Molecular Psychiatry最新文献

{"title":"Higher plasma soluble TREM2 correlates with reduced cerebral tau accumulation in Alzheimer’s disease","authors":"Guoyu Lan, Anqi Li, Fernando Gonzalez-Ortiz, Jieqin Lv, Wenqing Ran, Yue Cai, Pan Sun, Lin Liu, Jie Yang, Laihong Zhang, Zhengbo He, Lili Fang, Xin Zhou, Yalin Zhu, Zhen Liu, Xiang Fan, Xuhui Chen, Linsen Xu, Qingyong Wang, Xinlu Wang, Kun Sun, Guanxun Cheng, Ying Han, Kaj Blennow, Lu Wang, Pengcheng Ran, Tengfei Guo","doi":"10.1038/s41380-025-02976-4","DOIUrl":"https://doi.org/10.1038/s41380-025-02976-4","url":null,"abstract":"<p>Loss-of-function mutation of triggering receptor expressed on myeloid cell 2 (TREM2) is associated with increased risks for Alzheimer’s disease (AD). Recent animal studies reveal that the activation of peripheral TREM2 signaling may affect cerebral β-amyloid (Aβ) and tau aggregates. However, the underlying relationship between peripheral TREM2 and brain AD pathology has not yet been well-elucidated in the aging population. In this study, we collected 318 Chinese older adults with Aβ PET and plasma biomarker measures, including soluble TREM2 (sTREM2) and glial fibrillary acidic protein (GFAP), a proxy for astrocyte reactivity. Additionally, 129 participants underwent tau PET scans. We explored the association between plasma sTREM2, GFAP, and primary AD pathology. Plasma sTREM2 was negatively associated with reduced temporal tau PET burden in participants with abnormal Aβ and tau pathology. Higher plasma sTREM2 was related to the weaker association of Aβ pathology and plasma phosphorylated tau with tau PET increases. In contrast, elevated plasma GFAP was related to greater Aβ and tau PET burden along with stronger Aβ-related tau accumulation. Finally, higher plasma sTREM2 was linked to attenuated strength of the association between plasma GFAP and tau PET increases at both pre-defined regions of interest and voxel levels. Altogether, our findings suggest distinct relationships between plasma sTREM2 and GFAP with cerebral tau pathology, providing novel insights into the roles of peripheral TREM2 signaling and astrocytic reactivity in AD neuropathological development. This study has important implications, such as targeting the peripheral TREM2 signature, which may be a potential strategy for future AD therapies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"12 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744880","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":"Cholinergic tone abnormalities and relationships with smoking severity in human cigarette smokers: exploratory positron emission tomography study using [18F]VAT","authors":"Scott J. Moeller, Jodi J. Weinstein, Benjamin Varnas, Olivia Orellano, Roberto Gil, Greg Perlman, Sameera Abeykoon, Jiayan Meng, Ingrid Oprea, Bao Hu, Wenchao Qu, Mark Slifstein, Anissa Abi-Dargham","doi":"10.1038/s41380-025-02985-3","DOIUrl":"https://doi.org/10.1038/s41380-025-02985-3","url":null,"abstract":"<p>Nicotine acts on the brain cholinergic system to drive the rewarding effects of cigarettes and perpetuate smoking. Prior studies in human smokers have used positron emission tomography (PET) to characterize differences in postsynaptic nicotinic acetylcholine receptors (nAChRs). However, preclinical studies indicate that nicotine also modulates presynaptic cholinergic targets that have implications for transmission, including the vesicular acetylcholine transporter (VAChT). To date, there is a paucity of studies imaging presynaptic targets in human smokers. We conducted an initial PET neuroimaging study with [¹⁸F]VAT, which indexes VAChT availability (presynaptic marker of cholinergic tone), in 12 healthy smokers and 13 demographically-matched healthy non-smokers. We tested for group differences in VAChT availability, measured as total distribution volume (V_T), in the striatum (main region of interest) and in multiple cortical and subcortical extrastriatal regions. Within smokers, we also tested correlations between VAChT availability and indices of smoking chronicity and tobacco self-administration. Smokers had higher [¹⁸F]VAT V_T than non-smokers in multiple cortical and subcortical regions (<i>p</i> &lt; 0.05_uncorrected). There were no group differences in the striatum. Within smokers, V_T in the dorsolateral prefrontal and temporal cortices was positively correlated with smoking chronicity (<i>p</i> &lt; 0.05_corrected). This study provides first-line evidence of presynaptic cholinergic differences between smokers and non-smokers, such that VAChT is upregulated in smokers and associated with chronicity. Future studies with larger samples are needed to verify these initial effects. With confirmation, these findings could inform the development of new VAChT-targeting therapeutics that could potentially benefit smokers who have been unable to quit with currently available treatments.