Nature neuroscience最新文献

{"title":"Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice","authors":"Antonio C. Pagano Zottola, Rebeca Martín-Jiménez, Gianluca Lavanco, Geneviève Hamel-Côté, Carla Ramon-Duaso, Rui S. Rodrigues, Yamuna Mariani, Mehtab Khan, Filippo Drago, Stephanie Jean, Itziar Bonilla-Del Río, Daniel Jimenez-Blasco, Jon Egaña-Huguet, Abel Eraso-Pichot, Sandra Beriain, Astrid Cannich, Laura Vidal-Palencia, Rosmara Infantino, Francisca Julio-Kalajzić, Doriane Gisquet, Ania Goncalves, Inas Al-Younis, Yann Baussan, Stephane Duvezin-Caubet, Anne Devin, Edgar Soria-Gomez, Nagore Puente, Juan P. Bolaños, Pedro Grandes, Sandrine Pouvreau, Arnau Busquets-Garcia, Giovanni Marsicano, Luigi Bellocchio, Etienne Hebert-Chatelain","doi":"10.1038/s41593-025-02032-y","DOIUrl":"10.1038/s41593-025-02032-y","url":null,"abstract":"Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (Gs) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction. Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-Gs) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-Gs abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer’s disease and frontotemporal dementia. Thus, mitoDREADD-Gs enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment. Activation of Gs signaling at mitochondria by mitoDREADD-Gs increases mitochondrial metabolism, leading to better memory in mouse models of dementia, directly linking brain mitochondrial deficits to cognitive symptoms of neurodegenerative diseases.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 9","pages":"1844-1857"},"PeriodicalIF":20.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812937","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":"Serotonergic modulation of the BNST–CeA pathway reveals sex differences in fear learning","authors":"Rebecca Ravenelle, Jinah Lee, Carolina Fernandes-Henriques, Jia Liu, Allyson K. Friedman, Ekaterina Likhtik, Nesha S. Burghardt","doi":"10.1038/s41593-025-02025-x","DOIUrl":"10.1038/s41593-025-02025-x","url":null,"abstract":"Post-traumatic stress disorder (PTSD) is characterized by intense fear memory formation and is diagnosed more often in women than men. Here we show that increasing serotonin pharmacologically before auditory fear conditioning promoted memory recall in female and male mice, and that females were more sensitive to this effect. Optogenetic stimulation of raphe terminals in the anterior dorsal bed nucleus of the stria terminalis (adBNST) during fear conditioning increased c-Fos expression in the BNST and central nucleus of the amygdala (CeA) and enhanced fear memory recall through activation of 5-HT2C receptors in the adBNST in females only. Likewise, serotonin stimulation during fear learning enhanced adBNST–CeA high gamma (90–140 Hz) synchrony and adBNST-to-CeA communication in high gamma during fear memory recall in females only. These findings suggest that sex differences in the raphe–BNST–CeA pathway may contribute to the higher risk of PTSD in women. Ravenelle et al. show that systematically increasing serotonin has sex-specific effects on fear learning in mice. In females only, increasing serotonin in the BNST enhances fear memory by promoting communication with the amygdala.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 9","pages":"1897-1909"},"PeriodicalIF":20.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786655","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":"Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson’s disease","authors":"Eizo Marutani, Maria Miranda, Timothy J. Durham, Sharon H. Kim, Dreson L. Russell, Presli P. Wiesenthal, Paul Lichtenegger, Marissa A. Menard, Charlotte F. Brzozowski, Haobo Li, Gary Ruvkun, Joshua D. Meisel, Laura Volpicelli-Daley, Vamsi K. Mootha, Fumito Ichinose","doi":"10.1038/s41593-025-02010-4","DOIUrl":"10.1038/s41593-025-02010-4","url":null,"abstract":"Parkinson’s disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes. Parkinson’s disease (PD) involves toxic protein buildup and energy failure in neurons. Continuously breathing low-oxygen air protected mice from PD-like neuronal loss and reversed symptoms, even after they began, suggesting that hypoxia may protect neurons.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 9","pages":"1858-1867"},"PeriodicalIF":20.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02010-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786654","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":"Big data for classifying ASD","authors":"Shari Wiseman","doi":"10.1038/s41593-025-02046-6","DOIUrl":"10.1038/s41593-025-02046-6","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 8","pages":"1577-1577"},"PeriodicalIF":20.