IF 15 1区医学

Neuron Pub Date : 2025-08-06 DOI: 10.1016/j.neuron.2025.07.013

Kent Imaizumi, Sergiu P Paşca

引用次数: 0

How the brain shifts between external and internal attention. 大脑如何在外部和内部注意力之间转换。

IF 15 1区医学

Neuron Pub Date : 2025-08-06 Epub Date: 2025-07-16 DOI: 10.1016/j.neuron.2025.06.013

Anna C Nobre, Daniela Gresch

引用次数: 0

Structural and functional basis of mechanosensitive TMEM63 channelopathies. 机械敏感性TMEM63通道病变的结构和功能基础。

IF 15 1区医学

Neuron Pub Date : 2025-08-06 Epub Date: 2025-06-05 DOI: 10.1016/j.neuron.2025.05.009

Wang Zheng, Augustus J Lowry, Harper E Smith, Jiale Xie, Shaun Rawson, Chen Wang, Jin Ou, Marcos Sotomayor, Tian-Min Fu, Huanghe Yang, Jeffrey R Holt

{"title":"Structural and functional basis of mechanosensitive TMEM63 channelopathies.","authors":"Wang Zheng, Augustus J Lowry, Harper E Smith, Jiale Xie, Shaun Rawson, Chen Wang, Jin Ou, Marcos Sotomayor, Tian-Min Fu, Huanghe Yang, Jeffrey R Holt","doi":"10.1016/j.neuron.2025.05.009","DOIUrl":"10.1016/j.neuron.2025.05.009","url":null,"abstract":"TMEM63A, -B, and -C constitute a mammalian family of mechanosensitive ion channels that are mutated in neurodevelopmental disorders. The molecular mechanisms underlying TMEM63 activation by force and the impact of disease-associated mutations have not been clarified. Here, we elucidate the structural and functional bases of a prevalent TMEM63B mutation p.V44M. We first found that TMEM63B p.V44M and the homologous TMEM63A p.V53M are gain-of-function mutations that do not enhance channel activity but instead evoke constitutive lipid scramblase activity. We then solved TMEM63A p.V53M mutant structures in both closed and lipid-open states, which revealed major rearrangements of pore-lining helices, creating a lateral cleft across the membrane. Simulation studies revealed lipid scrambling through this cleft. The structural rearrangements were triggered by disruption of a surface-proximal hydrophobic latch, a putative force-sensing module that includes a cluster of disease mutation sites. Our findings provide mechanistic insight into TMEM63 channelopathies and suggest a possible force-sensing mechanism.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2474-2489.e5"},"PeriodicalIF":15.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248975","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}

引用次数: 0

Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau. 选择性去除星形细胞PERK可防止淋巴损伤并减少β-淀粉样蛋白和tau蛋白的毒性聚集。

IF 15 1区医学

Neuron Pub Date : 2025-08-06 Epub Date: 2025-05-21 DOI: 10.1016/j.neuron.2025.04.027

Kai Chen, Yosuke M Morizawa, Tal Nuriel, Osama Al-Dalahmah, Zhongcong Xie, Guang Yang

{"title":"Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau.","authors":"Kai Chen, Yosuke M Morizawa, Tal Nuriel, Osama Al-Dalahmah, Zhongcong Xie, Guang Yang","doi":"10.1016/j.neuron.2025.04.027","DOIUrl":"10.1016/j.neuron.2025.04.027","url":null,"abstract":"Dysfunction of the glymphatic system, a brain-wide waste clearance network, is strongly linked to Alzheimer's disease (AD) and the accumulation of β-amyloid (Aβ) and tau proteins. Here, we identify an astrocytic signaling pathway that can be targeted to preserve glymphatic function and mitigate neurotoxic protein buildup. Analysis of astrocytes from both human AD brains and two transgenic mouse models (5XFAD and PS19) reveals robust activation of the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK)-α subunit of eukaryotic initiation factor 2 (eIF2α) branch of the unfolded protein response. Chronic PERK activation suppresses astrocytic protein synthesis and, through casein kinase 2 (CK2)-dependent mechanisms, disrupts the perivascular localization of aquaporin-4 (AQP4), a water channel essential for glymphatic flow. Importantly, astrocyte-specific PERK deletion or pharmacological inhibition restores AQP4 localization, enhances glymphatic clearance, reduces Aβ and tau pathology, and improves cognitive performance in mice. These findings highlight the critical role of the astrocytic PERK-CK2-AQP4 axis in glymphatic dysfunction and AD pathogenesis, positioning this pathway as a promising therapeutic target.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2438-2454.e6"},"PeriodicalIF":15.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128303","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}

