NeuronPub Date : 2025-10-01Epub Date: 2025-09-18DOI: 10.1016/j.neuron.2025.08.009
Baljit S Khakh
{"title":"On astrocyte-neuron interactions: Broad insights from the striatum.","authors":"Baljit S Khakh","doi":"10.1016/j.neuron.2025.08.009","DOIUrl":"10.1016/j.neuron.2025.08.009","url":null,"abstract":"<p><p>A long-standing question in biology and medicine concerns how astrocytes influence neurons. Here, progress concerning how astrocytes affect neurons and neural circuits is summarized by focusing on data and concepts from studies of the striatum, which has emerged as a model nucleus. Mechanisms broadly applicable across brain regions and disorders are emphasized, and knowledge gaps are described. Experiments spanning multiple scales of biology show that astrocytes regulate neural circuits by virtue of homeostatic signaling and through astrocyte-neuron interactions. During disease, astrocytes contribute to nervous system malfunction in context-specific ways through failures of normal functions and the development of maladaptive responses. As ideally positioned endogenous cellular neuromodulators, astrocytes can be targeted for strategies to regulate neural circuits in brain disorders. After a historically slow start for the field, astrocyte-neuron interactions are now recognized as consequential for physiology and behavior, critically involved in pathophysiology, and exploitable in disease.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3079-3107"},"PeriodicalIF":15.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092173","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}
NeuronPub Date : 2025-10-01Epub Date: 2025-07-28DOI: 10.1016/j.neuron.2025.07.001
Madigan M Reid, Shreya Menon, Hao Liu, Haoyue Zhou, Zhirui Hu, Simon Frerich, Bella Ding, Shahram Oveisgharan, Zimo Zhang, Sophia Nelson, Amanda Apolonio, David A Bennett, Martin Dichgans, Katherine S Pollard, M Ryan Corces, Andrew C Yang
{"title":"Human brain vascular multi-omics elucidates disease-risk associations.","authors":"Madigan M Reid, Shreya Menon, Hao Liu, Haoyue Zhou, Zhirui Hu, Simon Frerich, Bella Ding, Shahram Oveisgharan, Zimo Zhang, Sophia Nelson, Amanda Apolonio, David A Bennett, Martin Dichgans, Katherine S Pollard, M Ryan Corces, Andrew C Yang","doi":"10.1016/j.neuron.2025.07.001","DOIUrl":"10.1016/j.neuron.2025.07.001","url":null,"abstract":"<p><p>Cerebrovascular dysfunction underlies many neurological disorders, yet how genetic variants in brain vascular cells drive disease risk remains unknown. We developed MultiVINE-seq to simultaneously profile RNA and chromatin accessibility in vascular, perivascular, and immune cells from 30 human brains. Mapping genome-wide association study (GWAS) data to our multi-omic atlas linked thousands of GWAS disease-risk variants to target cell types and genes, including 2,605 previously unmapped. We found cerebrovascular and neurodegenerative disease variants have distinct mechanisms: cerebrovascular disease variants disrupt extracellular matrix genes in endothelial, mural, and fibroblast cells important for vessel structural integrity, while Alzheimer's disease (AD) variants dysregulate inflammatory adaptor proteins in endothelial and immune cells. Notably, a lead AD variant enhances PTK2B expression in brain CD8 T cells, providing genetic evidence for adaptive immunity in AD pathogenesis. This work provides a key resource for interpreting genetic risk and reveals how variants in vascular cells drive divergent pathogenic mechanisms across neurological diseases.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3143-3161.e5"},"PeriodicalIF":15.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuronPub Date : 2025-10-01DOI: 10.1016/j.neuron.2025.09.003
Kia M Barclay, Qingyun Li
