Neuron最新文献

{"title":"Specific targeting of brain endothelial cells using enhancer AAV vectors.","authors":"Eric Velazquez-Rivera, Oyshi Dey, Nayoon S Kim, Wenhao Cao, Qiao Ye, Pan Gao, Andy Thai, Jason K Nguyen, Hai Zhang, Jonathan T Ting, M Gopi, Bing Ren, Todd C Holmes, Xiangmin Xu","doi":"10.1016/j.neuron.2025.03.031","DOIUrl":"10.1016/j.neuron.2025.03.031","url":null,"abstract":"<p><p>Brain endothelial cells (BECs) in brain vasculature are critical structural and functional components of the blood brain barrier (BBB). Adeno-associated virus (AAV) capsids have previously been genetically engineered to confer specificity to endothelial cells, but these capsids show limited endothelial cell specificity that varies by delivery conditions. We developed a set of new BEC-enhancer AAV vectors that specifically target BECs based on the cis-regulatory elements identified from single-cell epigenetic datasets. Ex vivo and in vivo characterization of BEC-enhancer AAVs in wild-type, Ai9 reporter, and Alzheimer's disease model mouse brains show their utility for high transduction selectivity of the BECs with little off-target transduction in the liver. Our BEC-enhancer AAVs target the brain vasculature by systemic administration and can be minimally invasive in terms of the route of administration. They are useful new tools for delivering genetic payloads specifically to BECs for normal and diseased brain studies.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 10","pages":"1562-1578.e6"},"PeriodicalIF":14.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128371","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":"Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development.","authors":"Karun K Singh, Gianluca De Rienzo, Laurel Drane, Yingwei Mao, Zachary Flood, Jon Madison, Manuel Ferreira, Sarah Bergen, Cillian King, Pamela Sklar, Hazel Sive, Li-Huei Tsai","doi":"10.1016/j.neuron.2025.04.021","DOIUrl":"10.1016/j.neuron.2025.04.021","url":null,"abstract":"","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1647-1650"},"PeriodicalIF":14.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983558","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":"Machine learning identification of enhancers in the rhesus macaque genome.","authors":"Jing He, BaDoi N Phan, Willa G Kerkhoff, Aydin Alikaya, Tao Hong, Olivia R Brull, J Megan Fredericks, Morgan Sedorovitz, Chaitanya Srinivasan, Michael J Leone, Olivia M Wirfel, Ashley Brown, Samuel Dauby, Rachel K Tittle, Meng K Lin, Bryan M Hooks, Andreea C Bostan, Omar A Gharbawie, Leah C Byrne, Andreas R Pfenning, William R Stauffer","doi":"10.1016/j.neuron.2025.04.030","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.04.030","url":null,"abstract":"<p><p>Nonhuman primate (NHP) neuroanatomy and cognitive complexity make NHPs ideal models to study human neurobiology and disease. However, NHP circuit-function investigations are limited by the availability of molecular reagents that are effective in NHPs. This calls for reagent development approaches that prioritize NHPs. Therefore, we derived enhancers from the NHP genome. We defined cell-type-specific open chromatin regions (OCRs) in single-cell data from rhesus macaques. We trained machine-learning models to rank those OCRs according to their potential as cell-type-specific enhancers for cells in the dorsolateral prefrontal cortex (DLPFC). We packaged the top-ranked layer-3-pyramidal-neuron enhancer into AAV and injected it into the macaque DLPFC. Expression was mostly restricted to layers 2 and 3 and confirmed with light-driven activation of channelrhodopsin. These results provide a crucial tool for studying the causal functions of DLPFC and provide a roadmap for optimized gene delivery in primates.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 10","pages":"1548-1561.e8"},"PeriodicalIF":14.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128342","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":"MicroRNA mechanisms instructing Purkinje cell specification.","authors":"Norjin Zolboot, Yao Xiao, Jessica X Du, Marwan M Ghanem, Su Yeun Choi, Miranda J Junn, Federico Zampa, Zeyi Huang, Ian J MacRae, Giordano Lippi","doi":"10.1016/j.neuron.2025.03.009","DOIUrl":"10.1016/j.neuron.2025.03.009","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) are critical for brain development; however, if, when, and how miRNAs drive neuronal subtype specification remains poorly understood. To address this, we engineered technologies with vastly improved spatiotemporal resolution that allow the dissection of cell-type-specific miRNA-target networks. Fast and reversible miRNA loss of function showed that miRNAs are necessary for Purkinje cell (PC) differentiation, which previously appeared to be miRNA independent, and identified distinct critical miRNA windows for dendritogenesis and climbing fiber synaptogenesis, structural features defining PC identity. Using new mouse models that enable miRNA-target network mapping in rare cell types, we uncovered PC-specific post-transcriptional programs. Manipulation of these programs revealed that the PC-enriched miR-206 and targets Shank3, Prag1, En2, and Vash1, which are uniquely repressed in PCs, are critical regulators of PC-specific dendritogenesis and synaptogenesis, with miR-206 knockdown and target overexpression partially phenocopying miRNA loss of function. Our results suggest that gene expression regulation by miRNAs, beyond transcription, is critical for neuronal subtype specification.