. J.; Anggono, V.; Balistreri, G.; Joensuu, M.","author_corresponding":"Merja Joensuu","author_corresponding_institution":"Australian Institute for Bioengineering and Nanotechnology, and Queensland Brain Institute, The University of Queensland","doi":"10.1101\/2023.12.31.573799","date":"2024-01-01","version":"1","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/01\/2023.12.31.573799.source.xml","abstract":"Mitochondrial ATP production is fuelled by a fatty acid flux generated by phospholipase and triglyceride lipases in metabolically demanding tissues such as heart and liver, while the brain has long been believed to use almost solely glucose for energy. Phospholipase A1 enzyme DDHD2 is a major triglyceride lipase in the brain, and the loss of DDHD2 function results in a saturated free fatty acid (sFFA) imbalance and lipid droplet (LD) accumulation in the brain. The LD accumulation in neurons has been enigmatic as LDs are mainly considered to serve as a fuel storage. Here, we demonstrate that the loss of DDHD2 results in a mitochondrial respiratory dysfunction that leads to a significant decrease in ATP production and acetyl coenzyme A levels in neurons, even when the glycolytic breakdown of glycose occurs normally. Loss of DDHD2 also leads to a presynaptic defect as well as an imbalance in the global protein homeostasis in the neurons. These defects were rescued by external supplementation of the sFFA myristic acid coupled with its cofactor coenzyme A (Myr-CoA), indicating sFFA fuelling for neuronal {beta}-oxidation. We have thus discovered that the sFFAs released by the activity of DDHD2 play a central role in providing energy to fuel synaptic function.\n\nOne Sentence SummaryFree fatty acids released by DDHD2 activity play a central role in maintaining neuronal energy levels and synaptic function.","funder":"NA","published":"10.1038\/s42255-025-01367-x","server":"bioRxiv"},{"title":"How Absence Seizures Impair Sensory Perception: Insights from Awake fMRI and Simulation Studies in Rats","authors":"Stenroos, P.; Guillemain, I.; Tesler, F.; Montigon, O.; Collomb, N.; Stupar, V.; Destexhe, A.; Coizet, V.; David, O.; Barbier, E. L.","author_corresponding":"Emmanuel L Barbier","author_corresponding_institution":"Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, Grenoble, France","doi":"10.1101\/2023.07.26.550701","date":"2024-01-02","version":"2","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2023.07.26.550701.source.xml","abstract":"In patients suffering absence epilepsy, recurring seizures can significantly decrease their quality of life and lead to yet untreatable comorbidities. Absence seizures are characterized by spike-and- wave discharges on the electroencephalogram associated with a transient alteration of consciousness. However, it is still unknown how the brain responds to external stimuli during and outside of seizures.\n\nThis study aimed to investigate responsiveness to visual and somatosensory stimulation in GAERS, a well-established rat model for absence epilepsy. Animals were imaged under non-curarized awake state using a quiet, zero-echo-time, functional magnetic resonance imaging (fMRI) sequence. Sensory stimulations were applied during interictal and ictal periods. Whole brain hemodynamic responses were compared between these two states. Additionally, a mean-field simulation model was used to explain the changes of neural responsiveness to visual stimulation between states.\n\nDuring a seizure, whole-brain responses to both sensory stimulations were suppressed and spatially hindered. In the cortex, hemodynamic responses were negatively polarized during seizures, despite the application of a stimulus. The mean-field simulation revealed restricted propagation of activity due to stimulation and agreed well with fMRI findings. Results suggest that sensory processing is hindered or even suppressed by the occurrence of an absence seizure, potentially contributing to decreased responsiveness during this absence epileptic process.","funder":"NA","published":"10.7554\/elife.90318.4","server":"bioRxiv"},{"title":"Prioritized neural processing of social threats during perceptual decision-making","authors":"El Zein, M.; Mennella, R.; Sequestro, M.; Meaux, E.; Wyart, V.; Grezes, J.","author_corresponding":"Emilie  Meaux","author_corresponding_institution":"INSERM U960, LNC2, Ecole Normale Superieure de Paris, PSL University","doi":"10.1101\/859942","date":"2024-01-02","version":"4","type":"new