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"52 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736628","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":"Mutation of CHD7 impairs the output of neuroepithelium transition that is reversed by the inhibition of EZH2","authors":"Zhuxi Huang, Chenxi He, Guangfu Wang, Ming Zhu, Xiaoyu Tong, Yi Feng, Chenyang Zhang, Shuhua Dong, Yassin Harim, Hai-kun Liu, Wenhao Zhou, Fei Lan, Weijun Feng","doi":"10.1038/s41380-025-02990-6","DOIUrl":"https://doi.org/10.1038/s41380-025-02990-6","url":null,"abstract":"<p>Haploinsufficiency of <i>CHD7</i> (Chromo-Helicase-DNA binding protein 7) causes a severe congenital disease CHARGE syndrome. Brain anomaly such as microcephaly and olfactory bulb agenesis seen in CHARGE patients have not been mimicked in previous animal models. Here, we uncover an indispensable function of <i>CHD7</i> in the neuroepithelium (NE) but not in the neural stem cells (NSCs) after NE transition. Loss of <i>Chd7</i> in mouse NE resulted in CHARGE-like brain anomalies due to reduced proliferation and differentiation of neural stem and progenitor cells, which were recapitulated in <i>CHD7</i> KO human forebrain organoids. Mechanistically, we find that CHD7 activates neural transcription factors by removing the repressive histone mark H3K27me3 and promoting chromatin accessibility. Importantly, neurodevelopmental defects caused by <i>CHD7</i> loss in human brain organoids and mice were ameliorated by the inhibition of H3K27me3 methyltransferase EZH2. Altogether, by implementing appropriate experimental models, we uncover the pathogenesis of <i>CHD7</i>-associated neurodevelopmental diseases, and identify a potential therapeutic opportunity for CHARGE syndrome.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"56 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744883","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":"Metagenomic analysis characterizes stage-specific gut microbiota in Alzheimer’s disease","authors":"Longhao Jia, Yize Ke, Shuo Zhao, Jinxin Liu, Xiaohui Luo, Jixin Cao, Yujia Liu, Qihao Guo, Wei‑Hua Chen, Feng Chen, Jiao Wang, Hao Wu, Jing Ding, Xing‑Ming Zhao","doi":"10.1038/s41380-025-02973-7","DOIUrl":"https://doi.org/10.1038/s41380-025-02973-7","url":null,"abstract":"<p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a decade-long preclinical pathological period that can be divided into several stages. Emerging evidence has revealed that the microbiota-gut-brain axis plays an important role in AD pathology. However, the role of gut microbiota in different AD stages has not been well characterized. In this study, we performed fecal shotgun metagenomic analysis on a Chinese cohort with 476 participants across five stages of AD pathology to characterize stage-specific alterations in gut microbiota and evaluate their diagnostic potential. We discovered extensive gut dysbiosis that is associated with neuroinflammation and neurotransmitter dysregulation, with over 10% of microbial species and gene families showing significant alterations during AD progression. Furthermore, we demonstrated that microbial gene families exhibited strong diagnostic capabilities, evidenced by an average AUC of 0.80 in cross-validation and 0.75 in independent external validation. In the optimal model, the most discriminant gene families are primarily involved in the metabolism of carbohydrates, amino acids, energy, glycan and vitamins. We found that stage-specific microbial gene families in AD pathology could be validated by an in vitro gut simulator and were associated with specific genera. We also observed that the gut microbiota could affect the progression of cognitive decline in 5xFAD mice through fecal microbiota transplantation, which could be used for early intervention of AD. Our multi-stage large cohort metagenomic analysis demonstrates that alterations in gut microbiota occur from the very early stages of AD pathology, offering important etiological and diagnostic insights.