Boaz Mohar, Gabriela Michel, Yi-Zhi Wang, Veronica Hernandez, Jonathan B. Grimm, Jin-Yong Park, Ronak Patel, Morgan Clarke, Timothy A. Brown, Cornelius Bergmann, Kamil K. Gebis, Anika P. Wilen, Bian Liu, Richard Johnson, Austin Graves, Tatjana Tchumatchenko, Jeffrey N. Savas, Eugenio F. Fornasiero, Richard L. Huganir, Paul W. Tillberg, Luke D. Lavis, Karel Svoboda, Nelson Spruston
{"title":"DELTA: a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning","authors":"Boaz Mohar, Gabriela Michel, Yi-Zhi Wang, Veronica Hernandez, Jonathan B. Grimm, Jin-Yong Park, Ronak Patel, Morgan Clarke, Timothy A. Brown, Cornelius Bergmann, Kamil K. Gebis, Anika P. Wilen, Bian Liu, Richard Johnson, Austin Graves, Tatjana Tchumatchenko, Jeffrey N. Savas, Eugenio F. Fornasiero, Richard L. Huganir, Paul W. Tillberg, Luke D. Lavis, Karel Svoboda, Nelson Spruston","doi":"10.1038/s41593-025-01923-4","DOIUrl":"https://doi.org/10.1038/s41593-025-01923-4","url":null,"abstract":"<p>Synaptic plasticity alters neuronal connections in response to experience, which is thought to underlie learning and memory. However, the loci of learning-related synaptic plasticity, and the degree to which plasticity is localized or distributed, remain largely unknown. Here we describe a new method, DELTA, for mapping brain-wide changes in synaptic protein turnover with single-synapse resolution, based on Janelia Fluor dyes and HaloTag knock-in mice. During associative learning, the turnover of the ionotropic glutamate receptor subunit GluA2, an indicator of synaptic plasticity, was enhanced in several brain regions, most markedly hippocampal area CA1. More broadly distributed increases in the turnover of synaptic proteins were observed in response to environmental enrichment. In CA1, GluA2 stability was regulated in an input-specific manner, with more turnover in layers containing input from CA3 compared to entorhinal cortex. DELTA will facilitate exploration of the molecular and circuit basis of learning and memory and other forms of plasticity at scales ranging from single synapses to the entire brain.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"49 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736578","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}
Kaylo T. Littlejohn, Cheol Jun Cho, Jessie R. Liu, Alexander B. Silva, Bohan Yu, Vanessa R. Anderson, Cady M. Kurtz-Miott, Samantha Brosler, Anshul P. Kashyap, Irina P. Hallinan, Adit Shah, Adelyn Tu-Chan, Karunesh Ganguly, David A. Moses, Edward F. Chang, Gopala K. Anumanchipalli
{"title":"A streaming brain-to-voice neuroprosthesis to restore naturalistic communication","authors":"Kaylo T. Littlejohn, Cheol Jun Cho, Jessie R. Liu, Alexander B. Silva, Bohan Yu, Vanessa R. Anderson, Cady M. Kurtz-Miott, Samantha Brosler, Anshul P. Kashyap, Irina P. Hallinan, Adit Shah, Adelyn Tu-Chan, Karunesh Ganguly, David A. Moses, Edward F. Chang, Gopala K. Anumanchipalli","doi":"10.1038/s41593-025-01905-6","DOIUrl":"10.1038/s41593-025-01905-6","url":null,"abstract":"Natural spoken communication happens instantaneously. Speech delays longer than a few seconds can disrupt the natural flow of conversation. This makes it difficult for individuals with paralysis to participate in meaningful dialogue, potentially leading to feelings of isolation and frustration. Here we used high-density surface recordings of the speech sensorimotor cortex in a clinical trial participant with severe paralysis and anarthria to drive a continuously streaming naturalistic speech synthesizer. We designed and used deep learning recurrent neural network transducer models to achieve online large-vocabulary intelligible fluent speech synthesis personalized to the participant’s preinjury voice with neural decoding in 80-ms increments. Offline, the models demonstrated implicit speech detection capabilities and could continuously decode speech indefinitely, enabling uninterrupted use of the decoder and further increasing speed. Our framework also successfully generalized to other silent-speech interfaces, including single-unit recordings and electromyography. Our findings introduce a speech-neuroprosthetic paradigm to restore naturalistic spoken communication to people with paralysis. Naturalistic communication is an aim for neuroprostheses. Here the authors present a neuroprosthesis that restores the voice of a paralyzed person simultaneously with their speaking attempts, enabling naturalistic communication.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 4","pages":"902-912"},"PeriodicalIF":21.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744851","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}