results","license":"cc_by","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/859942.source.xml","abstract":"Emotional signals, notably those signaling threat, benefit from prioritized processing in the human brain. Yet, it remains unclear whether perceptual decisions about the emotional, threat-related aspects of stimuli involve specific or similar neural computations compared to decisions about their non-threatening\/non-emotional components. We developed a novel behavioral paradigm in which participants performed two different detection tasks (emotion vs. color) on the same, two-dimensional visual stimuli. Electroencephalographic (EEG) activity in a cluster of central electrodes reflected the amount of perceptual evidence around 100ms following stimulus onset, when the decision concerned emotion, not color. Second, participants choice could be predicted earlier for emotion (240ms) than for color (380ms) by the mu (10Hz) rhythm, which reflects motor preparation. Taken together, these findings indicate that perceptual decisions about threat-signaling dimensions of facial displays are associated with prioritized neural coding in action-related brain regions, supporting the motivational value of socially relevant signals.","funder":"NA","published":"10.1016\/j.isci.2024.109951","server":"bioRxiv"},{"title":"Rab10 regulates neuropeptide release by maintaining Ca2+ homeostasis and protein synthesis","authors":"Dong, J.; Chen, M.; van Weering, J. R. T.; Li, K. W.; Smit, A. B.; Toonen, R. F.; Verhage, M.","author_corresponding":"Matthijs Verhage","author_corresponding_institution":"VU Amsterdam","doi":"10.1101\/2024.01.02.573873","date":"2024-01-02","version":"1","type":"new results","license":"cc_by","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2024.01.02.573873.source.xml","abstract":"Dense core vesicles (DCVs) transport and release various neuropeptides and neurotrophins that control diverse brain functions, but the DCV secretory pathway remains poorly understood. Here, we tested a prediction emerging from invertebrate studies about the crucial role of the intracellular trafficking GTPase Rab10, by assessing DCV exocytosis at single-cell resolution upon acute Rab10 depletion in mature mouse hippocampal neurons, to circumvent potential confounding effects of Rab10s established role in neurite outgrowth. We observed a significant inhibition of DCV exocytosis in Rab10-depleted neurons, whereas synaptic vesicle exocytosis was unaffected. However, rather than a direct involvement in DCV trafficking, this effect was attributed to two ER-dependent processes, ER-regulated intracellular Ca2+ dynamics and protein synthesis. Gene ontology analysis of differentially expressed proteins upon Rab10 depletion identified substantial alterations in synaptic and ER\/ribosomal proteins, including the Ca2+-pump SERCA2. In addition, ER morphology and dynamics were altered, ER Ca2+ levels were depleted and Ca2+ homeostasis was impaired in Rab10-depleted neurons. However, Ca2+ entry using a Ca2+ ionophore still triggered less DCV exocytosis. Instead, leucine supplementation, which enhances protein synthesis, largely rescued DCV exocytosis deficiency. We conclude that Rab10 is required for neuropeptide release by maintaining Ca2+ dynamics and regulating protein synthesis. Furthermore, DCV exocytosis appeared more dependent on (acute) protein synthesis than synaptic vesicle exocytosis.","funder":"NA","published":"10.7554\/elife.94930","server":"bioRxiv"},{"title":"Using normative models pre-trained on cross-sectional data to evaluate longitudinal changes in neuroimaging data","authors":"Rehak Buckova, B.; Fraza, C.; Rehak, R.; Kolenic, M.; Beckmann, C.; Spaniel, F.; Marquand, A.; Hlinka, J.","author_corresponding":"Jaroslav Hlinka","author_corresponding_institution":"Institute of Computer Science of the Czech Academy of Sciences, Prague, Czech Republic","doi":"10.1101\/2023.06.09.544217","date":"2024-01-02","version":"2","type":"new results","license":"cc_by_nc","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2023.06.09.544217.source.xml","abstract":"Longitudinal neuroimaging studies offer valuable insight into intricate dynamics of brain development, ageing, and disease progression over time. However, prevailing analytical approaches rooted in our understanding of population variation are primarily tailored for cross-sectional studies. To fully harness the potential of longitudinal neuroimaging data, we have to develop and refine methodologies that are adapted to longitudinal designs, considering the complex interplay between population variation and individual dynamics.