bioRxiv - Neuroscience最新文献

{"title":"Synapse-to-synapse plasticity variability balanced to generate input-wide constancy of transmitter release","authors":"Krisha Aghi, Ryan Schultz, Zachary L. Newman, Philipe Mendonca, Dariya Bakshinska, Ehud Y. Isacoff","doi":"10.1101/2024.09.11.612562","DOIUrl":"https://doi.org/10.1101/2024.09.11.612562","url":null,"abstract":"Basal synaptic strength can vary greatly between synapses formed by an individual neuron because of diverse probabilities of action potential (AP) evoked transmitter release (Pr). Optical quantal analysis on large numbers of identified Drosophila larval glutamatergic synapses shows that short-term plasticity (STP) also varies greatly between synapses made by an individual type I motor neuron (MN) onto a single body wall muscle. Synapses with high and low Pr and different forms and level of STP have a random spatial distribution in the MN nerve terminal, and ones with very different properties can be located within 200 nm of one other. While synapses start off with widely diverse basal Pr at low MN AP firing frequency and change Pr differentially when MN firing frequency increases, the overall distribution of Pr remains remarkably constant due to a balance between the numbers of synapses that facilitate and depress as well as their degree of change and basal synaptic weights. This constancy in transmitter release can ensure robustness across changing behavioral conditions.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spontaneously regenerative corticospinal neurons in mice","authors":"Benjamin W Fait, Bianca Cotto, Tatsuya C Murakami, Michael Hagemann-Jensen, Huiqing Zhan, Corinne Freivald, Isadora Turbek, Yuan Gao, Zizhen Yao, Sharon W Way, Hongkui Zeng, Bosiljka Tasic, Oswald Steward, Nathaniel Heintz, Eric F Schmidt","doi":"10.1101/2024.09.09.612115","DOIUrl":"https://doi.org/10.1101/2024.09.09.612115","url":null,"abstract":"The spinal cord receives inputs from the cortex via corticospinal neurons (CSNs). While predominantly a contralateral projection, a less-investigated minority of its axons terminate in the ipsilateral spinal cord. We analyzed the spatial and molecular properties of these ipsilateral axons and their post-synaptic targets in mice and found they project primarily to the ventral horn, including directly to motor neurons. Barcode-based reconstruction of the ipsilateral axons revealed a class of primarily bilaterally-projecting CSNs with a distinct cortical distribution. The molecular properties of these ipsilaterally-projecting CSNs (IP-CSNs) are strikingly similar to the previously described molecular signature of embryonic-like regenerating CSNs. Finally, we show that IP-CSNs are spontaneously regenerative after spinal cord injury. The discovery of a class of spontaneously regenerative CSNs may prove valuable to the study of spinal cord injury. Additionally, this work suggests that the retention of juvenile-like characteristics may be a widespread phenomenon in adult nervous systems.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"73 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between maternal depressive symptoms and hair cortisol concentration during pregnancy with corpus callosum integrity in newborns","authors":"Isabella Lucia Chiara Mariani Wigley, Paula Mustonen, Linnea Karlsson, Saara Nolvi, Noora Scheinin, Susanna Kortesluoma, Massimiliano Pastore, Katja Tervahartiala, Bárbara Coimbra, Ana J Rodrigues, Nuno Sousa, Hasse Karlsson, Jetro J Tuulari","doi":"10.1101/2024.09.06.610927","DOIUrl":"https://doi.org/10.1101/2024.09.06.610927","url":null,"abstract":"Maternal prenatal depressive symptoms are linked to neurodevelopmental impairments in offspring. Maternal cortisol levels are hypothesized to moderate this association, but its relationship with depressive symptoms is inconsistent. This study examined how maternal prenatal depressive symptoms and cortisol levels predict infant brain development, focusing on neonatal corpus callosum (CC) integrity. Using data from the FinnBrain Birth Cohort Study, we analyzed 37 mother-infant dyads. MRI data were collected from 2 to 5 weeks old infants, and DTI imaging estimated fractional anisotropy (FA) in CC regions (Genu, Body, and Splenium). Maternal cortisol levels were assessed through hair cortisol concentration (HCC) from a 5cm hair segment, reflecting cortisol over the last five months of pregnancy. A factor score of maternal depressive symptoms was computed from EPDS questionnaire data collected at gestational weeks 14, 24, and 34. We employed multivariate regression models with a Bayesian approach for statistical testing, controlling for maternal and infant attributes. Results indicated that maternal prenatal depressive symptoms and HCC interact negatively in predicting infants' FA across all CC regions. Infants exposed to high prenatal depressive symptoms and low HCC (1 SD below the mean) showed higher FA in all CC regions. These findings highlight the complex dynamics between maternal prenatal cortisol levels and depressive symptoms, revealing a nuanced impact of those factors on the structural integrity of infants' CC.