Nature neuroscience最新文献

{"title":"CLEC16A in astrocytes promotes mitophagy and limits pathology in a multiple sclerosis mouse model","authors":"Atsushi Kadowaki, Michael A. Wheeler, Zhaorong Li, Brian M. Andersen, Hong-Gyun Lee, Tomer Illouz, Joon-Hyuk Lee, Alain Ndayisaba, Stephanie E. J. Zandee, Himanish Basu, Chun-Cheih Chao, Joao V. Mahler, Wendy Klement, Dylan Neel, Matthew Bergstresser, Veit Rothhammer, Gabriel Lipof, Lena Srun, Scott A. Soleimanpour, Isaac Chiu, Alexandre Prat, Vikram Khurana, Francisco J. Quintana","doi":"10.1038/s41593-025-01875-9","DOIUrl":"10.1038/s41593-025-01875-9","url":null,"abstract":"Astrocytes promote neuroinflammation and neurodegeneration in multiple sclerosis (MS) through cell-intrinsic activities and their ability to recruit and activate other cell types. In a genome-wide CRISPR-based forward genetic screen investigating regulators of astrocyte proinflammatory responses, we identified the C-type lectin domain-containing 16A gene (CLEC16A), linked to MS susceptibility, as a suppressor of nuclear factor-κB (NF-κB) signaling. Gene and small-molecule perturbation studies in mouse primary and human embryonic stem cell-derived astrocytes in combination with multiomic analyses established that CLEC16A promotes mitophagy, limiting mitochondrial dysfunction and the accumulation of mitochondrial products that activate NF-κB, the NLRP3 inflammasome and gasdermin D. Astrocyte-specific Clec16a inactivation increased NF-κB, NLRP3 and gasdermin D activation in vivo, worsening experimental autoimmune encephalomyelitis, a mouse model of MS. Moreover, we detected disrupted mitophagic capacity and gasdermin D activation in astrocytes in samples from individuals with MS. These findings identify CLEC16A as a suppressor of astrocyte pathological responses and a candidate therapeutic target in MS. The mechanisms of pathological astrocyte responses during multiple sclerosis remain unclear. Kadowaki et al. found in MS mouse models that CLEC16A suppresses astrocyte pathogenic activities related to mitochondria by boosting mitophagy.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 3","pages":"470-486"},"PeriodicalIF":21.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532411","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":"Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood–brain barrier alterations","authors":"Katarzyna A. Dudek, Sam E. J. Paton, Luisa Bandeira Binder, Adeline Collignon, Laurence Dion-Albert, Alice Cadoret, Manon Lebel, Olivier Lavoie, Jonathan Bouchard, Fernanda Neutzling Kaufmann, Valerie Clavet-Fournier, Claudia Manca, Manuel Guzmán, Matthew Campbell, Gustavo Turecki, Naguib Mechawar, Nicolas Flamand, Flavie Lavoie-Cardinal, Cristoforo Silvestri, Vincenzo Di Marzo, Caroline Menard","doi":"10.1038/s41593-025-01891-9","DOIUrl":"https://doi.org/10.1038/s41593-025-01891-9","url":null,"abstract":"<p>Blood–brain barrier (BBB) alterations contribute to stress vulnerability and the development of depressive behaviors. In contrast, neurovascular adaptations underlying stress resilience remain unclear. Here we report that high expression of astrocytic cannabinoid receptor 1 (CB1) in the nucleus accumbens (NAc) shell, particularly in the end-feet ensheathing blood vessels, is associated with resilience during chronic social stress in adult male mice. Viral-mediated overexpression of <i>Cnr1</i> in astrocytes of the NAc shell results in baseline anxiolytic effects and dampens stress-induced anxiety- and depression-like behaviors in male mice. It promotes the expression of vascular-related genes and reduces astrocyte inflammatory response and morphological changes following an immune challenge with the cytokine interleukin-6, linked to stress susceptibility and mood disorders. Physical exercise and antidepressant treatment increase the expression of astrocytic <i>Cnr1</i> in the perivascular region in male mice. In human tissue from male donors with major depressive disorder, we observe loss of <i>CNR1</i> in the NAc astrocytes. Our findings suggest a role for the astrocytic endocannabinoid system in stress responses via modulation of the BBB.