Molecular Psychiatry最新文献

{"title":"TNF-dependent regulation of synaptic plasticity and neuronal activity: implications for psychiatric disorders.","authors":"Dionysia Moschou, Houaria Adaïdi, David Stellwagen","doi":"10.1038/s41380-026-03861-4","DOIUrl":"https://doi.org/10.1038/s41380-026-03861-4","url":null,"abstract":"<p><p>Over 20 years ago, it was established that the pro-inflammatory cytokine tumor necrosis factor-α (TNF) can directly regulate neurotransmitter receptor trafficking. On pyramidal neurons, TNF signaling results in the synaptic insertion of AMPA receptors and the removal of GABA_A receptors, shifting the excitatory/inhibitory balance to a more excitable state. The glial release of TNF mediates homeostatic synaptic plasticity (HSP), a compensatory form of plasticity in response to chronic decreases in neuronal activity. This adaptive response can stabilize neuronal circuits, which may be beneficial during development and in certain psychiatric conditions. However, the homeostatic set-point may be dynamically regulated, in a process akin to allostasis. Under these conditions, TNF may act to create or maintain the altered circuit function underlying psychiatric disorders and disease states.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906558","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":"YTHDF1 modulates CAP1-mediated actin turnover to regulate synaptic function and anxiodepressive-like behaviors.","authors":"Xidan Zhou, Si Li, Chen Guo, Songfen Wu, Xiaoli Wu, Min Wu, Cuiting Wu, Kuan Li, Yihui Cui, Tao Zhou","doi":"10.1038/s41380-026-03840-9","DOIUrl":"https://doi.org/10.1038/s41380-026-03840-9","url":null,"abstract":"<p><p>Neuroplasticity and synaptic dysfunction are central to the pathophysiology of depression, yet their underlying mechanisms remain not fully understood. Here, we identify the m⁶A reader protein YTHDF1 as a key regulator of depression pathogenesis. Mice with genetic deletion of Ythdf1 exhibited anterior cingulate cortex (ACC) hyperactivity, hyperalgesia, heightened social stress sensitivity, and anxiodepressive-like behaviors following acute social stress. Using multi-omics approaches, we linked these effects to dysregulated actin cytoskeleton dynamics and identified cyclase-associated protein 1 (CAP1) as a downstream effector of YTHDF1. YTHDF1 deficiency reduced CAP1 expression from early postnatal stages, leading to F-actin accumulation, impaired synaptic function, and behavioral deficits. Strikingly, early postnatal re-expression of YTHDF1 in the ACC normalized CAP1 levels, restored synaptic integrity, and reversed depressive-like phenotypes. Similarly, CAP1 re-expression was sufficient to alleviate stress-induced psychomotor retardation and anxiety. Our findings establish the YTHDF1-CAP1 axis as a critical pathway governing synaptic function and depressive behaviors.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891649","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":"Pharmacological and non-pharmacological modulation of striatal dopamine release: a meta-analysis of [¹¹C]raclopride PET studies.","authors":"Mikael Eklund, Eman Hassanain, Tero Vahlberg, Juho Joutsa, Valtteri Kaasinen","doi":"10.1038/s41380-026-03826-7","DOIUrl":"https://doi.org/10.1038/s41380-026-03826-7","url":null,"abstract":"<p><p>The dopaminergic system has long been a central focus of functional neuroimaging. Positron emission tomography (PET) with the D2/D3 receptor radioligand [¹¹C]raclopride remains the most widely used method for indirectly quantifying striatal dopamine release in vivo. However, no previous meta-analysis has studied the relative magnitude and regional distribution of dopamine release across different interventions or cognitive interventions overall. To address this gap, in this meta-analysis of 92 [¹¹C]raclopride PET studies (n = 1640), we compared the magnitude and regional distribution of dopamine release induced by amphetamine, methylphenidate, ketamine, alcohol, and cognitive challenges with and without reward. Amphetamine induced approximately four-fold greater dopamine release than cognitive challenges (10.9 vs. 2.7%, p < 0.001), and approximately twice that of alcohol (4.8%, p < 0.001), with effects comparable to methylphenidate (11.5%) and slightly greater than ketamine (9.8%). Psychostimulant-induced increase in synaptic dopamine was greater in putamen and ventral striatum than in caudate, whereas alcohol preferentially engaged ventral striatum. Dopamine release did not differ between rewarded and non-rewarded cognitive tasks in the ventral striatum (p > 0.14) or overall striatum (p > 0.10). Methylphenidate-induced increases in synaptic dopamine appeared to attenuate with advancing age, whereas cognitive challenges were associated with greater dopamine release in older individuals. These findings demonstrate that individual pharmacological and cognitive interventions differ markedly in both magnitude and regional pattern of dopamine release. They also suggest that [¹¹C]raclopride PET may have limited sensitivity for distinguishing reward-related from non-reward-related dopamine release. These findings have implications for the design and interpretation of future neuroimaging studies of dopaminergic function in health and disease.