Pub Date : 2026-03-18Epub Date: 2026-02-04DOI: 10.1016/j.neuron.2025.12.005
Honghe Liu, Mingming Liu, Yang Liu, Gege Gui, Tapas Paul, Yu-Ning Lu, Zhiyuan Huang, Haocheng Wang, Yatao Xiao, Zhongfan Zheng, Goran Periz, Yingxiao Shi, Justin K Ichida, Sua Myong, Hongkai Ji, Jiou Wang
A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of action remain incompletely understood. Here, we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes (HQs) with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves resistance. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.
{"title":"C9orf72 hexanucleotide repeat RNA drives transcriptional dysregulation through genome-wide DNA:RNA hybrid G-quadruplexes.","authors":"Honghe Liu, Mingming Liu, Yang Liu, Gege Gui, Tapas Paul, Yu-Ning Lu, Zhiyuan Huang, Haocheng Wang, Yatao Xiao, Zhongfan Zheng, Goran Periz, Yingxiao Shi, Justin K Ichida, Sua Myong, Hongkai Ji, Jiou Wang","doi":"10.1016/j.neuron.2025.12.005","DOIUrl":"10.1016/j.neuron.2025.12.005","url":null,"abstract":"<p><p>A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of action remain incompletely understood. Here, we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes (HQs) with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves resistance. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1045-1065.e13"},"PeriodicalIF":15.0,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125889","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}
Pub Date : 2026-03-16DOI: 10.1016/j.neuron.2026.02.002
Ryszard Wimmer, Clarisse Brunet Avalos, Pauline Lestienne, Laure Coquand, Amandine Di Cicco, Christophe Chehade, Annasara Artioli, Matthieu Cortes, Anna-Sophie Macé, Xiuyu Wang, Jean-Baptiste Manneville, Bettina Bessière, Ananya Roy, Karin Forsberg-Nilsson, Julia Ladewig, Fabien Guimiot, Alexandre D. Baffet
The strong increase in the size of the human neocortex is supported by a neural stem cell population, the basal radial glial (bRG) cells. Using live imaging of human fetal tissue and cortical organoids, we identify two translocation mechanisms for bRG cell colonization of the human neocortex. On top of an actomyosin-dependent movement called mitotic somal translocation (MST), we identify a microtubule-dependent motion occurring during interphase that we call interphasic somal translocation (IST). We show that IST is driven by the dynein motor and its activator LIS1, which are recruited to the nuclear envelope by the LINC complex, while MST is controlled by the mitotic cell-rounding pathway. Eighty-five percent of bRG cell translocation is due to IST, resulting in a total movement of 0.67 mm per month of gestation. Our work identifies how bRG cells colonize the human fetal cortex and further shows that IST and MST also occur in bRG-related glioblastoma cells.
{"title":"Two translocation mechanisms drive neural stem cell dissemination into the human fetal cortex","authors":"Ryszard Wimmer, Clarisse Brunet Avalos, Pauline Lestienne, Laure Coquand, Amandine Di Cicco, Christophe Chehade, Annasara Artioli, Matthieu Cortes, Anna-Sophie Macé, Xiuyu Wang, Jean-Baptiste Manneville, Bettina Bessière, Ananya Roy, Karin Forsberg-Nilsson, Julia Ladewig, Fabien Guimiot, Alexandre D. Baffet","doi":"10.1016/j.neuron.2026.02.002","DOIUrl":"https://doi.org/10.1016/j.neuron.2026.02.002","url":null,"abstract":"The strong increase in the size of the human neocortex is supported by a neural stem cell population, the basal radial glial (bRG) cells. Using live imaging of human fetal tissue and cortical organoids, we identify two translocation mechanisms for bRG cell colonization of the human neocortex. On top of an actomyosin-dependent movement called mitotic somal translocation (MST), we identify a microtubule-dependent motion occurring during interphase that we call interphasic somal translocation (IST). We show that IST is driven by the dynein motor and its activator LIS1, which are recruited to the nuclear envelope by the LINC complex, while MST is controlled by the mitotic cell-rounding pathway. Eighty-five percent of bRG cell translocation is due to IST, resulting in a total movement of 0.67 mm per month of gestation. Our work identifies how bRG cells colonize the human fetal cortex and further shows that IST and MST also occur in bRG-related glioblastoma cells.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"44 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465285","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}
