Pub Date : 2025-11-25DOI: 10.1038/s41593-025-02086-y
Gonadal hormones shape brain structure across the lifespan. Using dense sampling in two female participants with typical cycles, one with endometriosis, and one using oral contraceptives, we show that distinct hormonal milieus influence widespread, coordinated fluctuations in brain volume across the cycle. These results highlight the importance of looking beyond the ‘typical’ menstrual cycle to understand how hormones drive structural brain plasticity in different conditions.
{"title":"Estrogen dominance drives distinct patterns of brain plasticity","authors":"","doi":"10.1038/s41593-025-02086-y","DOIUrl":"10.1038/s41593-025-02086-y","url":null,"abstract":"Gonadal hormones shape brain structure across the lifespan. Using dense sampling in two female participants with typical cycles, one with endometriosis, and one using oral contraceptives, we show that distinct hormonal milieus influence widespread, coordinated fluctuations in brain volume across the cycle. These results highlight the importance of looking beyond the ‘typical’ menstrual cycle to understand how hormones drive structural brain plasticity in different conditions.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 12","pages":"2413-2414"},"PeriodicalIF":20.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599444","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 : 2025-11-25DOI: 10.1038/s41593-025-02163-2
Carina Heller, Daniel Güllmar, Lejla Colic, Laura Pritschet, Martin Gell, Nooshin Javaheripour, Feliberto de la Cruz, Philine Rojczyk, Carina J. Koeppel, Bart Larsen, Habib Ganjgahi, Frederik J. Lange, Ann-Christine Buck, Tim L. Jesgarzewsky, Robert Dahnke, Michael Kiehntopf, Emily G. Jacobs, Zora Kikinis, Martin Walter, Ilona Croy, Christian Gaser
{"title":"Publisher Correction: Hormonal milieu influences whole-brain structural dynamics across the menstrual cycle using dense sampling in multiple individuals","authors":"Carina Heller, Daniel Güllmar, Lejla Colic, Laura Pritschet, Martin Gell, Nooshin Javaheripour, Feliberto de la Cruz, Philine Rojczyk, Carina J. Koeppel, Bart Larsen, Habib Ganjgahi, Frederik J. Lange, Ann-Christine Buck, Tim L. Jesgarzewsky, Robert Dahnke, Michael Kiehntopf, Emily G. Jacobs, Zora Kikinis, Martin Walter, Ilona Croy, Christian Gaser","doi":"10.1038/s41593-025-02163-2","DOIUrl":"10.1038/s41593-025-02163-2","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 12","pages":"2647-2647"},"PeriodicalIF":20.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02163-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599445","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}
Pub Date : 2025-11-24DOI: 10.1038/s41593-025-02111-0
Tjitse van der Molen, Alex Spaeth, Mattia Chini, Sebastian Hernandez, Gregory A. Kaurala, Hunter E. Schweiger, Cole Duncan, Sawyer McKenna, Jinghui Geng, Max Lim, Julian Bartram, Tobias Gänswein, Aditya Dendukuri, Zongren Zhang, Jesus Gonzalez-Ferrer, Kiran Bhaskaran-Nair, Aidan L. Morson, Cole R. K. Harder, Linda R. Petzold, Dowlette-Mary Alam El Din, Jason Laird, Maren Schenke, Lena Smirnova, Bradley M. Colquitt, Mohammed A. Mostajo-Radji, Paul K. Hansma, Mircea Teodorescu, Andreas Hierlemann, Keith B. Hengen, Ileana L. Hanganu-Opatz, Kenneth S. Kosik, Tal Sharf
{"title":"Preconfigured neuronal firing sequences in human brain organoids","authors":"Tjitse van der Molen, Alex Spaeth, Mattia Chini, Sebastian Hernandez, Gregory A. Kaurala, Hunter E. Schweiger, Cole Duncan, Sawyer McKenna, Jinghui Geng, Max Lim, Julian Bartram, Tobias Gänswein, Aditya Dendukuri, Zongren Zhang, Jesus Gonzalez-Ferrer, Kiran Bhaskaran-Nair, Aidan L. Morson, Cole R. K. Harder, Linda R. Petzold, Dowlette-Mary Alam El Din, Jason Laird, Maren Schenke, Lena Smirnova, Bradley M. Colquitt, Mohammed A. Mostajo-Radji, Paul K. Hansma, Mircea Teodorescu, Andreas Hierlemann, Keith B. Hengen, Ileana L. Hanganu-Opatz, Kenneth S. Kosik, Tal Sharf","doi":"10.1038/s41593-025-02111-0","DOIUrl":"https://doi.org/10.1038/s41593-025-02111-0","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"187 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582926","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 : 2025-11-24DOI: 10.1038/s41593-025-02125-8
Giulia Albertini, Magdalena Zielonka, Marie-Lynn Cuypers, An Snellinx, Ciana Xu, Suresh Poovathingal, Marta Wojno, Kristofer Davie, Veerle van Lieshout, Katleen Craessaerts, Leen Wolfs, Emanuela Pasciuto, Tom Jaspers, Katrien Horré, Lurgarde Serneels, Mark Fiers, Maarten Dewilde, Bart De Strooper
Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1 /osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer’s disease.
