Allan Motyer, Stacey Jackson, Bicheng Yang, Ivon Harliwong, Wei Tian, Wing In Avis Shiu, Yunchang Shao, Bo Wang, Catriona McLean, Michael Barnett, Trevor J. Kilpatrick, Stephen Leslie, Justin P. Rubio
{"title":"Neuronal somatic mutations are increased in multiple sclerosis lesions","authors":"Allan Motyer, Stacey Jackson, Bicheng Yang, Ivon Harliwong, Wei Tian, Wing In Avis Shiu, Yunchang Shao, Bo Wang, Catriona McLean, Michael Barnett, Trevor J. Kilpatrick, Stephen Leslie, Justin P. Rubio","doi":"10.1038/s41593-025-01895-5","DOIUrl":"10.1038/s41593-025-01895-5","url":null,"abstract":"Neuroinflammation underpins neurodegeneration and clinical progression in multiple sclerosis (MS), but knowledge of processes linking these disease mechanisms remains incomplete. Here we investigated somatic single-nucleotide variants (sSNVs) in the genomes of 106 single neurons from post-mortem brain tissue of ten MS cases and 16 controls to determine whether somatic mutagenesis is involved. We observed an increase of 43.9 sSNVs per year in neurons from chronic MS lesions, a 2.5 times faster rate than in neurons from normal-appearing MS and control tissues. This difference was equivalent to 1,291 excess sSNVs in lesion neurons at 70 years of age compared to controls. We performed mutational signature analysis to investigate mechanisms underlying neuronal sSNVs and identified a signature characteristic of lesions with a strong, age-associated contribution to sSNV counts. This research suggests that neuroinflammation is mutagenic in the MS brain, potentially contributing to disease progression. The link between neuroinflammation and the progression of multiple sclerosis (MS) is unclear. Here, the authors show that in MS lesions, neuronal somatic mutations accumulate 2.5 times faster than in controls, equivalent to 1,291 excess mutations by age 70, suggesting that neuroinflammation can be mutagenic.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 4","pages":"757-765"},"PeriodicalIF":21.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538431","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}
Joseph Del Rosario, Stefano Coletta, Soon Ho Kim, Zach Mobille, Kayla Peelman, Brice Williams, Alan J. Otsuki, Alejandra Del Castillo Valerio, Kendell Worden, Lou T. Blanpain, Lyndah Lovell, Hannah Choi, Bilal Haider
{"title":"Lateral inhibition in V1 controls neural and perceptual contrast sensitivity","authors":"Joseph Del Rosario, Stefano Coletta, Soon Ho Kim, Zach Mobille, Kayla Peelman, Brice Williams, Alan J. Otsuki, Alejandra Del Castillo Valerio, Kendell Worden, Lou T. Blanpain, Lyndah Lovell, Hannah Choi, Bilal Haider","doi":"10.1038/s41593-025-01888-4","DOIUrl":"10.1038/s41593-025-01888-4","url":null,"abstract":"Lateral inhibition is a central principle in sensory system function. It is thought to operate by the activation of inhibitory neurons that restrict the spatial spread of sensory excitation. However, the neurons, computations and mechanisms underlying cortical lateral inhibition remain debated, and its importance for perception remains unknown. Here we show that lateral inhibition from parvalbumin neurons in mouse primary visual cortex reduced neural and perceptual sensitivity to visual contrast in a uniform subtractive manner, whereas lateral inhibition from somatostatin neurons more effectively changed the slope (or gain) of neural and perceptual contrast sensitivity. A neural circuit model, anatomical tracing and direct subthreshold measurements indicated that the larger spatial footprint for somatostatin versus parvalbumin synaptic inhibition explains this difference. Together, these results define cell-type-specific computational roles for lateral inhibition in primary visual cortex, and establish their unique consequences on sensitivity to contrast, a fundamental aspect of the visual world. The role of lateral inhibition for perception and neural computation remains unsolved. Del Rosario et al. show that distinct types of cortical interneurons in V1 drive lateral inhibition that causes subtraction or division of visual sensitivity.