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TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43.
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-26 DOI: 10.1016/j.neuron.2025.03.004
Jens Rummens, Bilal Khalil, Günseli Yıldırım, Pedro Silva, Valentina Zorzini, Nicolas Peredo, Marta Wojno, Meine Ramakers, Ludo Van Den Bosch, Philip Van Damme, Kristofer Davie, Jelle Hendrix, Frederic Rousseau, Joost Schymkowitz, Sandrine Da Cruz

Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) are hallmarks of several neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been challenging. Here, we produced amyloid-like fibrils from recombinant TDP-43 low-complexity domain and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cells, including induced pluripotent stem cell (iPSC)-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin, and p62 accumulation, and recruit nuclear endogenous TDP-43, leading to its loss of function. A transcriptomic signature linked to both aggregation and nuclear loss of TDP-43, including disease-specific cryptic splicing, is identified. Cytoplasmic TDP-43 aggregates exhibit time-dependent heterogeneous morphologies as observed in patients-including compacted, filamentous, or fragmented-which involve upregulation/recruitment of protein clearance pathways. Ultimately, cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify TDP-43-templated aggregation as a key mechanism driving both cytoplasmic gain of function and nuclear loss of function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.

{"title":"TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43.","authors":"Jens Rummens, Bilal Khalil, Günseli Yıldırım, Pedro Silva, Valentina Zorzini, Nicolas Peredo, Marta Wojno, Meine Ramakers, Ludo Van Den Bosch, Philip Van Damme, Kristofer Davie, Jelle Hendrix, Frederic Rousseau, Joost Schymkowitz, Sandrine Da Cruz","doi":"10.1016/j.neuron.2025.03.004","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.004","url":null,"abstract":"<p><p>Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) are hallmarks of several neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been challenging. Here, we produced amyloid-like fibrils from recombinant TDP-43 low-complexity domain and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cells, including induced pluripotent stem cell (iPSC)-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin, and p62 accumulation, and recruit nuclear endogenous TDP-43, leading to its loss of function. A transcriptomic signature linked to both aggregation and nuclear loss of TDP-43, including disease-specific cryptic splicing, is identified. Cytoplasmic TDP-43 aggregates exhibit time-dependent heterogeneous morphologies as observed in patients-including compacted, filamentous, or fragmented-which involve upregulation/recruitment of protein clearance pathways. Ultimately, cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify TDP-43-templated aggregation as a key mechanism driving both cytoplasmic gain of function and nuclear loss of function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743168","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
Molecular pathways and diagnosis in spatially resolved Alzheimer's hippocampal atlas.
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-26 DOI: 10.1016/j.neuron.2025.03.002
Pan Wang, Lei Han, Lifang Wang, Quyuan Tao, Zhen Guo, Ting Luo, Youzhe He, Zhi Xu, Jiayi Yu, Yuyang Liu, Zihan Wu, Bin Xu, Bufan Jin, Yanrong Wei, Ying Yang, Mengnan Cheng, Yujia Jiang, Chen Tian, Huiwen Zheng, Zhongqin Fan, Peiran Jiang, Yue Gao, Juanli Wu, Shengpeng Wang, Bing Sun, Zheng Fang, Junjie Lei, Benyan Luo, Huiying Wen, Guoping Peng, Yuanchun Tang, Tao Yang, Jing Chen, Zhenkun Zhuang, Xinhui Su, Catherine Pan, Keqing Zhu, Yi Shen, Shiping Liu, Aimin Bao, Jianhua Yao, Jian Wang, Xun Xu, Xiao-Ming Li, Longqi Liu, Shumin Duan, Jing Zhang

We employed Stereo-seq combined with single-nucleus RNA sequencing (snRNA-seq) to investigate the gene expression and cell composition changes in human hippocampus with or without Alzheimer's disease (AD). The transcriptomic map, with single-cell precision, unveiled AD-associated alterations with spatial specificity, which include the following: (1) elevated synapse pruning gene expression in the fimbria of AD, with disrupted microglia-astrocyte communication likely leading to disorganized synaptic structure; (2) a globally increased energy generation in the cornu ammonis (CA) region, with varying degrees across its subregions; (3) a significant reduction in the number of CA1 neurons in AD, while CA4 neurons remained largely unaffected, potentially due to gene alterations in CA4 conferring resilience to AD; and (4) aggravated amyloid-beta (Aβ) plaques in CA1 and stratum lucidum, radiatum, and moleculare (SLRM), and integration of Stereo-seq map with Aβ staining revealed a sequential enrichment of microglia and astrocytes around Aβ plaques. Finally, reduced brain-derived extracellular vesicles carrying cholecystokinin (CCK) and peripheral myelin protein 2 (PMP2) in AD plasma highlighted their diagnostic potential for clinical applications.