{"title":"The Alzheimer’s therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia","authors":"Giulia Albertini, Magdalena Zielonka, Marie-Lynn Cuypers, An Snellinx, Ciana Xu, Suresh Poovathingal, Marta Wojno, Kristofer Davie, Veerle van Lieshout, Katleen Craessaerts, Leen Wolfs, Emanuela Pasciuto, Tom Jaspers, Katrien Horré, Lurgarde Serneels, Mark Fiers, Maarten Dewilde, Bart De Strooper","doi":"10.1038/s41593-025-02125-8","DOIUrl":"https://doi.org/10.1038/s41593-025-02125-8","url":null,"abstract":"Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon <jats:italic>γ</jats:italic> genes and antigen presentation. Finally, we identify <jats:italic>SPP1</jats:italic> /osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer’s disease.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"14 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582924","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 : 2025-11-24DOI: 10.1038/s41593-025-02117-8
Mengmeng Jin, Ziyuan Ma, Rui Dang, Haiwei Zhang, Rachael Kim, Haipeng Xue, Jesse Pascual, Hanwen Yu, Ava V. Papetti, Yan Liu, Steven Finkbeiner, Elizabeth Head, Ying Liu, Peng Jiang
{"title":"A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease","authors":"Mengmeng Jin, Ziyuan Ma, Rui Dang, Haiwei Zhang, Rachael Kim, Haipeng Xue, Jesse Pascual, Hanwen Yu, Ava V. Papetti, Yan Liu, Steven Finkbeiner, Elizabeth Head, Ying Liu, Peng Jiang","doi":"10.1038/s41593-025-02117-8","DOIUrl":"https://doi.org/10.1038/s41593-025-02117-8","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"1 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582927","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 : 2025-11-24DOI: 10.1038/s41593-025-02118-7
Christopher R. Bye, Elizabeth Qian, Katherine Lim, Maciej Daniszewski, Fleur C. Garton, Bảo C. Trần-Lê, Helena H. Liang, Tian Lin, John G. Lock, Duncan E. Crombie, Steven Morgan, Yi Hu, Samantha K. Barton, Lucy M. Palmer, Elvan Djouma, Saritha Kodikara, Kim-Anh Lê Cao, Thanuja Dharmadasa, Anjali K. Henders, Laura A. Ziser, Matthew C. Kiernan, Kevin Talbot, Merrilee Needham, Susan Fletcher, Paul Talman, Susan Mathers, Naomi R. Wray, Alex W. Hewitt, Alice Pebay, Bradley J. Turner
Heterogeneous and predominantly sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases; however, large-scale studies demonstrating accelerated neurodegeneration in patients with sporadic disease are limited. Here we generated an iPSC library from 100 patients with sporadic ALS (SALS) and conducted population-wide phenotypic screening. Motor neurons derived from patients with SALS recapitulated key aspects of the disease, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysregulation and pharmacological rescue by riluzole. Screening of drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration, reflecting trial outcomes and validating the SALS model. Combinatorial testing of effective drugs identified baricitinib, memantine and riluzole as a promising therapeutic combination for SALS. These findings demonstrate that patient-derived iPSC models can recapitulate sporadic disease features, paving the way for a new generation of disease modeling and therapeutic discovery in ALS.
{"title":"Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy","authors":"Christopher R. Bye, Elizabeth Qian, Katherine Lim, Maciej Daniszewski, Fleur C. Garton, Bảo C. Trần-Lê, Helena H. Liang, Tian Lin, John G. Lock, Duncan E. Crombie, Steven Morgan, Yi Hu, Samantha K. Barton, Lucy M. Palmer, Elvan Djouma, Saritha Kodikara, Kim-Anh Lê Cao, Thanuja Dharmadasa, Anjali K. Henders, Laura A. Ziser, Matthew C. Kiernan, Kevin Talbot, Merrilee Needham, Susan Fletcher, Paul Talman, Susan Mathers, Naomi R. Wray, Alex W. Hewitt, Alice Pebay, Bradley J. Turner","doi":"10.1038/s41593-025-02118-7","DOIUrl":"https://doi.org/10.1038/s41593-025-02118-7","url":null,"abstract":"Heterogeneous and predominantly sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases; however, large-scale studies demonstrating accelerated neurodegeneration in patients with sporadic disease are limited. Here we generated an iPSC library from 100 patients with sporadic ALS (SALS) and conducted population-wide phenotypic screening. Motor neurons derived from patients with SALS recapitulated key aspects of the disease, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysregulation and pharmacological rescue by riluzole. Screening of drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration, reflecting trial outcomes and validating the SALS model. Combinatorial testing of effective drugs identified baricitinib, memantine and riluzole as a promising therapeutic combination for SALS. These findings demonstrate that patient-derived iPSC models can recapitulate sporadic disease features, paving the way for a new generation of disease modeling and therapeutic discovery in ALS.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"70 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582931","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}
Brain atlases map the spatial organization of neural tissue and serve as anatomical references. Current mouse brain atlases define regions based primarily on cell density patterns but overlook how neurons extend their branches (dendrites) to form local networks. Here we show that mapping dendrites enhanced by their local neighborhoods—which we call microenvironments—reveals a finer-grained brain organization. We analyzed dendrite patterns from more than 100,000 neurons across 111 mouse brains and discovered that neurons group into distinct microenvironments that subdivide known brain regions, nearly doubling the number of identifiable areas compared with the standard Allen Common Coordinate Framework. Remarkably, hippocampal neurons with similar local dendrite arrangements tend to form long-range connections to similar distant targets, suggesting that local structure predicts global connectivity. This microenvironment atlas complements existing resources by revealing previously hidden subdivisions and correlations that align with functional differences, offering new insights into how brain structure relates to function.
