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
Alzheimer’s disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer’s disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience. Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4–10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence. CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies. Engineering human microglia with a Down-syndrome-linked myeloid gene variant resists tau-induced dysfunction and protects neurons in chimeric brains, offering proof of concept for transformative microglial replacement therapies in Alzheimer’s disease.
{"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":"10.1038/s41593-025-02117-8","url":null,"abstract":"Alzheimer’s disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer’s disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience. Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4–10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence. CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies. Engineering human microglia with a Down-syndrome-linked myeloid gene variant resists tau-induced dysfunction and protects neurons in chimeric brains, offering proof of concept for transformative microglial replacement therapies in Alzheimer’s disease.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"25-39"},"PeriodicalIF":20.0,"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/s41593-025-02125-8
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. Lecanemab, a leading therapy for Alzheimer’s disease, induces an Fc-mediated transcriptional program in human microglia, linked to osteopontin and enhanced plaque phagocytosis, suggesting alternative strategies to promote plaque clearance.
{"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":"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 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. Lecanemab, a leading therapy for Alzheimer’s disease, induces an Fc-mediated transcriptional program in human microglia, linked to osteopontin and enhanced plaque phagocytosis, suggesting alternative strategies to promote plaque clearance.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"100-110"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02125-8.pdf","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":"OA","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. In this study, the authors generated iPSC lines from more than 100 sporadic ALS cases, which recapitulated key disease phenotypes and enabled large-scale drug screening, identifying a promising combination therapy of baricitinib, memantine and riluzole.
{"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":"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. In this study, the authors generated iPSC lines from more than 100 sporadic ALS cases, which recapitulated key disease phenotypes and enabled large-scale drug screening, identifying a promising combination therapy of baricitinib, memantine and riluzole.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"40-52"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02118-7.pdf","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":"OA","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. The authors developed a mouse brain atlas using local dendritic morphological patterns from 101,136 neurons. This representation not only improves anatomical precision but also uncovers associations between local dendritic architecture and long-range neuronal projections.
{"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":"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. The authors developed a mouse brain atlas using local dendritic morphological patterns from 101,136 neurons. This representation not only improves anatomical precision but also uncovers associations between local dendritic architecture and long-range neuronal projections.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"111-122"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02119-6.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41593-025-02140-9
Qing Pei, Qixin Chen, Zhiqi Tian, Le Zhu, Yang Chen, Jihong Gong, Shen Wang, Yijuan Xiang, John S. Khamo, Jiaqi Fan, Yi Rong, Yi Yu, Yuyang Qin, Shiping Wu, Youssef Faragalla, Peng Cao, Kai Zhang, Ying Lai, Ling-Gang Wu, Cong Ma, Xiaofei Yang, Jiajie Diao
The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin mediates neuronal exocytosis and self-assembles into large clusters in the plasma membrane. The formation and function of these clusters, and whether they promote or inhibit synaptic-vesicle fusion, remain unclear. Here using optogenetic control of syntaxin clustering in vitro and in vivo, as a light-inducible gain-of-function assay, we show that light-enhanced clustering reduces both spontaneous and triggered vesicle fusion, and this impairs mouse hunting behavior. Cluster formation is induced by liquid–liquid phase separation (LLPS) of the SNARE domain of syntaxin. For the regulatory mechanism, Munc18, which is known to alter syntaxin conformation, acts to reduce LLPS for cluster formation, thereby promoting active syntaxin. These results suggest that exocytosis regulation involves LLPS-induced syntaxin clusters that serve as a syntaxin reservoir from which Munc18 captures syntaxin monomers to form a syntaxin–Munc18 complex, setting the stage for efficient fusion. Syntaxin-1A, a SNARE protein mediating membrane fusion for neurotransmission, forms clusters with unclear functions. Using light-controlled clustering, the authors found that phase-separation-driven clusters, regulated by Munc18, suppress fusion, revealing a new phase-separation-based mechanism.