{"title":"Molecular pathways and diagnosis in spatially resolved Alzheimer's hippocampal atlas.","authors":"Pan Wang, Lei Han, Lifang Wang, Quyuan Tao, Zhen Guo, Ting Luo, Youzhe He, Zhi Xu, Jiayi Yu, Yuyang Liu, Zihan Wu, Bin Xu, Bufan Jin, Yanrong Wei, Ying Yang, Mengnan Cheng, Yujia Jiang, Chen Tian, Huiwen Zheng, Zhongqin Fan, Peiran Jiang, Yue Gao, Juanli Wu, Shengpeng Wang, Bing Sun, Zheng Fang, Junjie Lei, Benyan Luo, Huiying Wen, Guoping Peng, Yuanchun Tang, Tao Yang, Jing Chen, Zhenkun Zhuang, Xinhui Su, Catherine Pan, Keqing Zhu, Yi Shen, Shiping Liu, Aimin Bao, Jianhua Yao, Jian Wang, Xun Xu, Xiao-Ming Li, Longqi Liu, Shumin Duan, Jing Zhang","doi":"10.1016/j.neuron.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.002","url":null,"abstract":"<p><p>We employed Stereo-seq combined with single-nucleus RNA sequencing (snRNA-seq) to investigate the gene expression and cell composition changes in human hippocampus with or without Alzheimer's disease (AD). The transcriptomic map, with single-cell precision, unveiled AD-associated alterations with spatial specificity, which include the following: (1) elevated synapse pruning gene expression in the fimbria of AD, with disrupted microglia-astrocyte communication likely leading to disorganized synaptic structure; (2) a globally increased energy generation in the cornu ammonis (CA) region, with varying degrees across its subregions; (3) a significant reduction in the number of CA1 neurons in AD, while CA4 neurons remained largely unaffected, potentially due to gene alterations in CA4 conferring resilience to AD; and (4) aggravated amyloid-beta (Aβ) plaques in CA1 and stratum lucidum, radiatum, and moleculare (SLRM), and integration of Stereo-seq map with Aβ staining revealed a sequential enrichment of microglia and astrocytes around Aβ plaques. Finally, reduced brain-derived extracellular vesicles carrying cholecystokinin (CCK) and peripheral myelin protein 2 (PMP2) in AD plasma highlighted their diagnostic potential for clinical applications.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764427","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
Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures.
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-26 DOI: 10.1016/j.neuron.2025.03.008
Carlo Scialò, Weijia Zhong, Somanath Jagannath, Oscar Wilkins, Davide Caredio, Marian Hruska-Plochan, Flavio Lurati, Martina Peter, Elena De Cecco, Luigi Celauro, Adriano Aguzzi, Giuseppe Legname, Pietro Fratta, Magdalini Polymenidou

Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43-seeding platform for quantitative assessment of TDP-43 aggregate uptake, cell-to-cell spreading, and loss of function within living cells, while they progress toward pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized by human neuron-like cells, efficiently recruited endogenous TDP-43, and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. Combining a fluorescent reporter of TDP-43 function with RNA sequencing and proteomics, we demonstrated aberrant cryptic splicing and a loss-of-function profile resulting from TDP-43-templated aggregation. Our data highlight known and novel pathological signatures in the context of seed-induced TDP-43 loss of function.

