eLife最新文献

{"title":"Micro-scale control of oligodendrocyte morphology and myelination by the intellectual disability-linked protein acyltransferase ZDHHC9.","authors":"Hey-Kyeong Jeong, Estibaliz Gonzalez-Fernandez, Ilan Crawley, Julia M Coakley, Jinha Hwang, Dale D O Martin, Shernaz X Bamji, Jong-Il Kim, Shin H Kang, Gareth M Thomas","doi":"10.7554/eLife.97151","DOIUrl":"10.7554/eLife.97151","url":null,"abstract":"<p><p>Mutations in the X-linked <i>ZDHHC9</i> gene cause cognitive deficits in humans, with a subset of patients suffering from epilepsy. X-linked intellectual disability (XLID) is often ascribed to neuronal deficits, but here we report that expression of human and mouse ZDHHC9 orthologs is far higher in myelinating oligodendrocytes (OLs) than in other CNS cell types. <i>ZDHHC9</i> codes for a protein acyltransferase (PAT), and we found that ZDHHC9 is the most highly expressed PAT in OLs. Wild-type ZDHHC9 localizes to Golgi outposts in OL processes, but other PATs and XLID mutant forms of ZDHHC9 are restricted to OL cell bodies. Using genetic tools for OL progenitor fate tracing and sparse cell labeling, we show that mice lacking <i>Zdhhc9</i> have grossly normal OL development but display extensive morphological and structural myelin abnormalities. Consistent with the hypothesis that these deficits are OL-autonomous, they are broadly phenocopied by acute <i>Zdhhc9</i> knockdown in cultured conditions. Finally, we found that ZDHHC9 palmitoylates Myelin Basic Protein (MBP) in heterologous cells, and that palmitoylation of MBP is impaired in the <i>Zdhhc9</i> knockout brain. Our findings provide critical insights into the mechanisms of <i>ZDHHC9</i>-associated XLID and shed new light on the palmitoylation-dependent control of myelination.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracing cell fates in embryos.","authors":"Ying Zhang, Qi Chen","doi":"10.7554/eLife.108962","DOIUrl":"10.7554/eLife.108962","url":null,"abstract":"<p><p>Differences in the activity of an enzyme called CARM1 influence the timing of blastomere polarization and whether they become part of the embryo or the placenta.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptations in wing morphology rather than wingbeat kinematics enable flight in small hoverfly species.","authors":"Camille Le Roy, Nina Tervelde, Thomas Engels, Florian T Muijres","doi":"10.7554/eLife.97839","DOIUrl":"10.7554/eLife.97839","url":null,"abstract":"<p><p>Due to physical scaling laws, size greatly affects animal locomotor ability and performance. Whether morphological and kinematic traits always jointly respond to size variation remains poorly known. Here, we examine the relative importance of morphological and kinematic changes in mitigating the consequence of size reduction on aerodynamic force production for weight support, focusing on the flight of hoverflies (Syrphidae). We compared the morphology of 28 hoverfly species, and the flight biomechanics and aerodynamics of eight species with body masses ranging from 5 to 100 mg. Our study reveals no significant effect of body mass on wingbeat kinematics among species, suggesting that morphological rather than kinematics changes compensate for the reduction in weight support associated with an isometric reduction in wing size. Computational fluid dynamics simulations confirmed that adaptations in wing morphology drive the ability of small hoverfly species to generate weight support, although variations in wingbeat kinematics among species cannot be entirely ignored. We show that smaller hoverflies have evolved relatively larger wings and aerodynamically more effective wing shapes, mitigating the reduction in aerodynamic weight support associated with isometric size reduction. Altogether, these results suggest that hoverfly flight underpins highly specialised wingbeat kinematics, largely conserved throughout evolution; instead, evolutionary adaptations in wing morphology enabled flight of small hoverflies.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nonlinear feedback modulation contributes to the optimization of flexible decision-making.","authors":"Xuanyu Wu, Yang Zhou","doi":"10.7554/eLife.96402","DOIUrl":"10.7554/eLife.96402","url":null,"abstract":"<p><p>Neural activity in the primate brain correlates with both sensory evaluation and action selection aspects of decision-making. However, the intricate interaction between these distinct neural processes and their impact on decision behaviors remains unexplored. Here, we examined the interplay of these decision processes in posterior parietal cortex (PPC) when monkeys performed a flexible decision task. We found that the PPC activity related to monkeys' abstract decisions about visual stimuli was nonlinearly modulated by monkeys' following saccade choices directed outside each neuron's response field. Recurrent neural network modeling indicated that the feedback connections, matching the learned stimuli-response associations during the task, might mediate such feedback modulation. Further analysis on network dynamics revealed that selectivity-specific feedback connectivity intensified the attractor basins of population activity underlying saccade choices, thereby increasing the reliability of flexible decisions. These results highlight an iterative computation between different decision processes, mediated primarily by precise feedback connectivity, contributing to the optimization of flexible decision-making.