Neuron最新文献

{"title":"Metabolic reprogramming through histone lactylation in microglia and macrophages recruits CD8⁺ T lymphocytes and aggravates spinal cord injury.","authors":"Xuhui Ge, Yufeng Zhu, Junjun Xiong, Yao Gu, Xiaokun Wang, Wu Ye, Haofan Wang, Yu Gao, Weihua Cai, Xuhui Zhou, Wei Liu","doi":"10.1016/j.neuron.2025.04.003","DOIUrl":"10.1016/j.neuron.2025.04.003","url":null,"abstract":"<p><p>Crosstalk between the central nervous system (CNS) and the immune system has recently gained increased attention; however, the interaction between innate and adaptive immunity after CNS injury remains unclear. Here, using single-cell RNA sequencing, we identified accumulation of CD8⁺ T lymphocytes in the cerebrospinal fluid of patients with spinal cord injury (SCI) and in spinal cords of injured mice, thus indicating poor neurological function. Furthermore, through genetic or pharmacologic interruption strategies, we found that CXCL16 chemokines derived from injury-activated microglia and macrophages (IAMs) recruited CXCR6⁺CD8⁺ T cells and further contributed to neuronal loss after SCI. Mechanistically, glycolytic reprogramming in IAMs enhanced histone-lactylation-mediated Cxcl16 transcription, whereas suppressing glycolysis through Pkm2 deletion partially reversed this effect. Notably, a pharmacologic intervention targeting the CXCL16-CXCR6 axis with Rutin promoted locomotor restoration after SCI. Our study highlights the crucial role of glycolytically reprogrammed IAM-derived CXCL16 chemokines in modulating a maladaptive innate/adaptive immune axis and reveals several potential therapeutic strategies.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2280-2296.e8"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network influence determines the impact of cortical ensembles on stimulus detection.","authors":"Hayley A Bounds, Hillel Adesnik","doi":"10.1016/j.neuron.2025.04.023","DOIUrl":"10.1016/j.neuron.2025.04.023","url":null,"abstract":"<p><p>Causally connecting neural activity patterns to behavioral decisions is essential to understand the neural code but requires direct perturbation of the pattern of interest with high specificity. We combined two-photon imaging and cellular-resolution holographic optogenetic photostimulation to causally test how neural activity in the mouse visual cortex is read out to detect visual stimuli. Contrary to expectations, targeted activation of visually sensitive neural ensembles did not preferentially modify behavior compared with targeting randomly selected ensembles. Instead, an activated ensemble's effect on local network activity was the main predictor of its impact on perception. This suggests that downstream regions summate visual cortex activity without preferentially weighting more informative neurons, a notion confirmed by analyzing the impact of photostimulation on decoding models of neural activity. This work challenges conventional notions for how sensory representations mediate perception and demonstrates that perturbing activity is essential to determine which features of neural activity drive behavior.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2358-2369.e5"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human brain vascular multi-omics elucidates disease-risk associations.","authors":"Madigan M Reid, Shreya Menon, Hao Liu, Haoyue Zhou, Zhirui Hu, Simon Frerich, Bella Ding, Shahram Oveisgharan, Zimo Zhang, Sophia Nelson, Amanda Apolonio, David A Bennett, Martin Dichgans, Katherine S Pollard, M Ryan Corces, Andrew C Yang","doi":"10.1016/j.neuron.2025.07.001","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.07.001","url":null,"abstract":"<p><p>Cerebrovascular dysfunction underlies many neurological disorders, yet how genetic variants in brain vascular cells drive disease risk remains unknown. We developed MultiVINE-seq to simultaneously profile RNA and chromatin accessibility in vascular, perivascular, and immune cells from 30 human brains. Mapping genome-wide association study (GWAS) data to our multi-omic atlas linked thousands of GWAS disease-risk variants to target cell types and genes, including 2,605 previously unmapped. We found cerebrovascular and neurodegenerative disease variants have distinct mechanisms: cerebrovascular disease variants disrupt extracellular matrix genes in endothelial, mural, and fibroblast cells important for vessel structural integrity, while Alzheimer's disease (AD) variants dysregulate inflammatory adaptor proteins in endothelial and immune cells. Notably, a lead AD variant enhances PTK2B expression in brain CD8 T cells, providing genetic evidence for adaptive immunity in AD pathogenesis. This work provides a key resource for interpreting genetic risk and reveals how variants in vascular cells drive divergent pathogenic mechanisms across neurological diseases.