IF 14.7 1区医学

Neuron Pub Date : 2025-04-22 DOI: 10.1016/j.neuron.2025.03.034

Alexandra M Lish, Elyssa F L Grogan, Courtney R Benoit, Richard V Pearse, Sarah E Heuer, Tain Luquez, Gwendolyn A Orme, Paige C Galle, Giedre Milinkeviciute, Kim N Green, Kellianne D Alexander, Seeley B Fancher, Andrew M Stern, Masashi Fujita, David A Bennett, Nicholas T Seyfried, Philip L De Jager, Vilas Menon, Tracy L Young-Pearse

{"title":"CLU alleviates Alzheimer's disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density.","authors":"Alexandra M Lish, Elyssa F L Grogan, Courtney R Benoit, Richard V Pearse, Sarah E Heuer, Tain Luquez, Gwendolyn A Orme, Paige C Galle, Giedre Milinkeviciute, Kim N Green, Kellianne D Alexander, Seeley B Fancher, Andrew M Stern, Masashi Fujita, David A Bennett, Nicholas T Seyfried, Philip L De Jager, Vilas Menon, Tracy L Young-Pearse","doi":"10.1016/j.neuron.2025.03.034","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.034","url":null,"abstract":"Genetic studies implicate clusterin (CLU) in the pathogenesis of Alzheimer's disease (AD), yet its precise molecular impact remains unclear. Through unbiased proteomic profiling and functional validation in CLU-deficient astrocytes, we identify increased nuclear factor κB (NF-κB)-dependent signaling and complement C3 secretion. Reduction of astrocyte CLU induced microglia-dependent modulation of extracellular apolipoprotein E (APOE) and phosphorylated tau, as well as increased microglial phagocytosis and reduced synapse numbers. By integrating mouse and human cellular models with comprehensive analyses of human plasma and brain tissue, we demonstrate that CLU AD-risk alleles are associated with reduced CLU protein and heightened inflammatory profiles. These findings establish a mechanistic link between AD genetic risk factors, astrocyte reactivity, and microglia-mediated effects on synaptic integrity. Collectively, these results support a model in which CLU upregulation in response to neuropathology is associated with maintenance of cognitive function, while diminished astrocyte CLU levels heighten disease susceptibility.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012658","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

Integrating endocannabinoid signaling, CCK interneurons, and hippocampal circuit dynamics in behaving animals. 行为动物内源性大麻素信号、CCK中间神经元和海马回路动力学的整合。

IF 14.7 1区医学

Neuron Pub Date : 2025-04-19 DOI: 10.1016/j.neuron.2025.03.016

Shreya Malhotra, Florian Donneger, Jordan S Farrell, Barna Dudok, Attila Losonczy, Ivan Soltesz

引用次数: 0

Anatomically resolved oscillatory bursts reveal dynamic motifs of thalamocortical activity during naturalistic stimulus viewing. 解剖解决振荡爆发揭示动态动机丘脑皮质活动在自然刺激观看。

IF 14.7 1区医学

Neuron Pub Date : 2025-04-18 DOI: 10.1016/j.neuron.2025.03.030

Lukas Sebastian Meyerolbersleben, Anton Sirota, Laura Busse

{"title":"Anatomically resolved oscillatory bursts reveal dynamic motifs of thalamocortical activity during naturalistic stimulus viewing.","authors":"Lukas Sebastian Meyerolbersleben, Anton Sirota, Laura Busse","doi":"10.1016/j.neuron.2025.03.030","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.030","url":null,"abstract":"Natural vision requires circuit mechanisms which process complex spatiotemporal stimulus features in parallel. In the mammalian forebrain, one signature of circuit activation is fast oscillatory dynamics, reflected in the local field potential (LFP). Using data from the Allen Neuropixels Visual Coding project, we show that local visual features in naturalistic stimuli induce in mouse primary visual cortex (V1) retinotopically specific oscillations in various frequency bands and V1 layers. Specifically, layer 4 (L4) narrowband gamma was linked to luminance, low-gamma to optic flow, and L4/L5 epsilon oscillations to contrast. These feature-specific oscillations were associated with distinct translaminar spike-phase coupling patterns, which were conserved across a range of stimuli containing the relevant visual features, suggesting that they might constitute feature-specific circuit motifs. Our findings highlight visually induced fast oscillations as markers of dynamic circuit motifs, which may support differential and multiplexed coding of complex visual input and thalamocortical information propagation.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003107","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

