Molecular Psychiatry最新文献

{"title":"Is cold exposure a viable lifestyle intervention for mental health? Reviewing evidence and mechanisms.","authors":"Liam Browning, Nicholas Fabiano, Brandon Luu, Kirsten Brinkmeier, David Puder","doi":"10.1038/s41380-026-03878-9","DOIUrl":"https://doi.org/10.1038/s41380-026-03878-9","url":null,"abstract":"<p><p>Cold exposure has gained substantial popularity as a wellness intervention, with growing public interest in its potential to alleviate symptoms of depression, anxiety, and stress-related disorders. While early observational studies and anecdotal reports suggest mental health benefits, the empirical evidence remains limited and methodologically inconsistent. This review critically evaluates the current state of research on cold exposure and mental health, with a focus on three key physiological systems implicated in its proposed effects: the catecholamine system, the hypothalamic-pituitary-adrenal (HPA) axis, and immune-inflammatory pathways. We examine evidence from randomized controlled trials (RCTs), observational studies, and translational models, highlighting both promising findings-such as acute mood enhancement and stress modulation-and persistent uncertainties regarding mechanism and clinical relevance. Despite theoretical plausibility and preliminary support, existing studies are hindered by small sample sizes, heterogeneous protocols, lack of active placebo controls, and selection bias stemming from self-selected, health-motivated participants. Psychological improvements reported in several studies have not been consistently linked to objective biological changes. We conclude that cold exposure represents a promising, yet still unproven, adjunct for mood regulation. Future research should prioritize standardized protocols, active control conditions, and recruitment of clinical populations to clarify its therapeutic potential and underlying mechanisms.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977331","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":"Gut single-microbe landscape in patients with major depressive disorder and bipolar disorder.","authors":"Yi Chen, Anying Tang, Xinxin Xu, Jie Li, Kaijing Ding, Yunbo Chen, Yongcheng Wang, Shaohua Hu, Jianbo Lai","doi":"10.1038/s41380-026-03882-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03882-z","url":null,"abstract":"<p><p>Microbial communities in the human gut are highly diverse and complex, and many play critical roles in health and disease. Their functioning depends not only on species composition and diversity but also on intra- and intercellular transcriptional dynamics. Robust technologies capable of capturing single-microbe RNA sequencing information are urgently needed to understand microbial heterogeneity and host interactions. In this exploratory study, we applied droplet-based single-microbe RNA sequencing (smRNA-seq2) to analyze gut microbiomes from five patients with major depressive disorder (MDD), five with bipolar disorder (BD), and five healthy participants (HP), generating a transcriptional atlas of 33,174 single microbial cells. Unsupervised clustering based on RNA expression profiles partitioned these cells into 37 distinct clusters, reflecting both taxonomic diversity and intra-species functional heterogeneity. The most dominant clusters were identified as Fusicatenibacter saccharivorans, Phocaeicola dorei, Enterocloster sp000431375, and Clostridium_Q sp003024715. Compositional and transcriptional differences were observed across diagnostic groups, with clustering patterns appearing to be influenced by disease, gender, and age. Functional heterogeneity was evident in oxidative stress and metabolic genes such as sodB, mdh2, and eno2 in Phocaeicola dorei, while stress-response genes (htpG_1, groL, dnaK, clpB) were upregulated in BD. Focusing on the ko03110 pathway (chaperones and folding catalysts), species-specific patterns emerged: Clostridium_Q_sp003024715 was positively associated with health but decreased in disease status; Enterocloster_sp000431375 and Fusicatenibacter saccharivorans were upregulated in BD; and Phocaeicola dorei was downregulated in MDD. Together, these findings suggest the presence of functional and phenotypic heterogeneity within the gut microbiome in mood disorders and identify exploratory microbial transcriptomic features that may be associated with group-level differences, warranting further validation in larger cohorts.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970104","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":"Genome-wide association meta-analysis of eating behavior traits revealed one susceptibility locus for emotional eating.","authors":"Manon Muntaner, Katrin Horn, Blandine de Lauzon-Guillain, Muriel Tafflet, Teemu Palviainen, Kirsi H Pietiläinen, Guiomar Masip, Braxton D Mitchell, Christian Couture, Marie-Claude Vohl, Janne Pott, Philippe Amouyel, Monique Romon, Louis Perusse, Nanette Steinle, Jaakko Kaprio, Barbara Heude, Anke Tönjes, Peter Kovacs, Markus Scholz, Aline Meirhaeghe","doi":"10.1038/s41380-026-03889-6","DOIUrl":"https://doi.org/10.1038/s41380-026-03889-6","url":null,"abstract":"<p><p>In order to identify new and genome-wide significant loci for eating behavior traits (cognitive restraint, uncontrolled eating and emotional eating), we conducted a meta-GWAS with seven studies of European ancestry (n = 11,250). Eating behavior was assessed using the Three-Factor Eating Questionnaire. Genotype effects of single studies were estimated using additive models adjusting for age, sex, BMI, and principal components and single study results were combined by