{"title":"Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures.","authors":"Carlo Scialò, Weijia Zhong, Somanath Jagannath, Oscar Wilkins, Davide Caredio, Marian Hruska-Plochan, Flavio Lurati, Martina Peter, Elena De Cecco, Luigi Celauro, Adriano Aguzzi, Giuseppe Legname, Pietro Fratta, Magdalini Polymenidou","doi":"10.1016/j.neuron.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.008","url":null,"abstract":"<p><p>Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43-seeding platform for quantitative assessment of TDP-43 aggregate uptake, cell-to-cell spreading, and loss of function within living cells, while they progress toward pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized by human neuron-like cells, efficiently recruited endogenous TDP-43, and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. Combining a fluorescent reporter of TDP-43 function with RNA sequencing and proteomics, we demonstrated aberrant cryptic splicing and a loss-of-function profile resulting from TDP-43-templated aggregation. Our data highlight known and novel pathological signatures in the context of seed-induced TDP-43 loss of function.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743060","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
Comprehensive characterization of metabolic consumption and production by the human brain.
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-24 DOI: 10.1016/j.neuron.2025.03.003
Yilong Wang, Lebo Zhou, Nan Wang, Baoshan Qiu, Di Yao, Jie Yu, Miaoqing He, Tong Li, Yufeng Xie, Xiaoqian Yu, Zhanying Bi, Xiangli Sun, Xunming Ji, Zhen Li, Dapeng Mo, Woo-Ping Ge

Metabolism is vital for brain function. However, a systematic investigation to understand the metabolic exchange between the human brain and circulatory system has been lacking. Here, we compared metabolomes and lipidomes of blood samples from the cerebral venous sinus and femoral artery to profile the brain's uptake and release of metabolites and lipids (1,365 metabolites and 140 lipids). We observed a high net uptake of glucose, taurine, and hypoxanthine and identified glutamine and pyruvate as significantly released metabolites by the brain. Triacylglycerols are the most prominent class of lipid consumed by the brain. The brain with cerebral venous sinus stenosis (CVSS) consumed more glucose and lactate and released more glucose metabolism byproducts than the brain with cerebral venous sinus thrombosis (CVST). Our data also showed age-related alterations in the uptake and release of metabolites. These results provide a comprehensive view of metabolic consumption and production processes within the human brain.

{"title":"Comprehensive characterization of metabolic consumption and production by the human brain.","authors":"Yilong Wang, Lebo Zhou, Nan Wang, Baoshan Qiu, Di Yao, Jie Yu, Miaoqing He, Tong Li, Yufeng Xie, Xiaoqian Yu, Zhanying Bi, Xiangli Sun, Xunming Ji, Zhen Li, Dapeng Mo, Woo-Ping Ge","doi":"10.1016/j.neuron.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.003","url":null,"abstract":"<p><p>Metabolism is vital for brain function. However, a systematic investigation to understand the metabolic exchange between the human brain and circulatory system has been lacking. Here, we compared metabolomes and lipidomes of blood samples from the cerebral venous sinus and femoral artery to profile the brain's uptake and release of metabolites and lipids (1,365 metabolites and 140 lipids). We observed a high net uptake of glucose, taurine, and hypoxanthine and identified glutamine and pyruvate as significantly released metabolites by the brain. Triacylglycerols are the most prominent class of lipid consumed by the brain. The brain with cerebral venous sinus stenosis (CVSS) consumed more glucose and lactate and released more glucose metabolism byproducts than the brain with cerebral venous sinus thrombosis (CVST). Our data also showed age-related alterations in the uptake and release of metabolites. These results provide a comprehensive view of metabolic consumption and production processes within the human brain.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730945","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
Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development.
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-24 DOI: 10.1016/j.neuron.2025.03.005
Adam P Caccavano, Anna Vlachos, Nadiya McLean, Sarah Kimmel, June Hoan Kim, Geoffrey Vargish, Vivek Mahadevan, Lauren Hewitt, Anthony M Rossi, Ilona Spineux, Sherry Jingjing Wu, Elisabetta Furlanis, Min Dai, Brenda Leyva Garcia, Yating Wang, Ramesh Chittajallu, Edra London, Xiaoqing Yuan, Steven Hunt, Daniel Abebe, Mark A G Eldridge, Alex C Cummins, Brendan E Hines, Anya Plotnikova, Arya Mohanty, Bruno B Averbeck, Kareem A Zaghloul, Jordane Dimidschstein, Gord Fishell, Kenneth A Pelkey, Chris J McBain

Within adult rodent hippocampus (HPC), opioids suppress inhibitory parvalbumin-expressing interneurons (PV-INs), disinhibiting local microcircuits. However, it is unknown whether this disinhibitory motif is conserved across cortical regions, species, or development. We observed that PV-IN-mediated inhibition is robustly suppressed by opioids in HPC proper but not primary neocortex in mice and non-human primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif is established in early development when PV-INs and opioids regulate early population activity. Morphine pretreatment partially occludes this acute opioid-mediated suppression, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Our findings demonstrate that PV-INs exhibit divergent opioid sensitivity across brain regions, which is remarkably conserved over evolution, and highlight the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