Novelty signals in the brain drive exploration and learning. While the perceived novelty of a stimulus is known to depend on previous experience, it remains elusive how generalization between familiar and novel stimuli impacts novelty computation. Specifically, existing models of novelty computation fail to account for the effects of stimulus similarities that are abundant in naturalistic tasks. Here, we present a biologically plausible model that captures how stimulus similarities modulate novelty signals in the brain and influence novelty-driven exploration. By applying our model to two publicly available datasets, we show (1) how generalization across similar visual stimuli affects novelty responses in the mouse visual cortex and (2) how generalization across nearby locations impacts mouse exploration in an unfamiliar environment. Our model explains distinct neural and behavioral signatures of novelty, makes mechanistic predictions about synaptic plasticity rules in novelty-computing circuits, and enables theory-driven experiment design.
{"title":"Representational similarity modulates neural and behavioral signatures of novelty.","authors":"Sophia Becker, Alireza Modirshanechi, Wulfram Gerstner","doi":"10.1016/j.neuron.2026.01.007","DOIUrl":"https://doi.org/10.1016/j.neuron.2026.01.007","url":null,"abstract":"<p><p>Novelty signals in the brain drive exploration and learning. While the perceived novelty of a stimulus is known to depend on previous experience, it remains elusive how generalization between familiar and novel stimuli impacts novelty computation. Specifically, existing models of novelty computation fail to account for the effects of stimulus similarities that are abundant in naturalistic tasks. Here, we present a biologically plausible model that captures how stimulus similarities modulate novelty signals in the brain and influence novelty-driven exploration. By applying our model to two publicly available datasets, we show (1) how generalization across similar visual stimuli affects novelty responses in the mouse visual cortex and (2) how generalization across nearby locations impacts mouse exploration in an unfamiliar environment. Our model explains distinct neural and behavioral signatures of novelty, makes mechanistic predictions about synaptic plasticity rules in novelty-computing circuits, and enables theory-driven experiment design.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147494380","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}
Myelin injury, a hallmark of several neurological diseases, is highly sensitive to glucose metabolism disruptions. Here, we reveal that oligodendrocytes (OLs) within demyelinating lesions exhibit reduced glycolytic efficiency and lactate production compared with mature OLs. Administration of lactate, the product of glycolysis, or specific overexpression of lactate dehydrogenase A (LDHA), the enzyme in lactate production, in Olig1+ OLs significantly enhances remyelination. In contrast, conditional knockout of LDHA in the Olig1+ lineage or CNPase+ premyelinating OLs leads to severe neuropathy with dysmyelination in a development-dependent and cell-specific manner. Mechanistic insights show that OLs within demyelinating lesions undergo lactylation silencing, a lactate-induced epigenetic modification that impedes myelin restoration. Furthermore, lactylation of LDHA and carbonic anhydrase II (CAII) couples glycolysis with OL maturation. Our findings elucidate the metabolic interplay among glycolysis, lactylation, and OL maturation and provide novel enzymatic therapeutic perspectives for demyelinating disorders, for which effective therapies are currently lacking.
