bioRxiv - Neuroscience最新文献

{"title":"Antagonist actions of CMK-1/CaMKI and TAX-6/Calcineurin along the C. elegans thermal avoidance circuit orchestrate nociceptive habituation","authors":"Martina Rudgalvyte, Zehan Hu, Dieter Kressler, Joern Dengjel, Dominique A Glauser","doi":"10.1101/2024.09.18.613419","DOIUrl":"https://doi.org/10.1101/2024.09.18.613419","url":null,"abstract":"Habituation is a conserved physiological phenomenon, during which responses decrease following repeated exposure to innocuous or noxious stimuli. Impaired nociceptive habituation is associated with several pain conditions in human, but the underpinning molecular mechanisms are only partially understood. In the nematode Caenorhabditis elegans, thermo-nociceptive habituation was previously shown to be regulated by the Ca2+/Calmodulin-dependent protein kinase 1 (named CMK-1), but its downstream effectors were unknown. Here, using in vitro kinase assays coupled with mass-spectrometry-based phosphoproteomics, we empirically identified hundreds of CMK-1 phospho-substrates. Among them, we found that CMK-1 can phosphorylate the calcineurin A (CnA) protein TAX-6 in a highly conserved regulatory domain. Combined genetic and pharmacological manipulations revealed a network of antagonistic actions between CMK-1 and calcineurin pathways in the regulation of the responsiveness of naive worms and their habituation to repeated noxious heat stimuli. We further highlighted multiple places of action of the two signaling pathways in a subset of thermosensory neurons and downstream interneurons mediating avoidance behaviors. As a whole, our study has identified (i) CMK-1 substrate candidates, which will fuel further research on the intracellular actuation of CMK-1-dependent signaling, and (ii) a complex set of antagonistic interactions between CMK-1 and calcineurin signaling operating at distributed loci within a sensory-behavior circuit, acting to adjust baseline thermo-nociception and regulate thermo-nociceptive habituation.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268745","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 scope and limits of fine-grained image and category information in the ventral visual pathway","authors":"Markus W. Badwal, Johanna Bergmann, Johannes Roth, Christian F. Doeller, Martin N. Hebart","doi":"10.1101/2024.08.04.606507","DOIUrl":"https://doi.org/10.1101/2024.08.04.606507","url":null,"abstract":"Humans can easily abstract incoming visual information into discrete semantic categories. Previous research employing functional MRI (fMRI) in humans has identified cortical organizing principles that allow not only for coarse-scale distinctions such as animate versus inanimate objects but also more fine-grained distinctions at the level of individual objects. This suggests that fMRI carries rather fine-grained information about individual objects. However, most previous work investigating fine-grained category representations either additionally included coarse-scale category comparisons of objects, which confounds fine-grained and coarse-scale distinctions, or only used a single exemplar of each object, which confounds visual and semantic information. To address these challenges, here we used multisession human fMRI (female and male) paired with a broad yet homogenous stimulus class of 48 terrestrial mammals, with 2 exemplars per mammal. Multivariate decoding and representational similarity analysis (RSA) revealed high image-specific reliability in low- and high-level visual regions, indicating stable representational patterns at the image level. In contrast, analyses across exemplars of the same animal yielded only small effects in the lateral occipital complex (LOC), indicating rather subtle category effects in this region. Variance partitioning with a deep neural network and shape model showed that across exemplar effects in EVC were largely explained by low-level visual appearance, while representations in LOC appeared to also contain higher category-specific information. These results suggest that representations typically measured with fMRI are dominated by image-specific visual or coarse-grained category information but indicate that commonly employed fMRI protocols may reveal subtle yet reliable distinctions between individual objects.