{"title":"Munc18 modulates syntaxin phase separation to promote exocytosis","authors":"Qing Pei, Qixin Chen, Zhiqi Tian, Le Zhu, Yang Chen, Jihong Gong, Shen Wang, Yijuan Xiang, John S. Khamo, Jiaqi Fan, Yi Rong, Yi Yu, Yuyang Qin, Shiping Wu, Youssef Faragalla, Peng Cao, Kai Zhang, Ying Lai, Ling-Gang Wu, Cong Ma, Xiaofei Yang, Jiajie Diao","doi":"10.1038/s41593-025-02140-9","DOIUrl":"10.1038/s41593-025-02140-9","url":null,"abstract":"The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin mediates neuronal exocytosis and self-assembles into large clusters in the plasma membrane. The formation and function of these clusters, and whether they promote or inhibit synaptic-vesicle fusion, remain unclear. Here using optogenetic control of syntaxin clustering in vitro and in vivo, as a light-inducible gain-of-function assay, we show that light-enhanced clustering reduces both spontaneous and triggered vesicle fusion, and this impairs mouse hunting behavior. Cluster formation is induced by liquid–liquid phase separation (LLPS) of the SNARE domain of syntaxin. For the regulatory mechanism, Munc18, which is known to alter syntaxin conformation, acts to reduce LLPS for cluster formation, thereby promoting active syntaxin. These results suggest that exocytosis regulation involves LLPS-induced syntaxin clusters that serve as a syntaxin reservoir from which Munc18 captures syntaxin monomers to form a syntaxin–Munc18 complex, setting the stage for efficient fusion. Syntaxin-1A, a SNARE protein mediating membrane fusion for neurotransmission, forms clusters with unclear functions. Using light-controlled clustering, the authors found that phase-separation-driven clusters, regulated by Munc18, suppress fusion, revealing a new phase-separation-based mechanism.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"306-314"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582925","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 : 2025-11-21DOI: 10.1038/s41593-025-02115-w
Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R. Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky, Benjamin Deneen
Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer’s disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes through the regulation of the phagocytic receptor MEGF10, which is sufficient to preserve cognitive function in AD models. Collectively, these studies highlight a role for astrocytic Sox9 during aging and AD while identifying Sox9−MEGF10 signaling as a prospective astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease. Astrocytes are associated with Alzheimer’s disease pathogenesis. We found that the transcription factor Sox9 functions to enhance astrocytic phagocytosis of Aβ plaques via MEGF10, and this clearance of plaques is associated with the preservation of cognitive function in mouse models.
{"title":"Astrocytic Sox9 overexpression in Alzheimer’s disease mouse models promotes Aβ plaque phagocytosis and preserves cognitive function","authors":"Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R. Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky, Benjamin Deneen","doi":"10.1038/s41593-025-02115-w","DOIUrl":"10.1038/s41593-025-02115-w","url":null,"abstract":"Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer’s disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes through the regulation of the phagocytic receptor MEGF10, which is sufficient to preserve cognitive function in AD models. Collectively, these studies highlight a role for astrocytic Sox9 during aging and AD while identifying Sox9−MEGF10 signaling as a prospective astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease. Astrocytes are associated with Alzheimer’s disease pathogenesis. We found that the transcription factor Sox9 functions to enhance astrocytic phagocytosis of Aβ plaques via MEGF10, and this clearance of plaques is associated with the preservation of cognitive function in mouse models.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"88-99"},"PeriodicalIF":20.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559942","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}
Pub Date : 2025-11-20DOI: 10.1038/s41593-025-02138-3
Early tactile deficits in patients with Alzheimer disease (AD) and AD mouse models map to tau pathology in spinal cholecystokinin (CCK) neurons. In AD mice, reducing tau or c-Maf levels in spinal CCK neurons restores touch and benefits cognition, suggesting that these deficits are a noninvasive peripheral indication of early AD and offer a tractable target for intervention.
{"title":"Tau pathology in mouse spinal neurons underlies early touch loss and heralds cognitive decline","authors":"","doi":"10.1038/s41593-025-02138-3","DOIUrl":"10.1038/s41593-025-02138-3","url":null,"abstract":"Early tactile deficits in patients with Alzheimer disease (AD) and AD mouse models map to tau pathology in spinal cholecystokinin (CCK) neurons. In AD mice, reducing tau or c-Maf levels in spinal CCK neurons restores touch and benefits cognition, suggesting that these deficits are a noninvasive peripheral indication of early AD and offer a tractable target for intervention.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"252-253"},"PeriodicalIF":20.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559021","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 : 2025-11-19DOI: 10.1038/s41593-025-02172-1
Erica Korb, Carol L. Wilkinson, Ryan N. Delgado, Kathryn L. Lovero, Steven Finkbeiner
{"title":"Author Correction: Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity","authors":"Erica Korb, Carol L. Wilkinson, Ryan N. Delgado, Kathryn L. Lovero, Steven Finkbeiner","doi":"10.1038/s41593-025-02172-1","DOIUrl":"10.1038/s41593-025-02172-1","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 12","pages":"2646-2646"},"PeriodicalIF":20.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02172-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545463","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 : 2025-11-18DOI: 10.1038/s41593-025-02116-9
Miguel Vivar-Lazo, Christopher R. Fetsch
Decision confidence plays a key role in flexible behavior and (meta)cognition, but its underlying neural mechanisms remain elusive. To uncover the latent dynamics of confidence formation at the level of single neurons and population activity, we trained nonhuman primates to report a perceptual choice and the associated level of confidence with a single eye movement on every trial. Monkey behavior was well fit by a bounded accumulator model, where choice and confidence are processed concurrently, but not by a serial model, where choice is resolved first, followed by postdecision accumulation for confidence. Neurons in the lateral intraparietal area (LIP) reflected concurrent accumulation, showing covariation of choice and confidence signals across the population, and within-trial dynamics consistent with parallel updating at near-zero time lag. The results demonstrate that the primate brain can process a single stream of evidence in service of two computational goals simultaneously and suggest area LIP as a candidate neural substrate for this ability. Confidence is key to decision-making, but the dynamics of confidence formation remain elusive. We show that neural populations in parietal cortex reflect the parallel processes of forming a decision and confidence in the decision.
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