Doyeon Kim, Pojeong Park, Xiuyuan Li, J. David Wong-Campos, He Tian, Eric M. Moult, Jonathan B. Grimm, Luke D. Lavis, Adam E. Cohen
{"title":"EPSILON: a method for pulse-chase labeling to probe synaptic AMPAR exocytosis during memory formation","authors":"Doyeon Kim, Pojeong Park, Xiuyuan Li, J. David Wong-Campos, He Tian, Eric M. Moult, Jonathan B. Grimm, Luke D. Lavis, Adam E. Cohen","doi":"10.1038/s41593-025-01922-5","DOIUrl":"https://doi.org/10.1038/s41593-025-01922-5","url":null,"abstract":"<p>A tool to map changes in synaptic strength during a defined time window could provide powerful insights into the mechanisms of learning and memory. Here we developed a technique, Extracellular Protein Surface Labeling in Neurons (EPSILON), to map α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) exocytosis in vivo by sequential pulse-chase labeling of surface AMPARs with membrane-impermeable dyes. This approach yields synaptic-resolution maps of AMPAR exocytosis, a proxy for synaptic potentiation, in genetically targeted neurons during memory formation. In mice undergoing contextual fear conditioning, we investigated the relationship between synapse-level AMPAR exocytosis in CA1 pyramidal neurons and cell-level expression of the immediate early gene product cFos, a frequently used marker of engram neurons. We observed a strong correlation between AMPAR exocytosis and cFos expression, suggesting a synaptic mechanism for the association of cFos expression with memory engrams. The EPSILON technique is a useful tool for mapping synaptic plasticity and may be extended to investigate trafficking of other transmembrane proteins.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"131 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736610","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}
Zhuolei Jiao, Taosha Gao, Xiaofei Wang, Ao Wang, Yawen Ma, Li Feng, Le Gao, Lingfeng Gou, Wen Zhang, Nasim Biglari, Emma E. Boxer, Lukas Steuernagel, Xiaojing Ding, Zixian Yu, Mingjuan Li, Mengtong Gao, Mingkun Hao, Hua Zhou, Xuanzi Cao, Shuaishuai Li, Tao Jiang, Jiamei Qi, Xueyan Jia, Zhao Feng, Biyu Ren, Yu Chen, Xiaoxue Shi, Dan Wang, Xinran Wang, Luyao Han, Yikai Liang, Liuqin Qian, Chenxi Jin, Jiawen Huang, Wei Deng, Congcong Wang, E Li, Yue Hu, Zi Tao, Humingzhu Li, Xiang Yu, Min Xu, Hung-Chun Chang, Yifeng Zhang, Huatai Xu, Jun Yan, Anan Li, Qingming Luo, Ron Stoop, Scott M. Sternson, Jens C. Brüning, David J. Anderson, Mu-ming Poo, Yidi Sun, Shengjing Xu, Hui Gong, Yan-Gang Sun, Xiaohong Xu
{"title":"Projectome-based characterization of hypothalamic peptidergic neurons in male mice","authors":"Zhuolei Jiao, Taosha Gao, Xiaofei Wang, Ao Wang, Yawen Ma, Li Feng, Le Gao, Lingfeng Gou, Wen Zhang, Nasim Biglari, Emma E. Boxer, Lukas Steuernagel, Xiaojing Ding, Zixian Yu, Mingjuan Li, Mengtong Gao, Mingkun Hao, Hua Zhou, Xuanzi Cao, Shuaishuai Li, Tao Jiang, Jiamei Qi, Xueyan Jia, Zhao Feng, Biyu Ren, Yu Chen, Xiaoxue Shi, Dan Wang, Xinran Wang, Luyao Han, Yikai Liang, Liuqin Qian, Chenxi Jin, Jiawen Huang, Wei Deng, Congcong Wang, E Li, Yue Hu, Zi Tao, Humingzhu Li, Xiang Yu, Min Xu, Hung-Chun Chang, Yifeng Zhang, Huatai Xu, Jun Yan, Anan Li, Qingming Luo, Ron Stoop, Scott M. Sternson, Jens C. Brüning, David J. Anderson, Mu-ming Poo, Yidi Sun, Shengjing Xu, Hui Gong, Yan-Gang Sun, Xiaohong Xu","doi":"10.1038/s41593-025-01919-0","DOIUrl":"https://doi.org/10.1038/s41593-025-01919-0","url":null,"abstract":"<p>The hypothalamus coordinately regulates physiological homeostasis and innate behaviors, yet the detailed arrangement of hypothalamic axons remains unclear. Here we mapped the whole-brain projections of over 7,000 hypothalamic neurons expressing distinct neuropeptides in male mice, identifying 2 main classes and 31 types using single-neuron projectome analysis. These classes/types exhibited regionally biased soma distribution and specific neuropeptide enrichment. Notably, many projectome types extended long-range axon collaterals to distinct brain regions, allowing single axons to co-regulate multiple targets. We uncovered topographic organization of certain peptidergic axons at specific targets, along with diverse single-neuron projectome patterns in <i>Orexin</i>, <i>Agrp</i> and <i>Pomc</i> populations. Furthermore, hypothalamic peptidergic neurons showed correlated innervation of subdomains in the periaqueductal gray and organized into modular subnetworks within the hypothalamus, providing a structural basis for coordinated outputs. This dataset highlights the complexity of hypothalamic axonal projections and lays a foundation for future investigation of the circuit mechanisms underlying hypothalamic functions.