\n\nWe build on normative modelling framework, which enables the evaluation of an individuals position compared to a population standard. We extend this framework to evaluate an individuals longitudinal change compared to the longitudinal change reflected by the (population) standard dynamics. Thus, we exploit the existing normative models pre-trained on over 58,000 individuals and adapt the framework so that they can also be used in the evaluation of longitudinal studies. Specifically, we introduce a quantitative metric termed \"z-diff\" score, which serves as an indicator of a temporal change of an individual compared to a population standard. Notably, our framework offers advantages such as flexibility in dataset size and ease of implementation.\n\nTo illustrate our approach, we applied it to a longitudinal dataset of 98 patients diagnosed with early-stage schizophrenia who underwent MRI examinations shortly after diagnosis and one year later.\n\nCompared to cross-sectional analyses, which showed global thinning of grey matter at the first visit, our method revealed a significant normalisation of grey matter thickness in the frontal lobe over time. Furthermore, this result was not observed when using more traditional methods of longitudinal analysis, making our approach more sensitive to temporal changes.\n\nOverall, our framework presents a flexible and effective methodology for analysing longitudinal neuroimaging data, providing insights into the progression of a disease that would otherwise be missed when using more traditional approaches.","funder":"NA","published":"10.7554\/eLife.95823","server":"bioRxiv"},{"title":"Association between electrophysiological phenotypes and Kv2.1 potassium channel expression explained by geometrical analysis","authors":"Reyes-Garibaldi, J. C.; Herrera-Valdez, M. A.","author_corresponding":"Marco Arieli Herrera-Valdez","author_corresponding_institution":"Laboratorio de Dinamica, Biofisica, y Fisiologia de Sistemas, Facultad de Ciencias, Universidad Nacional Autonoma de Mexico","doi":"10.1101\/2023.12.20.572720","date":"2024-01-02","version":"2","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2023.12.20.572720.source.xml","abstract":"Excitable cells exhibit different electrophysiological profiles while responding to current stimulation in current-clamp experiments. In theory, the differences could be explained by changes in the expression of proteins mediating transmembrane ion transport. Experimental verification by performing systematic, controlled variations in the expression of proteins of the same type (e.g. voltage-dependent, noninactivating Kv2.1 channels) is difficult to achieve in the absence of other changes. However, biophysical models enable this possibility and allows us to assess and characterise the electrophysiological phenotypes associated to different levels of expression of non-inactivating voltage-dependent K-channels of type Kv2.1. To do so, we use a 2-dimensional biophysical model of neuronal membrane potential and study the phase plane geometry and bifurcation structures associated with different levels of Kv2.1 expression with the input current as bifurcation parameter. We find that increasing the expression of Kv2.1 channels reduces the size of the region of the phase plane from which action potentials can be initiated. The changes in expression can also be related to different transitions between rest and repetitive firing in current clamp experiments. For instance, increasing the number of Kv2.1 channels shifts the rheobase current to higher levels, but also expands the dynamic range in which excitatory external current produces repetitive spiking. Our analysis shows that changes in the responses to increasing input currents can be associated to different sequences of fixed point bifurcations. In general, the fixed points are attracting, then repulsive, and later become attracting again as the input current increases, but the bifurcation sequences also include changes in fixed point type, and change qualitatively with the expression of Kv2.1 channels. In the non-repetitive spiking regime with low current stimulation, low expression of Kv2.1 channels yields bifurcation sequences that include transitions between 3 and 1 fixed points, and repetitive firing starts with delays that decrease with increasing current (aggregation). For higher expression of Kv2.1 channels there is only one fixed point that changes in type and attractivity as the input current increases, convergence to rest tends to be oscillatory (resonance), and repetitive spiking starts without noticeable delays. Our models explain how the same neuron is theoretically be capable of including both aggregating and resonant modes of integration for synaptic input, as shown in current clamp experiments.