Pub Date : 2025-12-24DOI: 10.1038/s41593-025-02186-9
Charles D Nichols
{"title":"Psychedelic research must be grounded in pharmacology.","authors":"Charles D Nichols","doi":"10.1038/s41593-025-02186-9","DOIUrl":"https://doi.org/10.1038/s41593-025-02186-9","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145823991","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 : 2025-12-23DOI: 10.1038/s41593-025-02166-z
Benjamin Yost Hayden, Sarah R. Heilbronner, Seng Bum Michael Yoo
Parcellation of the cerebral cortex into functionally modular brain areas is foundational to cognitive and systems neuroscience. Here, we question the central status of brain areas from the perspectives of neuroanatomy and electrophysiology. We argue that the major ostensible determinants of brain function, such as cytoarchitecture and connectivity, seldom produce convergent parcellations. Brain areas themselves are just one of several equally important organizing principles; others include macroscale gradients, distributed networks, layers, columns and patches. We further argue that the evidence for a close correspondence between areal parcellation and cognitive function is weaker than is generally supposed. Indeed, many important cognitive functions appear to be implemented in a broadly distributed manner, whereas others appear to obey organizations that have little relationship to brain areas, including distributed networks and functional gradients. We conclude by suggesting a set of guiding principles for performing systems and cognitive neuroscience without the intellectual foundation provided by arealization. Parcellation of the cortex into functionally modular brain areas is foundational to neuroscience. Here, Hayden, Heilbronner and Yoo question the central status of brain areas in neuroscience from the perspectives of neuroanatomy and electrophysiology and propose an alternative approach.
{"title":"Rethinking the centrality of brain areas in understanding functional organization","authors":"Benjamin Yost Hayden, Sarah R. Heilbronner, Seng Bum Michael Yoo","doi":"10.1038/s41593-025-02166-z","DOIUrl":"10.1038/s41593-025-02166-z","url":null,"abstract":"Parcellation of the cerebral cortex into functionally modular brain areas is foundational to cognitive and systems neuroscience. Here, we question the central status of brain areas from the perspectives of neuroanatomy and electrophysiology. We argue that the major ostensible determinants of brain function, such as cytoarchitecture and connectivity, seldom produce convergent parcellations. Brain areas themselves are just one of several equally important organizing principles; others include macroscale gradients, distributed networks, layers, columns and patches. We further argue that the evidence for a close correspondence between areal parcellation and cognitive function is weaker than is generally supposed. Indeed, many important cognitive functions appear to be implemented in a broadly distributed manner, whereas others appear to obey organizations that have little relationship to brain areas, including distributed networks and functional gradients. We conclude by suggesting a set of guiding principles for performing systems and cognitive neuroscience without the intellectual foundation provided by arealization. Parcellation of the cortex into functionally modular brain areas is foundational to neuroscience. Here, Hayden, Heilbronner and Yoo question the central status of brain areas in neuroscience from the perspectives of neuroanatomy and electrophysiology and propose an alternative approach.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"267-278"},"PeriodicalIF":20.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813555","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 : 2025-12-23DOI: 10.1038/s41593-025-02152-5
Chloé Maëlle Benoit, Dan Alin Ganea, Ricardo Paricio-Montesinos, Julia Esser, Christian Thome, Jan Maximilian Janssen, Andrea Sattin, Sabrina Milena Innocenti, Sabine Krabbe, Andreas Lüthi, Tommaso Fellin, Maren Engelhardt, Jan Gründemann
The axon initial segment (AIS) is the site of action potential generation and exhibits structural and functional plasticity upon adaptation of neuronal excitability and disease. Performing in vivo longitudinal two-photon imaging of AIS in the medial prefrontal cortex of male mice, we reveal dynamic AIS remodeling during associative fear learning and extinction. These results demonstrate that AIS plasticity is not only crucial for homeostatic adaptation but also a hallmark of memory formation.