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"210 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507099","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":"Nasal anti-CD3 monoclonal antibody ameliorates traumatic brain injury, enhances microglial phagocytosis and reduces neuroinflammation via IL-10-dependent Treg–microglia crosstalk","authors":"Saef Izzy,&nbsp;Taha Yahya,&nbsp;Omar Albastaki,&nbsp;Hadi Abou-El-Hassan,&nbsp;Michael Aronchik,&nbsp;Tian Cao,&nbsp;Marilia Garcia De Oliveira,&nbsp;Kuan-Jung Lu,&nbsp;Thais G. Moreira,&nbsp;Patrick da Silva,&nbsp;Masen L. Boucher,&nbsp;Leah C. Beauchamp,&nbsp;Danielle S. LeServe,&nbsp;Wesley Nogueira Brandao,&nbsp;Ana Carolina Durão,&nbsp;Toby Lanser,&nbsp;Federico Montini,&nbsp;Joon-Hyuk Lee,&nbsp;Joshua D. Bernstock,&nbsp;Megha Kaul,&nbsp;Gabriel Pasquarelli-do-Nascimento,&nbsp;Kusha Chopra,&nbsp;Rajesh Krishnan,&nbsp;Rebekah Mannix,&nbsp;Rafael M. Rezende,&nbsp;Francisco J. Quintana,&nbsp;Oleg Butovsky,&nbsp;Howard L. Weiner","doi":"10.1038/s41593-025-01877-7","DOIUrl":"10.1038/s41593-025-01877-7","url":null,"abstract":"Neuroinflammation plays a crucial role in traumatic brain injury (TBI), contributing to both damage and recovery, yet no effective therapy exists to mitigate central nervous system (CNS) injury and promote recovery after TBI. In the present study, we found that nasal administration of an anti-CD3 monoclonal antibody ameliorated CNS damage and behavioral deficits in a mouse model of contusional TBI. Nasal anti-CD3 induced a population of interleukin (IL)-10-producing regulatory T cells (Treg cells) that migrated to the brain and closely contacted microglia. Treg cells directly reduced chronic microglia inflammation and regulated their phagocytic function in an IL-10-dependent manner. Blocking the IL-10 receptor globally or specifically on microglia in vivo abrogated the beneficial effects of nasal anti-CD3. However, the adoptive transfer of IL-10-producing Treg cells to TBI-injured mice restored these beneficial effects by enhancing microglial phagocytic capacity and reducing microglia-induced neuroinflammation. These findings suggest that nasal anti-CD3 represents a promising new therapeutic approach for treating TBI and potentially other forms of acute brain injury. Nasal anti-CD3 therapy shows promise for treating traumatic brain injury by reducing neuroinflammation and aiding recovery in mice. It induces interleukin-10-producing regulatory T cells that enhance microglial phagocytic activity and reduce chronic inflammation, potentially aiding brain repair.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 3","pages":"499-516"},"PeriodicalIF":21.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-025-01877-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507097","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":"Endocannabinoid protection of the brain vasculature leads to stress resilience","authors":"","doi":"10.1038/s41593-025-01892-8","DOIUrl":"https://doi.org/10.1038/s41593-025-01892-8","url":null,"abstract":"Changes in blood–brain barrier (BBB) properties and endocannabinoid system function contribute to stress responses and have been implicated in the development of mood disorders. Here, we report a mechanism linking both systems, in which neurovascular endocannabinoids prevented loss of BBB integrity induced by stress-related inflammation, resulting in stress resilience.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"51 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495324","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":"Neuronal polyunsaturated fatty acids are protective in ALS/FTD","authors":"Ashling Giblin, Alexander J. Cammack, Niek Blomberg, Sharifah Anoar, Alla Mikheenko, Mireia Carcolé, Magda L. Atilano, Alex Hull, Dunxin Shen, Xiaoya Wei, Rachel Coneys, Lele Zhou, Yassene Mohammed, Damien Olivier-Jimenez, Lian Y. Wang, Kerri J. Kinghorn, Teresa Niccoli, Alyssa N. Coyne, Rik van der Kant, Tammaryn Lashley, Martin Giera, Linda Partridge, Adrian M. Isaacs","doi":"10.1038/s41593-025-01889-3","DOIUrl":"https://doi.org/10.1038/s41593-025-01889-3","url":null,"abstract":"<p>Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a <i>Drosophila</i> model of <i>C9orf72</i> repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD <i>Drosophila</i>, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"6 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485672","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":"Floyd E. Bloom (1936–2025)","authors":"Gary Aston-Jones, Stephen L. Foote, John H. Morrison","doi":"10.1038/s41593-025-01901-w","DOIUrl":"https://doi.org/10.1038/s41593-025-01901-w","url":null,"abstract":"A founding father of neuroscience.