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778508","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":"Alzheimer’s disease transcriptional landscape in ex vivo human microglia","authors":"Roman Kosoy, John F. Fullard, Jaroslav Bendl, Steven P. Kleopoulos, Zhiping Shao, Stathis Argyriou, Deepika Mathur, Konstantina Psychogyiou, Periklis Malakates, James Vicari, Yixuan Ma, Jack Humphrey, Erica Brophy, Towfique Raj, Pavel Katsel, Georgios Voloudakis, Donghoon Lee, David A. Bennett, Vahram Haroutunian, Gabriel E. Hoffman, Panos Roussos","doi":"10.1038/s41593-025-02020-2","DOIUrl":"10.1038/s41593-025-02020-2","url":null,"abstract":"Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer’s disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood. Here, we present a transcriptional analysis of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, such as 63 patients representing the full clinical and pathological spectra of AD. We identified changes associated with multiple AD phenotypes, capturing the severity of dementia and neuropathological lesions. Transcript-level analyses identified additional genes with heterogeneous isoform usage and AD phenotypes. We identified changes in gene–gene coordination in AD, dysregulation of coexpression modules and disease subtypes with distinct gene expression patterns. Taken together, these data further our understanding of the key role that microglia have in AD biology and nominate candidates for therapeutic intervention. Here the authors provide a comprehensive transcriptomic dataset of human primary microglia for Alzheimer’s disease and healthy aging. They identify dysregulation of immune-related microglial functions as a hallmark of disease.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 9","pages":"1830-1843"},"PeriodicalIF":20.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769988","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":"Neurons feed tumors","authors":"Laura Zelenka","doi":"10.1038/s41593-025-02048-4","DOIUrl":"10.1038/s41593-025-02048-4","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 8","pages":"1577-1577"},"PeriodicalIF":20.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778438","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":"The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation","authors":"Isak K. Aarrestad, Lindsay P. Cameron, Ethan M. Fenton, Austen B. Casey, Daniel R. Rijsketic, Seona D. Patel, Rohini Sambyal, Shane B. Johnson, Calvin Ly, Jayashri Viswanathan, Eden V. Barragan, Stephanie A. Lozano, Nicolas Seban, Hongru Hu, Noel A. Powell, Milan Chytil, Retsina Meyer, David Rose, Chris Hempel, Eric Olson, Hanne D. Hansen, Clara A. Madsen, Gitte M. Knudsen, Chase Redd, Damian G. Wheeler, Nathaniel Guanzon, Jessie Muir, Joseph J. Hennessey, Gerald Quon, John D. McCorvy, Sunil P. Gandhi, Kurt Rasmussen, Conor Liston, John A. Gray, Boris D. Heifets, Alex S. Nord, Christina K. Kim, David E. Olson","doi":"10.1038/s41593-025-02021-1","DOIUrl":"10.1038/s41593-025-02021-1","url":null,"abstract":"Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to psychedelics for promoting neuronal growth and treating various brain conditions. Currently, it is unclear whether 5-hydroxytryptamine 2A (5-HT2A) receptors and immediate early gene (IEG) activation have a role in the neuroplasticity-promoting effects of nonhallucinogenic psychoplastogens. Here, we use pharmacological and genetic tools in rodents to show that nonhallucinogenic psychoplastogens promote cortical neuroplasticity through the same biochemical pathway—involving 5-HT2A, TrkB, mTOR and AMPA receptor activation—as classic psychedelics and that TBG-induced cortical spinogenesis is required for the sustained antidepressant-like behavioral effect of TBG. In contrast to psychedelics, TBG does not induce an immediate glutamate burst or IEG activation. As these effects have been assumed to be necessary for psychedelic-induced neuroplasticity, our results shed light on the mechanisms by which certain psychoplastogens can promote cortical neuroplasticity in the absence of hallucinogenic effects. Aarrestad et al. show that, in contrast to psychedelics, the nonhallucinogenic psychoplastogen tabernanthalog promotes neuroplasticity through 5-HT2AR activation without immediately increasing extracellular glutamate levels or immediate early gene expression.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 9","pages":"1919-1931"},"PeriodicalIF":20.