Yi Liu, Troy W. Whitfield, George W. Bell, Ruisi Guo, Anthony Flamier, Richard A. Young, Rudolf Jaenisch
{"title":"Exploring the complexity of MECP2 function in Rett syndrome","authors":"Yi Liu, Troy W. Whitfield, George W. Bell, Ruisi Guo, Anthony Flamier, Richard A. Young, Rudolf Jaenisch","doi":"10.1038/s41583-025-00926-1","DOIUrl":"https://doi.org/10.1038/s41583-025-00926-1","url":null,"abstract":"<p>Rett syndrome (RTT) is a neurodevelopmental disorder that is mainly caused by mutations in the methyl-DNA-binding protein MECP2. MECP2 is an important epigenetic regulator that plays a pivotal role in neuronal gene regulation, where it has been reported to function as both a repressor and an activator. Despite extensive efforts in mechanistic studies over the past two decades, a clear consensus on how MECP2 dysfunction impacts molecular mechanisms and contributes to disease progression has not been reached. Here, we review recent insights from epigenomic, transcriptomic and proteomic studies that advance our understanding of MECP2 as an interacting hub for DNA, RNA and transcription factors, orchestrating diverse processes that are crucial for neuronal function. By discussing findings from different model systems, we identify crucial epigenetic details and cofactor interactions, enriching our understanding of the multifaceted roles of MECP2 in transcriptional regulation and chromatin structure. These mechanistic insights offer potential avenues for rational therapeutic design for RTT.</p>","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"54 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939978","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":"From avoidance to new action: the multifaceted role of the striatal indirect pathway","authors":"Jaeeon Lee, Bernardo L. Sabatini","doi":"10.1038/s41583-025-00925-2","DOIUrl":"https://doi.org/10.1038/s41583-025-00925-2","url":null,"abstract":"<p>A hallmark of optimal reinforcement learning is that an agent learns to avoid actions that lead to negative outcomes while still exploring alternative actions that could lead to better outcomes. Although the basal ganglia have been hypothesized to contribute to this computation, the mechanisms by which they do so are still unclear. Here, we focus on the function of the striatal indirect pathway and propose that it is regulated by a synaptic plasticity rule that allows an animal to avoid actions that lead to suboptimal outcomes. We consider current theories of striatal indirect pathway function in light of recent experimental findings and discuss studies that suggest that indirect pathway activity is potentiated by the suppression of dopamine release in the striatum. Furthermore, we highlight recent studies showing that activation of the indirect pathway can trigger an action, allowing animals to explore new actions while suppressing suboptimal actions. We show how our framework can reconcile previously conflicting results regarding the indirect pathway and suggest experiments for future investigation.</p>","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"37 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920271","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":"Getting anxious about immune system activation","authors":"Sian Lewis","doi":"10.1038/s41583-025-00928-z","DOIUrl":"https://doi.org/10.1038/s41583-025-00928-z","url":null,"abstract":"A possible mechanism for the increased incidence of mood disorders in people with immune system disorders such as psoriasis is revealed where, in mice, elevated serum levels of the cytokines IL-17A and IL-17C induce anxiety-like symptoms via activation of neurons in the anterior basolateral amygdala.","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"26 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915674","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":"Functional diversity of amacrine cells","authors":"Darran Yates","doi":"10.1038/s41583-025-00931-4","DOIUrl":"https://doi.org/10.1038/s41583-025-00931-4","url":null,"abstract":"A new study reveals over 40 functionally different types of amacrine cell in the mouse retina.","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"12 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910506","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":"Dynorphin acts via a disinhibitory circuit mechanism","authors":"Jake Rogers","doi":"10.1038/s41583-025-00927-0","DOIUrl":"https://doi.org/10.1038/s41583-025-00927-0","url":null,"abstract":"Dynorphin regulates motivated behaviour in mice via κ-opioid receptor signalling in a nucleus accumbens–ventral pallidum (VP) disinhibitory circuit that increases activity of VP cholinergic neurons projecting to the basolateral amygdala.","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"7 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901417","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":"Interictal network dysfunction and cognitive impairment in epilepsy","authors":"Jennifer N. Gelinas, Dion Khodagholy","doi":"10.1038/s41583-025-00924-3","DOIUrl":"https://doi.org/10.1038/s41583-025-00924-3","url":null,"abstract":"<p>Epilepsy is diagnosed when neural networks become capable of generating excessive or hypersynchronous activity patterns that result in observable seizures. In many cases, epilepsy is associated with cognitive comorbidities that persist between seizures and negatively impact quality of life. Dysregulation of the coordinated physiological network interactions that are required for cognitive function has been implicated in mediating these enduring symptoms, but the causal mechanisms are often elusive. Here, we provide an overview of neural network abnormalities with the potential to contribute to cognitive dysfunction in epilepsy. We examine these pathological interactions across spatial and temporal scales, additionally highlighting the dynamics that arise in response to the brain’s intrinsic capacity for plasticity. Understanding these processes will facilitate development of network-level interventions to address cognitive comorbidities that remain undertreated by currently available epilepsy therapeutics.</p>","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"43 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884832","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}