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"8 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744882","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":"Deep graph learning of multimodal brain networks defines treatment-predictive signatures in major depression","authors":"Yong Jiao, Kanhao Zhao, Xinxu Wei, Nancy B. Carlisle, Corey J. Keller, Desmond J. Oathes, Gregory A. Fonzo, Yu Zhang","doi":"10.1038/s41380-025-02974-6","DOIUrl":"https://doi.org/10.1038/s41380-025-02974-6","url":null,"abstract":"<p>Major depressive disorder (MDD) presents a substantial health burden with low treatment response rates. Predicting antidepressant efficacy is challenging due to MDD’s complex and varied neuropathology. Identifying biomarkers for antidepressant treatment requires thorough analysis of clinical trial data. Multimodal neuroimaging, combined with advanced data-driven methods, can enhance our understanding of the neurobiological processes influencing treatment outcomes. To address this, we analyzed resting-state fMRI and EEG connectivity data from 130 patients treated with sertraline and 135 patients with placebo from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study. A deep learning framework was developed using graph neural networks to integrate data-augmented connectivity and cross-modality correlation, aiming to predict individual symptom changes by revealing multimodal brain network signatures. The results showed that our model demonstrated promising prediction accuracy, with an R² value of 0.24 for sertraline and 0.20 for placebo. It also exhibited potential in transferring predictions using only EEG. Key brain regions identified for predicting sertraline response included the inferior temporal gyrus (fMRI) and posterior cingulate cortex (EEG), while for placebo response, the precuneus (fMRI) and supplementary motor area (EEG) were critical. Additionally, both modalities identified the superior temporal gyrus and posterior cingulate cortex as significant for sertraline response, while the anterior cingulate cortex and postcentral gyrus were common predictors in the placebo arm. Additionally, variations in the frontoparietal control, ventral attention, dorsal attention, and limbic networks were notably associated with MDD treatment. By integrating fMRI and EEG, our study established novel multimodal brain network signatures to predict individual responses to sertraline and placebo in MDD, providing interpretable neural circuit patterns that may guide future targeted interventions. Trial Registration: Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) ClinicalTrials.gov Identifier: NCT#01407094.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"37 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744821","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":"PD-L1/PD-1 checkpoint pathway regulates astrocyte morphogenesis and myelination during brain development","authors":"Yanyan Wang, Mengtian Zhang, Tianyu Zhang, Shukui Zhang, Fen Ji, Jie Qin, Hong Li, Jianwei Jiao","doi":"10.1038/s41380-025-02969-3","DOIUrl":"https://doi.org/10.1038/s41380-025-02969-3","url":null,"abstract":"<p>Programmed cell death protein 1 (PD-1) and its primary ligand PD-L1 are integral components of a significant immune checkpoint pathway, widely recognized for its central role in cancer immunotherapy. However, emerging evidence highlights their broader involvement in both the central and peripheral nervous systems. In this study, we demonstrate that PD-L1/PD-1 signaling in astrocytes during mouse brain development regulates astrocyte maturation and morphogenesis via the MEK/ERK pathway by targeting the downstream effector cysteine and glycine rich protein 1 (CSRP1). This enhanced astrocyte morphological complexity results in increased end-foot coverage of blood vessels. Additionally, aberrant secretion of CSRP1 by astrocytes interacts with oligodendrocyte precursor cells (OPCs) membrane proteins annexin A1 (ANXA1) and annexin A2 (ANXA2), leading to the exclusion of migrating OPCs from blood vessels. This disruption in OPC migration and differentiation results in abnormal myelination and is associated with cognitive deficits in the mice. Our results provide critical insights into the function of PD-L1/PD-1 signaling in astrocyte-OPC interactions and underscore its relevance to glial cell development and pathogenesis in neurodevelopmental disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"5 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744822","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":"Correction: Investigating dopaminergic abnormalities in schizophrenia and first-episode psychosis with normative modelling and multisite molecular neuroimaging.","authors":"Alessio Giacomel, Daniel Martins, Giovanna Nordio, Rubaida Easmin, Oliver Howes, Pierluigi Selvaggi, Steven C R Williams, Federico Turkheimer, Marius De Groot, Ottavia Dipasquale, Mattia Veronese","doi":"10.1038/s41380-025-02987-1","DOIUrl":"https://doi.org/10.1038/s41380-025-02987-1","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753571","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":"Rac1 in parvalbumin neurons of the medial prefrontal cortex governs rapid forgetting of social