The gut microbiota promotes pain in fibromyalgia. 肠道微生物群促进纤维肌痛症的疼痛。

IF 14.7 1区医学

Neuron Pub Date : 2025-04-18 DOI: 10.1016/j.neuron.2025.03.032

Weihua Cai, May Haddad, Rana Haddad, Inbar Kesten, Tseela Hoffman, Reut Laan, Susan Westfall, Manon Defaye, Nasser S Abdullah, Calvin Wong, Nicole Brown, Shannon Tansley, Kevin C Lister, Mehdi Hooshmandi, Feng Wang, Louis-Etienne Lorenzo, Volodya Hovhannisyan, David Ho-Tieng, Vibhu Kumar, Behrang Sharif, Bavanitha Thurairajah, Jonathan Fan, Tali Sahar, Charlotte Clayton, Neil Wu, Ji Zhang, Haggai Bar-Yoseph, Milena Pitashny, Emerson Krock, Jeffrey S Mogil, Masha Prager-Khoutorsky, Philippe Séguéla, Christophe Altier, Irah L King, Yves De Koninck, Nicholas J B Brereton, Emmanuel Gonzalez, Yoram Shir, Amir Minerbi, Arkady Khoutorsky

{"title":"The gut microbiota promotes pain in fibromyalgia.","authors":"Weihua Cai, May Haddad, Rana Haddad, Inbar Kesten, Tseela Hoffman, Reut Laan, Susan Westfall, Manon Defaye, Nasser S Abdullah, Calvin Wong, Nicole Brown, Shannon Tansley, Kevin C Lister, Mehdi Hooshmandi, Feng Wang, Louis-Etienne Lorenzo, Volodya Hovhannisyan, David Ho-Tieng, Vibhu Kumar, Behrang Sharif, Bavanitha Thurairajah, Jonathan Fan, Tali Sahar, Charlotte Clayton, Neil Wu, Ji Zhang, Haggai Bar-Yoseph, Milena Pitashny, Emerson Krock, Jeffrey S Mogil, Masha Prager-Khoutorsky, Philippe Séguéla, Christophe Altier, Irah L King, Yves De Koninck, Nicholas J B Brereton, Emmanuel Gonzalez, Yoram Shir, Amir Minerbi, Arkady Khoutorsky","doi":"10.1016/j.neuron.2025.03.032","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.032","url":null,"abstract":"Fibromyalgia is a prevalent syndrome characterized by widespread pain in the absence of evident tissue injury or pathology, making it one of the most mysterious chronic pain conditions. The composition of the gut microbiota in individuals with fibromyalgia differs from that of healthy controls, but its functional role in the syndrome is unknown. Here, we show that fecal microbiota transplantation from fibromyalgia patients, but not from healthy controls, into germ-free mice induces pain and numerous molecular phenotypes that parallel known changes in fibromyalgia patients, including immune activation and metabolomic profile alterations. Replacing the fibromyalgia microbiota with a healthy microbiota substantially alleviated pain in mice. An open-label trial in women with fibromyalgia (Registry MOH_2021-11-04_010374) showed that transplantation of a healthy microbiota is associated with reduced pain and improved quality of life. We conclude that altered gut microbiota has a role in fibromyalgia pain, highlighting it as a promising target for therapeutic interventions.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022038","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

Differential modification of ascending spinal outputs in acute and chronic pain states. 急性和慢性疼痛状态下上升脊髓输出的差异改变。

IF 14.7 1区医学

Neuron Pub Date : 2025-04-16 Epub Date: 2025-02-28 DOI: 10.1016/j.neuron.2025.01.031

David A Yarmolinsky, Xiangsunze Zeng, Natalie MacKinnon-Booth, Caitlin A Greene, Chloe Kim, Yu-Ting Cheng, Bruna Lenfers Turnes, Clifford J Woolf

{"title":"Differential modification of ascending spinal outputs in acute and chronic pain states.","authors":"David A Yarmolinsky, Xiangsunze Zeng, Natalie MacKinnon-Booth, Caitlin A Greene, Chloe Kim, Yu-Ting Cheng, Bruna Lenfers Turnes, Clifford J Woolf","doi":"10.1016/j.neuron.2025.01.031","DOIUrl":"10.1016/j.neuron.2025.01.031","url":null,"abstract":"Pain hypersensitivity arises from the induction of plasticity in peripheral and spinal somatosensory neurons, which modifies nociceptive input to the brain, altering pain perception. We applied longitudinal calcium imaging of spinal dorsal projection neurons to determine whether and how the representation of somatosensory stimuli in the anterolateral tract, the principal pathway transmitting nociceptive signals to the brain, changes between distinct pain states. In healthy mice, we identified stable outputs selective for cooling or warming and a neuronal ensemble activated by noxious thermal and mechanical stimuli. Induction of acute peripheral sensitization by topical capsaicin transiently re-tuned nociceptive output neurons to encode low-intensity stimuli. In contrast, peripheral nerve injury resulted in a persistent suppression of innocuous spinal outputs coupled with persistent activation of a normally silent population of high-threshold neurons. These results demonstrate differential modulation of spinal outputs to the brain during nociceptive and neuropathic pain states.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1223-1239.e5"},"PeriodicalIF":14.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537487","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

Astrocytic GPR37L1: A new guardian against the onset and chronicity of neuropathic pain. 星形胶质细胞GPR37L1：抗神经性疼痛发病和慢性的新守护者。