{"title":"Microglial ADGRG1: AD glial resilience generator.","authors":"Kia M Barclay, Qingyun Li","doi":"10.1016/j.neuron.2025.09.003","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.09.003","url":null,"abstract":"<p><p>Microglial states underlying Alzheimer's disease (AD) have been well characterized in animal models and human samples, yet their regulation remains elusive. In this issue of Neuron, Zhu et al.<sup>1</sup> uncover Adgrg1, which governs a protective microglia phenotype through MYC activation.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 19","pages":"3070-3072"},"PeriodicalIF":15.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213346","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}
NeuronPub Date : 2025-10-01Epub Date: 2025-07-25DOI: 10.1016/j.neuron.2025.06.020
Beika Zhu, Andi Wangzhou, Diankun Yu, Tao Li, Rachael Schmidt, Stacy L De Florencio, Lauren Chao, Alicia L Thurber, Minqi Zhou, Zeina Msheik, Yonatan Perez, Lea T Grinberg, Salvatore Spina, Richard M Ransohoff, Arnold R Kriegstein, William W Seeley, Tomasz Nowakowski, Xianhua Piao
{"title":"G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.","authors":"Beika Zhu, Andi Wangzhou, Diankun Yu, Tao Li, Rachael Schmidt, Stacy L De Florencio, Lauren Chao, Alicia L Thurber, Minqi Zhou, Zeina Msheik, Yonatan Perez, Lea T Grinberg, Salvatore Spina, Richard M Ransohoff, Arnold R Kriegstein, William W Seeley, Tomasz Nowakowski, Xianhua Piao","doi":"10.1016/j.neuron.2025.06.020","DOIUrl":"10.1016/j.neuron.2025.06.020","url":null,"abstract":"<p><p>Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms enabling protective microglial responses remain elusive. Here, we investigate the role of microglial ADGRG1, an adhesion G-protein-coupled receptor (aGPCR) specifically expressed in yolk-sac-derived microglia, in AD pathology using the 5xFAD mouse model. Transcriptomic analyses reveal that ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions, thereby promoting a protective microglial state. We demonstrate that deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, exacerbated neuronal loss, and cognitive deficits. Functional assays in mouse models and human embryonic stem cell-derived microglia confirm that ADGRG1 is required for Aβ phagocytosis. These findings uncover a GPCR-mediated pathway that drives a protective microglial state via MYC activation, suggesting potential therapeutic strategies to alleviate AD progression by enhancing microglial functional competence.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3224-3242.e7"},"PeriodicalIF":15.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuronPub Date : 2025-09-30DOI: 10.1016/j.neuron.2025.08.030
Zhiwen Ye, Andrew M Shelton, Jordan R Shaker, Julien Boussard, Jennifer Colonell, Daniel Birman, Sahar Manavi, Susu Chen, Charlie Windolf, Cole Hurwitz, Han Yu, Tomoyuki Namima, Federico Pedraja, Shahaf Weiss, Bogdan C Raducanu, Torbjørn V Ness, Xiaoxuan Jia, Giulia Mastroberardino, L Federico Rossi, Matteo Carandini, Michael Häusser, Gaute T Einevoll, Gilles Laurent, Nathaniel B Sawtell, Wyeth Bair, Anitha Pasupathy, Carolina Mora Lopez, Barundeb Dutta, Liam Paninski, Joshua H Siegle, Christof Koch, Shawn R Olsen, Timothy D Harris, Nicholas A Steinmetz
