NeuronPub Date : 2025-07-23DOI: 10.1016/j.neuron.2025.06.024
Jeff Y L Lam, Kai Wang, Guojun Bu
{"title":"A p16 pathway to prevention: Senescence as a driver of tau-mediated neurodegeneration.","authors":"Jeff Y L Lam, Kai Wang, Guojun Bu","doi":"10.1016/j.neuron.2025.06.024","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.06.024","url":null,"abstract":"<p><p>In this issue of Neuron, Graves et al.<sup>1</sup> report that genetically reducing senescent cells by deleting p16 in a tauopathy mouse model significantly lessens tau pathology, neurovascular dysfunction, and behavioral deficits. Their study highlights the crucial role of p16-dependent senescence in microglia and endothelial cells as active drivers of neurodegeneration.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 14","pages":"2215-2217"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708320","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}
NeuronPub Date : 2025-07-23DOI: 10.1016/j.neuron.2025.06.006
Jing Cai, Dayu Lin
{"title":"Danger is coming for the 100<sup>th</sup> time: Run or stay?","authors":"Jing Cai, Dayu Lin","doi":"10.1016/j.neuron.2025.06.006","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.06.006","url":null,"abstract":"<p><p>Immediate escape and gradual habituation are both crucial for animal survival in response to repeated threat exposures. In this issue of Neuron, Liu et al. identified key neural circuits supporting each of these two responsive patterns to repeated visual threats.<sup>1</sup>.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 14","pages":"2220-2222"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The paraventricular thalamus mediates visceral pain and anxiety-like behaviors via two distinct pathways.","authors":"Di Li, Yong-Chang Li, Zheng-Yan Zhu, Fu-Chao Zhang, Qiu-Ying Zhao, Jia-Hui Jiang, Biyu Shen, Yong Tang, Guang-Yin Xu","doi":"10.1016/j.neuron.2025.04.019","DOIUrl":"10.1016/j.neuron.2025.04.019","url":null,"abstract":"<p><p>Chronic visceral pain (CVP) often accompanies emotional disorders. However, the lack of suitable animal models has hindered research into their underlying molecular and neural circuitry mechanisms. Early-life stress is a key factor in developing both visceral hypersensitivity and emotional disorders, yet its pathological mechanisms are not well understood. This study showed that adult offspring of prenatal maternal stress (PMS)-exposed mice exhibited visceral hypersensitivity and anxiety-like behaviors. Glutamatergic neurons in the anterior paraventricular thalamus (aPVT) responded to visceral pain, while those in the posterior PVT (pPVT) were more responsive to anxiety. The aPVT-basolateral amygdala (BLA) and pPVT-central amygdala (CeA) circuits regulated CVP and anxiety, respectively. Notably, increased Cacna1e expression in aPVT enhanced both visceral pain and anxiety, while Grin2a upregulation in pPVT facilitated only anxiety. These findings highlight the distinct roles of aPVT<sup>Glu</sup>-BLA<sup>Glu</sup>-CeA<sup>GABA</sup> and pPVT<sup>Glu</sup>-CeA<sup>GABA</sup> circuits, providing insights for therapeutic approaches in CVP and anxiety comorbidity.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2310-2324.e7"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974688","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}
NeuronPub Date : 2025-07-23Epub Date: 2025-05-09DOI: 10.1016/j.neuron.2025.04.018
Xuemei Liu, Juan Lai, Chuanliang Han, Hao Zhong, Kang Huang, Yuanming Liu, Xutao Zhu, Pengfei Wei, Liming Tan, Fuqiang Xu, Liping Wang