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Predictive coding in the auditory brainstem","authors":"de Cheveigne, A.","author_corresponding":"Alain de Cheveigne","author_corresponding_institution":"Centre National de la Recherche Scientifique, Ecole normale superieure (Paris)","doi":"10.1101\/2023.12.31.573202","date":"2024-01-02","version":"1","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2023.12.31.573202.source.xml","abstract":"Predictive coding is an influential concept in sensory and cognitive neuroscience. It is often understood as involving top-down prediction of bottom-up sensory patterns, but the term also applies to feed-forward predictive mechanisms, for example in the retina. Here, I discuss a recent model of low-level predictive processing in the auditory brainstem that is of the feed-forward flavor. Past sensory input from the cochlea is delayed and compared with the current input, with a delay that is tuned with the objective of minimizing prediction error. This operation can be performed uniformly across peripheral channels, or independently within each peripheral channel with parameters local to that channel. The result is a sensory representation that is invariant to a certain class of masking sounds (harmonic, quasi-harmonic, or spectrally sparse), thus contributing to Auditory Scene Analysis. The purpose of this paper is to discuss that model in the light of predictive coding, and examine how it might fit within a wider hierarchical model that supports the perceptual representation of objects and events in the world.","funder":[{"name":"Agence Nationale de la Recherche","id":"https:\/\/ror.org\/00rbzpz17","id-type":"ROR","award":"ANR-17-EURE-0017;"}],"published":"NA","server":"bioRxiv"},{"title":"Translating phenotypic prediction models from big to small anatomical MRI data using meta-matching","authors":"Wulan, N.; An, L.; Zhang, C.; Kong, R.; Chen, P.; Bzdok, D.; Eickhoff, S. B.; Holmes, A. J.; Yeo, B. T. T.","author_corresponding":"B. T. Thomas Yeo","author_corresponding_institution":"National University of Singapore","doi":"10.1101\/2023.12.31.573801","date":"2024-01-02","version":"1","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2023.12.31.573801.source.xml","abstract":"Individualized phenotypic prediction based on structural MRI is an important goal in neuroscience. Prediction performance increases with larger samples, but small-scale datasets with fewer than 200 participants are often unavoidable. We have previously proposed a \"meta-matching\" framework to translate models trained from large datasets to improve the prediction of new unseen phenotypes in small collection efforts. Meta-matching exploits correlations between phenotypes, yielding large improvement over classical machine learning when applied to prediction models using resting-state functional connectivity as input features. Here, we adapt the two best performing meta-matching variants (\"meta-matching finetune\" and \"meta-matching stacking\") from our previous study to work with T1-weighted MRI data by changing the base neural network architecture to a 3D convolution neural network. We compare the two meta-matching variants with elastic net and classical transfer learning using the UK Biobank (N = 36,461), Human Connectome Project Young Adults (HCP-YA) dataset (N = 1,017) and HCP-Aging dataset (N = 656). We find that meta-matching outperforms elastic net and classical transfer learning by a large margin, both when translating models within the same dataset, as well as translating models across datasets with different MRI scanners, acquisition protocols and demographics. For example, when translating a UK Biobank model to 100 HCP-YA participants, meta-matching finetune yielded a 136% improvement in variance explained over transfer learning, with an average absolute gain of 2.6% (minimum = -0.9%, maximum = 17.6%) across 