{"title":"Ultra-high-density Neuropixels probes improve detection and identification in neuronal recordings.","authors":"Zhiwen Ye, Andrew M Shelton, Jordan R Shaker, Julien Boussard, Jennifer Colonell, Daniel Birman, Sahar Manavi, Susu Chen, Charlie Windolf, Cole Hurwitz, Han Yu, Tomoyuki Namima, Federico Pedraja, Shahaf Weiss, Bogdan C Raducanu, Torbjørn V Ness, Xiaoxuan Jia, Giulia Mastroberardino, L Federico Rossi, Matteo Carandini, Michael Häusser, Gaute T Einevoll, Gilles Laurent, Nathaniel B Sawtell, Wyeth Bair, Anitha Pasupathy, Carolina Mora Lopez, Barundeb Dutta, Liam Paninski, Joshua H Siegle, Christof Koch, Shawn R Olsen, Timothy D Harris, Nicholas A Steinmetz","doi":"10.1016/j.neuron.2025.08.030","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.08.030","url":null,"abstract":"<p><p>To understand the neural basis of behavior, it is essential to sensitively and accurately measure neural activity at single-neuron and single-spike resolution. Extracellular electrophysiology delivers this, but it has biases in the neurons it detects and it imperfectly resolves their action potentials. To minimize these limitations, we developed a silicon probe with much smaller and denser recording sites than previous designs, called Neuropixels Ultra (NP Ultra). Using NP Ultra, neuronal yield in mouse visual cortex recordings increased by more than 2-fold. With ultra-high spatial resolution, we discovered that a feature of extracellular waveforms, the spatial extent or \"footprint,\" distinguished axonal from somatic recordings. In addition, three genetically identified cortical cell types could be discriminated from one another with ∼80% accuracy and from other neurons with ∼85% accuracy. NP Ultra improves yield, detection of subcellular compartments, and cell type identification to enable a more powerful dissection of neural circuit activity during behavior.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207035","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":"Treg-microglia partnership in the injured spinal cord preserves Treg cell function and regulates microglial cholesterol metabolism.","authors":"Tao Qin, Tao Jiang, Zihan Zhou, Mengyuan Wu, Yuanzhen Zhang, Zhenqi Yang, Ziyang Zheng, Jiang Yi, Xiaowei Wang, Mingran Luo, Peng Gao, Jiayun Liu, Yifan Huang, Hao Liu, Qingqing Li, Wei Zhou, Shujun Zhang, Xiaodong Guo, Baorong He, Yongxiang Wang, Jin Fan, Shujie Zhao, Jian Chen, Guoyong Yin","doi":"10.1016/j.neuron.2025.09.001","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.09.001","url":null,"abstract":"<p><p>The spatiotemporal dynamics and specific roles of regulatory T (Treg) cells in spinal cord injury (SCI) remain unclear. Using single-cell RNA sequencing, flow cytometry, and immunofluorescence, we found that thymus-derived Treg cells infiltrate the injured spinal cord via peripheral blood around 3 days post-SCI. Treg cell depletion worsened SCI and impaired long-term recovery. Transcriptomic profiling revealed strong anti-inflammatory functions of Treg cells and the potential to regulate cholesterol metabolism in neighboring microglia. Further single-cell RNA sequencing uncovered the clonality of SCI-associated Treg cells. Major histocompatibility complex class II (MHC II) expression on microglia, not macrophages, was crucial for sustaining Treg cell numbers and neuroprotective function, with myelin-phagocytosing microglia-activated Treg cells showing significant neuroprotective effects. Treg cells mitigated microglial inflammation via CTLA-4 and upregulated the ATP-binding cassette transporter G1 (Abcg1) receptor in microglia, helping to manage myelin load and reduce lipid droplet formation. Our findings offer mechanistic insights into SCI-associated Treg cells and lay the groundwork for future Treg-based therapies in SCI treatment.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200489","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}
NeuronPub Date : 2025-09-27DOI: 10.1016/j.neuron.2025.09.030
Debpali Sur, Yi Zeng, Hiroki Kobayashi, Xiaofei Zhi, Mara R Goetz, Clara M Müller, Anastasia-Maria Zavitsanou, Caroline C Picoli, Andre A Martel Matos, Javier Pareja, Brajesh K Savita, Taeho Lee, Jair P Cunha-Junior, Jaime Henrique Amorim, Amin Reza Nikpoor, Alissa Dory, Ajitha Thanabalasuriar, Pedro A F Galante, Vincent T Ma, Aaron W James, Andrew J Shepherd, Madeleine J Oudin, Yuri L Bunimovich, Nicole N Scheff, Nisha J D'Silva, Karen O Dixon, Ishmail Abdus-Saboor, Timothy C Wang, Sebastien Talbot, Alexander Birbrair