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive Coding of Reward in the Hippocampus","authors":"Mohammad Hassan Yaghoubi, Andres Nieto-Pasadas, Coralie-Anne Mosser, Thomas Gisiger, Emmanuel Wilson, Sylvain Williams, Mark P Brandon","doi":"10.1101/2024.09.03.611040","DOIUrl":"https://doi.org/10.1101/2024.09.03.611040","url":null,"abstract":"A fundamental objective of the brain is to anticipate future outcomes. This process requires learning the states of the world as well as the transitional relationships between those states. The hippocampal cognitive map is believed to be one such internal model. However, evidence for predictive coding and reward sensitivity in the hippocampal neuronal representation suggests that its role extends beyond purely spatial representation. In fact, it raises the question of what kind of spatial representation is most useful for learning and maximizing future rewards? Here, we track the evolution of reward representation over weeks as mice learn to solve a cognitively demanding reward-based task. Our findings reveal a highly organized restructuring of hippocampal reward representations during the learning process. Specifically, we found multiple lines of evidence, both at the population and single-cell levels, that hippocampal representation becomes predictive of reward over weeks. Namely, both population-level information about reward and the percentage of reward-tuned neurons decrease over time. At the same time, the representation of the animals' choice and reward approach period (the period between choice and reward) increased over time. By tracking individual reward cells across sessions, we found that neurons initially tuned for reward shifted their tuning towards choice and reward approach periods, indicating that reward cells backpropagate their tuning to anticipate reward with experience. These findings underscore the dynamic nature of hippocampal representations, highlighting their critical role in learning through the prediction of future outcomes.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The epitranscriptomic m6A RNA modification modulates synaptic function in ageing and in a mouse model of synucleinopathy","authors":"Avika Chopra, Mary Xylaki, Fanzheng Yin, Ricardo Castro-Hernandez, Madiha Merghani, Valentina Grande, Brit Mollenhauer, Andre Fischer, Tiago Fleming Outeiro","doi":"10.1101/2024.09.12.612649","DOIUrl":"https://doi.org/10.1101/2024.09.12.612649","url":null,"abstract":"N6-methyladenosine (m6A) is the most abundant and conserved transcriptional modification in eukaryotic RNA, regulating RNA fate. While the functions of m6A in the development of the mammalian brain have been extensively studied, its roles in synaptic plasticity, cognitive decline, motor function, or other brain circuits remain underexplored. To date, the role of this modification in Parkinson's disease (PD) and other synucleinopathies has been largely unknown. Here, we investigated the m6A epitranscriptome in a mouse model of synucleinopathy. We performed m6A RNA immunoprecipitation sequencing (meRIP-seq) to obtain the m6A epitranscriptome of the midbrain in young (3 mo) and aged (15 mo) A30P-aSyn transgenic mice (aSyn Tg) and C57BL6 control wild type (Wt) mice. We observed hypermethylation of synaptic genes in 3 mo aSyn Tg mice compared to age-matched Wt mice. This methylation was reduced during ageing, with synaptic genes becoming increasingly hypomethylated. Using immunofluorescence imaging alongside biochemical analysis, we further investigated the expression of m6A regulatory enzymes writer, N6-Adenosine-Methyltransferase Complex Catalytic Subunit (METTL3); reader, YTH N6-methyladenosine RNA-binding protein (YTHDF1); and eraser, fat mass and obesity-associated protein (FTO) in the cortex, striatum, hippocampus, and cerebellum of Wt and aSyn Tg mice, as well as in primary cortical neuronal cultures. We observed that the levels of METTL3, YTHDF1 and FTO were similar between Wt and aSyn Tg mice. Interestingly, the writer protein METTL3 was found in both the nucleus and in the post-synaptic compartment in neuronal cultures. Our findings suggest that alterations in the regulation of m6A RNA methylation may be associated with neurodegeneration and ageing and that this level of epitranscriptomic regulation plays a significant role at the synapse.