Floris L. Wuyts, Choi Deblieck, Charlot Vandevoorde, Marco Durante
{"title":"Brains in space: impact of microgravity and cosmic radiation on the CNS during space exploration","authors":"Floris L. Wuyts, Choi Deblieck, Charlot Vandevoorde, Marco Durante","doi":"10.1038/s41583-025-00923-4","DOIUrl":"https://doi.org/10.1038/s41583-025-00923-4","url":null,"abstract":"<p>Solar system exploration is a grand endeavour of humankind. Space agencies have been planning crewed missions to the Moon and Mars for several decades. However, several environmental stress factors in space, such as microgravity and cosmic radiation, confer health risks for human explorers. This Review examines the effects of microgravity and exposure to cosmic radiation on the CNS. Microgravity presents challenges for the brain, necessitating the development of adaptive movement and orientation strategies to cope with alterations in sensory information. Exposure to microgravity also affects cognitive function to a certain extent. Recent MRI results show that microgravity affects brain structure and function. Post-flight recovery from these changes is gradual, with some lasting up to a year. Regarding cosmic radiation, animal experiments suggest that the brain could be much more sensitive to this stressor than may be expected from experiences on Earth. This may be due to the presence of energetic heavy ions in space that have an impact on cognitive function, even at low doses. However, all data about space radiation risk stem from rodent experiments, and extrapolation of these data to humans carries a high degree of uncertainty. Here, after presenting an overview of current knowledge in the above areas, we provide a concise description of possible counter-measures to protect the brain against microgravity and cosmic radiation during future space missions.</p>","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"35 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841013","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":"Neural manifolds: more than the sum of their neurons","authors":"Juan Alvaro Gallego","doi":"10.1038/s41583-025-00919-0","DOIUrl":"https://doi.org/10.1038/s41583-025-00919-0","url":null,"abstract":"In this Journal Club, Juan Gallego discusses a 2014 article that provided a first causal hint that neural manifolds may not only be a convenient way to interpret neural population activity.","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"59 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813635","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}
Adriano B. L. Tort, Diego A. Laplagne, Andreas Draguhn, Joaquin Gonzalez
{"title":"Global coordination of brain activity by the breathing cycle","authors":"Adriano B. L. Tort, Diego A. Laplagne, Andreas Draguhn, Joaquin Gonzalez","doi":"10.1038/s41583-025-00920-7","DOIUrl":"https://doi.org/10.1038/s41583-025-00920-7","url":null,"abstract":"<p>Neuronal activities that synchronize with the breathing rhythm have been found in humans and a host of mammalian species, not only in brain areas closely related to respiratory control or olfactory coding but also in areas linked to emotional and higher cognitive functions. In parallel, evidence is mounting for modulations of perception and action by the breathing cycle. In this Review, we discuss the extent to which brain activity locks to breathing across areas, levels of organization and brain states, and the physiological origins of this global synchrony. We describe how waves of sensory activity evoked by nasal airflow spread through brain circuits, synchronizing neuronal populations to the breathing cycle and modulating faster oscillations, cell assembly formation and cross-area communication, thereby providing a mechanistic link from breathing to neural coding, emotion and cognition. We argue that, through evolution, the breathing rhythm has come to shape network functions across species.</p>","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"23 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813666","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":"Dopamine signals threat-coping behaviour in threat–reward conflicts","authors":"Jake Rogers","doi":"10.1038/s41583-025-00918-1","DOIUrl":"https://doi.org/10.1038/s41583-025-00918-1","url":null,"abstract":"A naturalistic threat–reward conflict reveals that dopamine dynamics in tail of the striatum in mice regulate not only avoidance of potential threats but also learning to overcome them.","PeriodicalId":19082,"journal":{"name":"Nature Reviews Neuroscience","volume":"73 1","pages":""},"PeriodicalIF":34.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758356","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}