{"title":"Oligodendrocyte-encoded lactate dehydrogenase A couples glycolysis to remyelination via protein lactylation","authors":"Ming-Yue Bao, Xiu-Qing Li, Qing-Qing Sun, Yan He, Yu-Jing Yin, Si-Han Li, Ruo-Yan Du, Gai-Xin Ma, Chen-Yu Feng, Bing Han, Rui Jia, Xuan Wang, Li-Bin Wang, Ya-Ping Yan, Xing Li, Yuan Zhang","doi":"10.1016/j.neuron.2026.02.032","DOIUrl":"https://doi.org/10.1016/j.neuron.2026.02.032","url":null,"abstract":"Myelin injury, a hallmark of several neurological diseases, is highly sensitive to glucose metabolism disruptions. Here, we reveal that oligodendrocytes (OLs) within demyelinating lesions exhibit reduced glycolytic efficiency and lactate production compared with mature OLs. Administration of lactate, the product of glycolysis, or specific overexpression of lactate dehydrogenase A (LDHA), the enzyme in lactate production, in Olig1<ce:sup loc=\"post\">+</ce:sup> OLs significantly enhances remyelination. In contrast, conditional knockout of LDHA in the Olig1<ce:sup loc=\"post\">+</ce:sup> lineage or CNPase<ce:sup loc=\"post\">+</ce:sup> premyelinating OLs leads to severe neuropathy with dysmyelination in a development-dependent and cell-specific manner. Mechanistic insights show that OLs within demyelinating lesions undergo lactylation silencing, a lactate-induced epigenetic modification that impedes myelin restoration. Furthermore, lactylation of LDHA and carbonic anhydrase II (CAII) couples glycolysis with OL maturation. Our findings elucidate the metabolic interplay among glycolysis, lactylation, and OL maturation and provide novel enzymatic therapeutic perspectives for demyelinating disorders, for which effective therapies are currently lacking.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"31 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465284","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}
Pub Date : 2026-03-16DOI: 10.1016/j.neuron.2026.01.033
Karen Haenraets, Robert P. Ganley, Francesca Pietrafesa, Donald Iain MacDonald, Marília Sousa, Sina Schalbetter, Raquel Mendes, Fabienne Luzi, Hendrik Wildner, Hanns Ulrich Zeilhofer
Acute stress is a powerful inducer of endogenous analgesia. Several brainstem and midbrain areas have been identified that are activated during stress and send descending axons to suppress spinal nociception. The spinal effector circuits and neurons have, however, remained largely elusive. Here, we demonstrate that GABAergic interneurons of the superficial dorsal horn expressing the transcription factor gastrulation brain homeobox 1 (Gbx1) are key elements of these circuits. Their inhibition had little effect on nociception under resting conditions but completely abolished swim stress-induced analgesia. Retrograde monosynaptic tracing revealed input from several brain areas, most prominently from the rostral ventromedial medulla (RVM). Optogenetic circuit tracing demonstrated that this input is inhibitory and that Gbx1 neurons in turn inhibit projection neurons targeting the lateral parabrachial nucleus, a key area in supraspinal pain relay. Our results thus identify a subpopulation of GABAergic neurons in the superficial dorsal horn as key elements of a disinhibitory circuit for stress-induced analgesia.
{"title":"GABAergic Gbx1 neurons of the superficial dorsal horn are critical elements of a spinal circuit for stress-induced analgesia","authors":"Karen Haenraets, Robert P. Ganley, Francesca Pietrafesa, Donald Iain MacDonald, Marília Sousa, Sina Schalbetter, Raquel Mendes, Fabienne Luzi, Hendrik Wildner, Hanns Ulrich Zeilhofer","doi":"10.1016/j.neuron.2026.01.033","DOIUrl":"https://doi.org/10.1016/j.neuron.2026.01.033","url":null,"abstract":"Acute stress is a powerful inducer of endogenous analgesia. Several brainstem and midbrain areas have been identified that are activated during stress and send descending axons to suppress spinal nociception. The spinal effector circuits and neurons have, however, remained largely elusive. Here, we demonstrate that GABAergic interneurons of the superficial dorsal horn expressing the transcription factor gastrulation brain homeobox 1 (Gbx1) are key elements of these circuits. Their inhibition had little effect on nociception under resting conditions but completely abolished swim stress-induced analgesia. Retrograde monosynaptic tracing revealed input from several brain areas, most prominently from the rostral ventromedial medulla (RVM). Optogenetic circuit tracing demonstrated that this input is inhibitory and that Gbx1 neurons in turn inhibit projection neurons targeting the lateral parabrachial nucleus, a key area in supraspinal pain relay. Our results thus identify a subpopulation of GABAergic neurons in the superficial dorsal horn as key elements of a disinhibitory circuit for stress-induced analgesia.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"60 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465286","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}
Pub Date : 2026-03-16DOI: 10.1016/j.neuron.2026.01.028
Johannes J Letzkus, Henning Sprekeler, Harald Binder, Joschka Bödecker, Ilka Diester, Claudio Elgueta, Sabine Grosser, Matthias Haberl, Akos Kulik, Matthew Larkum, Christian Leibold, Christian Madry, Hannah Monyer, James F A Poulet, Jonas-Frederic Sauer, Jan Schmoranzer, Susanne Schreiber, Julia Veit, Silvia Viana da Silva, Andreas Vlachos, Imre Vida, Jörg R P Geiger, Marlene Bartos
Inhibitory interneuron diversity is a central feature of cortical circuits. The IN-CODE consortium seeks to combine large-scale recordings of interneuron types with machine-learning tools to identify the role of their physiological features, connectivity motifs, and cooperativity in cognitive functions.
{"title":"A population approach to cortical GABAergic interneuron function.","authors":"Johannes J Letzkus, Henning Sprekeler, Harald Binder, Joschka Bödecker, Ilka Diester, Claudio Elgueta, Sabine Grosser, Matthias Haberl, Akos Kulik, Matthew Larkum, Christian Leibold, Christian Madry, Hannah Monyer, James F A Poulet, Jonas-Frederic Sauer, Jan Schmoranzer, Susanne Schreiber, Julia Veit, Silvia Viana da Silva, Andreas Vlachos, Imre Vida, Jörg R P Geiger, Marlene Bartos","doi":"10.1016/j.neuron.2026.01.028","DOIUrl":"https://doi.org/10.1016/j.neuron.2026.01.028","url":null,"abstract":"<p><p>Inhibitory interneuron diversity is a central feature of cortical circuits. The IN-CODE consortium seeks to combine large-scale recordings of interneuron types with machine-learning tools to identify the role of their physiological features, connectivity motifs, and cooperativity in cognitive functions.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474469","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}
Pub Date : 2026-03-14DOI: 10.1016/j.neuron.2026.03.010
Timothy A. Zolnik, Britta J. Eickholt, Zoltán Molnár, Matthew E. Larkum
{"title":"The layer 6b theory of attention","authors":"Timothy A. Zolnik, Britta J. Eickholt, Zoltán Molnár, Matthew E. Larkum","doi":"10.1016/j.neuron.2026.03.010","DOIUrl":"https://doi.org/10.1016/j.neuron.2026.03.010","url":null,"abstract":"","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"16 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447616","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}
Pub Date : 2026-03-12DOI: 10.1016/j.neuron.2026.01.027
Colleen N. McLaughlin, Hui Ji, Katherine X. Dong, Chuanyun Xu, Kenneth Kin Lam Wong, Zhuoran Li, David J. Luginbuhl, Charles Xu, Cheng Lyu, Wei Qin, Jiefu Li, Namrata D. Udeshi, Steven A. Carr, Alice Y. Ting, Liqun Luo
{"title":"Endocytome profiling uncovers cell-surface protein dynamics underlying neuronal connectivity","authors":"Colleen N. McLaughlin, Hui Ji, Katherine X. Dong, Chuanyun Xu, Kenneth Kin Lam Wong, Zhuoran Li, David J. Luginbuhl, Charles Xu, Cheng Lyu, Wei Qin, Jiefu Li, Namrata D. Udeshi, Steven A. Carr, Alice Y. Ting, Liqun Luo","doi":"10.1016/j.neuron.2026.01.027","DOIUrl":"https://doi.org/10.1016/j.neuron.2026.01.027","url":null,"abstract":"","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"57 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447619","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}
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