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250449","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":"Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi-Goutières Syndrome neuropathology","authors":"Kelsey M Nemec, Genevieve Uy, V. Sai Chaluvadi, Freddy S Purnell, Bilal Elfayoumi, Carleigh O'Brien, William H Aisenberg, Sonia I Lombroso, Xinfeng Guo, Niklas Blank, Chet Huan Oon, Fazeela Yaqoob, Brian Temsamrit, Priyanka Rawat, Christoph Thaiss, Qingde Wang, Mariko L Bennett, F. Chris Bennett","doi":"10.1101/2024.09.18.613629","DOIUrl":"https://doi.org/10.1101/2024.09.18.613629","url":null,"abstract":"Microglia, the brain’s resident macrophages, can be reconstituted by surrogate cells - a process termed “microglia replacement.” To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived (BMD) macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this system’s power for studying the effects of disease mutations on microglia in vivo, we created stable, <em>Adar1</em>-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi-Goutières Syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that <em>Adar1 </em>knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo - phenotypes that can be rescued with concurrent mutation of <em>Ifih1 </em>(MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific <em>Adar1 </em>mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268742","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":"Ventrolateral prefrontal cortex in macaques guides decisions in different learning contexts","authors":"Atsushi Fujimoto, Catherine Elorette, Satoka Hashimoto Fujimoto, Lazar Fleysher, Brian E. Russ, Peter H. Rudebeck","doi":"10.1101/2024.09.18.613767","DOIUrl":"https://doi.org/10.1101/2024.09.18.613767","url":null,"abstract":"Flexibly adjusting our behavioral strategies based on the environmental context is critical to maximize rewards. Ventrolateral prefrontal cortex (vlPFC) has been implicated in both learning and decision-making for probabilistic rewards, although how context influences these processes remains unclear. We collected functional neuroimaging data while rhesus macaques performed a probabilistic learning task in two contexts: one with novel and another with familiar visual stimuli. We found that activity in vlPFC encoded rewards irrespective of the context but encoded behavioral strategies that depend on reward outcome (win-stay/lose-shift) preferentially in novel contexts. Functional connectivity between vlPFC and anterior cingulate cortex varied with behavioral strategy in novel learning blocks. By contrast, connectivity between vlPFC and mediodorsal thalamus was highest when subjects repeated a prior choice. Furthermore, pharmacological D2-receptor blockade altered behavioral strategies during learning and resting-state vlPFC activity. Taken together, our results suggest that multiple vlPFC-linked circuits contribute to adaptive decision-making in different contexts.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268743","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":"Dopamine release in striatal striosome compartments in response to rewards and aversive outcomes during classical conditioning in mice","authors":"Tomohiko Yoshizawa, Makoto Funahashi","doi":"10.1101/2024.09.18.613611","DOIUrl":"https://doi.org/10.1101/2024.09.18.613611","url":null,"abstract":"The striatum consists of two anatomically and neurochemically distinct compartments, striosomes and the matrix, which receive dopaminergic inputs from the midbrain and exhibit distinct dopamine release dynamics in acute brain slices. Striosomes comprise approximately 15% of the striatum by volume and are distributed mosaically. Therefore, it is difficult to selectively record dopamine dynamics in striosomes using traditional neurochemical measurements in behaving animals, and it is unclear whether distinct dynamics play a role in associative learning. In this study, we used transgenic mice selectively expressing Cre in striosomal neurons, combined with a fiber photometry technique, to selectively record dopamine release in striosomes during classical conditioning. Water-restricted mice could distinguish the conditioned stimulus (CS) associated with saccharin water from the air-puff-associated CS. The air-puff-associated CS evoked phasic dopamine release only in striosomes. Furthermore, air puff presentation induced dopamine release to striosomal neurons but suppressed release to putative matrix neurons. These findings suggest that dopamine is released in a differential manner in striosomes and the matrix in behaving animals and that dopamine release in striosomes is preferentially induced by the air-puff-associated CS and air puff presentation. These findings support the hypothesis that striosomal neurons play a dominant role in aversive stimuli prediction.