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"183 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703200","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":"A neuroprotective role of polyunsaturated fatty acids in C9orf72-ALS/FTD","authors":"Sandeep Kumar Dubey, Hugo J. Bellen","doi":"10.1038/s41593-025-01920-7","DOIUrl":"10.1038/s41593-025-01920-7","url":null,"abstract":"New research shows that lipid metabolism genes are downregulated in patient samples and Drosophila models of amyotrophic lateral sclerosis or frontotemporal dementia associated with expansions in C9orf72, resulting in reduced levels of phospholipids containing polyunsaturated fatty acids. Importantly, increasing polyunsaturated fatty acids through diet or genetic modulation of C9orf72 in Drosophila or induced pluripotent stem cell-derived motor neurons significantly improves neuronal survival.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 4","pages":"710-712"},"PeriodicalIF":21.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703199","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}
Ming-Dong Zhang, Jussi Kupari, Jie Su, Kajsa A. Magnusson, Yizhou Hu, Laura Calvo-Enrique, Dmitry Usoskin, Gioele W. Albisetti, Mikaela M. Ceder, Katharina Henriksson, Andrew D. Leavitt, Hanns Ulrich Zeilhofer, Tomas Hökfelt, Malin C. Lagerström, Patrik Ernfors
{"title":"Neural ensembles that encode nocifensive mechanical and heat pain in mouse spinal cord","authors":"Ming-Dong Zhang, Jussi Kupari, Jie Su, Kajsa A. Magnusson, Yizhou Hu, Laura Calvo-Enrique, Dmitry Usoskin, Gioele W. Albisetti, Mikaela M. Ceder, Katharina Henriksson, Andrew D. Leavitt, Hanns Ulrich Zeilhofer, Tomas Hökfelt, Malin C. Lagerström, Patrik Ernfors","doi":"10.1038/s41593-025-01921-6","DOIUrl":"https://doi.org/10.1038/s41593-025-01921-6","url":null,"abstract":"<p>Acute pain is an unpleasant experience caused by noxious stimuli. How the spinal neural circuits attribute differences in quality of noxious information remains unknown. By means of genetic capturing, activity manipulation and single-cell RNA sequencing, we identified distinct neural ensembles in the adult mouse spinal cord encoding mechanical and heat pain. Reactivation or silencing of these ensembles potentiated or stopped, respectively, paw shaking, lifting and licking within but not across the stimuli modalities. Within ensembles, polymodal <i>Gal</i><sup>+</sup> inhibitory neurons with monosynaptic contacts to A-fiber sensory neurons gated pain transmission independent of modality. Peripheral nerve injury led to inferred microglia-driven inflammation and an ensemble transition with decreased recruitment of <i>Gal</i><sup>+</sup> inhibitory neurons and increased excitatory drive. Forced activation of <i>Gal</i><sup>+</sup> neurons reversed hypersensitivity associated with neuropathy. Our results reveal the existence of a spinal representation that forms the neural basis of the discriminative and defensive qualities of acute pain, and these neurons are under the control of a shared feed-forward inhibition.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"123 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677654","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}
Stefanie Liebe, Johannes Niediek, Matthijs Pals, Thomas P. Reber, Jennifer Faber, Jan Boström, Christian E. Elger, Jakob H. Macke, Florian Mormann
{"title":"Phase of firing does not reflect temporal order in sequence memory of humans and recurrent neural networks","authors":"Stefanie Liebe, Johannes Niediek, Matthijs Pals, Thomas P. Reber, Jennifer Faber, Jan Boström, Christian E. Elger, Jakob H. Macke, Florian Mormann","doi":"10.1038/s41593-025-01893-7","DOIUrl":"10.1038/s41593-025-01893-7","url":null,"abstract":"The temporal order of a sequence of events has been thought to be reflected in the ordered firing of neurons at different phases of theta oscillations. Here we assess this by measuring single neuron activity (1,420 neurons) and local field potentials (921 channels) in the medial temporal lobe of 16 patients with epilepsy performing a working-memory task for temporal order. During memory maintenance, we observe theta oscillations, preferential firing of single neurons to theta phase and a close relationship between phase of firing and item position. However, the firing order did not match item order. Training recurrent neural networks to perform an analogous task, we also show the generation of theta oscillations, theta phase-dependent firing related to item position and, again, no match between firing and item order. Rather, our results suggest a mechanistic link between phase order, stimulus timing and oscillation frequency. In both biological and artificial neural networks, we provide evidence supporting the role of phase of firing in working-memory processing. The temporal order of events in working memory is thought to be reflected by ordered neuronal firing at different phases. Here the authors show that this is not the case and that phase order is linked to stimulus timing and oscillation frequency.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 4","pages":"873-882"},"PeriodicalIF":21.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-025-01893-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677869","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}