引用次数: 0

Constitutive lipid scramblase activity underpins mechanosensitive TMEM63 channelopathies. 组成性脂质合成酶活性支持机械敏感性TMEM63通道病变。

IF 15 1区医学

Neuron Pub Date : 2025-08-06 DOI: 10.1016/j.neuron.2025.07.004

Remi Brynn, Kate Poole

引用次数: 0

The VI-P of the leptomeninges. 轻脑膜的VI-P。

IF 15 1区医学

Neuron Pub Date : 2025-08-06 DOI: 10.1016/j.neuron.2025.07.006

Sol Kim, Julie A Siegenthaler

引用次数: 0

Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics. R6/2 HD小鼠大脑中不同的分子模式：来自时空转录组学的见解。

IF 15 1区医学

Neuron Pub Date : 2025-08-06 Epub Date: 2025-06-06 DOI: 10.1016/j.neuron.2025.05.014

Mara S Burns, Ricardo Miramontes, Jie Wu, Ravinder Gulia, Madhu S Saddala, Alice L Lau, Tiffany Quach, John C Reidling, Vivek Swarup, Albert R La Spada, Ryan G Lim, Leslie M Thompson

{"title":"Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics.","authors":"Mara S Burns, Ricardo Miramontes, Jie Wu, Ravinder Gulia, Madhu S Saddala, Alice L Lau, Tiffany Quach, John C Reidling, Vivek Swarup, Albert R La Spada, Ryan G Lim, Leslie M Thompson","doi":"10.1016/j.neuron.2025.05.014","DOIUrl":"10.1016/j.neuron.2025.05.014","url":null,"abstract":"Huntington's disease (HD) is marked by widespread cellular dysregulation. To understand disease mechanisms, we and others have utilized bulk and single-cell transcriptomics, which provide cell-type information but limited spatial information. We used 10× Genomics Visium spatial transcriptomics integrated with matched single-nuclei RNA sequencing (snRNA-seq) in the rapidly progressing HD R6/2 mouse brain (post-natal day 0 [P0], 4 weeks, and 12 weeks). Our data suggest regional, temporal, and cell-type-specific regulatory pathways that establish distinct gene expression changes. Synaptic dysfunction is observed broadly throughout the brain, whereas we observed early dysregulation of the transcription factor 4 (Tcf4) that may drive cortical changes. Mitochondrial deficits are the earliest changes, beginning at P0 in the striatum. Striatal identity genes show early increased expression that becomes progressively downregulated. Finally, we identified a time-dependent dysregulation of neuropeptide Y signaling and potential interaction with the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway, which may be involved in the imbalance between Drd1 and Drd2 neuron vulnerability.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2416-2437.e6"},"PeriodicalIF":15.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248972","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}

引用次数: 0

Identification of the velum interpositum as a meningeal-CNS route for myeloid cell trafficking into the brain. 鉴别膜间质作为髓细胞进入脑的脑膜-中枢神经系统通路。

IF 15 1区医学

Neuron Pub Date : 2025-08-06 Epub Date: 2025-06-03 DOI: 10.1016/j.neuron.2025.05.004

Lindsay A Hohsfield, Sung Jin Kim, Rocio A Barahona, Caden M Henningfield, Kimiya Mansour, Kristen D Vallejo, Kate I Tsourmas, Nellie E Kwang, Yasamine Ghorbanian, Julio Alejandro Ayala Angulo, Pan Gao, Collin Pachow, Matthew A Inlay, Craig M Walsh, Xiangmin Xu, Thomas E Lane, Kim N Green