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1629-1646.e15"},"PeriodicalIF":14.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780736","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":"Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits.","authors":"Avery C Hunker, Morgan E Wirthlin, Gursajan Gill, Nelson J Johansen, Marcus Hooper, Victoria Omstead, Sara Vargas, M Nathaly Lerma, Naz Taskin, Natalie Weed, William D Laird, Yemeserach M Bishaw, Jacqueline L Bendrick, Bryan B Gore, Yoav Ben-Simon, Ximena Opitz-Araya, Refugio A Martinez, Sharon W Way, Bargavi Thyagarajan, Sven Otto, Raymond E A Sanchez, Jason R Alexander, Avalon Amaya, Adam Amster, Joel Arbuckle, Angela Ayala, Pam M Baker, Tyler Barcelli, Stuard Barta, Darren Bertagnolli, Cameron Bielstein, Prajal Bishwakarma, Jessica Bowlus, Gabriella Boyer, Krissy Brouner, Brittny Casian, Tamara Casper, Anish Bhaswanth Chakka, Rushil Chakrabarty, Peter Chong, Michael Clark, Kaity Colbert, Scott Daniel, Tim Dawe, Maxwell Departee, Peter DiValentin, Nicholas P Donadio, Nadezhda I Dotson, Deepanjali Dwivedi, Tom Egdorf, Tim Fliss, Amanda Gary, Jeff Goldy, Conor Grasso, Erin L Groce, Kathryn Gudsnuk, Warren Han, Zeb Haradon, Sam Hastings, Olivia Helback, Windy V Ho, Cindy Huang, Tye Johnson, Danielle L Jones, Zoe Juneau, Jaimie Kenney, Madison Leibly, Su Li, Elizabeth Liang, Henry Loeffler, Nicholas A Lusk, Zachary Madigan, Jessica Malloy, Jocelin Malone, Rachel McCue, Jose Melchor, John K Mich, Skyler Moosman, Elyse Morin, Robyn Naidoo, Dakota Newman, Kiet Ngo, Katrina Nguyen, Aaron L Oster, Ben Ouellette, Alana A Oyama, Nick Pena, Trangthanh Pham, Elliot Phillips, Christina Pom, Lydia Potekhina, Shea Ransford, Patrick L Ray, Melissa Reding, Dean F Rette, Cade Reynoldson, Christine Rimorin, Ana Rios Sigler, Dana B Rocha, Kara Ronellenfitch, Augustin Ruiz, Lane Sawyer, Josh P Sevigny, Nadiya V Shapovalova, Noah Shepard, Lyudmila Shulga, Sherif Soliman, Brian Staats, Michael J Taormina, Michael Tieu, Yimin Wang, Josh Wilkes, Toren Wood, Thomas Zhou, Ali Williford, Nick Dee, Tyler Mollenkopf, Lydia Ng, Luke Esposito, Brian E Kalmbach, Shenqin Yao, Jeanelle Ariza, Forrest Collman, Shoaib Mufti, Kimberly Smith, Jack Waters, Ina Ersing, Marcella Patrick, Hongkui Zeng, Ed S Lein, Yoshiko Kojima, Greg Horwitz, Scott F Owen, Boaz P Levi, Tanya L Daigle, Bosiljka Tasic, Trygve E Bakken, Jonathan T Ting","doi":"10.1016/j.neuron.2025.04.035","DOIUrl":"10.1016/j.neuron.2025.04.035","url":null,"abstract":"<p><p>We present an enhancer-AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct- and indirect-pathway MSNs, Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, by three different routes of virus delivery, and with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell-type-specific labeling under different experimental contexts. We demonstrate direct pathway circuit-selective optogenetic perturbation of behavior and multiplex labeling of striatal interneuron types for targeted analysis of cellular features. Lastly, we show conserved in vivo activity for exemplary MSN enhancers in rats and macaques. This collection of striatal enhancer AAVs offers greater versatility compared to available transgenic lines and can readily be applied for cell type and circuit studies in diverse mammalian species beyond the mouse model.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 10","pages":"1507-1524.e17"},"PeriodicalIF":14.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128335","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":"Deciphering enhancers of hearing loss genes for efficient and targeted gene therapy of hereditary deafness.","authors":"Simeng Zhao, Qiuxiang Yang, Zehua Yu, Cenfeng Chu, Shengqi Dai, Hongli Li, Min Diao, Lingyue Feng, Junzi Ke, Yilin Xue, Qifang Zhou, Yan Liu, Hanhui Ma, Chao-Po Lin, Yong-Gang Yao, Guisheng Zhong","doi":"10.1016/j.neuron.2025.03.023","DOIUrl":"10.1016/j.neuron.2025.03.023","url":null,"abstract":"<p><p>Hereditary hearing loss accounts for about 60% of congenital deafness. Although adeno-associated virus (AAV)-mediated gene therapy shows substantial potential for treating genetic hearing impairments, there remain significant concerns regarding the specificity and safety of AAV vectors. The sophisticated nature of the cochlea further complicates the challenge of precisely targeting gene delivery. Here, we introduced an AAV-reporter-based in vivo transcriptional enhancer reconstruction (ARBITER) workflow, enabling efficient and reliable dissection of enhancers. With ARBITER, we successfully demonstrated that the conserved non-coding elements (CNEs) within the gene locus collaboratively regulate the expression of Slc26a5, which was further validated using knockout mouse models. We also assessed the potential of identified enhancers to treat hereditary hearing loss by conducting gene therapy in Slc26a5 mutant mice. Based on the original Slc26a5 enhancer with limited efficiency, we engineered a highly efficient and outer hair cell (OHC)-specific enhancer, B8, which successfully restored hearing of Slc26a5 knockout mice.