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sparse innervation and local heterogeneity in the vibrissal corticostriatal projection.","authors":"Kenza Amroune, Lorenzo Fontolan, Agnès Baude, David Robbe, Ingrid Bureau","doi":"10.7554/eLife.106621","DOIUrl":"10.7554/eLife.106621","url":null,"abstract":"<p><p>The density and overlap of cortical axons in the dorsolateral striatum (DLS) have suggested that striatal neurons integrate widespread information from cortical regions that are functionally related. However, in vivo, DLS neuronal responses to sensory stimuli have shown unexpectedly high selectivity, raising questions about the actual degree of convergence of functional corticostriatal projections on individual striatal cells. Here, we investigated this question by focusing on the projections from different whisker cortical columns in mice, as they overlap in the striatum and are co-active during behavior. Using ex vivo patch-clamp recordings in the DLS and glutamate uncaging for focal stimulations in the barrel cortex, we were able to map the location of presynaptic neurons to individual striatal projection neurons (SPNs). We found that each SPN was innervated by cells located in a small number of whisker cortical columns scattered across the barrel field in the slice. Connectivity of single SPNs with cortical neurons was thus highly discontinuous horizontally, despite the presence of more potential connections. Moreover, connectivity patterns were specific to each cell, with neighboring SPNs sharing few common clusters of presynaptic cells in the cortex. Despite this sparse and distinct innervation of individual SPNs, the projection was topographically organized at the population level. Finally, we found similar innervation patterns for D1- and D2-type SPNs, but observed differences in synaptic strength in their connections with certain cortical layers, notably the associative layer 2/3. Our results suggest that the high convergence of somatosensory inputs to the striatum, enabled by diffuse and overlapping cortical innervation, is accomplished through sparse yet complementary connectivity to individual SPNs.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Representation of male features in the female mouse accessory olfactory bulb, and their stability during the estrus cycle.","authors":"Oksana Cohen, Yoram Ben-Shaul","doi":"10.7554/eLife.103959","DOIUrl":"10.7554/eLife.103959","url":null,"abstract":"<p><p>Most behaviors result from integration of external and internal inputs. For example, social behavior requires information about conspecifics and internal physiological states. Like many other mammals, female mice undergo a reproductive cycle during which their physiology and behavioral responses to males change dramatically: during estrus, they are more receptive to male mating attempts. A critical element in reproductive behavior is the investigative stage, which in mice and many other species, strongly relies on chemosensation. While the initial approach mostly involves the main olfactory system (MOS), once physical contact is established, the vomeronasal system (VNS) is engaged to provide information about potential partners' characteristics. Given the estrus-stage-dependent behavioral response, we asked whether representations of male features in the first brain relay of the VNS, namely, the accessory olfactory bulb (AOB), change during the cycle. To this end, we used a stimulus set comprising urine samples from males of different strains and virility levels, as well as from estrus and non-estrus females. The stimulus set was designed to reveal if response patterns of AOB neurons conform to ethologically relevant dimensions such as sex, strain, and particularly, male virility state. Using extracellular recordings in anesthetized female mice, we find that most ethological categories contained in our dataset are not overrepresented by AOB neurons, suggesting that early stages of VNS processing encode conspecific information efficiently. Then, comparing neuronal activity in estrus and non-estrus females, we found that overall, response characteristics at the single neuron and population levels remain stable during the reproductive cycle. The few changes that do occur are not consistent with a systematic modulation of responses to male features. Our findings imply that the AOB presents a stable account of conspecific features to more advanced processing stages.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Observational activation of anterior cingulate cortical neurons coordinates hippocampal replay in social learning.","authors":"Xiang Mou, Daoyun Ji","doi":"10.7554/eLife.97884","DOIUrl":"10.7554/eLife.97884","url":null,"abstract":"<p><p>Social learning enables a subject to make decisions by observing the actions of another. How neural circuits acquire relevant information during observation to guide subsequent behavior is unknown. Utilizing an observational spatial working memory task, we show that neurons in the rat anterior cingulate cortex (ACC) associated with spatial trajectories during self-running in a maze are reactivated when observing another rat running the same maze. The observation-induced ACC activities are reduced in error trials and are correlated with activities of