Anton Arkhipov, Nuno da Costa, Saskia de Vries, Trygve Bakken, Corbett Bennett, Amy Bernard, Jim Berg, Michael Buice, Forrest Collman, Tanya Daigle, Marina Garrett, Nathan Gouwens, Peter A. Groblewski, Julie Harris, Michael Hawrylycz, Rebecca Hodge, Tim Jarsky, Brian Kalmbach, Jerome Lecoq, Brian Lee, Ed Lein, Boaz Levi, Stefan Mihalas, Lydia Ng, Shawn Olsen, Clay Reid, Joshua H. Siegle, Staci Sorensen, Bosiljka Tasic, Carol Thompson, Jonathan T. Ting, Cindy van Velthoven, Shenqin Yao, Zizhen Yao, Christof Koch, Hongkui Zeng
{"title":"Integrating multimodal data to understand cortical circuit architecture and function","authors":"Anton Arkhipov, Nuno da Costa, Saskia de Vries, Trygve Bakken, Corbett Bennett, Amy Bernard, Jim Berg, Michael Buice, Forrest Collman, Tanya Daigle, Marina Garrett, Nathan Gouwens, Peter A. Groblewski, Julie Harris, Michael Hawrylycz, Rebecca Hodge, Tim Jarsky, Brian Kalmbach, Jerome Lecoq, Brian Lee, Ed Lein, Boaz Levi, Stefan Mihalas, Lydia Ng, Shawn Olsen, Clay Reid, Joshua H. Siegle, Staci Sorensen, Bosiljka Tasic, Carol Thompson, Jonathan T. Ting, Cindy van Velthoven, Shenqin Yao, Zizhen Yao, Christof Koch, Hongkui Zeng","doi":"10.1038/s41593-025-01904-7","DOIUrl":"10.1038/s41593-025-01904-7","url":null,"abstract":"In recent years there has been a tremendous growth in new technologies that allow large-scale investigation of different characteristics of the nervous system at an unprecedented level of detail. There is a growing trend to use combinations of these new techniques to determine direct links between different modalities. In this Perspective, we focus on the mouse visual cortex, as this is one of the model systems in which much progress has been made in the integration of multimodal data to advance understanding. We review several approaches that allow integration of data regarding various properties of cortical cell types, connectivity at the level of brain areas, cell types and individual cells, and functional neural activity in vivo. The increasingly crucial contributions of computation and theory in analyzing and systematically modeling data are also highlighted. Together with open sharing of data, tools and models, integrative approaches are essential tools in modern neuroscience for improving our understanding of the brain architecture, mechanisms and function. This paper discusses how experimental and computational studies integrating multimodal data, such as RNA expression, connectivity and neural activity, are advancing our understanding of the architecture, mechanisms and function of cortical circuits.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 4","pages":"717-730"},"PeriodicalIF":21.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677656","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":"Cancer research needs neuroscience and neuroscientists","authors":"Michelle Monje, Frank Winkler","doi":"10.1038/s41593-025-01925-2","DOIUrl":"https://doi.org/10.1038/s41593-025-01925-2","url":null,"abstract":"The nervous system can drive the initiation, growth, spread, and therapy resistance of cancer, and cancer can manipulate the nervous system in ways that further support disease progression. Tumors growing within the brain or elsewhere in the body connect with neuronal networks in circuit-specific manners, via neuron-to-cancer synaptic interactions and paracrine crosstalk. Moreover, neural factors govern critical components of the tumor environment, such as the immune system, and cancer can use neural mechanisms in a malignant cell-intrinsic manner. Here we provide a personal view on the burgeoning field of cancer neuroscience and highlight the need to approach cancer research from a neuroscience perspective — together with neuroscientists.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"86 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660923","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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