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adrenergic C1 neurons enhance anxiety via projections to PAG","authors":"Carlos Fernandez-Pena, Rachel L Pace, Lourds M Fernando, Brittany G Pittman, Lindsay A Schwarz","doi":"10.1101/2024.09.11.612440","DOIUrl":"https://doi.org/10.1101/2024.09.11.612440","url":null,"abstract":"Anxiety is an emotional state precipitated by the anticipation of real or potential threats. Anxiety disorders are the most prevalent psychiatric illnesses globally and increase the risk of developing comorbid conditions that negatively impact the brain and body. The etiology of anxiety disorders remains unresolved, limiting improvement of therapeutic strategies to alleviate anxiety-related symptoms with increased specificity and efficacy. Here, we applied novel intersectional tools to identify a discrete population of brainstem adrenergic neurons, named C1 cells, that promote aversion and anxiety-related behaviors via projections to the periaqueductal gray matter (PAG). While C1 cells have traditionally been implicated in modulation of autonomic processes, rabies tracing revealed that they receive input from brain areas with diverse functions. Calcium-based in vivo imaging showed that activation of C1 cells enhances excitatory responses in vlPAG, activity that is exacerbated in times of heightened stress. Furthermore, inhibition of C1 cells impedes the development of anxiety-like behaviors in response to stressful situations. Overall, these findings suggest that C1 neurons are positioned to integrate complex information from the brain and periphery for the promotion of anxiety-like behaviors.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing Synaptic Vesicle Release and Recycling Mechanism for Molecule Delivery to Neurons","authors":"Karen KL Yee, Junichi Kumamoto, Daijiro Inomata, Naoki Suzuki, Ryuhei Harada, Norihiro Yumoto","doi":"10.1101/2024.09.11.612569","DOIUrl":"https://doi.org/10.1101/2024.09.11.612569","url":null,"abstract":"Neurodegenerative clinical trials often fail due to insufficient drug doses in reaching targeted cells and the unintended delivery to non-targeted cells. This study demonstrates an alternative neuron-selective drug delivery system, which utilizes the synaptic vesicle release and recycling mechanism (SVRM) by antibody shuttles targeting synaptic vesicle transmembrane proteins for molecule delivery. Using Synaptotagmin-2 (SYT2), we exemplify that intravenously administered anti-SYT2 antibodies localize to neuromuscular junctions, undergo uptake, and retrograde transport to ChAT-positive motor neurons (MNs) in the spinal cord and brainstem. The delivery of anti-microtubule agent and Malat1 gapmer antisense oligonucleotide to MNs with anti-SYT2 antibodies induces axon degeneration and reduction of Malat1 RNA expression, respectively. This approach circumvents the blood-spinal cord barrier, enabling selective delivery of therapeutic molecules to neurons while minimizing effects in non-targeted cells. Thus harnessing SVRM presents a promising strategy for enhancing drug concentrations in neurons and improving treatment efficacy for neurodegenerative diseases.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Positive Allosteric Modulation of the α5-GABAA receptors prevents neuronal atrophy and cognitive decline independently of tau tangle accumulation in the PS19 mouse model","authors":"Ravinder Naik Dharavath, Ashley Bernardo, Cassandra Marceau-Linhares, Michael Marcotte, Kayla Wong, Celeste Pina-Leblanc, Adrien Bouchet, Dishary Sharmin, James Cook, Kamal Prasad Pandey, Thomas Damien Prevot, Etienne Sibille","doi":"10.1101/2024.09.07.611810","DOIUrl":"https://doi.org/10.1101/2024.09.07.611810","url":null,"abstract":"Background: Dysregulated tau phosphorylation is one of the hallmarks of Alzheimer's disease (AD), and it results in cognitive impairments, neuronal atrophy, and neurofibrillary tangle accumulation. Evidence shows that impaired somatostatin (SST) expression, particularly in SST-expressing GABAergic neurons, significantly contributes to AD-related pathophysiology and may increase cognitive burden. Additionally, SST+ interneurons in cortical layers and the hippocampus inhibit the dendrites of excitatory neurons, primarily through α5-GABAA receptors involved in cognitive regulation. Leveraging the potential of a newly developed small molecule that targets the α5-GABAA receptors via positive allosteric modulation (α5-PAM), we aim to assess its effects on tau phosphorylation-related neuronal morphology, cognitive deficits and protein expression.