memory","authors":"Meng Li, Shi-Zhe Wang, Ya-Bo Zhao, Xun Tang, Lin Xu, Hongsheng Wang, Qi-Xin Zhou","doi":"10.1038/s41380-025-02963-9","DOIUrl":"https://doi.org/10.1038/s41380-025-02963-9","url":null,"abstract":"<p>Social memory can undergo rapid forgetting at first according to the Ebbinghaus forgetting curve, for which the underlying mechanism remains entirely unknown. Here, we reported that rapid forgetting of social memory did not occur as indicated by social preference on stranger 2 (S2) over stranger 1 (S1) mouse, tested shortly after social interaction with S1. However, rapid forgetting of both social and object memories occurred as indicated by no social or object preference, respectively, when the constitutive active (CA) variant of Rac1 was knocked-in parvalbumin (PV) but not somatostatin (SST) neurons of the brain. Furthermore, rapid forgetting of only social memory occurred if this CA variant was knocked-in PV but not SST neurons of the medial prefrontal cortex (mPFC). By contrast, rapid forgetting of social memory was prevented by the dominant negative (DN) variant of Rac1 knocked-in PV neurons of the mPFC. Moreover, fiber photometry revealed that PV but not SST neurons of the mPFC generated dual calcium peaks to delineate each social interaction event. Thus, PV-specific Rac1 activity of the mPFC is both necessary and sufficient for controlling social behavior via rapid forgetting of social memory, providing a novel understanding of social behaviors under health and disease conditions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"30 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733983","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":"COMMENT Targeting hippocampal networks: frequency- and state-dependent effects of transcranial alternating current stimulation","authors":"","doi":"10.1038/s41380-025-02983-5","DOIUrl":"https://doi.org/10.1038/s41380-025-02983-5","url":null,"abstract":"<p>Non-invasive brain stimulation is increasingly recognized as a viable therapeutic strategy for neurological and psychiatric disorders. However, its efficacy depends on understanding how stimulation parameters interact with brain state and network dynamics. A recent study by Luo et al. (2025) provides robust intracranial evidence that transcranial alternating current stimulation (tACS) exerts frequency-specific and state-dependent effects on neural oscillations in the hippocampus and amygdala [1].</p><p>Using multi-site intracranial recordings from patients undergoing stereo electroencephalography (SEEG), the authors demonstrated that 10 Hz tACS elicits a selective and sustained response in the hippocampus, with pronounced modulation of oscillatory activity. This finding aligns with prior work suggesting that alpha-frequency stimulation plays a role in memory consolidation and cognitive enhancement. In contrast, responses in the amygdala were more variable and less predictable across different frequencies, indicating differential network sensitivity to external stimulation.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"102 4 Pt 1 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736490","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":"Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D3 dopamine receptors","authors":"Roberto Cadeddu, Caterina Branca, Giulia Braccagni, Teresa Musci, Ignazio S. Piras, Collin J. Anderson, Mario R. Capecchi, Matthew J. Huentelman, Philip J. Moos, Marco Bortolato","doi":"10.1038/s41380-025-02970-w","DOIUrl":"https://doi.org/10.1038/s41380-025-02970-w","url":null,"abstract":"<p>The gene <i>CELSR3</i> (Cadherin EGF LAG Seven‐pass-G‐type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally, <i>Celsr3</i> mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile of <i>Celsr3</i> mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed that <i>Celsr3</i> mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum of <i>Celsr3</i> mutants. Single-nucleus transcriptomics also showed significant upregulation of the <i>Drd3</i> gene, encoding the dopamine D₃ receptor, in striosomal D₁-positive neurons. In situ hybridization and immunofluorescence confirmed dysregulated D₃ receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D₁-positive neurons. Activating and blocking D₃ receptors amplified or decreased tic-like jerks and stereotypies in <i>Celsr3</i>-deficient mice, respectively. These findings suggest that modifications of D₃ receptor distribution contribute to the tic-like responses associated with <i>Celsr3</i> deficiency.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"29 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723196","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}