35 phenotypes. Overall, our results highlight the versatility of the meta-matching framework.","funder":"NA","published":"10.1162\/imag_a_00251","server":"bioRxiv"},{"title":"BCI Toolbox: An Open-Source Python Package for the Bayesian Causal Inference Model","authors":"Zhu, H.; Beierholm, U.; Shams, L.","author_corresponding":"Ladan Shams","author_corresponding_institution":"UCLA","doi":"10.1101\/2024.01.02.573851","date":"2024-01-02","version":"1","type":"new results","license":"cc_by","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2024.01.02.573851.source.xml","abstract":"Psychological and neuroscientific research over the past two decades has shown that the Bayesian causal inference (BCI) is a potential unifying theory that can account for a wide range of perceptual and sensorimotor processes in humans. Therefore, we introduce the BCI Toolbox, a statistical and analytical tool in Python, enabling researchers to conveniently perform quantitative modeling and analysis of behavioral data. Additionally, we describe the algorithm of the BCI model and test its stability and reliability via parameter recovery. The present BCI toolbox offers a robust platform for BCI model implementation as well as a hands-on tool for learning and understanding the model, facilitating its widespread use and enabling researchers to delve into the data to uncover underlying cognitive mechanisms.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"ABCA7-dependent Neuropeptide-Y signalling is a resilience mechanism required for synaptic integrity in Alzheimer's disease","authors":"Tayran, H.; Yilmaz, E.; Bhattarai, P.; Min, Y.; Wang, X.; Ma, Y.; Nelson, N.; Kassara, N.; Cosacak, M. I.; Dogru, R. M.; Reyes-Dumeyer, D.; Reddy, J.; Qiao, M.; Flaherty, D.; Teich, A. F.; Gunasekaran, T. I.; Yang, Z.; Tosto, G.; Vardarajan, B. N.; Is, O.; Ertekin-Taner, N.; Mayeux, R.; Kizil, C.","author_corresponding":"Caghan Kizil","author_corresponding_institution":"Columbia University Irving Medical Center, New York, NY, USA","doi":"10.1101\/2024.01.02.573893","date":"2024-01-02","version":"1","type":"new results","license":"cc_no","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2024.01.02.573893.source.xml","abstract":"Alzheimers disease (AD) remains a complex challenge characterized by cognitive decline and memory loss. Genetic variations have emerged as crucial players in the etiology of AD, enabling hope for a better understanding of the disease mechanisms; yet the specific mechanism of action for those genetic variants remain uncertain. Animal models with reminiscent disease pathology could uncover previously uncharacterized roles of these genes. Using CRISPR\/Cas9 gene editing, we generated a knockout model for abca7, orthologous to human ABCA7 - an established AD-risk gene. The abca7+\/- zebrafish showed reduced astroglial proliferation, synaptic density, and microglial abundance in response to amyloid beta 42 (A{beta}42). Single-cell transcriptomics revealed abca7-dependent neuronal and glial cellular crosstalk through neuropeptide Y (NPY) signaling. The abca7 knockout reduced the expression of npy, bdnf and ngfra, which are required for synaptic integrity and astroglial proliferation. With clinical data in humans, we showed reduced NPY in AD correlates with elevated Braak stage, predicted regulatory interaction between NPY and BDNF, identified genetic variants in NPY associated with AD, found segregation of variants in ABCA7, BDNF and NGFR in AD families, and discovered epigenetic changes in the promoter regions of NPY, NGFR and BDNF in humans with specific single nucleotide polymorphisms in ABCA7. These results suggest that ABCA7-dependent NPY signaling is required for synaptic integrity, the impairment of which generates a risk factor for AD through compromised brain resilience.