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The estrous cycle modulates hippocampal spine dynamics, dendritic processing, and spatial coding.","authors":"Nora S Wolcott, William T Redman, Marie Karpinska, Emily G Jacobs, Michael J Goard","doi":"10.1016/j.neuron.2025.04.014","DOIUrl":"10.1016/j.neuron.2025.04.014","url":null,"abstract":"<p><p>Histological evidence suggests that the estrous cycle exerts a powerful influence on CA1 neurons in the mammalian hippocampus. Decades have passed since this landmark observation, yet how the estrous cycle shapes dendritic spine dynamics and hippocampal spatial coding in vivo remains a mystery. Here, we used a custom hippocampal microperiscope and two-photon calcium imaging to track CA1 pyramidal neurons in female mice across multiple cycles. Estrous cycle stage had a potent effect on spine dynamics, with spine density peaking during proestrus when estradiol levels are highest. These morphological changes coincided with greater somatodendritic coupling and increased infiltration of back-propagating action potentials into the apical dendrite. Finally, tracking CA1 response properties during navigation revealed greater place field stability during proestrus, evident at both the single-cell and population levels. These findings demonstrate that the estrous cycle drives large-scale structural and functional plasticity in hippocampal neurons essential for learning and memory.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2297-2309.e7"},"PeriodicalIF":15.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12289434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.","authors":"Beika Zhu, Andi Wangzhou, Diankun Yu, Tao Li, Rachael Schmidt, Stacy L De Florencio, Lauren Chao, Alicia L Thurber, Minqi Zhou, Zeina Msheik, Yonatan Perez, Lea T Grinberg, Salvatore Spina, Richard M Ransohoff, Arnold R Kriegstein, William W Seeley, Tomasz Nowakowski, Xianhua Piao","doi":"10.1016/j.neuron.2025.06.020","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.06.020","url":null,"abstract":"<p><p>Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms enabling protective microglial responses remain elusive. Here, we investigate the role of microglial ADGRG1, an adhesion G-protein-coupled receptor (aGPCR) specifically expressed in yolk-sac-derived microglia, in AD pathology using the 5xFAD mouse model. Transcriptomic analyses reveal that ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions, thereby promoting a protective microglial state. We demonstrate that deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, exacerbated neuronal loss, and cognitive deficits. Functional assays in mouse models and human embryonic stem cell-derived microglia confirm that ADGRG1 is required for Aβ phagocytosis. These findings uncover a GPCR-mediated pathway that drives a protective microglial state via MYC activation, suggesting potential therapeutic strategies to alleviate AD progression by enhancing microglial functional competence.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selectively vulnerable deep cortical layer 5/6 fast-spiking interneurons in Alzheimer's disease models in vivo.","authors":"Amalia Papanikolaou, David Graykowski, Byung Il Lee, Mengke Yang, Robert Ellingford, Jana Zünkler, Suraya A Bond, James M Rowland, Rikesh M Rajani, Samuel S Harris, David J Sharp, Marc Aurel Busche","doi":"10.1016/j.neuron.2025.04.010","DOIUrl":"10.1016/j.neuron.2025.04.010","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is initiated by amyloid-beta (Aβ) accumulation in the neocortex; however, the cortical layers and neuronal cell types first susceptible to Aβ remain unknown. Using in vivo two-photon Ca²⁺ imaging in the visual cortex of AD mouse models, we found that cortical layer 5 neurons displayed abnormally prolonged Ca²⁺ transients before substantial plaque formation. Neuropixels recordings revealed that these abnormal transients were associated with reduced spiking and impaired visual tuning of parvalbumin (PV)-positive fast-spiking interneurons (FSIs) in layers 5/6, whereas PV-FSIs in superficial layers remained unaffected. These dysfunctions occurred alongside a deep-layer-specific reduction in neuronal pentraxin 2 (NPTX2) within excitatory neurons, decreased GluA4 in PV-FSIs, and fewer excitatory synapses onto PV-FSIs. Notably, NPTX2 overexpression increased excitatory input onto layers 5/6 PV-FSIs and rectified their spiking activity. Thus, our findings reveal an early selective impairment of deep cortical layers 5/6 in AD models and identify deep-layer PV-FSIs as therapeutic targets.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2265-2279.e7"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep cortical layers are more vulnerable in Alzheimer's disease.","authors":"S Zehra H Kazmi, Corette J Wierenga","doi":"10.1016/j.neuron.2025.06.022","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.06.022","url":null,"abstract":"<p><p>Network hyperexcitability is one of the hallmarks of the early stage of Alzheimer's disease (AD). In this issue of Neuron, Papanikolaou¹ and coworkers show that AD-mediated alterations start at the excitatory-inhibitory subcircuit in the deep layers of the cortex.