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"15 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485669","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":"PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors","authors":"Tyrone DeSpenza Jr.,&nbsp;Emre Kiziltug,&nbsp;Garrett Allington,&nbsp;Daniel G. Barson,&nbsp;Stephen McGee,&nbsp;David O’Connor,&nbsp;Stephanie M. Robert,&nbsp;Kedous Y. Mekbib,&nbsp;Pranav Nanda,&nbsp;Ana B. W. Greenberg,&nbsp;Amrita Singh,&nbsp;Phan Q. Duy,&nbsp;Francesca Mandino,&nbsp;Shujuan Zhao,&nbsp;Anna Lynn,&nbsp;Benjamin C. Reeves,&nbsp;Arnaud Marlier,&nbsp;Stephanie A. Getz,&nbsp;Carol Nelson-Williams,&nbsp;Hermela Shimelis,&nbsp;Lauren K. Walsh,&nbsp;Junhui Zhang,&nbsp;Wei Wang,&nbsp;Mackenzi L. Prina,&nbsp;Annaliese OuYang,&nbsp;Asan F. Abdulkareem,&nbsp;Hannah Smith,&nbsp;John Shohfi,&nbsp;Neel H. Mehta,&nbsp;Evan Dennis,&nbsp;Laetitia R. Reduron,&nbsp;Jennifer Hong,&nbsp;William Butler,&nbsp;Bob S. Carter,&nbsp;Engin Deniz,&nbsp;Evelyn M. R. Lake,&nbsp;R. Todd Constable,&nbsp;Mustafa Sahin,&nbsp;Siddharth Srivastava,&nbsp;Kellen Winden,&nbsp;Ellen J. Hoffman,&nbsp;Marina Carlson,&nbsp;Murat Gunel,&nbsp;Richard P. Lifton,&nbsp;Seth L. Alper,&nbsp;Sheng Chih Jin,&nbsp;Michael C. Crair,&nbsp;Andres Moreno-De-Luca,&nbsp;Bryan W. Luikart,&nbsp;Kristopher T. Kahle","doi":"10.1038/s41593-024-01865-3","DOIUrl":"10.1038/s41593-024-01865-3","url":null,"abstract":"Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an under-recognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene PTEN are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1+ neural progenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or postnatal everolimus treatment corrects ventriculomegaly, rescues cortical deficits and increases survival by antagonizing mTORC1-dependent Nkx2.1+ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1+ NPCs. These results implicate a nonsurgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select individuals with CH. The authors show PTEN mutations, which can cause both congenital hydrocephalus and autism spectrum disorder, disrupt CSF homeostasis and brain connectivity in mice. Reducing mTORC1 activation ameliorates ventricular enlargement and neuronal deficits.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 3","pages":"536-557"},"PeriodicalIF":21.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477727","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":"Distinct effects of early-stage and late-stage socioeconomic factors on brain and behavioral traits","authors":"Qiang Xu,&nbsp;Su Lui,&nbsp;Yuan Ji,&nbsp;Jingliang Cheng,&nbsp;Long Jiang Zhang,&nbsp;Bing Zhang,&nbsp;Wenzhen Zhu,&nbsp;Zuojun Geng,&nbsp;Guangbin Cui,&nbsp;Quan Zhang,&nbsp;Weihua Liao,&nbsp;Yongqiang Yu,&nbsp;Hui Zhang,&nbsp;Bo Gao,&nbsp;Xiaojun Xu,&nbsp;Tong Han,&nbsp;Zhenwei Yao,&nbsp;Wen Qin,&nbsp;Feng Liu,&nbsp;Meng Liang,&nbsp;Jilian Fu,&nbsp;Jiayuan Xu,&nbsp;Peng Zhang,&nbsp;Wei Li,&nbsp;Dapeng Shi,&nbsp;Caihong Wang,&nbsp;Jia-Hong Gao,&nbsp;Zhihan Yan,&nbsp;Feng Chen,&nbsp;Jiance Li,&nbsp;Jing Zhang,&nbsp;Dawei Wang,&nbsp;Wen Shen,&nbsp;Yanwei Miao,&nbsp;Junfang Xian,&nbsp;Meiyun Wang,&nbsp;Zhaoxiang Ye,&nbsp;Xiaochu Zhang,&nbsp;Xi-Nian Zuo,&nbsp;Kai Xu,&nbsp;Shijun Qiu,&nbsp;Chunshui Yu,&nbsp;The CHIMGEN Consortium","doi":"10.1038/s41593-025-01882-w","DOIUrl":"10.1038/s41593-025-01882-w","url":null,"abstract":"Socioeconomic status (SES) is a time-varying multidimensional construct with ill-defined dimension-specific and age-specific effects on brain and behavior. We investigated these effects in 4,228 young adults. From 16 socioeconomic indicators, assessed for early (0–10 years) and late (&gt;10 years) stages, we constructed family, provincial, family adverse and neighborhood adverse socioeconomic dimensions. Generally, family SES was associated with brain structure and connectivity along with cognitive function, whereas family adverse and neighborhood adverse SES were associated with personality and emotion. Most associations were observed for both early and late-stage SES; however, adjusting for the effect of early stage SES revealed late-stage-specific SES effects. Changes in SES were associated with personality and cognitive function. Cerebellar and medial frontal volumes and functional connectivity within the left frontoparietal network mediated the associations between family SES and memory and openness. These results inform both more precise interventions for reducing the consequences of adverse SES and experimental designs for excluding confounding socioeconomic effects on human health. Socioeconomic status is multidimensional and can change over time. Xu, Lui, Ji et al. found dimension-specific, late-stage-specific and change-specific socioeconomic effects on brain, cognition, personality and emotion.