在成年啮齿动物的海马(HPC)中,阿片类药物会抑制抑制性的副发光体表达中间神经元(PV-INs),从而解除对局部微电路的抑制。然而,这种抑制作用是否在不同皮质区域、物种或发育过程中保持不变,目前尚不清楚。我们观察到,在小鼠和非人灵长类动物中,PV-IN 介导的抑制作用在 HPC 本体中受到阿片类药物的强力抑制,但在原发性新皮质中却没有受到抑制,切除的人体组织中的自发抑制张力也呈现出一致的两极分化。当 PV-INs 和阿片类药物调节早期群体活动时,这种海马抑制模式在早期发育中就已确立。吗啡预处理可部分阻断这种由阿片类药物介导的急性抑制,从而影响阿片类药物对学习和记忆具有重要作用的海马网络活动。我们的研究结果表明,PV-INs 在不同脑区表现出不同的阿片类药物敏感性,这种敏感性在进化过程中保持了显著的一致性,并强调了阿片类药物通过未成熟的 PV-INs 在塑造海马发育过程中所起的作用未得到充分重视。
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引用次数: 0
Key-value memory in the brain.
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-21 DOI: 10.1016/j.neuron.2025.02.029
Samuel J Gershman, Ila Fiete, Kazuki Irie

Classical models of memory in psychology and neuroscience rely on similarity-based retrieval of stored patterns, where similarity is a function of retrieval cues and the stored patterns. Although parsimonious, these models do not allow distinct representations for storage and retrieval, despite their distinct computational demands. Key-value memory systems, in contrast, distinguish representations used for storage (values) and those used for retrieval (keys). This allows key-value memory systems to optimize simultaneously for fidelity in storage and discriminability in retrieval. We review the computational foundations of key-value memory, its role in modern machine-learning systems, related ideas from psychology and neuroscience, applications to a number of empirical puzzles, and possible biological implementations.

心理学和神经科学中的经典记忆模型依赖于基于相似性的存储模式检索,其中相似性是检索线索和存储模式的函数。这些模型虽然简洁明了,但并不允许在存储和检索时使用不同的表征,尽管它们的计算需求各不相同。相反,键值记忆系统区分了用于存储的表征(值)和用于检索的表征(键)。这使得键值记忆系统可以同时优化存储的保真度和检索的可辨别性。我们回顾了键值记忆的计算基础、它在现代机器学习系统中的作用、心理学和神经科学中的相关观点、在一些经验性难题中的应用以及可能的生物学实现。
{"title":"Key-value memory in the brain.","authors":"Samuel J Gershman, Ila Fiete, Kazuki Irie","doi":"10.1016/j.neuron.2025.02.029","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.02.029","url":null,"abstract":"<p><p>Classical models of memory in psychology and neuroscience rely on similarity-based retrieval of stored patterns, where similarity is a function of retrieval cues and the stored patterns. Although parsimonious, these models do not allow distinct representations for storage and retrieval, despite their distinct computational demands. Key-value memory systems, in contrast, distinguish representations used for storage (values) and those used for retrieval (keys). This allows key-value memory systems to optimize simultaneously for fidelity in storage and discriminability in retrieval. We review the computational foundations of key-value memory, its role in modern machine-learning systems, related ideas from psychology and neuroscience, applications to a number of empirical puzzles, and possible biological implementations.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730949","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
Vascular motion in the dorsal root ganglion sensed by Piezo2 in sensory neurons triggers episodic neuropathic pain.
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-21 DOI: 10.1016/j.neuron.2025.03.006
Wenrui Xie, Debora Denardin Lückemeyer, Katherine A Qualls, Arthur Silveira Prudente, Temugin Berta, Mingxia Gu, Judith A Strong, Xinzhong Dong, Jun-Ming Zhang

Spontaneous pain, characterized by episodic shooting or stabbing sensations, is a major complaint among neuropathic pain patients, yet its mechanisms remain poorly understood. Recent research indicates a connection between this pain condition and "clustered firing," wherein adjacent sensory neurons fire simultaneously. This study presents evidence that the triggers of spontaneous pain and clustered firing are the dynamic movements of small blood vessels within the nerve-injured sensory ganglion, along with increased blood vessel density/angiogenesis and increased number of pericytes around blood vessels. Pharmacologically or mechanically evoked myogenic vascular responses increase both spontaneous pain and clustered firing in a mouse model of neuropathic pain. The mechanoreceptor Piezo2 in sensory neurons plays a critical role in detecting blood vessel movements. An anti-VEGF monoclonal antibody that inhibits angiogenesis effectively blocks spontaneous pain and clustered firing. These findings suggest targeting Piezo2, angiogenesis, or abnormal vascular dynamics as potential therapeutic strategies for neuropathic spontaneous pain.