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 4","pages":"836-847"},"PeriodicalIF":21.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532409","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}
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
{"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}
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
{"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":"10.1038/s41593-025-01891-9","url":null,"abstract":"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 Cnr1 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 Cnr1 in the perivascular region in male mice. In human tissue from male donors with major depressive disorder, we observe loss of CNR1 in the NAc astrocytes. Our findings suggest a role for the astrocytic endocannabinoid system in stress responses via modulation of the BBB. The mechanisms of neurovascular adaptations underlying stress resilience remain unclear. Here the authors show that the astrocytic endocannabinoid system modulates the blood–brain barrier changes during stress in adult mice.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 4","pages":"766-782"},"PeriodicalIF":21.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-025-01891-9.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Saef Izzy, Taha Yahya, Omar Albastaki, Hadi Abou-El-Hassan, Michael Aronchik, Tian Cao, Marilia Garcia De Oliveira, Kuan-Jung Lu, Thais G. Moreira, Patrick da Silva, Masen L. Boucher, Leah C. Beauchamp, Danielle S. LeServe, Wesley Nogueira Brandao, Ana Carolina Durão, Toby Lanser, Federico Montini, Joon-Hyuk Lee, Joshua D. Bernstock, Megha Kaul, Gabriel Pasquarelli-do-Nascimento, Kusha Chopra, Rajesh Krishnan, Rebekah Mannix, Rafael M. Rezende, Francisco J. Quintana, Oleg Butovsky, Howard L. Weiner
{"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, Taha Yahya, Omar Albastaki, Hadi Abou-El-Hassan, Michael Aronchik, Tian Cao, Marilia Garcia De Oliveira, Kuan-Jung Lu, Thais G. Moreira, Patrick da Silva, Masen L. Boucher, Leah C. Beauchamp, Danielle S. LeServe, Wesley Nogueira Brandao, Ana Carolina Durão, Toby Lanser, Federico Montini, Joon-Hyuk Lee, Joshua D. Bernstock, Megha Kaul, Gabriel Pasquarelli-do-Nascimento, Kusha Chopra, Rajesh Krishnan, Rebekah Mannix, Rafael M. Rezende, Francisco J. Quintana, Oleg Butovsky, 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":"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":"28 4","pages":"715-716"},"PeriodicalIF":21.2,"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}
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
{"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":"10.1038/s41593-025-01889-3","url":null,"abstract":"Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 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 Drosophila, 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. Lipidomics revealed that neurons of patients with ALS/FTD have reduced levels of polyunsaturated fatty acid (PUFA)-containing phospholipids. Increasing neuronal PUFA levels increased survival of Drosophila models of ALS/FTD and patient neurons, suggesting that interventions that increase neuronal PUFA levels in patients with ALS/FTD may also be beneficial.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 4","pages":"737-747"},"PeriodicalIF":21.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-025-01889-3.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gary Aston-Jones, Stephen L. Foote, John H. Morrison