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"141 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250167","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":"Speed modulations in grid cell information geometry","authors":"Zeyuan Ye, Ralf Wessel","doi":"10.1101/2024.09.18.613797","DOIUrl":"https://doi.org/10.1101/2024.09.18.613797","url":null,"abstract":"Grid cells, known for their hexagonal spatial firing patterns, are widely regarded as essential to the brain's internal representation of the external space. Maintaining an accurate internal spatial representation is challenging when an animal is running at high speeds, as its self-location constantly changes. Previous studies of speed modulation of grid cells focused on individual or pairs of grid cells, yet neurons represent information via collective population activity. Population noise covariance can have significant impact on information coding that is impossible to infer from individual neuron analysis. To address this issue, we developed a novel Gaussian Process with Kernel Regression (GKR) method that allows study the simultaneously recorded neural population representation from an information geometry framework. We applied GKR to grid cell population activity, and found that running speed increases both grid cell activity toroidal-like manifold size and noise strength. Importantly, the effect of manifold dilation outpaces the effect of noise increasement, as indicated by the overall higher Fisher information at increasing speeds. This result is further supported by improved spatial information decoding accuracy at high speeds. Finally, we showed that the existence of noise covariance is information detrimental because it causes more noise projected onto the manifold surface. In total, our results indicate that grid cell spatial coding improves with increasing running speed. GKR provides a useful tool to understand neural population coding from an intuitive information geometric perspective.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250162","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":"Unsupervised alignment reveals structural commonalities and differences in neural representations of natural scenes across individuals and brain areas","authors":"Ken Takeda, Kota Abe, Jun Kitazono, Masafumi Oizumi","doi":"10.1101/2024.09.18.613792","DOIUrl":"https://doi.org/10.1101/2024.09.18.613792","url":null,"abstract":"Neuroscience research has extensively explored the commonality of neural representations of sensory stimuli across individuals to uncover universal neural mechanisms in the encoding of sensory information. To compare neural representations across different brains, Representational Similarity Analysis (RSA) has been used, which focuses on the similarity structures of neural representations for different stimuli. Despite the broad applicability and utility of RSA, one limitation is that its conventional framework assumes that neural representations of particular stimuli correspond directly to those of the same stimuli in different brains. This assumption excludes the possibility that neural representations correspond differently and limits the exploration of finer structural similarities. To overcome this limitation, we propose to use an unsupervised alignment framework based on Gromov-Wasserstein Optimal Transport (GWOT) to compare similarity structures without presupposing stimulus correspondences. This method allows for the identification of optimal correspondence between neural representations of stimuli based solely on internal neural representation relationships, and thereby provides a more detailed comparison of neural similarity structures across individuals. We applied this unsupervised alignment to investigate the commonality of representational similarity structures of natural scenes, using large datasets of Neuropixels recordings in mice and fMRI recordings in humans. We found that the similarity structure of neural representations in the same visual cortical areas can be well aligned across individuals in an unsupervised manner in both mice and humans. In contrast, we found that the degree of alignment across different brain areas cannot be fully explained by proximity in the visual processing hierarchy alone, but also found some reasonable alignment results, such that the similarity structures of higher-order visual areas can be well aligned with each other but not with lower-order visual areas. We expect that our unsupervised approach will be useful for revealing more detailed structural commonalities or differences that may not be captured by the conventional supervised approach.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"136 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250166","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":"Postnatal Development Of Dendritic Morphology And Action Potential Shape In Rat Substantia Nigra Dopaminergic Neurons","authors":"Estelle M Moubarak, Florian Wernert, Fabien Tell, Jean-Marc Goaillard","doi":"10.1101/2024.09.18.613620","DOIUrl":"https://doi.org/10.1101/2024.09.18.613620","url":null,"abstract":"Substantia nigra pars compacta (SNc) dopaminergic (DA) neurons are characterized by specific morphological and electrophysiological properties. First, in ~90% of the cases, their axon arises from an axon-bearing dendrite (ABD) at highly variable distances from the soma. Second, they display a highly regular pattern of spontaneous activity (aka