{"title":"Vascular motion in the dorsal root ganglion sensed by Piezo2 in sensory neurons triggers episodic neuropathic pain.","authors":"Wenrui Xie, Debora Denardin Lückemeyer, Katherine A Qualls, Arthur Silveira Prudente, Temugin Berta, Mingxia Gu, Judith A Strong, Xinzhong Dong, Jun-Ming Zhang","doi":"10.1016/j.neuron.2025.03.006","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.006","url":null,"abstract":"<p><p>Spontaneous pain, characterized by episodic shooting or stabbing sensations, is a major complaint among neuropathic pain patients, yet its mechanisms remain poorly understood. Recent research indicates a connection between this pain condition and \"clustered firing,\" wherein adjacent sensory neurons fire simultaneously. This study presents evidence that the triggers of spontaneous pain and clustered firing are the dynamic movements of small blood vessels within the nerve-injured sensory ganglion, along with increased blood vessel density/angiogenesis and increased number of pericytes around blood vessels. Pharmacologically or mechanically evoked myogenic vascular responses increase both spontaneous pain and clustered firing in a mouse model of neuropathic pain. The mechanoreceptor Piezo2 in sensory neurons plays a critical role in detecting blood vessel movements. An anti-VEGF monoclonal antibody that inhibits angiogenesis effectively blocks spontaneous pain and clustered firing. These findings suggest targeting Piezo2, angiogenesis, or abnormal vascular dynamics as potential therapeutic strategies for neuropathic spontaneous pain.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743202","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
Single-cell spatial transcriptomic atlas of the whole mouse brain.
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-20 DOI: 10.1016/j.neuron.2025.02.015
Lei Han, Zhen Liu, Zehua Jing, Yuxuan Liu, Yujie Peng, Huizhong Chang, Junjie Lei, Kexin Wang, Yuanfang Xu, Wei Liu, Zihan Wu, Qian Li, Xiaoxue Shi, Mingyuan Zheng, He Wang, Juan Deng, Yanqing Zhong, Hailin Pan, Junkai Lin, Ruiyi Zhang, Yu Chen, Jinhua Wu, Mingrui Xu, Biyu Ren, Mengnan Cheng, Qian Yu, Xinxiang Song, Yanbing Lu, Yuanchun Tang, Nini Yuan, Suhong Sun, Yingjie An, Wenqun Ding, Xing Sun, Yanrong Wei, Shuzhen Zhang, Yannong Dou, Yun Zhao, Luyao Han, Qianhua Zhu, Junfeng Xu, Shiwen Wang, Dan Wang, Yinqi Bai, Yikai Liang, Yuan Liu, Mengni Chen, Chun Xie, Binshi Bo, Mei Li, Xinyan Zhang, Wang Ting, Zhenhua Chen, Jiao Fang, Shuting Li, Yujia Jiang, Xing Tan, Guolong Zuo, Yue Xie, Huanhuan Li, Quyuan Tao, Yan Li, Jianfeng Liu, Yuyang Liu, Mingkun Hao, Jingjing Wang, Huiying Wen, Jiabing Liu, Yizhen Yan, Hui Zhang, Yifan Sheng, Shui Yu, Xiaoyan Liao, Xuyin Jiang, Guangling Wang, Huanlin Liu, Congcong Wang, Ning Feng, Xin Liu, Kailong Ma, Xiangjie Xu, Tianyue Han, Huateng Cao, Huiwen Zheng, Yadong Chen, Haorong Lu, Zixian Yu, Jinsong Zhang, Bo Wang, Zhifeng Wang, Qing Xie, Shanshan Pan, Chuanyu Liu, Chan Xu, Luman Cui, Yuxiang Li, Shiping Liu, Sha Liao, Ao Chen, Qing-Feng Wu, Jian Wang, Zhiyong Liu, Yidi Sun, Jan Mulder, Huanming Yang, Xiaofei Wang, Chao Li, Jianhua Yao, Xun Xu, Longqi Liu, Zhiming Shen, Wu Wei, Yan-Gang Sun

A comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding the function of the brain. Here, using single-nucleus RNA sequencing (snRNA-seq) and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters at single-cell resolution, involving over 4 million cells, as well as for 29,655 genes. We have identified cell clusters exhibiting preference for cortical subregions and explored their associations with brain-related diseases. Additionally, we pinpointed 155 genes with distinct regional expression patterns within the brainstem and unveiled 513 long non-coding RNAs showing region-enriched expression in the adult brain. Parcellation of brain regions based on spatial transcriptomic information revealed fine structure for several brain areas. Furthermore, we have uncovered 411 transcription factor regulons showing distinct spatiotemporal dynamics during neurodevelopment. Thus, we have constructed a single-cell-resolution spatial transcriptomic atlas of the mouse brain with genome-wide coverage.

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引用次数: 0
A pontine center in descending pain control.
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-20 DOI: 10.1016/j.neuron.2025.02.028
Tianming Li, Wenjie Zhou, Jin Ke, Matthew Chen, Zhen Wang, Lauren Hayashi, Xiaojing Su, Wenbin Jia, Wenxi Huang, Chien-Sheng Wang, Kapsa Bengyella, Yang Yang, Rafael Hernandez, Yan Zhang, Xinglei Song, Tianle Xu, Tianwen Huang, Yuanyuan Liu

Pain sensation changes according to expectation, context, and mood, illustrating how top-down circuits affect somatosensory processing. Here, we used an intersectional strategy to identify anatomical and molecular-spatial features of supraspinal descending neurons activated by distinct noxious stimulation. This approach captured known descending pain pathways as well as spinal projecting neurons that are anatomically mapped to Barrington's nucleus in the dorsal pontine tegmentum. We determined that this population of neurons expresses corticotropin-releasing hormone in Barrington's nucleus (BarCrh) and exhibits time-locked firing in response to noxious stimulation. Chemogenetic activation of BarCrh neurons attenuated nocifensive responses as well as tactile neuropathic pain, while silencing these neurons resulted in thermal hyperalgesia and mechanical allodynia. Mechanistically, we demonstrated that pain-related input from the ventrolateral periaqueductal gray recruits BarCrh neurons, reduces ascending nociceptive transmission, and preferentially activates spinal dynorphin neurons to mediate analgesia. Our data expose a pontine inhibitory descending pathway that powerfully controls nocifensive sensory input to the brain.

{"title":"A pontine center in descending pain control.","authors":"Tianming Li, Wenjie Zhou, Jin Ke, Matthew Chen, Zhen Wang, Lauren Hayashi, Xiaojing Su, Wenbin Jia, Wenxi Huang, Chien-Sheng Wang, Kapsa Bengyella, Yang Yang, Rafael Hernandez, Yan Zhang, Xinglei Song, Tianle Xu, Tianwen Huang, Yuanyuan Liu","doi":"10.1016/j.neuron.2025.02.028","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.02.028","url":null,"abstract":"<p><p>Pain sensation changes according to expectation, context, and mood, illustrating how top-down circuits affect somatosensory processing. Here, we used an intersectional strategy to identify anatomical and molecular-spatial features of supraspinal descending neurons activated by distinct noxious stimulation. This approach captured known descending pain pathways as well as spinal projecting neurons that are anatomically mapped to Barrington's nucleus in the dorsal pontine tegmentum. We determined that this population of neurons expresses corticotropin-releasing hormone in Barrington's nucleus (Bar<sup>Crh</sup>) and exhibits time-locked firing in response to noxious stimulation. Chemogenetic activation of Bar<sup>Crh</sup> neurons attenuated nocifensive responses as well as tactile neuropathic pain, while silencing these neurons resulted in thermal hyperalgesia and mechanical allodynia. Mechanistically, we demonstrated that pain-related input from the ventrolateral periaqueductal gray recruits Bar<sup>Crh</sup> neurons, reduces ascending nociceptive transmission, and preferentially activates spinal dynorphin neurons to mediate analgesia. Our data expose a pontine inhibitory descending pathway that powerfully controls nocifensive sensory input to the brain.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710900","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
Parental origin of transgene modulates amyloid-β plaque burden in the 5xFAD mouse model of Alzheimer's disease. 在5xFAD小鼠阿尔茨海默病模型中,亲本来源的转基因调节淀粉样蛋白-β斑块负荷。
IF 14.7 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-03-19 Epub Date: 2025-01-20 DOI: 10.1016/j.neuron.2024.12.025
Andrew Octavian Sasmita, Erinne Cherisse Ong, Taisiia Nazarenko, Shuying Mao, Lina Komarek, Maik Thalmann, Veronika Hantakova, Lena Spieth, Stefan A Berghoff, Helena J Barr, Maximilian Hingerl, Friederike Börensen, Johannes Hirrlinger, Mikael Simons, Beth Stevens, Constanze Depp, Klaus-Armin Nave