{"title":"Floyd E. Bloom (1936–2025)","authors":"Gary Aston-Jones, Stephen L. Foote, John H. Morrison","doi":"10.1038/s41593-025-01901-w","DOIUrl":"10.1038/s41593-025-01901-w","url":null,"abstract":"A founding father of neuroscience.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 4","pages":"707-708"},"PeriodicalIF":21.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-025-01901-w.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tyrone DeSpenza Jr., Emre Kiziltug, Garrett Allington, Daniel G. Barson, Stephen McGee, David O’Connor, Stephanie M. Robert, Kedous Y. Mekbib, Pranav Nanda, Ana B. W. Greenberg, Amrita Singh, Phan Q. Duy, Francesca Mandino, Shujuan Zhao, Anna Lynn, Benjamin C. Reeves, Arnaud Marlier, Stephanie A. Getz, Carol Nelson-Williams, Hermela Shimelis, Lauren K. Walsh, Junhui Zhang, Wei Wang, Mackenzi L. Prina, Annaliese OuYang, Asan F. Abdulkareem, Hannah Smith, John Shohfi, Neel H. Mehta, Evan Dennis, Laetitia R. Reduron, Jennifer Hong, William Butler, Bob S. Carter, Engin Deniz, Evelyn M. R. Lake, R. Todd Constable, Mustafa Sahin, Siddharth Srivastava, Kellen Winden, Ellen J. Hoffman, Marina Carlson, Murat Gunel, Richard P. Lifton, Seth L. Alper, Sheng Chih Jin, Michael C. Crair, Andres Moreno-De-Luca, Bryan W. Luikart, Kristopher T. Kahle
{"title":"PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors","authors":"Tyrone DeSpenza Jr., Emre Kiziltug, Garrett Allington, Daniel G. Barson, Stephen McGee, David O’Connor, Stephanie M. Robert, Kedous Y. Mekbib, Pranav Nanda, Ana B. W. Greenberg, Amrita Singh, Phan Q. Duy, Francesca Mandino, Shujuan Zhao, Anna Lynn, Benjamin C. Reeves, Arnaud Marlier, Stephanie A. Getz, Carol Nelson-Williams, Hermela Shimelis, Lauren K. Walsh, Junhui Zhang, Wei Wang, Mackenzi L. Prina, Annaliese OuYang, Asan F. Abdulkareem, Hannah Smith, John Shohfi, Neel H. Mehta, Evan Dennis, Laetitia R. Reduron, Jennifer Hong, William Butler, Bob S. Carter, Engin Deniz, Evelyn M. R. Lake, R. Todd Constable, Mustafa Sahin, Siddharth Srivastava, Kellen Winden, Ellen J. Hoffman, Marina Carlson, Murat Gunel, Richard P. Lifton, Seth L. Alper, Sheng Chih Jin, Michael C. Crair, Andres Moreno-De-Luca, Bryan W. Luikart, 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}
Qiang Xu, Su Lui, Yuan Ji, Jingliang Cheng, Long Jiang Zhang, Bing Zhang, Wenzhen Zhu, Zuojun Geng, Guangbin Cui, Quan Zhang, Weihua Liao, Yongqiang Yu, Hui Zhang, Bo Gao, Xiaojun Xu, Tong Han, Zhenwei Yao, Wen Qin, Feng Liu, Meng Liang, Jilian Fu, Jiayuan Xu, Peng Zhang, Wei Li, Dapeng Shi, Caihong Wang, Jia-Hong Gao, Zhihan Yan, Feng Chen, Jiance Li, Jing Zhang, Dawei Wang, Wen Shen, Yanwei Miao, Junfang Xian, Meiyun Wang, Zhaoxiang Ye, Xiaochu Zhang, Xi-Nian Zuo, Kai Xu, Shijun Qiu, Chunshui Yu, The CHIMGEN Consortium
{"title":"Distinct effects of early-stage and late-stage socioeconomic factors on brain and behavioral traits","authors":"Qiang Xu, Su Lui, Yuan Ji, Jingliang Cheng, Long Jiang Zhang, Bing Zhang, Wenzhen Zhu, Zuojun Geng, Guangbin Cui, Quan Zhang, Weihua Liao, Yongqiang Yu, Hui Zhang, Bo Gao, Xiaojun Xu, Tong Han, Zhenwei Yao, Wen Qin, Feng Liu, Meng Liang, Jilian Fu, Jiayuan Xu, Peng Zhang, Wei Li, Dapeng Shi, Caihong Wang, Jia-Hong Gao, Zhihan Yan, Feng Chen, Jiance Li, Jing Zhang, Dawei Wang, Wen Shen, Yanwei Miao, Junfang Xian, Meiyun Wang, Zhaoxiang Ye, Xiaochu Zhang, Xi-Nian Zuo, Kai Xu, Shijun Qiu, Chunshui Yu, 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 (>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}