{"title":"Axon initial segment dynamics during associative fear learning","authors":"Chloé Maëlle Benoit, Dan Alin Ganea, Ricardo Paricio-Montesinos, Julia Esser, Christian Thome, Jan Maximilian Janssen, Andrea Sattin, Sabrina Milena Innocenti, Sabine Krabbe, Andreas Lüthi, Tommaso Fellin, Maren Engelhardt, Jan Gründemann","doi":"10.1038/s41593-025-02152-5","DOIUrl":"https://doi.org/10.1038/s41593-025-02152-5","url":null,"abstract":"The axon initial segment (AIS) is the site of action potential generation and exhibits structural and functional plasticity upon adaptation of neuronal excitability and disease. Performing in vivo longitudinal two-photon imaging of AIS in the medial prefrontal cortex of male mice, we reveal dynamic AIS remodeling during associative fear learning and extinction. These results demonstrate that AIS plasticity is not only crucial for homeostatic adaptation but also a hallmark of memory formation.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"13 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808167","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 : 2025-12-22DOI: 10.1038/s41593-025-02153-4
Haruna Nakajo, Ran Cao, Supriya A. Mula, Justin McKetney, Nicholas J. Silva, Kathy H. Li, Robert J. Chalkley, Lisa K. Randolph, Muskaan Shah, Indigo V. L. Rose, Martin Kampmann, Danielle L. Swaney, Christoph Kirst, Anna V. Molofsky
The extracellular matrix (ECM) regulates synaptic plasticity via mechanisms that are still being defined and have been studied predominantly in adulthood. Here, using live imaging of excitatory synapses in zebrafish hindbrain, we observed a bimodal distribution of short-lived (dynamic) and longer-lived (stable) synapses. Disruption of ECM via digestion or brevican deletion destabilized dynamic synapses and led to decreased synapse density. Conversely, loss of matrix metalloproteinase 14 (MMP14) led to accumulation of brevican and increased the lifetime of the dynamic synapse pool without affecting the stable synapse pool, resulting in increased overall synapse density. Microglial MMP14 was essential to these effects in both fish and human induced pluripotent stem cell-derived cultures. Both MMP14 and brevican were required for experience-dependent synapse plasticity in a motor learning assay. These data, complemented by mathematical modeling, define an essential role of ECM remodeling in maintaining a dynamic subset of synapses during brain development.
{"title":"Extracellular matrix proteolysis maintains synapse plasticity during brain development","authors":"Haruna Nakajo, Ran Cao, Supriya A. Mula, Justin McKetney, Nicholas J. Silva, Kathy H. Li, Robert J. Chalkley, Lisa K. Randolph, Muskaan Shah, Indigo V. L. Rose, Martin Kampmann, Danielle L. Swaney, Christoph Kirst, Anna V. Molofsky","doi":"10.1038/s41593-025-02153-4","DOIUrl":"https://doi.org/10.1038/s41593-025-02153-4","url":null,"abstract":"The extracellular matrix (ECM) regulates synaptic plasticity via mechanisms that are still being defined and have been studied predominantly in adulthood. Here, using live imaging of excitatory synapses in zebrafish hindbrain, we observed a bimodal distribution of short-lived (dynamic) and longer-lived (stable) synapses. Disruption of ECM via digestion or brevican deletion destabilized dynamic synapses and led to decreased synapse density. Conversely, loss of matrix metalloproteinase 14 (MMP14) led to accumulation of brevican and increased the lifetime of the dynamic synapse pool without affecting the stable synapse pool, resulting in increased overall synapse density. Microglial MMP14 was essential to these effects in both fish and human induced pluripotent stem cell-derived cultures. Both MMP14 and brevican were required for experience-dependent synapse plasticity in a motor learning assay. These data, complemented by mathematical modeling, define an essential role of ECM remodeling in maintaining a dynamic subset of synapses during brain development.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"31 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801612","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 : 2025-12-22DOI: 10.1038/s41593-025-02155-2
Zachary Gershon, Alessandra Bonito-Oliva, Matt Kanke, Andrea Terceros, Genelle Rankin, John Fak, Yujin Harada, Andrew F. Iannone, Millennium Gebremedhin, Brian Fabella, Natalia V. De Marco García, Praveen Sethupathy, Priya Rajasethupathy
The genetic factors and resulting neural circuit physiology driving variation in attention are poorly understood. Here we took an unbiased forward genetics approach to identify genes of large effect on attention. We studied 200 genetically diverse mice and, through genetic mapping, identified a small locus on chromosome 13 (95% CI 92.22–94.09 Mb) that is significantly associated with variation in pre-attentive processing. Within the locus we identified a gene, Homer1, encoding a synaptic protein, whose downregulation during development led to improvements in multiple measures of attention in adulthood. Mechanistically, reduced Homer1 levels resulted in an upscaling of GABA receptors and enhanced inhibitory tone in the prefrontal cortex, leading to improved neural signal to noise and attentional performance. We thus identify a single genetic locus of large effect on attention and propose Homer1-dependent inhibitory tone, sculpted during a developmental sensitive period, as a key regulator and potential therapeutic target for attentional performance.