hippocampal place cells representing the same trajectories. The ACC activities during observation also predict subsequent hippocampal place cell activities during sharp-wave ripples and spatial contents of hippocampal replay prior to self-running. The results support that ACC neurons involved in decisions during self-running are reactivated during observation and interact with hippocampal replay to guide subsequent spatial navigation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A drug repurposing approach reveals targetable epigenetic pathways in <i>Plasmodium vivax</i> hypnozoites.","authors":"Steven P Maher, Malina A Bakowski, Amélie Vantaux, Erika L Flannery, Chiara Andolina, Mohit Gupta, Yevgeniya Antonova-Koch, Magdalena Argomaniz, Monica Cabrera-Mora, Brice Campo, Alexander T Chao, Arnab K Chatterjee, Wayne T Cheng, Vorada Chuenchob, Caitlin A Cooper, Karissa Cottier, Mary R Galinski, Anke Harupa-Chung, Hana Ji, Sean B Joseph, Todd Lenz, Stefano Lonardi, Jessica Matheson, Sebastian A Mikolajczak, Timothy Moeller, Agnes Orban, Vivian Padín-Irizarry, Kastin Pan, Julie Péneau, Jacques Prudhomme, Camille Roesch, Anthony Ruberto, Saniya S Sabnis, Celia L Saney, Jetsumon Sattabongkot, Saleh Sereshki, Sangrawee Suriyakan, Ratawan Ubalee, Yinsheng Wang, Praphan Wasisakun, Jiekai Yin, Jean Popovici, Case W McNamara, Chester Joyner, François H Nosten, Benoît Witkowski, Karine G Le Roch, Dennis E Kyle","doi":"10.7554/eLife.98221","DOIUrl":"10.7554/eLife.98221","url":null,"abstract":"<p><p>Radical cure of <i>Plasmodium vivax</i> malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against <i>P. vivax</i> liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against <i>P. vivax</i> and <i>P. cynomolgi</i> hypnozoites. These include DNA methyltransferase inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of <i>Plasmodium</i> liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in <i>P. vivax</i>. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against <i>P. falciparum</i> blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diverse calcium dynamics underlie place field formation in hippocampal CA1 pyramidal cells.","authors":"Mate Sumegi, Gaspar Olah, Istvan Paul Lukacs, Martin Blazsek, Judit K Makara, Zoltan Nusser","doi":"10.7554/eLife.103676","DOIUrl":"10.7554/eLife.103676","url":null,"abstract":"<p><p>Every explored environment is represented in the hippocampus by the activity of distinct populations of pyramidal cells (PCs) that typically fire at specific locations called their place fields (PFs). New PFs are constantly born even in familiar surroundings (during representational drift), and many rapidly emerge when the animal explores a new or altered environment (during global or partial remapping). Behavioral time scale synaptic plasticity (BTSP), a plasticity mechanism based on prolonged somatic action potential (AP) bursts induced by dendritic Ca²⁺/NMDA plateau potentials, was recently proposed as the main cellular mechanism underlying new PF formations (PFFs), but it is unclear whether burst-associated large somatic [Ca²⁺] transients are always necessary and/or sufficient for PFF. To address this issue, here we performed in vivo two-photon [Ca²⁺] imaging of hippocampal CA1 PCs in head-restrained mice to investigate somatic [Ca²⁺] dynamics underlying PFFs in familiar and novel virtual environments. Our results demonstrate that although many PFs are formed by BTSP-like events, PFs also emerge with initial [Ca²⁺] dynamics that do not match any of the characteristics of BTSP. BTSP- and non-BTSP-like new PFFs occur spontaneously in familiar environments, during neuronal representational switches, and instantaneously in new environments. Our data also reveal that solitary [Ca²⁺] transients with larger amplitudes than those evoking BTSP-like PFFs frequently occur without inducing PFs, demonstrating that large [Ca²⁺] transients per se are not sufficient for PFF.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design principles of transcription factors with intrinsically disordered regions.","authors":"Wencheng Ji, Ori Hachmo, Naama Barkai, Ariel Amir","doi":"10.7554/eLife.104956","DOIUrl":"10.7554/eLife.104956","url":null,"abstract":"<p><p>Transcription factors (TFs) are proteins crucial for regulating gene expression. Effective regulation requires the TFs to rapidly bind to their correct target, enabling the cell to respond efficiently to stimuli such as nutrient availability or the presence of toxins. However, the search process is hindered by slow diffusive movement and the presence of 'false' targets - DNA segments that are similar to the true target. In eukaryotic cells, most TFs contain an intrinsically disordered region (IDR), which is commonly assumed to behave as a long, flexible polymeric tail composed of hundreds of amino acids. Recent experimental findings indicate that the IDR of certain TFs plays a pivotal role in the search process. However, the principles underlying the IDR's role remain unclear. Here, we reveal key design principles of the IDR related to TF binding affinity and search time. Our results demonstrate that the IDR significantly enhances both of these aspects. Furthermore, our model shows good agreement with experimental results, and we propose further experiments to validate the model's predictions.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}