fixed-effect meta-analysis.For cognitive restraint and uncontrolled eating, no genome-wide significant association could be detected. For emotional eating, one genomic region on chromosome 5 comprising two polymorphisms attained genome-wide significance (P = 4.0×10^-8 for rs6877636 and P = 3.2×10^-8 for rs6897090). The minor alleles were associated with higher emotional eating scores (β=0.093 ± 0.017), with a similar direction of effect in each study. Both SNPs, in near perfect linkage disequilibrium, mapped to RP11-24P24.1, a processed pseudogene of ornithine decarboxylase 1 (ODC1). Enrichment analysis revealed a significant overlap between genome-wide BMI-associated variants and nominal emotional eating variants, supporting the hypothesis that shared genetic factors may influence both eating behavior traits and obesity risk. Finally, we observed a number of interesting associations reaching suggestive significance (P < 10^-6) involving BMI candidate genes, including a suggestive association between FTO variants and cognitive restraint (rs9922708, β = 0.069, P = 5.9×10^-7).In conclusion, our meta-GWAS identified for the first time a robust chromosomal region associated with emotional eating in seven studies. Given that emotional eating strongly influences body weight but is often stigmatized, recognizing genetic susceptibility to certain eating behaviors may help reduce stigma and alleviate guilt.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970077","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":"Prevalent and characteristic alterations in blood-brain transcriptomic-functional imaging coupling in schizophrenia.","authors":"Yu-Sha Ji, Yi-Feng Liu, Zhi-Qiang Mu, Liu Fang-Fang, Miao-Yan Liu, Min Liu, Jia-Ni Zhao, Wen-Jun Wu, Di Wu, Ya-Hong Zhang, Xiao-Hui Li, Yong-Bin Wei, Fang-Lin Guan, Yue-Lang Zhang, Hua-Ning Wang, Kun Chen, Long-Biao Cui, An-An Yin, Yuan-Ming Wu","doi":"10.1038/s41380-026-03873-0","DOIUrl":"https://doi.org/10.1038/s41380-026-03873-0","url":null,"abstract":"<p><p>Schizophrenia (SCZ) is increasingly recognized as a multi-system disorder characterized by peripheral immunometabolic dysregulation. To investigate system-level blood-brain integration, we analyzed peripheral blood transcriptomics, resting-state fMRI (fALFF), and cognitive data from two cohorts (Discovery: 43 SCZ, 60 HCs; Validation: 41 SCZ, 29 HCs). Seven robust peripheral blood gene co-expression modules associated with SCZ were identified, enriched for immune and metabolic pathways. These modules showed reproducible disease associations in independent blood cohorts. Widespread alterations in functional coupling between these gene modules and intrinsic brain activity (fALFF) were observed in SCZ, characterized by a network-specific reconfiguration with an inverse pattern of correlation changes between limbic and frontoparietal/default mode networks. This dysregulated coupling pattern was highly reproducible across cohorts. We further identified putative core disease-associated module-network pairs: a downregulated metabolic module coupled with frontoparietal/default mode regions, and an upregulated ribosomal module coupled with limbic regions. Integration of these multimodal features yielded a proof-of-concept improvement in SCZ diagnostic classification (AUCs: 0.71-0.77 in an independent temporal but local validation cohort). Correlation and mediation analyses suggested that brain functional activity in these coupled regions may mediate the relationship between peripheral gene expression and cognitive impairment. Collectively, these findings reveal distinct, reproducible dysregulation of peripheral-central functional coupling in SCZ, offering a multi-scale framework for understanding its pathophysiology and highlighting the potential of trans-scale features as candidate biomarkers for diagnosis and mechanistic insight.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970043","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":"Young minds in distress: Exploring the global rise in youth mental health diagnoses.","authors":"Huey-Ling Chiang, Yi-Ling Chien, Susan Shur-Fen Gau","doi":"10.1038/s41380-026-03884-x","DOIUrl":"https://doi.org/10.1038/s41380-026-03884-x","url":null,"abstract":"<p><p>Adolescence represents a critical neurobiological period marked by a developmental \"mismatch\" between early-maturing limbic systems and the later-maturing prefrontal cortex, conferring heightened vulnerability to the onset of psychiatric disorders. This review synthesizes global epidemiological trends, differentiates true increases in morbidity from diagnostic inflation, and integrates evidence-based intervention strategies. In high-income countries, youth depression, suicide mortality, and self-harm have risen substantially, supported by objective indicators of illness severity that extend beyond changes in diagnostic practices. Key environmental drivers include pervasive digital engagement, cyberbullying, sleep disruption, and academic pressure, with sleep disturbances emerging as a central transdiagnostic risk factor. The COVID-19 pandemic accelerated these pre-existing trajectories of mental health deterioration, with particularly marked effects on eating-disorder incidence and social-emotional development. To address these challenges, we suggest a three-tiered intervention framework. Universal approaches should emphasize regulation of digital environments, implementation of Social-Emotional Learning, and institutional support for regular physical activity. Selective interventions should target high-risk youth by proactively monitoring sleep health and mitigating achievement-related stress in academically competitive settings. Indicated care requires integrated delivery of evidence-based psychotherapies alongside structured return-to-learn protocols following psychiatric hospitalization. Ultimately, translating epidemiological risk into effective prevention demands a shift from reactive, diagnosis-centered models to proactive frameworks that prioritize early risk reduction and the reinforcement of protective factors. By fostering environments that promote circadian stability, physical activity, emotional regulation, and peer connectedness, youth mental health can be strengthened as a foundation for societal well-being, resilience, and adaptive functioning in an increasingly complex world.