遗传因素和由此产生的神经回路生理驱动的注意力变化是知之甚少。在这里，我们采用无偏的正向遗传学方法来确定对注意力有很大影响的基因。我们研究了200只基因多样化的小鼠，并通过遗传定位，确定了13号染色体上的一个小位点（95% CI 92.22-94.09 Mb），该位点与前注意加工的变异显著相关。在这个基因座中，我们发现了一个编码突触蛋白的基因Homer1，该基因在发育过程中的下调导致了成年后注意力的多项指标的改善。从机制上讲，Homer1水平的降低导致GABA受体的增加和前额叶皮层抑制性张力的增强，从而导致对噪音和注意力表现的神经信号的改善。因此，我们确定了一个对注意力有重大影响的单一基因位点，并提出在发育敏感期形成的依赖于homer1的抑制性音调，作为注意力表现的关键调节因子和潜在治疗靶点。
{"title":"Genetic mapping identifies Homer1 as a developmental modifier of attention","authors":"Zachary Gershon, Alessandra Bonito-Oliva, Matt Kanke, Andrea Terceros, Genelle Rankin, John Fak, Yujin Harada, Andrew F. Iannone, Millennium Gebremedhin, Brian Fabella, Natalia V. De Marco García, Praveen Sethupathy, Priya Rajasethupathy","doi":"10.1038/s41593-025-02155-2","DOIUrl":"https://doi.org/10.1038/s41593-025-02155-2","url":null,"abstract":"The genetic factors and resulting neural circuit physiology driving variation in attention are poorly understood. Here we took an unbiased forward genetics approach to identify genes of large effect on attention. We studied 200 genetically diverse mice and, through genetic mapping, identified a small locus on chromosome 13 (95% CI 92.22–94.09 Mb) that is significantly associated with variation in pre-attentive processing. Within the locus we identified a gene, Homer1, encoding a synaptic protein, whose downregulation during development led to improvements in multiple measures of attention in adulthood. Mechanistically, reduced Homer1 levels resulted in an upscaling of GABA receptors and enhanced inhibitory tone in the prefrontal cortex, leading to improved neural signal to noise and attentional performance. We thus identify a single genetic locus of large effect on attention and propose Homer1-dependent inhibitory tone, sculpted during a developmental sensitive period, as a key regulator and potential therapeutic target for attentional performance.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"123 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801592","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 : 2025-12-22DOI: 10.1038/s41593-025-02101-2
Diana Piol, Bilal Khalil, Tessa Robberechts, Theo Killian, Maria Georgopoulou, Gabriele Partel, David Wouters, Nikolai Hecker, Paraskevi Tziortzouda, Yana Verresen, Nikky Corthout, Sam Kint, Katy Vandereyken, Philip Van Damme, Thierry Voet, Kristofer Davie, Suresh Poovathingal, Ludo Van Den Bosch, Stein Aerts, Alejandro Sifrim, Sandrine Da Cruz
Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development. Piol et al. uncover that impaired eukaryotic initiation factor 5a (Eif5a) hypusination disrupts axonal translation and neuronal activity in fused in sarcoma-amyotrophic lateral sclerosis (FUS-ALS) by applying spatial transcriptomics in motor axons. In vitro and in vivo targeting Eif5a hypusination via spermidine supplementation improves ALS model phenotypes.
{"title":"Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS","authors":"Diana Piol, Bilal Khalil, Tessa Robberechts, Theo Killian, Maria Georgopoulou, Gabriele Partel, David Wouters, Nikolai Hecker, Paraskevi Tziortzouda, Yana Verresen, Nikky Corthout, Sam Kint, Katy Vandereyken, Philip Van Damme, Thierry Voet, Kristofer Davie, Suresh Poovathingal, Ludo Van Den Bosch, Stein Aerts, Alejandro Sifrim, Sandrine Da Cruz","doi":"10.1038/s41593-025-02101-2","DOIUrl":"10.1038/s41593-025-02101-2","url":null,"abstract":"Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development. Piol et al. uncover that impaired eukaryotic initiation factor 5a (Eif5a) hypusination disrupts axonal translation and neuronal activity in fused in sarcoma-amyotrophic lateral sclerosis (FUS-ALS) by applying spatial transcriptomics in motor axons. In vitro and in vivo targeting Eif5a hypusination via spermidine supplementation improves ALS model phenotypes.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"53-66"},"PeriodicalIF":20.0,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02101-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801613","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 : 2025-12-19DOI: 10.1038/s41593-025-02145-4
We explored how external conditions shape cognitive function. Classical olfactory learning assays revealed that Caenorhabditis elegans kept on ice or treated with lithium exhibited delayed forgetting of olfactory memories. We showed that the worm’s cold-tolerance internal state ‘switch’ and diacylglycerol (DAG) pathway activity in AWC neurons regulate memory retention.