{"title":"Neural circuit underlying individual differences in visual escape habituation.","authors":"Xuemei Liu, Juan Lai, Chuanliang Han, Hao Zhong, Kang Huang, Yuanming Liu, Xutao Zhu, Pengfei Wei, Liming Tan, Fuqiang Xu, Liping Wang","doi":"10.1016/j.neuron.2025.04.018","DOIUrl":"10.1016/j.neuron.2025.04.018","url":null,"abstract":"<p><p>Emotions like fear help organisms respond to threats. Repeated predator exposure leads to adaptive responses with unclear neural mechanisms behind individual variability. We identify two escape behaviors in mice-persistent escape (T1) and rapid habituation (T2)-linked to unique arousal states under repetitive looming stimuli. Combining multichannel recording, circuit mapping, optogenetics, and behavioral analyses, we find parallel pathways from the superior colliculus (SC) to the basolateral amygdala (BLA) via the ventral tegmental area (VTA) for T1 and via the mediodorsal thalamus (MD) for T2. T1 involves heightened arousal, while T2 features rapid habituation. The MD integrates SC and insular cortex inputs to modulate arousal and defensive behaviors. This work reveals neural circuits underpinning adaptive threat responses and individual variability.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2344-2357.e5"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991777","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}
NeuronPub Date : 2025-07-23Epub Date: 2025-05-15DOI: 10.1016/j.neuron.2025.04.024
Rhiana C Simon, Weston T Fleming, Brandy A Briones, Marta Trzeciak, Pranav Senthilkumar, Kentaro K Ishii, Madelyn M Hjort, Madison M Martin, Koichi Hashikawa, Andrea D Sanders, Sam A Golden, Garret D Stuber
{"title":"Opioid-driven disruption of the septum reveals a role for neurotensin-expressing neurons in withdrawal.","authors":"Rhiana C Simon, Weston T Fleming, Brandy A Briones, Marta Trzeciak, Pranav Senthilkumar, Kentaro K Ishii, Madelyn M Hjort, Madison M Martin, Koichi Hashikawa, Andrea D Sanders, Sam A Golden, Garret D Stuber","doi":"10.1016/j.neuron.2025.04.024","DOIUrl":"10.1016/j.neuron.2025.04.024","url":null,"abstract":"<p><p>Opioid withdrawal is an intensively aversive experience and often drives relapse. The lateral septum (LS) is a forebrain structure that is important in aversion processing and has been linked to substance use disorders, but which LS cell types contribute to the maladaptive state of withdrawal is unknown. We used single-nucleus RNA sequencing to interrogate cell-type-specific gene expression changes induced by chronic morphine exposure and discovered that morphine globally disrupts LS cell types, but neurotensin-expressing neurons (LS-Nts) are selectively activated by naloxone. Using two-photon calcium imaging and ex vivo electrophysiology, we next demonstrate that LS-Nts neurons receive elevated glutamatergic drive in morphine-dependent mice and remain hyperactivated during withdrawal. Finally, we show that manipulating LS-Nts neurons during opioid withdrawal regulates pain coping and sociability. Together, these results suggest that LS-Nts neurons are a key neural substrate involved in opioid withdrawal and establish the LS as a crucial regulator of adaptive behaviors.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2325-2343.e9"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086630","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}
NeuronPub Date : 2025-07-23Epub Date: 2025-04-28DOI: 10.1016/j.neuron.2025.03.036
Ava V Papetti, Mengmeng Jin, Ziyuan Ma, Alessandro C Stillitano, Peng Jiang
{"title":"Chimeric brain models: Unlocking insights into human neural development, aging, diseases, and cell therapies.","authors":"Ava V Papetti, Mengmeng Jin, Ziyuan Ma, Alessandro C Stillitano, Peng Jiang","doi":"10.1016/j.neuron.2025.03.036","DOIUrl":"10.1016/j.neuron.2025.03.036","url":null,"abstract":"<p><p>Human-rodent chimeric brain models serve as a unique platform for investigating the pathophysiology of human cells within a living brain environment. These models are established by transplanting human tissue- or human pluripotent stem cell (hPSC)-derived macroglial, microglial, or neuronal lineage cells, as well as cerebral organoids, into the brains of host animals. This approach has opened new avenues for exploring human brain development, disease mechanisms, and regenerative processes. Here, we highlight recent advancements in using chimeric models to study human neural development, aging, and disease. Additionally, we explore the potential applications of these models for studying human glial cell-replacement therapies, studying in vivo human glial-to-neuron reprogramming, and harnessing single-cell omics and advanced functional assays to uncover detailed insights into human neurobiology. Finally, we discuss strategies to enhance the precision and translational relevance of these models, expanding their impact in stem cell and neuroscience research.