{"title":"A mouse brain atlas based on dendritic microenvironments","authors":"Yufeng Liu, Sujun Zhao, Zhixi Yun, Feng Xiong, Hanchuan Peng","doi":"10.1038/s41593-025-02119-6","DOIUrl":"https://doi.org/10.1038/s41593-025-02119-6","url":null,"abstract":"Brain atlases map the spatial organization of neural tissue and serve as anatomical references. Current mouse brain atlases define regions based primarily on cell density patterns but overlook how neurons extend their branches (dendrites) to form local networks. Here we show that mapping dendrites enhanced by their local neighborhoods—which we call microenvironments—reveals a finer-grained brain organization. We analyzed dendrite patterns from more than 100,000 neurons across 111 mouse brains and discovered that neurons group into distinct microenvironments that subdivide known brain regions, nearly doubling the number of identifiable areas compared with the standard Allen Common Coordinate Framework. Remarkably, hippocampal neurons with similar local dendrite arrangements tend to form long-range connections to similar distant targets, suggesting that local structure predicts global connectivity. This microenvironment atlas complements existing resources by revealing previously hidden subdivisions and correlations that align with functional differences, offering new insights into how brain structure relates to function.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"15 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582923","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 : 2025-11-20DOI: 10.1038/s41593-025-02079-x
Lauren E. Miner, Aditya K. Gautham, Michael A. Crickmore
Repeated experiences can cause behavior-specific fatigue. We use Drosophila to study this common form of motivational change, finding that prior matings make males more likely to abandon future copulations when challenged. Here we show that, during mating, dopamine signals through the D2-like receptor (D2R) to promote resilience to challenges that might otherwise cause the male to switch behaviors. This motivating dopamine signal suppresses the output of the copulation decision neurons (CDNs), which can truncate matings when pushed past threshold. Repetition-induced devaluation of mating results from β-arrestin-dependent desensitization of the D2R on the CDNs, rendering them temporarily resistant to naturally released or experimentally supplied dopamine. When local desensitization to dopamine is prevented, the male shows no signs of fatigue, treating each mating as if it were his first. These findings explain a widespread motivational phenomenon and reveal a natural function for the notorious susceptibility of the D2R to drug-induced desensitization. The dopamine motivating animals to perform a current behavior also desensitizes local D2 dopamine receptors. Dopamine signaling is less effective in subsequent rounds, resulting in repetition-induced devaluation of behavior.
{"title":"Behavioral devaluation by local resistance to dopamine","authors":"Lauren E. Miner, Aditya K. Gautham, Michael A. Crickmore","doi":"10.1038/s41593-025-02079-x","DOIUrl":"10.1038/s41593-025-02079-x","url":null,"abstract":"Repeated experiences can cause behavior-specific fatigue. We use Drosophila to study this common form of motivational change, finding that prior matings make males more likely to abandon future copulations when challenged. Here we show that, during mating, dopamine signals through the D2-like receptor (D2R) to promote resilience to challenges that might otherwise cause the male to switch behaviors. This motivating dopamine signal suppresses the output of the copulation decision neurons (CDNs), which can truncate matings when pushed past threshold. Repetition-induced devaluation of mating results from β-arrestin-dependent desensitization of the D2R on the CDNs, rendering them temporarily resistant to naturally released or experimentally supplied dopamine. When local desensitization to dopamine is prevented, the male shows no signs of fatigue, treating each mating as if it were his first. These findings explain a widespread motivational phenomenon and reveal a natural function for the notorious susceptibility of the D2R to drug-induced desensitization. The dopamine motivating animals to perform a current behavior also desensitizes local D2 dopamine receptors. Dopamine signaling is less effective in subsequent rounds, resulting in repetition-induced devaluation of behavior.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 12","pages":"2493-2501"},"PeriodicalIF":20.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554411","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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