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891736","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":"Developmental and cellular vulnerabilities underlie genetic architecture of schizophrenia.","authors":"Yong Wu, Yuan Gao, Miao Li, Chu-Yi Zhang, Yibo Qu, Xiao Xiao","doi":"10.1038/s41380-026-03862-3","DOIUrl":"https://doi.org/10.1038/s41380-026-03862-3","url":null,"abstract":"<p><p>Schizophrenia (SZ) is a highly heritable neuropsychiatric condition with complex polygenic architecture. Elucidating the cellular and developmental substrates vulnerable to the genetic risk is essential for understanding the underlying neurobiological mechanisms. Here, we integrated genome-wide association study (GWAS) and whole-exome sequencing (WES) data with a developmental multi-omics atlas of the human cortex (including 5 cortical regions), comprising about 3 million single-nucleus RNA sequencing (snRNA-Seq) and single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-Seq) profiles across 8 neurodevelopmental processes, to map cell-type-specific enrichment of SZ genetic risk. Our enrichment analyses revealed that both common and rare genetic liabilities converged on broad excitatory and inhibitory neuronal classes. Across different statistical frameworks, we identified genetic enrichment within intratelencephalic (IT) projection neurons and layer 6b excitatory neurons (Ex-L6b) networks across multiple cortical regions. Stage-resolved developmental mapping in the frontal cortex showed that genetic liabilities, particularly the rare variants, are predominantly concentrated within early developmental processes, namely neurogenesis and neuronal migration. Differential expression analysis in postmortem frontal cortex snRNA-Seq datasets cross-validated the cellular substrates of the genetic liabilities. Collectively, our findings establish a high-resolution cellular and temporal framework of SZ susceptibility, implicating mature associative IT microcircuits, deep-layer thalamocortical-regulating networks, and early developmental specification windows as primary points of genetic convergence in SZ.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887388","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":"Severe PTSD symptoms magnify episodic memory-encoding deficits and amygdala-ACC attenuation during unpredictable threat in male combat veterans.","authors":"Kristoffer C Aberg, Shai Efrati, Sagi Idan, Rachel Merzbach, Rony Paz, Keren Doenyas-Barak","doi":"10.1038/s41380-026-03845-4","DOIUrl":"https://doi.org/10.1038/s41380-026-03845-4","url":null,"abstract":"<p><p>PTSD is marked by atypical coupling between emotion and learning, yet it remains unclear how threat that is situational (the presence of potential danger) shapes episodic memory. We investigated whether unpredictability-driven threat alters incidental memory formation as a function of PTSD symptom severity (PTSDss). Sixty male combat veterans underwent fMRI scanning during incidental encoding of everyday objects presented under unpredictable threat (U), predictable threat (P), or no threat (N). Threat was operationalized as potential exposure to a highly aversive sound. An unexpected recognition test followed 90 min later. We related memory (hit rates), subjective anxiety, and encoding-related BOLD activity to PTSDss assessed with CAPS-5. Greater PTSDss predicted heightened anxiety and poorer memory for items specifically presented under unpredictable threat. While amygdala and dorsal anterior cingulate activity during encoding tracked overall memory success, these responses were attenuated with increasing PTSDss in the U condition. By linking unpredictable threat to both behavioral and neural markers of disrupted episodic memory encoding, the study helps explain how memory-related symptoms may develop and persist in PTSD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887429","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":"Advanced glycation end products drive blood-brain barrier lipid dysregulation via RAGE-ABCA1 signaling to promote neurovascular dysfunction in Alzheimer's disease.","authors":"Firoz Akhter, Asma Akhter, Xinying Guo, Xiongwei Zhu, Zhen Zhao, Donghui