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2230-2250"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043571","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}
NeuronPub Date : 2025-07-23Epub Date: 2025-05-16DOI: 10.1016/j.neuron.2025.04.020
Sara I Graves, Charlton F Meyer, Karthik B Jeganathan, Darren J Baker
{"title":"p16-expressing microglia and endothelial cells promote tauopathy and neurovascular abnormalities in PS19 mice.","authors":"Sara I Graves, Charlton F Meyer, Karthik B Jeganathan, Darren J Baker","doi":"10.1016/j.neuron.2025.04.020","DOIUrl":"10.1016/j.neuron.2025.04.020","url":null,"abstract":"<p><p>Cellular senescence is characterized by irreversible cell-cycle exit, a pro-inflammatory secretory phenotype, macromolecular damage, and deregulated metabolism. Senescent cells are highly associated with age-related diseases. We previously demonstrated that targeted elimination of senescent cells prevents neurodegenerative disease in tau (MAPT<sup>P301S</sup>;PS19) mutant mice. Here, we show that genetic ablation of the senescence mediator p16<sup>Ink4a</sup> is sufficient to attenuate senescence signatures in PS19 mice. Disease phenotypes-including neuroinflammation, phosphorylated tau, neurodegeneration, and cognitive impairment-were blunted in the absence of p16<sup>Ink4a</sup>. Additionally, we found that PS19 mouse brains display p16<sup>Ink4</sup>-dependent neurovascular alterations such as vessel dilation, increased vessel density, deregulated endothelial cell extracellular matrix, and astrocytic endfoot depolarization. Finally, we show that p16<sup>Ink4a</sup> deletion in endothelial cells and microglia alone attenuates many of the same phenotypes. Altogether, these results indicate that neurodegenerative disease in PS19 mice is driven, at least in part, by p16<sup>Ink4a</sup>-expressing endothelial cells and microglia.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2251-2264.e4"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094401","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":"Dissecting human cortical similarity networks across the lifespan.","authors":"Xinyuan Liang, Lianglong Sun, Mingrui Xia, Tengda Zhao, Gaolang Gong, Qiongling Li, Xuhong Liao, Zaixu Cui, Dingna Duan, Chenxuan Pang, Qian Wang, Qian Yu, Yanchao Bi, Pindong Chen, Rui Chen, Yuan Chen, Taolin Chen, Jingliang Cheng, Yuqi Cheng, Zhengjia Dai, Yao Deng, Yuyin Ding, Qi Dong, Jia-Hong Gao, Qiyong Gong, Ying Han, Zaizhu Han, Chu-Chung Huang, Ruiwang Huang, Ran Huo, Lingjiang Li, Ching-Po Lin, Qixiang Lin, Bangshan Liu, Chao Liu, Ningyu Liu, Ying Liu, Yong Liu, Jing Lu, Leilei Ma, Weiwei Men, Shaozheng Qin, Wen Qin, Jiang Qiu, Shijun Qiu, Tianmei Si, Shuping Tan, Yanqing Tang, Sha Tao, Dawei Wang, Fei Wang, Jiali Wang, Jinhui Wang, Pan Wang, Xiaoqin Wang, Yanpei Wang, Dongtao Wei, Yankun Wu, Peng Xie, Xiufeng Xu, Yuehua Xu, Zhilei Xu, Liyuan Yang, Chunshui Yu, Huishu Yuan, Zilong Zeng, Haibo Zhang, Xi Zhang, Gai Zhao, Yanting Zheng, Suyu Zhong, Yong He","doi":"10.1016/j.neuron.2025.06.018","DOIUrl":"10.1016/j.neuron.2025.06.018","url":null,"abstract":"<p><p>The human cortex exhibits remarkable morphometric similarity between regions; however, the form and extent of lifespan network remodeling remain unknown. Here, we show the spatiotemporal maturation of morphometric brain networks, using multimodal neuroimaging data from 33,937 healthy participants aged 0-80 years. Global