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1579-1596.e5"},"PeriodicalIF":14.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008754","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":"PIEZO1 in the enteric nervous system keeps the gut going.","authors":"Britya Ghosh, Kara L Marshall","doi":"10.1016/j.neuron.2025.04.032","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.04.032","url":null,"abstract":"<p><p>Recently in Cell, Xie and Rose et al.¹ revealed a role for the mechanosensory ion channel PIEZO1 in the enteric nervous system, showing that it influences colonic motility and peristalsis, and highlighted its importance in the complex immuno-mechanical control of gastrointestinal function.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 10","pages":"1466-1468"},"PeriodicalIF":14.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128363","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":"Rooted in regulation: MicroRNAs as gardeners of the Purkinje cell dendritic arbor.","authors":"Cheryl Brandenburg, Roy V Sillitoe","doi":"10.1016/j.neuron.2025.04.016","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.04.016","url":null,"abstract":"<p><p>Zolboot et al.¹ developed tools to manipulate and map microRNA function in cerebellar Purkinje cells with temporal precision, revealing key roles in dendritic development and circuit connectivity. Their approach provides insight into microRNA-mediated regulation of neurodevelopment in sparse neuronal populations.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 10","pages":"1463-1465"},"PeriodicalIF":14.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128369","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":"GADD45G operates as a pathological sensor orchestrating reactive gliosis and neurodegeneration.","authors":"Tianjin Shen, Wenjiao Tai, Dongfang Jiang, Shuaipeng Ma, Xiaoling Zhong, Yuhua Zou, Chun-Li Zhang","doi":"10.1016/j.neuron.2025.04.033","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.04.033","url":null,"abstract":"<p><p>Reactive gliosis is a hallmark of neuropathology and offers a potential target for addressing numerous neurological diseases. Here, we show that growth arrest and DNA damage inducible gamma (GADD45G), a stress sensor in astrocytes, is a nodal orchestrator of reactive gliosis and neurodegeneration. GADD45G expression in astrocytes is sufficient to incite astrogliosis, microgliosis, synapse loss, compromised animal behavior, and the aggravation of Alzheimer's disease (AD). Conversely, silencing GADD45G specifically in astrocytes preserves synapses and rescues the histological and behavioral phenotypes of AD. Mechanistically, GADD45G controls the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) and neuroimmune signaling pathways, including nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3), leading to profound molecular changes and the secretion of various factors that regulate both cell-autonomous and cell-nonautonomous reactive gliosis and glia-neuron interactions. These results uncover GADD45G signaling as a promising therapeutic target for AD and potentially for numerous other neurological disorders.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132561","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":"Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau.","authors":"Kai Chen, Yosuke M Morizawa, Tal Nuriel, Osama Al-Dalahmah, Zhongcong Xie, Guang Yang","doi":"10.1016/j.neuron.2025.04.027","DOIUrl":"10.1016/j.neuron.2025.04.027","url":null,"abstract":"<p><p>Dysfunction of the glymphatic system, a brain-wide waste clearance network, is strongly linked to Alzheimer's disease (AD) and the accumulation of β-amyloid (Aβ) and tau proteins. Here, we identify an astrocytic signaling pathway that can be targeted to preserve glymphatic function and mitigate neurotoxic protein buildup. Analysis of astrocytes from both human AD brains and two transgenic mouse models (5XFAD and PS19) reveals robust activation of the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK)-α subunit of eukaryotic initiation factor 2 (eIF2α) branch of the unfolded protein response. Chronic PERK activation suppresses astrocytic protein synthesis and, through casein kinase 2 (CK2)-dependent mechanisms, disrupts the perivascular localization of aquaporin-4 (AQP4), a water channel essential for glymphatic flow. Importantly, astrocyte-specific PERK deletion or pharmacological inhibition restores AQP4 localization, enhances glymphatic clearance, reduces Aβ and tau pathology, and improves cognitive performance in mice. These findings highlight the critical role of the astrocytic PERK-CK2-AQP4 axis in glymphatic dysfunction and AD pathogenesis, positioning this pathway as a promising therapeutic target.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128303","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}