pacemaking) and a broad action potential (AP) that faithfully back-propagate through the entire dendritic arbor. In previous studies (Moubarak et al., 2019; Moubarak et al., 2022), we demonstrated that the presence of a high density of sodium current in the ABD and the complexity of this dendrite played a critical role in the robustness of pacemaking and setting the half-width of the AP. In the current study, we investigated the postnatal development of both morphology and AP shape in SNc DA neurons in order to determine when and how the mature electrophysiological phenotype of these neurons was achieved. To do so, we performed electrophysiological recordings of SNc DA neurons at 4 postnatal ages (P3, P7, P14, P21) and fully reconstructed their dendritic and proximal axon morphology. Our results show that several morphological parameters, including the length of the ABD, display abrupt changes between P7 and P14, such that a mature morphology is reached by P14. We then showed that AP shape followed a similar timecourse. Using realistic multicompartment Hodgkin-Huxley modeling, we then demonstrated that the rapid morpho-electrical maturation of SNc DA neurons likely arises from synergistic increases in dendritic length and in somatodendritic sodium channel density.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250165","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":"Flexible Adjustment of Oxytocin Neuron Activity in Mother Mice Revealed by Microendoscopy","authors":"Kasane Yaguchi, Kazunari Miyamichi, Gen-ichi Tasaka","doi":"10.1101/2024.09.18.613777","DOIUrl":"https://doi.org/10.1101/2024.09.18.613777","url":null,"abstract":"Oxytocin (OT) neurons in the hypothalamic paraventricular nucleus (PVH) play an important role in a range of physiological and behavioral processes, including the initiation of milk ejection and the regulation of parental behaviors in mothers. However, their activity patterns at the single-cell level remain poorly understood. Using microendoscopic Ca2+ imaging in freely moving mother mice, we demonstrate highly correlated pulsatile activity among individual OT neurons during lactation. The number of OT neurons engaged in the pulsatile activity, along with the characteristics of individual waveforms, was dynamically modulated by lactation and weaning experiences. Notably, only approximately 10% of the imaged OT neurons exhibited a significantly elevated response during pup retrieval, a hallmark of maternal behaviors, with a magnitude 18 times smaller than that observed during lactation. Collectively, these findings demonstrate the utility of microendoscopic imaging for PVH OT neurons and highlight the flexible adjustments of their individual activity patterns in freely behaving mother mice.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250161","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":"Accept-reject decision-making revealed via a quantitative and ethological study of C. elegans foraging","authors":"Jessica A Haley, Tianyi Chen, Mikio Aoi, Sreekanth H Chalasani","doi":"10.1101/2024.09.18.613674","DOIUrl":"https://doi.org/10.1101/2024.09.18.613674","url":null,"abstract":"Decision-making is a ubiquitous component of animal behavior that is often studied in the context of foraging. Foragers make a series of decisions while locating food (food search), choosing between food types (diet or patch choice), and allocating time spent within patches of food (patch-leaving). Here, we introduce a framework for investigating foraging decisions using detailed analysis of individual behavior and quantitative modeling in the nematode Caenorhabditis elegans. We demonstrate that C. elegans make accept-reject patch choice decisions upon encounter with food. Specifically, we show that when foraging amongst small, dispersed, and dilute patches of bacteria, C. elegans initially reject several bacterial patches, opting to prioritize exploration of the environment, before switching to a more exploitatory foraging strategy during subsequent encounters. Observed across a range of bacterial patch densities, sizes, and distributions, we use a quantitative model to show that this decision to explore or exploit is guided by available sensory information, internal satiety signals, and learned environmental statistics related to the bacterial density of recently encountered and exploited patches. We behaviorally validated model predictions on animals that had been food-deprived, animals foraging in environments with multiple patch densities, and null mutants with defective chemosensation. Broadly, we present a framework to study ecologically relevant foraging decisions that could guide future investigations into the cellular and molecular mechanisms underlying decision-making.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250198","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}