Zhu","doi":"10.1038/s41380-026-03865-0","DOIUrl":"https://doi.org/10.1038/s41380-026-03865-0","url":null,"abstract":"<p><p>Neurovascular dysfunction is an early and critical contributor to Alzheimer's disease (AD), yet the molecular mechanisms linking vascular pathology to metabolic dysregulation remain incompletely understood. Advanced glycation end products (AGEs), which accumulate during aging and metabolic stress, have been implicated in AD pathology; however, their role in cerebrovascular lipid homeostasis is unclear. Here, we demonstrate that AGE accumulation within cerebral microvessels promotes lipid droplet (LD) formation in endothelial cells through receptor for AGE (RAGE)-dependent disruption of cholesterol efflux pathways. In aged APP transgenic mice and human AD brains, we observe increased AGE deposition concomitant with elevated RAGE, DGAT1, and perilipin expression, alongside reduced ABCA1 levels. In human brain endothelial cells, AGE exposure induces lipid metabolic reprogramming characterized by enhanced LD accumulation, upregulation of lipogenic machinery, and suppression of cholesterol efflux. Mechanistically, RAGE silencing restores ABCA1 expression and attenuates LD formation, identifying RAGE as a key upstream regulator. Pharmacological activation of ABCA1 reverses AGE-induced lipid accumulation and reduces RAGE expression, highlighting a therapeutic axis. Furthermore, AGE exposure disrupts blood-brain barrier (BBB) integrity and impairs amyloid-β transport in an in vitro BBB model. In vivo, aging is associated with progressive microvascular LD accumulation, linking metabolic dysfunction to vascular pathology. Together, our findings establish an AGE-RAGE-ABCA1 signaling axis that drives endothelial lipid dysregulation and BBB impairment, providing a mechanistic framework connecting metabolic stress to neurovascular dysfunction in AD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880885","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":"Heterogeneous structural brain signatures of methamphetamine and ketamine use disorders revealed by normative modeling.","authors":"Yunkai Sun, Yehong Fang, Pu Peng, Qiuxia Wu, Jinsong Tang, Yanhui Liao","doi":"10.1038/s41380-026-03859-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03859-y","url":null,"abstract":"<p><p>Marked interindividual heterogeneity in substance use disorder (SUD) impedes the identification of consistent neuroanatomical alterations, limiting the development of robust markers for clinical risk stratification. We applied a normative modeling framework to explore individual neuroanatomical deviations in individuals with SUD across two distinct substance classes, and assessed their potential for classification and risk prediction. We established a developmental normative model of gray matter volume (GMV) using T1-weighted images from 1209 healthy individuals aged 18-65 years. Deviations from this normative model were then estimated for 184 individuals with methamphetamine use disorder (MUD), 94 with ketamine use disorder (KUD), and 220 healthy controls (HC) collected from two independent sites. Based on these individual deviation scores, a machine learning model was constructed to identify individuals at risk for SUD. The normative model revealed high interindividual heterogeneity in GMV deviations among individuals with MUD and KUD. Cross-substance extreme negative deviations were primarily located in regions of the default mode network (DMN). Notably, individual-level deviations could successfully distinguish both MUD and KUD from HC, and replicated in an external dataset. We further identified significant associations between abnormal GMV trajectories and neurobiological features, particularly myelination and neurotransmitter systems. These findings enhance our understanding of the heterogeneous neurobiology underlying SUD, providing potential neurobiological biomarkers for clinical diagnosis, risk stratification, and prevention.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881112","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":"Striatal dopaminergic function and cortical functional connectivity in 22q11.2 deletion syndrome: an integrative multimodal ¹⁸F-DOPA PET and magnetic resonance imaging study.","authors":"Valentina Mancini, Maria Rogdaki, Sameer Jauhar, Manuela Moretto, Mattia Veronese, Federico Turkheimer, Oliver D Howes, Robert A McCutcheon","doi":"10.1038/s41380-026-03839-2","DOIUrl":"https://doi.org/10.1038/s41380-026-03839-2","url":null,"abstract":"<p><p>Dopaminergic signalling is critical for regulating large-scale brain network dynamics and is implicated in the pathophysiology of psychotic disorders. 