{"title":"Freezing forgetting in C. elegans to extend memory retention","authors":"","doi":"10.1038/s41593-025-02145-4","DOIUrl":"10.1038/s41593-025-02145-4","url":null,"abstract":"We explored how external conditions shape cognitive function. Classical olfactory learning assays revealed that Caenorhabditis elegans kept on ice or treated with lithium exhibited delayed forgetting of olfactory memories. We showed that the worm’s cold-tolerance internal state ‘switch’ and diacylglycerol (DAG) pathway activity in AWC neurons regulate memory retention.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"254-255"},"PeriodicalIF":20.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786283","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}
Temperature compensation stabilizes the speed of circadian clocks. Uncompensated molecular clock cycles would accelerate severalfold with each 10 °C increase, precluding reliable timekeeping. Despite such thermal buffering, some clock-controlled behavioral cycles complete by up to two hours earlier or later depending on environmental temperatures. We show that temperature-dependent changes in the speed of behavioral cycles can be explained by changes in the speed of the clock itself. Although the speed of all clocks is insensitive to thermal energy, we found that in neurons the clock speed is regulated by temperature information. When the threshold of ~26 °C is exceeded for ~24 h, a pathway mediated by the LIM-homeodomain transcription factor Lim1 instructs the clocks in the Drosophila brain to accelerate. Clock acceleration enables earlier morning awakening. This work suggests that modestly altering the clock speed enables behavioral thermoadaptation, via regulated steps that do not compromise the reliability of circadian timekeeping. This study shows that animals can adapt behaviorally to warm environments by speeding up their internal clocks. Suprathreshold temperatures activate the Lim1 pathway in the fly brain, resulting in accelerated circadian clock activity and increased early morning activity.
{"title":"Behavioral adaptation to warm conditions via Lim1-mediated acceleration of neuronal clocks","authors":"Zhihua Liu, Dapeng Xie, Stephen X. Zhang, Wenji Cai, Hao Zhou, Dragana Rogulja","doi":"10.1038/s41593-025-02139-2","DOIUrl":"10.1038/s41593-025-02139-2","url":null,"abstract":"Temperature compensation stabilizes the speed of circadian clocks. Uncompensated molecular clock cycles would accelerate severalfold with each 10 °C increase, precluding reliable timekeeping. Despite such thermal buffering, some clock-controlled behavioral cycles complete by up to two hours earlier or later depending on environmental temperatures. We show that temperature-dependent changes in the speed of behavioral cycles can be explained by changes in the speed of the clock itself. Although the speed of all clocks is insensitive to thermal energy, we found that in neurons the clock speed is regulated by temperature information. When the threshold of ~26 °C is exceeded for ~24 h, a pathway mediated by the LIM-homeodomain transcription factor Lim1 instructs the clocks in the Drosophila brain to accelerate. Clock acceleration enables earlier morning awakening. This work suggests that modestly altering the clock speed enables behavioral thermoadaptation, via regulated steps that do not compromise the reliability of circadian timekeeping. This study shows that animals can adapt behaviorally to warm environments by speeding up their internal clocks. Suprathreshold temperatures activate the Lim1 pathway in the fly brain, resulting in accelerated circadian clock activity and increased early morning activity.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"374-386"},"PeriodicalIF":20.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786288","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 : 2025-12-18DOI: 10.1038/s41593-025-02154-3
Nicole F. O. Green, Gavin J. Sutton, Javier Pérez-Burillo, Juli Wang, Samuel Bagot, Hannah G. Danon, Kieran Walsh, Akira Gokool, Samantha A. Miles, Guang Yang, Charles A. Herring, Yuheng Liang, Grant Pfundstein, Vladimir Sytnyk, Hamid Alinejad-Rokny, Ryan Lister, Joseph Rosenbluh, Johann A. Gagnon-Bartsch, Irina Voineagu
Genetic variants associated with complex traits often lie in distal enhancers. While candidate enhancers have been mapped genome wide, their functional state and gene targets in specific cell types remain unclear. Here we present AstroREG, a resource of enhancer–gene interactions in human primary astrocytes, generated by combining CRISPR inhibition (CRISPRi), single-cell RNA-seq and machine learning. By functionally testing nearly 1,000 PsychENCODE enhancers, we identified more than 150 regulatory interactions, revealing enhancers that control key astrocyte functions and genes implicated in Alzheimer’s disease. The CRISPRi screen also provided valuable ground-truth data from a primary cell type for training and benchmarking prediction models of enhancer activity. We thus developed EGrf, a random forest (RF) model trained on these data, and applied it genome wide to predict regulatory interactions with high specificity. Together, our data provide a comprehensive functional map of enhancer-mediated regulation in a key glial cell type, shedding light on brain function and disease.