architecture matures from birth to early adulthood through enhanced modularity and small worldness. Early development features cytoarchitecturally distinct remodeling: sensory cortices exhibit increased morphometric differentiation, paralimbic cortices show increased morphometric similarity, and association cortices retain stable hub roles. Morphology-function coupling peaks in early adolescence and then decreases, supporting protracted functional maturation. These growth patterns of morphometric networks are correlated with gene expression related to synaptic signaling, neurodevelopment, and metabolism. Normative models based on morphometric networks identify person-specific, connectivity-phenotypic deviations in 1,202 patients with brain disorders. These data provide a blueprint for elucidating the principle of cortical network reconfiguration and a benchmark for quantifying interindividual network variations.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708319","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}
NeuronPub Date : 2025-07-23DOI: 10.1016/j.neuron.2025.06.021
Celine M Cammarata, Lindsey L Glickfeld
{"title":"How to make a decision? Trust the wisdom of the masses.","authors":"Celine M Cammarata, Lindsey L Glickfeld","doi":"10.1016/j.neuron.2025.06.021","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.06.021","url":null,"abstract":"<p><p>How is information in sensory cortex used to guide behavior? In this issue, Bounds and Adesnik<sup>1</sup> manipulate the activity of specific neural ensembles to demonstrate that total network activation, not just activation of the most sensitive neurons, determines behavioral outcomes.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":"113 14","pages":"2222-2224"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708323","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}
NeuronPub Date : 2025-07-23Epub Date: 2025-05-05DOI: 10.1016/j.neuron.2025.04.003
Xuhui Ge, Yufeng Zhu, Junjun Xiong, Yao Gu, Xiaokun Wang, Wu Ye, Haofan Wang, Yu Gao, Weihua Cai, Xuhui Zhou, Wei Liu
{"title":"Metabolic reprogramming through histone lactylation in microglia and macrophages recruits CD8<sup>+</sup> T lymphocytes and aggravates spinal cord injury.","authors":"Xuhui Ge, Yufeng Zhu, Junjun Xiong, Yao Gu, Xiaokun Wang, Wu Ye, Haofan Wang, Yu Gao, Weihua Cai, Xuhui Zhou, Wei Liu","doi":"10.1016/j.neuron.2025.04.003","DOIUrl":"10.1016/j.neuron.2025.04.003","url":null,"abstract":"<p><p>Crosstalk between the central nervous system (CNS) and the immune system has recently gained increased attention; however, the interaction between innate and adaptive immunity after CNS injury remains unclear. Here, using single-cell RNA sequencing, we identified accumulation of CD8<sup>+</sup> T lymphocytes in the cerebrospinal fluid of patients with spinal cord injury (SCI) and in spinal cords of injured mice, thus indicating poor neurological function. Furthermore, through genetic or pharmacologic interruption strategies, we found that CXCL16 chemokines derived from injury-activated microglia and macrophages (IAMs) recruited CXCR6<sup>+</sup>CD8<sup>+</sup> T cells and further contributed to neuronal loss after SCI. Mechanistically, glycolytic reprogramming in IAMs enhanced histone-lactylation-mediated Cxcl16 transcription, whereas suppressing glycolysis through Pkm2 deletion partially reversed this effect. Notably, a pharmacologic intervention targeting the CXCL16-CXCR6 axis with Rutin promoted locomotor restoration after SCI. Our study highlights the crucial role of glycolytically reprogrammed IAM-derived CXCL16 chemokines in modulating a maladaptive innate/adaptive immune axis and reveals several potential therapeutic strategies.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2280-2296.e8"},"PeriodicalIF":14.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007041","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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