\u0000Methods: In the PS19 transgenic mouse mode, we administered the α5-PAM, GL-II-73, either acutely or chronically at 3 and 6 months. We assessed spatial working memory using the Y-maze. Golgi staining analyzed dendritic morphology in chronically exposed mice to α5-PAM. Western blotting was used to quantify p-Tau and Tau expression.\u0000Results: α5-PAM effectively reverses spatial working memory deficits induced by tau phosphorylation both acutely and chronically. Chronic treatment at 3and 6 months mitigates tau-induced loss of spine density. However, α5-PAM does not directly influence p-Tau levels, suggesting cognitive and neurotrophic benefits of GL-II-73s are independent of Tau burden.\u0000Conclusions: These results demonstrate the potential for both symptomatic and disease-modifying effects, highlighting the promise of α5-GABAA receptor positive allosteric modulation as a novel therapeutic strategy for addressing cognitive deficits associated with tau phosphorylation in AD pathology.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct input-specific mechanisms enable presynaptic homeostatic plasticity","authors":"Chun Chien, Kaikai He, Sarah Perry, Elizabeth Tchitchkan, Yifu Han, Xiling Li, Dion Dickman","doi":"10.1101/2024.09.10.612361","DOIUrl":"https://doi.org/10.1101/2024.09.10.612361","url":null,"abstract":"Synapses are endowed with the flexibility to change through experience, but must be sufficiently stable to last a lifetime. This tension is illustrated at the Drosophila neuromuscular junction (NMJ), where two motor inputs that differ in structural and functional properties co-innervate most muscles to coordinate locomotion. To stabilize NMJ activity, motor neurons augment neurotransmitter release following diminished postsynaptic glutamate receptor functionality, termed presynaptic homeostatic potentiation (PHP). How these distinct inputs contribute to PHP plasticity remains enigmatic. We have used a botulinum neurotoxin to selectively silence each input and resolve their roles in PHP, demonstrating that PHP is input-specific: Chronic (genetic) PHP selectively targets the tonic MN-Ib, where active zone remodeling enhances Ca2+ influx to promote increased glutamate release. In contrast, acute (pharmacological) PHP selectively increases vesicle pools to potentiate phasic MN-Is. Thus, distinct homeostatic modulations in active zone nanoarchitecture, vesicle pools, and Ca2+ influx collaborate to enable input-specific PHP expression.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural Dynamics Underlying False Alarms in Extrastriate Cortex","authors":"Bikash Sahoo, Adam Snyder","doi":"10.1101/2024.09.06.611738","DOIUrl":"https://doi.org/10.1101/2024.09.06.611738","url":null,"abstract":"The unfolding of neural population activity can be approximated as a dynamical system. Stability in the latent dynamics that characterize neural population activity has been linked with consistency in animal behavior, such as motor control or value-based decision-making. However, whether similar dynamics characterize perceptual activity and decision-making in the visual cortex is not well understood. To test this, we recorded V4 populations in monkeys engaged in a non-match-to-sample visual change-detection task that required sustained engagement. We measured how the stability in the latent dynamics in V4 might affect monkeys' perceptual behavior. Specifically, we reasoned that unstable sensory neural activity around dynamic attractor boundaries may make animals susceptible to taking incorrect actions when withholding action would have been correct (\"false alarms\"). We made three key discoveries: 1) greater stability was associated with longer trial sequences; 2) false alarm rate decreased (and reaction times slowed) when neural dynamics were more stable; and, 3) low stability predicted false alarms on a single-trial level, and this relationship depended on the elapsed time during the trial, consistent with the latent neural state approaching an attractor boundary. Our results suggest the same outward false alarm behavior can be attributed to two different potential strategies that can be disambiguated by examining neural stability: 1) premeditated false alarms that might lead to greater stability in population dynamics and faster reaction time and 2) false alarms due to unstable sensory activity consistent with misperception.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}