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC=\"FIGDIR\/small\/573893v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (73K):\norg.highwire.dtl.DTLVardef@eecf7forg.highwire.dtl.DTLVardef@78d8e0org.highwire.dtl.DTLVardef@1e65d71org.highwire.dtl.DTLVardef@100db01_HPS_FORMAT_FIGEXP  M_FIG Graphical abstract\n\nC_FIG","funder":"NA","published":"10.1016\/j.xgen.2024.100642","server":"bioRxiv"},{"title":"Cholinergic input to mouse visual cortex signals a movement state and acutely enhances layer 5 responsiveness","authors":"Yogesh, B.; Keller, G. B.","author_corresponding":"Georg B Keller","author_corresponding_institution":"Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland","doi":"10.1101\/2023.06.07.543871","date":"2024-01-02","version":"2","type":"new results","license":"cc_by_nc","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2023.06.07.543871.source.xml","abstract":"Acetylcholine is released in visual cortex by axonal projections from the basal forebrain. The signals conveyed by these projections and their computational significance are still unclear. Using two-photon calcium imaging in behaving mice, we show that basal forebrain cholinergic axons in the mouse visual cortex provide a binary locomotion state signal. In these axons, we found no evidence of responses to visual stimuli or visuomotor prediction errors. While optogenetic activation of cholinergic axons in visual cortex in isolation did not drive local neuronal activity, when paired with visuomotor stimuli, it resulted in layer-specific increases of neuronal activity. Responses in layer 5 neurons to both top-down and bottom-up inputs were increased in amplitude and decreased in latency, whereas those in layer 2\/3 neurons remained unchanged. Using opto- and chemogenetic manipulations of cholinergic activity, we found acetylcholine to underlie the locomotion-associated decorrelation of activity between neurons in both layer 2\/3 and layer 5. Our results suggest that acetylcholine augments the responsiveness of layer 5 neurons to inputs from outside of the local network, possibly enabling faster switching between internal representations during locomotion.","funder":"NA","published":"10.7554\/eLife.89986.5","server":"bioRxiv"},{"title":"Sensory experience steers representational drift in mouse visual cortex","authors":"Bauer, J.; Lewin, U.; Herbert, E.; Gjorgjieva, J.; Schoonover, C. E.; Fink, A. J. P.; Rose, T.; Bonhoeffer, T.; Hu\u0308bener, M.","author_corresponding":"Joel Bauer","author_corresponding_institution":"Max Planck Institute for Biological Intelligence","doi":"10.1101\/2023.09.22.558966","date":"2024-01-02","version":"2","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2023.09.22.558966.source.xml","abstract":"Representational drift - the gradual continuous change of neuronal representations - has been observed across many brain areas. It is unclear whether drift is caused by synaptic plasticity elicited by sensory experience, or by the intrinsic volatility of synapses. Here, using chronic two-photon calcium imaging in mouse primary visual cortex, we find that the preferred stimulus orientation of individual neurons slowly drifts over the course of weeks. By using cylinder lens goggles to limit visual experience to a narrow range of orientations, we show that the direction of drift, but not its magnitude, is biased by the statistics of visual input. A network model suggests that drift of preferred orientation largely results from synaptic volatility, which under normal visual conditions is counteracted by experience-driven Hebbian mechanisms, stabilizing preferred orientation. Under deprivation conditions these Hebbian mechanisms enable adaptation. Thus, Hebbian synaptic plasticity steers drift to match the statistics of the environment.","funder":"NA","published":"10.1038\/s41467-024-53326-x","server":"bioRxiv"},{"title":"Impaired microglial phagocytosis promotes seizure development","authors":"Bosco, D. B.; Kremen, V.; Haruwaka, K.; Zhao, S.; Wang, L.; Ebner, B. A.; Zheng, J.; Perry, J.; Xie, M.; Nguyen, A. T.; Worrell, G. A.; Wu, L.-J.","author_corresponding":"Long-Jun Wu","author_corresponding_institution":"Mayo Clinic","doi":"10.1101\/2023.12.31.573794","date":"2024-01-02","version":"1","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2023.12.31.573794.source.xml","abstract":"In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. TREM2 plays an important role in neurodegenerative diseases, such as Alzheimers disease and amyotrophic lateral sclerosis. However, little is known about the role TREM2 plays in epileptogenesis. To investigate this, we utilized TREM2 knockout (KO) mice within the murine intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both acute status epilepticus and spontaneous recurrent seizures characteristic of chronic focal epilepsy. Mechanistically, phagocytic clearance of damaged neurons by microglia was impaired in TREM2 KO mice and the reduced phagocytic capacity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between microglial phagocytic activity and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity may be important to epileptogenesis and the progression of focal temporal lobe epilepsy.