{"title":"CRISPRi screening in cultured human astrocytes uncovers distal enhancers controlling genes dysregulated in Alzheimer’s disease","authors":"Nicole F. O. Green, Gavin J. Sutton, Javier Pérez-Burillo, Juli Wang, Samuel Bagot, Hannah G. Danon, Kieran Walsh, Akira Gokool, Samantha A. Miles, Guang Yang, Charles A. Herring, Yuheng Liang, Grant Pfundstein, Vladimir Sytnyk, Hamid Alinejad-Rokny, Ryan Lister, Joseph Rosenbluh, Johann A. Gagnon-Bartsch, Irina Voineagu","doi":"10.1038/s41593-025-02154-3","DOIUrl":"https://doi.org/10.1038/s41593-025-02154-3","url":null,"abstract":"Genetic variants associated with complex traits often lie in distal enhancers. While candidate enhancers have been mapped genome wide, their functional state and gene targets in specific cell types remain unclear. Here we present AstroREG, a resource of enhancer–gene interactions in human primary astrocytes, generated by combining CRISPR inhibition (CRISPRi), single-cell RNA-seq and machine learning. By functionally testing nearly 1,000 PsychENCODE enhancers, we identified more than 150 regulatory interactions, revealing enhancers that control key astrocyte functions and genes implicated in Alzheimer’s disease. The CRISPRi screen also provided valuable ground-truth data from a primary cell type for training and benchmarking prediction models of enhancer activity. We thus developed EGrf, a random forest (RF) model trained on these data, and applied it genome wide to predict regulatory interactions with high specificity. Together, our data provide a comprehensive functional map of enhancer-mediated regulation in a key glial cell type, shedding light on brain function and disease.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"23 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770707","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}
The persistence of memory reflects not only how it is formed but also how forgetting is delayed. The mechanisms controlling forgetting remain obscure, and in particular it is unclear to what degree this process is actively regulated. We discovered that cold exposure delays forgetting of specific olfactory memories by more than eight-fold and that adaptation to cold abolishes this effect. To study the underlying mechanism, we performed RNA sequencing, mutant analyses and pharmacological assays. Here we show that regulation of membrane properties underlies the presence and absence of cold-induced delayed forgetting. Furthermore, lithium can also delay forgetting in cold-sensitive worms but not in cold-tolerant worms; this effect involves downregulation of the diacylglycerol pathway in AWC neurons and long-term suppression of activity in the downstream AIY interneurons. Thus, the genetic tractability of worms might be harnessed to study the mechanism of action of lithium and cold exposure and, more fundamentally, how memory is stored and lost. In this study, we identify an actively regulated process that governs the rate of forgetting in Caenorhabditis elegans, modulated by both temperature and the mood-stabilizing drug lithium.
{"title":"Cold and lithium delay forgetting of olfactory memories in Caenorhabditis elegans","authors":"Dana Landschaft-Berliner, Kesem Goldstein, Guy Teichman, Sarit Anava, Hila Gingold, Yehuda Salzberg, Itai Rieger, Noam Levy, Vladyslava Pechuk, Hagar Setty, Priti Agarwal, Dror Sagi, Dror Cohen, Evelina Nikelshparg, Anat Ben-Zvi, Antonio Miranda-Vizuete, Ronen Zaidel-Bar, Meital Oren-Suissa, Oded Rechavi","doi":"10.1038/s41593-025-02143-6","DOIUrl":"10.1038/s41593-025-02143-6","url":null,"abstract":"The persistence of memory reflects not only how it is formed but also how forgetting is delayed. The mechanisms controlling forgetting remain obscure, and in particular it is unclear to what degree this process is actively regulated. We discovered that cold exposure delays forgetting of specific olfactory memories by more than eight-fold and that adaptation to cold abolishes this effect. To study the underlying mechanism, we performed RNA sequencing, mutant analyses and pharmacological assays. Here we show that regulation of membrane properties underlies the presence and absence of cold-induced delayed forgetting. Furthermore, lithium can also delay forgetting in cold-sensitive worms but not in cold-tolerant worms; this effect involves downregulation of the diacylglycerol pathway in AWC neurons and long-term suppression of activity in the downstream AIY interneurons. Thus, the genetic tractability of worms might be harnessed to study the mechanism of action of lithium and cold exposure and, more fundamentally, how memory is stored and lost. In this study, we identify an actively regulated process that governs the rate of forgetting in Caenorhabditis elegans, modulated by both temperature and the mood-stabilizing drug lithium.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"387-398"},"PeriodicalIF":20.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02143-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770708","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：