22q11.2 deletion syndrome (22q11DS), a high-penetrance genetic risk factor for schizophrenia, is associated with both dopaminergic alterations and disruptions in functional connectivity (FC), yet the degree to which these separate people with 22q11DS from healthy controls and their inter-relationship remains unclear. Eighteen individuals with 22q11DS (no history of psychosis or antipsychotic use) and 22 controls underwent [¹⁸F]-DOPA PET imaging to assess striatal dopamine synthesis (indexed by Ki^cer values) and resting-state fMRI to examine FC. Classification performance using FC, dopamine measures, and their combination was assessed via repeated 10-fold cross-validation. Associations between Ki^cer, connectivity, and psychotic symptoms were evaluated using linear regression. FC alone classified 22q11DS with 68% balanced accuracy (p = 0.004), Ki^cer alone with 77% (p < 0.001), and combined measures with 85% balanced accuracy (p < 0.001), indicating additive value. The somatomotor and auditory networks contributed most to group discrimination. Across individuals, higher Ki^cer was significantly associated with more control-like connectivity profiles (p = 0.011), with significant effects in all striatal subdivisions. No association was found between FC and subclinical psychotic symptoms. This multimodal study demonstrates a significant association between striatal dopamine synthesis capacity and functional brain network architecture in 22q11DS. Higher dopamine synthesis was linked to more normative FC, potentially suggesting FC differences reflect a compensatory, rather than pathogenic role. These findings bridge genetic risk at the 22q11.2 locus with dopamine dysfunction and large-scale networks, offering novel insights into the neurobiology of 22q11DS and related neuropsychiatric risk.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881081","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: Mechanistic insights into cannabidiol-mediated TrkB activation via FRS2 interaction in attenuating Alzheimer's disease pathology and cognitive impairment.","authors":"Jiantao Liu, Feiyuan Peng, Penghui Li, Chuangyu Yao, Sha Jin, Guoli Wu, Tianshu Zhang, Qiulian Liang, Xiaohui Wang, Xiubo Du","doi":"10.1038/s41380-026-03864-1","DOIUrl":"10.1038/s41380-026-03864-1","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881124","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":"Maternal immune activation disrupts epigenomic and functional maturation of cortical excitatory neurons.","authors":"Chi-Yu Lai, Jessica Arzavala, Antonio Pinto-Duarte, Shiyuan Wang, Junhao Li, Hanqing Liu, Julia Osteen, Rosa Gomez Castanon, Joseph Nery, Susan B Powell, Joseph R Ecker, Eran A Mukamel, M Margarita Behrens","doi":"10.1038/s41380-026-03856-1","DOIUrl":"10.1038/s41380-026-03856-1","url":null,"abstract":"<p><p>Elevated levels of maternal pro-inflammatory cytokines following severe infection during gestation can disrupt offspring neural development and increase the risk of neurodevelopmental disorders. The viral mimetic Poly(I:C) reproduces the effects of gestational influenza exposure, leading to behavioral outcomes that recapitulate neurodevelopmental disorder phenotypes. Although Poly(I:C)-induced maternal immune activation (PIC-MIA) alters the epigenome, behavior and cognition of offspring in adulthood, it remains unclear when these changes occur and how MIA influences the epigenomic regulatory programming across the transition from embryonic development to the mature brain. Here, we examined the effects of PIC-MIA on the epigenomic maturation of the frontal cortex, focusing on excitatory neuron-specific DNA methylation and transcriptomic dynamics throughout perinatal development. Mid-gestation PIC-MIA disrupted development of the excitatory neuron transcriptome, with the largest alterations observed at birth. PIC-MIA altered the development of the mature DNA methylation program of excitatory neurons at thousands of genomic regulatory regions that normally gain or lose methylation during development. Transcription factor binding site analyses of these differentially methylated regions revealed a significant enrichment of Tbr1 motifs within hyper-methylated deep-layer neuron-specific regions at birth. Notably, transcriptional targets of Tbr1 were down-regulated at birth despite up-regulation of Tbr1 transcription, suggesting PIC-MIA uncouples Tbr1 expression from its regulatory function in deep-layer neurons. Electrophysiological recordings of intrinsic and firing properties further confirmed a lasting disruption in deep-layer neuronal activity. Our results suggest that mid-gestation MIA may alter the development of deep-layer neurons through an epigenomic blockade of Tbr1 function, thereby perturbing normal cortical circuit formation.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881132","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}