{"title":"Entangled cellular and molecular relationships at the sensory neuron-cancer interface.","authors":"Debpali Sur, Yi Zeng, Hiroki Kobayashi, Xiaofei Zhi, Mara R Goetz, Clara M Müller, Anastasia-Maria Zavitsanou, Caroline C Picoli, Andre A Martel Matos, Javier Pareja, Brajesh K Savita, Taeho Lee, Jair P Cunha-Junior, Jaime Henrique Amorim, Amin Reza Nikpoor, Alissa Dory, Ajitha Thanabalasuriar, Pedro A F Galante, Vincent T Ma, Aaron W James, Andrew J Shepherd, Madeleine J Oudin, Yuri L Bunimovich, Nicole N Scheff, Nisha J D'Silva, Karen O Dixon, Ishmail Abdus-Saboor, Timothy C Wang, Sebastien Talbot, Alexander Birbrair","doi":"10.1016/j.neuron.2025.09.030","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.09.030","url":null,"abstract":"","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186408","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}
NeuronPub Date : 2025-09-26DOI: 10.1016/j.neuron.2025.08.029
Jingnan Du, Vaibhav Tripathi, Maxwell L Elliott, Joanna Ladopoulou, Wendy Sun, Mark C Eldaief, Randy L Buckner
{"title":"Within-individual precision mapping of brain networks exclusively using task data.","authors":"Jingnan Du, Vaibhav Tripathi, Maxwell L Elliott, Joanna Ladopoulou, Wendy Sun, Mark C Eldaief, Randy L Buckner","doi":"10.1016/j.neuron.2025.08.029","DOIUrl":"10.1016/j.neuron.2025.08.029","url":null,"abstract":"<p><p>Precision mapping of brain networks within individuals prevailingly relies on functional connectivity analysis of resting-state data. Here, we explored whether networks can be estimated using only task data. Correlation matrices estimated from task data were similar to those derived from resting-state data. The largest factor affecting similarity was the amount of data. Precision networks estimated from task data showed strong spatial overlap with those derived from resting-state data and predicted the same triple functional dissociation in independent data. To illustrate novel possibilities enabled by the present methods, we mapped the detailed organization of thalamic association zones within individuals by pooling extensive resting-state and task data. We also demonstrated how task data can be used to estimate networks while simultaneously extracting task responses. Broadly, these findings suggest that there is an underlying, stable network architecture that is idiosyncratic to the individual and persists across task states.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182046","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}
NeuronPub Date : 2025-09-22DOI: 10.1016/j.neuron.2025.08.026
Golia Shafiei, Nathalia B Esper, Mauricio S Hoffmann, Lei Ai, Andrew A Chen, Jon Cluce, Sydney Covitz, Steven Giavasis, Connor Lane, Kahini Mehta, Tyler M Moore, Taylor Salo, Tinashe M Tapera, Monica E Calkins, Stanley Colcombe, Christos Davatzikos, Raquel E Gur, Ruben C Gur, Pedro M Pan, Andrea P Jackowski, Ariel Rokem, Luis A Rohde, Russell T Shinohara, Nim Tottenham, Xi-Nian Zuo, Matthew Cieslak, Alexandre R Franco, Gregory Kiar, Giovanni A Salum, Michael P Milham, Theodore D Satterthwaite