\n\nOne Sentence SummaryPhagocytic activity of microglia may impact generalized seizure development within both mice and humans.","funder":"NA","published":"10.1016\/j.bbi.2024.09.034","server":"bioRxiv"},{"title":"Rapid nongenomic estrogen signaling controls alcohol drinking behavior","authors":"Zallar, L. J.; Rivera-Irizarry, J. K.; Hamor, P. U.; Pigulevskiy, I.; Liu, D.; Welday, J. P.; Rico Rozo, A.-S.; Bender, R.; Asfouri, J.; Skelly, M. J.; Fecteau, K. M.; Hadley, C. K.; Levine, O. B.; Mehanna, H.; Nelson, S.; Miller, J.; Ghazal, P.; Bellotti, P.; Erikson, D. W.; Geri, J.; Pleil, K. E.","author_corresponding":"Kristen E Pleil","author_corresponding_institution":"Weill Cornell Medicine","doi":"10.1101\/2023.11.02.565358","date":"2024-01-02","version":"2","type":"new results","license":"cc_by_nc_nd","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2023.11.02.565358.source.xml","abstract":"Ovarian-derived estrogen is a key modulator of numerous physiological processes via genomic and nongenomic mechanisms, including signaling non-canonically at membrane-associated estrogen receptors in the brain to rapidly regulate neuronal function. However, the mechanisms mediating estrogen regulation of behaviors such as alcohol consumption remain unclear. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen levels, but a causal role for estrogen signaling in driving alcohol drinking in gonadally-intact animals has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance behavior when circulating estrogen was high during the proestrus phase of the estrous cycle than when it was low, contributing to sex differences in these behaviors. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen state occurred via rapid estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking behavior. This study is the first to demonstrate a rapid, nongenomic signaling mechanism for ovarian-derived estrogen signaling in the brain controlling behavior in gonadally intact females, and it establishes a causal role for estrogen in an intact hormonal context for driving alcohol consumption that contributes to known sex differences in this behavior.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Musicians' brains at rest: Multilayer network analysis of MEG data","authors":"Mandke, K.; Tewarie, P.; Adjamian, P.; Schuermann, M.; Meier, J.","author_corresponding":"Kanad Mandke","author_corresponding_institution":"University of Cambridge","doi":"10.1101\/2024.01.02.573886","date":"2024-01-02","version":"1","type":"new results","license":"cc_by","category":"neuroscience","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2024\/01\/02\/2024.01.02.573886.source.xml","abstract":"The ability to proficiently play a musical instrument requires a fine-grained synchronisation between several sensorimotor and cognitive brain regions. Previous studies have demonstrated that the brain undergoes functional changes with musical training, identifiable also in resting-state data. These studies analysed fMRI or electrophysiological frequency-specific brain networks in isolation. While the analysis of such \"mono-layer\" networks has proven useful, it fails to capture the complexities of multiple interacting networks. To this end, we applied a multilayer network framework for analysing publicly available data (Open MEG Archive) obtained with magnetoencephalography (MEG). We investigated resting-state differences between participants with musical training (n=31) and those without (n=31). While single-layer analysis did not demonstrate any group differences, multilayer analysis revealed that musicians show a modular organisation that spans visuomotor and frontotemporal areas, known to be involved in musical performance execution, which is significantly different from non-musicians. Differences between the two groups are primarily observed in the theta (6.5-8Hz), alpha1 (8.5-10Hz) and beta1 (12.5-16Hz) frequency bands.\n\nWe demonstrate that the multilayer method provides additional information that single-layer analysis cannot. Overall, the multilayer network method provides a unique opportunity to explore the pan-spectral nature of oscillatory networks, with studies of brain plasticity as a potential future application.","funder":"NA","published":"10.1093\/cercor\/bhaf153","server":"bioRxiv"}]}