{"title":"Identification of the velum interpositum as a meningeal-CNS route for myeloid cell trafficking into the brain.","authors":"Lindsay A Hohsfield, Sung Jin Kim, Rocio A Barahona, Caden M Henningfield, Kimiya Mansour, Kristen D Vallejo, Kate I Tsourmas, Nellie E Kwang, Yasamine Ghorbanian, Julio Alejandro Ayala Angulo, Pan Gao, Collin Pachow, Matthew A Inlay, Craig M Walsh, Xiangmin Xu, Thomas E Lane, Kim N Green","doi":"10.1016/j.neuron.2025.05.004","DOIUrl":"10.1016/j.neuron.2025.05.004","url":null,"abstract":"The borders of the central nervous system (CNS) host a repertoire of immune cells and mediate critical neuroimmune interactions, including the infiltration of peripheral myeloid cells into the CNS. Despite the fundamental role of leukocyte infiltration under physiological and pathological conditions, the neuroanatomical route of cell entry into the brain remains unclear. Here, we describe a specialized structure underneath the hippocampus, the velum interpositum (VI), that serves as a site for myeloid cell entry into the CNS. The VI functions as an extra-parenchymal leptomeningeal extension containing distinct myeloid cells subsets. Fate-mapping studies confirm meningeal and peripheral myeloid cell occupancy within the VI. Additionally, we highlight the distinct use of this route in the developing, irradiated, and demyelinating disease brain, indicating that myeloid cell trafficking through the VI could have important clinical implications for neurological disease.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"2455-2473.e6"},"PeriodicalIF":15.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12331438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226084","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}

引用次数: 0

A neural basis for distinguishing imagination from reality. 区分想象和现实的神经基础。

IF 15 1区医学

Neuron Pub Date : 2025-08-06 Epub Date: 2025-06-05 DOI: 10.1016/j.neuron.2025.05.015

Nadine Dijkstra, Thomas von Rein, Peter Kok, Stephen M Fleming

引用次数: 0

Competitive integration of time and reward explains value-sensitive foraging decisions and frontal cortex ramping dynamics. 时间和奖励的竞争性整合解释了价值敏感的觅食决策和额叶皮质斜坡动力学。

IF 15 1区医学

Neuron Pub Date : 2025-08-06 DOI: 10.1016/j.neuron.2025.07.008

Michael Bukwich, Malcolm G Campbell, David Zoltowski, Lyle Kingsbury, Momchil S Tomov, Joshua Stern, HyungGoo R Kim, Jan Drugowitsch, Scott W Linderman, Naoshige Uchida

{"title":"Competitive integration of time and reward explains value-sensitive foraging decisions and frontal cortex ramping dynamics.","authors":"Michael Bukwich, Malcolm G Campbell, David Zoltowski, Lyle Kingsbury, Momchil S Tomov, Joshua Stern, HyungGoo R Kim, Jan Drugowitsch, Scott W Linderman, Naoshige Uchida","doi":"10.1016/j.neuron.2025.07.008","DOIUrl":"10.1016/j.neuron.2025.07.008","url":null,"abstract":"Patch foraging is a ubiquitous decision-making process in which animals decide when to abandon a resource patch of diminishing value to pursue an alternative. We developed a virtual foraging task in which mouse behavior varied systematically with patch value. Behavior could be explained by models integrating time and rewards antagonistically, scaled by a slowly varying latent patience state. Describing a mechanism rather than a normative prescription, these models quantitatively captured deviations from optimal foraging theory. Neuropixels recordings throughout frontal areas revealed distributed ramping signals, concentrated in the frontal cortex, from which multiple integrator models' decision variables could be decoded equally well. These signals reflected key aspects of decision models: they ramped gradually, responded oppositely to time and rewards, were sensitive to patch richness, and retained memory of reward history. Together, these results identify integration via frontal cortex ramping dynamics as a candidate mechanism for solving patch-foraging problems.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804389","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}

引用次数: 0

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