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 14","pages":"2218-2220"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The polypharmacology of psychedelics reveals multiple targets for potential therapeutics","authors":"Manish K. Jain, Ryan H. Gumpper, Samuel T. Slocum, Gavin P. Schmitz, Jakob S. Madsen, Tia A. Tummino, Carl-Mikael Suomivuori, Xi-Ping Huang, Laura Shub, Jeffrey F. DiBerto, Kuglae Kim, Chelsea DeLeon, Brain E. Krumm, Jonathan F. Fay, Michael Keiser, Alexander S. Hauser, Ron O. Dror, Brian Shoichet, David E. Gloriam, David E. Nichols, Bryan L. Roth","doi":"10.1016/j.neuron.2025.06.012","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.06.012","url":null,"abstract":"The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT<ce:inf loc=\"post\">2A</ce:inf> serotonin receptor (5-HT<ce:inf loc=\"post\">2A</ce:inf>R). Recent clinical studies have suggested that classical psychedelics may additionally have therapeutic potential for many neuropsychiatric conditions including depression, anxiety, migraine and cluster headaches, drug abuse, and post-traumatic stress disorder. In this study, we investigated the pharmacology of 41 classical psychedelics from the tryptamine, phenethylamine, and lysergamide chemical classes. We profiled these compounds against 318 human G-protein-coupled receptors (GPCRs) to elucidate their target profiles, and in the case of LSD, against more than 450 human kinases. We found that psychedelics have potent and efficacious actions at nearly every serotonin, dopamine, and adrenergic receptor. We quantified their activation for multiple transducers and found that psychedelics stimulate multiple 5-HT<ce:inf loc=\"post\">2A</ce:inf>R transducers, each of which correlates with psychedelic drug-like actions <ce:italic>in vivo</ce:italic>. Our results suggest that multiple molecular targets likely contribute to the actions of psychedelics.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"3 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerating biomedical discoveries in brain health through transformative neuropathology of aging and neurodegeneration","authors":"Melissa E. Murray, Colin Smith, Vilas Menon, C. Dirk Keene, Ed Lein, Michael Hawrylycz, Adriano Aguzzi, Brett Benedetti, Katja Brose, Kelsey Caetano-Anolles, Maria Inmaculada Cobos Sillero, John F. Crary, Philip L. De Jager, Arline Faustin, Margaret E. Flanagan, Ozgun Gokce, Seth G.N. Grant, Lea T. Grinberg, David A. Gutman, Elizabeth M.C. Hillman, Zhi Huang, David J. Irwin, David T. Jones, Alifiya Kapasi, Celeste M. Karch, Walter T. Kukull, Tammaryn Lashley, Edward B. Lee, Thomas Lehner, Laura Parkkinen, Maria Pedersen, Dominique Pritchett, Matthew H. Rutledge, Julie A. Schneider, William W. Seeley, Claire E. Shepherd, Tara L. Spires-Jones, Judith A. Steen, Margaret Sutherland, Sanja Vickovic, Bin Zhang, David J. Stewart, Michael J. Keiser, Jacob W. Vogel, Brittany N. Dugger, Hemali Phatnani","doi":"10.1016/j.neuron.2025.06.014","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.06.014","url":null,"abstract":"Transformative neuropathology is redefining human brain research by integrating foundational descriptive pathology with advanced methodologies. These approaches, spanning multi-omics studies and machine learning applications, will drive discovery for the identification of biomarkers, therapeutic targets, and complex disease patterns through comprehensive analyses of postmortem human brain tissue. Yet critical challenges remain, including the sustainability of brain banks, expanding donor participation, strengthening training pipelines, enabling rapid autopsies, supporting collaborative platforms, and integrating data across modalities. Innovations in digital pathology, tissue quality enhancement, harmonization of data standards, and machine learning integration offer opportunities to accelerate tissue-level “pathomics” research in brain health through cross-disciplinary collaborations. Lessons from neuroimaging, particularly in establishing common data frameworks and multi-site collaborations, offer a valuable roadmap for streamlining innovations. In this perspective, we outline actionable solutions for leveraging existing resources and strengthening collaboration -where we envision future opportunities to drive translational discoveries stemming from transformative neuropathology.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"24 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroanatomical organization of electroacupuncture in modulating gastric function in mice and humans.","authors":"Shun Dong, Lijuan Zhao, Jing Liu, Xuan Sha, Yi Wu, Weili Liu, Junlong Sun, Yangshuai Su, Zhidi Zhuang, Jian Chen, Ying Dong, Beijing Xie, Anqi Zhou, Hongyan Ji, Yuchun Wang, Xiaoman Deng, Xianghong Jing, Qiufu Ma, Nianhong Wang, Shenbin Liu","doi":"10.1016/j.neuron.2025.06.023","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.06.023","url":null,"abstract":"<p><p>Somatosensory-vagal reflexes evoked by electroacupuncture (EA) can modulate visceral functions. However, the underlying principles and neural mechanisms remain poorly understood, hindering further optimization. Here, we identified key neural components essential for EA topographically driving the somatosensory-vagal-gastric reflex in mice. EA drove this reflex via activation of a subset of transient receptor potential vanilloid-1 (TRPV1)⁺ nociceptors marked by the expression of Adra2a and located exclusively in deep fascial tissues. Through TRPV1⁺ fibers, EA activated a subtype of gastro-projecting Oxtr⁺ fibers originating from the dorsal motor nucleus of the vagus (DMV). Genetic ablation of TRPV1⁺ fibers or Oxtr⁺ DMV neurons attenuated EA-induced gastric reflexes. Conversely, optogenetic activation of these neurons was sufficient to drive gastric motility in mice. Using similar stimulation parameters, we demonstrated that EA successfully improved gastric functions in patients with dysmotility-like functional dyspepsia (chictr.org.cn: ChiCTR2300072636). Our findings thus provide a neural anatomical basis for EA topographically to promote and treat gastric motility disorders.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}