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144770010","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":"Swapping microglia to treat ALSP","authors":"Rebecca Wright","doi":"10.1038/s41593-025-02047-5","DOIUrl":"10.1038/s41593-025-02047-5","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 8","pages":"1577-1577"},"PeriodicalIF":20.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778456","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":"Individual differences in decision-making shape how mesolimbic dopamine regulates choice confidence and change-of-mind","authors":"Adrina Kocharian, A. David Redish, Patrick E. Rothwell","doi":"10.1038/s41593-025-02015-z","DOIUrl":"10.1038/s41593-025-02015-z","url":null,"abstract":"Nucleus accumbens dopamine signaling is an important neural substrate for decision-making. Dominant theories generally discretize and homogenize decision-making, when it is in fact a continuous process, with evaluation and re-evaluation components that extend beyond simple outcome prediction into consideration of past and future value. Extensive work has examined mesolimbic dopamine in the context of reward prediction error, but major gaps persist in our understanding of how dopamine regulates volitional and self-guided decision-making. Moreover, there is little consideration of individual differences in value processing that may shape how dopamine regulates decision-making. Here, using an economic foraging task in mice, we found that dopamine dynamics in the nucleus accumbens core reflected decision confidence during evaluation of decisions as well as both past and future value during re-evaluation and change-of-mind. Optogenetic manipulations of mesolimbic dopamine release selectively altered evaluation and re-evaluation of decisions in mice whose dopamine dynamics and behavior reflected future value. Differences in neuroeconomic decision-making influence nucleus accumbens dopamine dynamics and reflect choice confidence during evaluation, as well as past and future value during re-evaluation, which can causally lead to change-of-mind behaviors.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 9","pages":"1883-1896"},"PeriodicalIF":20.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736741","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":"An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus","authors":"Jacqueline R. Thompson, Erik D. Nelson, Madhavi Tippani, Anthony D. Ramnauth, Heena R. Divecha, Ryan A. Miller, Nicholas J. Eagles, Elizabeth A. Pattie, Sang Ho Kwon, Svitlana V. Bach, Uma M. Kaipa, Jianing Yao, Christine Hou, Joel E. Kleinman, Leonardo Collado-Torres, Shizhong Han, Kristen R. Maynard, Thomas M. Hyde, Keri Martinowich, Stephanie C. Page, Stephanie C. Hicks","doi":"10.1038/s41593-025-02022-0","DOIUrl":"10.1038/s41593-025-02022-0","url":null,"abstract":"Cell types in the hippocampus with unique morphology, physiology and connectivity serve specialized functions associated with cognition and mood. These cell types are spatially organized, necessitating molecular profiling strategies that retain cytoarchitectural organization. Here we generated spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from anterior human hippocampus in ten adult neurotypical donors. Using non-negative matrix factorization (NMF) and label transfer, we integrated these data by defining gene expression patterns within the snRNA-seq data and then inferring expression in the SRT data. These patterns captured transcriptional variation across neuronal cell types and indicated spatial organization of excitatory and inhibitory postsynaptic specializations. Leveraging the NMF and label transfer approach with rodent datasets, we identified putative patterns of activity-dependent transcription and circuit connectivity in the human SRT dataset. Finally, we characterized the spatial organization of NMF patterns corresponding to pyramidal neurons and identified regionally-specific snRNA-seq clusters of the retrohippocampus, subiculum and presubiculum. To make this molecular atlas widely accessible, raw and processed data are freely available, including through interactive web applications. The topographical organization of cells in the hippocampus reflects its ability to regulate mood and cognition. Here the authors generate a spatially resolved gene expression map in the human hippocampus to enable cross-species and functional interpretation.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 9","pages":"1990-2004"},"PeriodicalIF":20.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02022-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736735","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}