IF 14.7 1区医学

Neuron Pub Date : 2025-04-16 DOI: 10.1016/j.neuron.2025.03.013

Yuta Kohro, Makoto Tsuda

引用次数: 0

The interpeduncular nucleus blunts the rewarding effect of nicotine. 针间核减弱了尼古丁的奖赏作用。

IF 14.7 1区医学

Neuron Pub Date : 2025-04-16 DOI: 10.1016/j.neuron.2025.03.035

Joachim Jehl, Maria Ciscato, Eléonore Vicq, Nicolas Guyon, Gabrielle Dejean de la Batie, Sarah Mondoloni, Jacinthe Frangieh, Monir Mohayyaei, Claire Nguyen, Stéphanie Pons, Uwe Maskos, Jean-Pierre Hardelin, Fabio Marti, Pierre-Jean Corringer, Philippe Faure, Alexandre Mourot

{"title":"The interpeduncular nucleus blunts the rewarding effect of nicotine.","authors":"Joachim Jehl, Maria Ciscato, Eléonore Vicq, Nicolas Guyon, Gabrielle Dejean de la Batie, Sarah Mondoloni, Jacinthe Frangieh, Monir Mohayyaei, Claire Nguyen, Stéphanie Pons, Uwe Maskos, Jean-Pierre Hardelin, Fabio Marti, Pierre-Jean Corringer, Philippe Faure, Alexandre Mourot","doi":"10.1016/j.neuron.2025.03.035","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.035","url":null,"abstract":"Nicotine stimulates ventral tegmental area (VTA) dopaminergic neurons, producing a rewarding effect that drives tobacco consumption. The interpeduncular nucleus (IPN) is thought to become engaged at high nicotine doses to limit drug intake, but its response dynamics are unknown. We developed a chemogenetic approach using a \"suicide\" antagonist that selectively attaches to designer β4 nicotinic acetylcholine receptors (nAChRs) in genetically modified mice, enabling sustained and pharmacologically specific antagonism. Local infusion in the IPN revealed that nicotine, even at low doses, simultaneously activates and inhibits two distinct populations of IPN neurons, with β4-containing nAChRs mediating only the activation response. Blocking nicotine-induced IPN activation enhanced VTA responses and increased the drug's rewarding effect in a conditioned place preference paradigm. Moreover, optogenetic inhibition of IPN projections to the laterodorsal tegmental nucleus (LDTg) replicated these behavioral effects. Our findings indicate that the IPN acts as a regulatory brake on the nicotine reward circuit via the LDTg.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009363","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

PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD. ptpσ介导的PI3P调节C9ORF72-ALS/FTD的神经退行性变。

IF 14.7 1区医学

Neuron Pub Date : 2025-04-16 Epub Date: 2025-03-11 DOI: 10.1016/j.neuron.2025.02.005

Zhe Zhang, Xiujuan Fu, Noelle Wright, Weiren Wang, Yingzhi Ye, Julie Asbury, Yini Li, Chengzhang Zhu, Rong Wu, Shaopeng Wang, Shuying Sun

{"title":"PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD.","authors":"Zhe Zhang, Xiujuan Fu, Noelle Wright, Weiren Wang, Yingzhi Ye, Julie Asbury, Yini Li, Chengzhang Zhu, Rong Wu, Shaopeng Wang, Shuying Sun","doi":"10.1016/j.neuron.2025.02.005","DOIUrl":"10.1016/j.neuron.2025.02.005","url":null,"abstract":"The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein phosphatase S (PTPσ) as a strong modifier of poly-GR-mediated toxicity. We showed that reducing PTPσ promotes the survival of both poly-GR- and poly-PR-expressing neurons by elevating phosphatidylinositol 3-phosphate (PI3P), accompanied by restored early endosomes and lysosomes. Remarkably, PTPσ knockdown or inhibition substantially rescues the PI3P-endolysosomal defects and improves the survival of C9ORF72-ALS/FTD patient-derived neurons. Furthermore, the PTPσ inhibitor diminishes GR toxicity and rescues pathological and behavioral phenotypes in mice. Overall, these findings emphasize the critical role of PI3P-mediated endolysosomal deficits induced by R-DPRs in disease pathogenesis and reveal the therapeutic potential of targeting PTPσ in C9ORF72-ALS/FTD.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1190-1205.e9"},"PeriodicalIF":14.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616559","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

Strategies for mitigating data heterogeneities in AI-based neuro-disease detection. 缓解基于人工智能的神经疾病检测中数据异质性的策略。

IF 14.7 1区医学

Neuron Pub Date : 2025-04-16 Epub Date: 2025-03-03 DOI: 10.1016/j.neuron.2025.01.028

Matthew Leming, Kyungsu Kim, Rose Bruffaerts, Hyungsoon Im

引用次数: 0

The rhythm of sequential behavioral transitions: Neuromodulatory dynamics and male sexual behavior. 顺序行为转变的节奏：神经调节动力学和男性性行为。

IF 14.7 1区医学

Neuron Pub Date : 2025-04-16 DOI: 10.1016/j.neuron.2025.03.015

Pom Jantarachanatanthiti, Daniel W Bayless

引用次数: 0

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