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 3","pages":"676-687"},"PeriodicalIF":21.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477728","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":"Astrocyte heterogeneity reveals region-specific astrogenesis in the white matter","authors":"Riccardo Bocchi,&nbsp;Manja Thorwirth,&nbsp;Tatiana Simon-Ebert,&nbsp;Christina Koupourtidou,&nbsp;Solène Clavreul,&nbsp;Keegan Kolf,&nbsp;Patrizia Della Vecchia,&nbsp;Sara Bottes,&nbsp;Sebastian Jessberger,&nbsp;Jiafeng Zhou,&nbsp;Gulzar Wani,&nbsp;Gregor-Alexander Pilz,&nbsp;Jovica Ninkovic,&nbsp;Annalisa Buffo,&nbsp;Swetlana Sirko,&nbsp;Magdalena Götz,&nbsp;Judith Fischer-Sternjak","doi":"10.1038/s41593-025-01878-6","DOIUrl":"10.1038/s41593-025-01878-6","url":null,"abstract":"Astrocyte heterogeneity has been well explored, but our understanding of white matter (WM) astrocytes and their distinctions from gray matter (GM) astrocytes remains limited. Here, we compared astrocytes from cortical GM and WM/corpus callosum (WM/CC) using single-cell RNA sequencing and spatial transcriptomics of the murine forebrain. The comparison revealed similarities but also significant differences between WM and GM astrocytes, including cytoskeletal and metabolic hallmarks specific to WM astrocytes with molecular properties also shared with human WM astrocytes. When we compared murine astrocytes from two different WM regions, the cortex and cerebellum, we found that they exhibited distinct, region-specific molecular properties, with the cerebellum lacking, for example, a specific cluster of WM astrocytes expressing progenitor and proliferation genes. Functional experiments confirmed astrocyte proliferation in the WM/CC, but not in the cerebellar WM, suggesting that the WM/CC may be a source of continued astrogenesis. White matter (WM) astrocytes differ significantly from gray matter astrocytes, with WM astrocytes in the forebrain exhibiting unique proliferation capacity, which is absent in cerebellar WM, suggesting region-specific astrocyte generation.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 3","pages":"457-469"},"PeriodicalIF":21.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-025-01878-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477729","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":"Developmentally distinct architectures in top–down pathways controlling threat avoidance","authors":"Cassandra B. Klune, Caitlin M. Goodpaster, Michael W. Gongwer, Christopher J. Gabriel, Jennifer An, Rita Chen, Nico S. Jones, Owen H. Williams, Meelan Shari, Makayla Ramirez, Aliza Hacking, Timothy Andrade, Lindsay A. Schwarz, Laura A. DeNardo","doi":"10.1038/s41593-025-01890-w","DOIUrl":"https://doi.org/10.1038/s41593-025-01890-w","url":null,"abstract":"<p>The medial prefrontal cortex (mPFC) is critical for learning and decision-making processes, including responding to threats. The protracted maturation of the mPFC extends into early adulthood. Although prominent models suggest that increasing top–down control by the mPFC eventually allows adult behavioral repertoires to emerge, it is unclear how progressive strengthening can produce nonlinear behavioral changes observed across development. We use fiber photometry and optogenetics to establish causal links between frontolimbic pathway activity and threat avoidance strategies in juvenile, adolescent and adult mice. We uncover multiple developmental switches in the roles of mPFC pathways targeting the nucleus accumbens and basolateral amygdala. These changes are accompanied by axonal pruning, strengthening of synaptic connectivity and altered functional connectivity with downstream cell types, which occur in the mPFC–basolateral amygdala and mPFC–nucleus accumbens pathways at different rates. Our results reveal how developing mPFC pathways pass through distinct architectures that may make them optimally adapted to age-specific challenges.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"22 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443324","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}