In Alzheimer's disease (AD) research, the 5xFAD mouse model is commonly used as a heterozygote crossed with other genetic models to study AD pathology. We investigated whether the parental origin of the 5xFAD transgene affects plaque deposition. Using quantitative light-sheet microscopy, we found that paternal inheritance of the transgene led to a 2-fold higher plaque burden compared with maternal inheritance, a finding consistent across multiple 5xFAD colonies. This effect was not due to gestation in or rearing by 5xFAD females. Immunoblotting suggested that transgenic inheritance modulates transgenic protein expression, potentially due to genomic imprinting of the Thy1.2 promoter. Surprisingly, fewer than 20% of 5xFAD studies report breeding schemes, suggesting that this factor might confound previous findings. Our data highlight a significant determinant of plaque burden in 5xFAD mice and underscore the importance of reporting the parental origin of the transgene to improve scientific rigor and reproducibility in AD research.

在阿尔茨海默病(AD)的研究中,5xFAD小鼠模型通常作为杂合子与其他遗传模型杂交来研究AD的病理。我们研究了5xFAD转基因的亲本来源是否影响斑块沉积。使用定量光片显微镜,我们发现父系遗传的转基因导致比母系遗传高2倍的斑块负担,这一发现在多个5xFAD菌落中是一致的。这种影响不是由5xFAD雌性的妊娠或饲养引起的。免疫印迹表明,转基因遗传调节了转基因蛋白的表达,可能是由于Thy1.2启动子的基因组印迹。令人惊讶的是,只有不到20%的5xFAD研究报告了繁殖计划,这表明这个因素可能会混淆之前的发现。我们的数据强调了5xFAD小鼠斑块负荷的重要决定因素,并强调了报告转基因亲本来源对于提高AD研究的科学严谨性和可重复性的重要性。
{"title":"Parental origin of transgene modulates amyloid-β plaque burden in the 5xFAD mouse model of Alzheimer's disease.","authors":"Andrew Octavian Sasmita, Erinne Cherisse Ong, Taisiia Nazarenko, Shuying Mao, Lina Komarek, Maik Thalmann, Veronika Hantakova, Lena Spieth, Stefan A Berghoff, Helena J Barr, Maximilian Hingerl, Friederike Börensen, Johannes Hirrlinger, Mikael Simons, Beth Stevens, Constanze Depp, Klaus-Armin Nave","doi":"10.1016/j.neuron.2024.12.025","DOIUrl":"10.1016/j.neuron.2024.12.025","url":null,"abstract":"<p><p>In Alzheimer's disease (AD) research, the 5xFAD mouse model is commonly used as a heterozygote crossed with other genetic models to study AD pathology. We investigated whether the parental origin of the 5xFAD transgene affects plaque deposition. Using quantitative light-sheet microscopy, we found that paternal inheritance of the transgene led to a 2-fold higher plaque burden compared with maternal inheritance, a finding consistent across multiple 5xFAD colonies. This effect was not due to gestation in or rearing by 5xFAD females. Immunoblotting suggested that transgenic inheritance modulates transgenic protein expression, potentially due to genomic imprinting of the Thy1.2 promoter. Surprisingly, fewer than 20% of 5xFAD studies report breeding schemes, suggesting that this factor might confound previous findings. Our data highlight a significant determinant of plaque burden in 5xFAD mice and underscore the importance of reporting the parental origin of the transgene to improve scientific rigor and reproducibility in AD research.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"838-846.e4"},"PeriodicalIF":14.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009079","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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Neuron
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