{"title":"Reproducible Brain Charts: An open data resource for mapping brain development and its associations with mental health.","authors":"Golia Shafiei, Nathalia B Esper, Mauricio S Hoffmann, Lei Ai, Andrew A Chen, Jon Cluce, Sydney Covitz, Steven Giavasis, Connor Lane, Kahini Mehta, Tyler M Moore, Taylor Salo, Tinashe M Tapera, Monica E Calkins, Stanley Colcombe, Christos Davatzikos, Raquel E Gur, Ruben C Gur, Pedro M Pan, Andrea P Jackowski, Ariel Rokem, Luis A Rohde, Russell T Shinohara, Nim Tottenham, Xi-Nian Zuo, Matthew Cieslak, Alexandre R Franco, Gregory Kiar, Giovanni A Salum, Michael P Milham, Theodore D Satterthwaite","doi":"10.1016/j.neuron.2025.08.026","DOIUrl":"10.1016/j.neuron.2025.08.026","url":null,"abstract":"<p><p>Mental disorders are increasingly understood as disorders of brain development. Large and heterogeneous samples are required to define generalizable links between brain development and psychopathology. To this end, we introduce Reproducible Brain Charts (RBC), an open resource that integrates data from 5 large studies of brain development in youth from three continents (N = 6,346). Bifactor models were used to create harmonized psychiatric phenotypes, capturing major dimensions of psychopathology. Following rigorous quality assurance, neuroimaging data were carefully curated and processed using consistent pipelines in a reproducible manner. Initial analyses of RBC emphasize the benefit of careful quality assurance and data harmonization in delineating developmental effects and associations with psychopathology. Critically, all RBC data-including harmonized psychiatric phenotypes, unprocessed images, and fully processed imaging derivatives-are openly shared without a data use agreement via the International Neuroimaging Data-sharing Initiative. Together, RBC facilitates large-scale, reproducible, and generalizable research in developmental and psychiatric neuroscience.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131503","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}
NeuronPub Date : 2025-09-19DOI: 10.1016/j.neuron.2025.08.023
Josep-Maria Balaguer, Genis Prat-Ortega, Julia Ostrowski, Luigi Borda, Nikhil Verma, Prakarsh Yadav, Erynn Sorensen, Roberto de Freitas, Scott Ensel, Serena Donadio, Lucy Liang, Jonathan Ho, Arianna Damiani, Erinn M Grigsby, Daryl P Fields, Jorge A Gonzalez-Martinez, Peter C Gerszten, Lee E Fisher, Douglas J Weber, Elvira Pirondini, Marco Capogrosso
{"title":"Neural mechanisms underlying the recovery of voluntary control of motoneurons after paralysis with spinal cord stimulation.","authors":"Josep-Maria Balaguer, Genis Prat-Ortega, Julia Ostrowski, Luigi Borda, Nikhil Verma, Prakarsh Yadav, Erynn Sorensen, Roberto de Freitas, Scott Ensel, Serena Donadio, Lucy Liang, Jonathan Ho, Arianna Damiani, Erinn M Grigsby, Daryl P Fields, Jorge A Gonzalez-Martinez, Peter C Gerszten, Lee E Fisher, Douglas J Weber, Elvira Pirondini, Marco Capogrosso","doi":"10.1016/j.neuron.2025.08.023","DOIUrl":"10.1016/j.neuron.2025.08.023","url":null,"abstract":"<p><p>Spinal cord stimulation (SCS) improves motor control after paralysis. This evidence led to the hypothesis that SCS facilitates residual supraspinal inputs to spinal motoneurons. Here, we demonstrate that this hypothesis is not supported by experimental evidence. Instead, we show that residual supraspinal inputs modulate motoneurons' membrane potential to transform subthreshold SCS pulses into suprathreshold action potentials, thereby entraining motoneuron activity to SCS. Despite this entrainment, residual supraspinal inputs can control motoneuron firing rates by modulating the number of subthreshold SCS pulses transformed into action potentials, resulting in volitional modulation of motor output for a restricted set of SCS parameters. Furthermore, we predict that residual supraspinal inhibitory drive can silence unwanted suprathreshold motoneuron activity, enlarging the functional set of SCS parameters. Finally, we demonstrate that this set of functional stimulation parameters is further restricted by lesion severity, highlighting an intrinsic limitation of SCS in cases of severe injury.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102918","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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