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956143","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":"Common genetic variants are associated with increased likelihood of latent co-occurring neurodevelopmental and mental health factors among autistic individuals.","authors":"Adeniran Okewole, Vincent-Raphael Bourque, Mahmoud Koko, Guillaume Huguet, Anders D Borglum, Jakob Grove, Sebastien Jacquemont, Simon Baron-Cohen, Varun Warrier","doi":"10.1038/s41380-026-03880-1","DOIUrl":"https://doi.org/10.1038/s41380-026-03880-1","url":null,"abstract":"<p><p>Autistic individuals show elevated rates of co-occurring neurodevelopmental and mental health conditions, yet the genetic architecture of those comorbidities remains unclear. Using phenotypic (N = 74,204) and genetic (N = 17,582) data from the SPARK study, we investigated the factor structure, heritability, genetic correlation with autism (pleiotropy) and corresponding conditions in the general population (additivity). First, confirmatory factor analysis identified three correlated factors mirroring general population patterns: behavioural (ADHD, disruptive behaviour disorders), cothymic (depression, anxiety), and thought disorder (schizophrenia, bipolar). Second, all three factors had significant SNP heritabilities whilst rare variants were not associated with the tested factors in our sample. Third, polygenic scores and genetic correlations revealed positive shared genetics between the three factors and corresponding conditions in the general population but not with autism, supporting the additivity hypothesis. Fourth, within-family analyses (N = 5236 trios) demonstrated direct but not indirect genetic effects for the behavioural and cothymic factors. In sum, we find evidence for additive effects of other genetic factors in contributing to some latent co-occurring neurodevelopmental and mental health conditions in autism.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956148","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":"PQBP1-dependent alternative RNA splicing underlies high calorie diet-induced cognitive impairment.","authors":"Yong Huang, Hidenori Homma, Yuki Yoshioka, Takaki Watanabe, Shuhei Fujino, Kyoko Matsuyama, Xigui Chen, Kyota Fujita, Hiroki Shiwaku, Albert R La Spada, Masanobu Kano, Hikari Tanaka, Hitoshi Okazawa","doi":"10.1038/s41380-026-03868-x","DOIUrl":"10.1038/s41380-026-03868-x","url":null,"abstract":"<p><p>High calorie-high fat diet (HFD) has been implicated as a pathological modifier of brain diseases including neurodegenerative dementias, but the detailed molecular mechanisms remain largely unknown. Here we report that HFD suppresses PPARγ-mediated transcriptional expression of PQBP1, a RNA splicing factor implicated in human intellectual disability and Alzheimer's disease. RNAseq-based comprehensive analyses of alternative RNA splicing (AS) in HFD-fed mice for 1 or 6 weeks and in PQBP1-cKO mice reveal their common changes, which weigh on synapse-related genes. Betweenness-based extraction of core molecules from the common changes reveals CASK, Cacnb1 and Cyfip2 as key molecules of the network. Both CASK and Cacnb1 regulate STXBP1, a causative gene for infantile epilepsy syndrome and an essential factor for synapse vesicle release, via their direct interaction. In addition, our analysis suggests that Syt1 plays a role specifically in HFD for 1 week. HFD-induced AS isoforms of CASK, Cacnb1, Cyfip2 and Syt1 impair pre-synapse vesicle release in primary neurons. AAV-PQBP1, AAV-CASK, AAV-Cacnb1, AAV-Cyfip2 or AAV-Syt1 rescues synapse and/or cognitive dysfunctions in HFD mice, genetically supporting the pathological PQBP1-presynapse axis in HFD. Moreover, immunohistochemistry experiments suggest that the pathological axis plays roles not only in excitatory neurons, but also in inhibitory neurons of the brain. Collectively, our results unravel a novel molecular mechanism for brain dysfunction when mice are exposed to a HFD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956146","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":"Characterizing features of the genetic architecture underlying autism from a multi-ancestry perspective","authors":"Marla Mendes,Chen Yang Xu,Worrawat Engchuan,Brett Trost,Xiaopu Zhou,Bruno Akio Miwa,Nelson Bautista Salazar,Jack Iglar,Bhooma Thiruvahindrapuram,Liam Wallich,Thales Henrique de Paiva,Eduardo Tarazona-Santos,Bridget Fernandez,Victor Borda,Stephen W. Scherer","doi":"10.1038/s41380-026-03886-9","DOIUrl":"https://doi.org/10.1038/s41380-026-03886-9","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"55 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923252","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":"The psychiatric risk gene CACNA1C encodes distinct full-length isoforms in human brain, heart and aorta","authors":"Nicola AL Hall,Arne W. Mould,Isar Nassiri,Sofia Kudasheva,David J. Wright,Li Chen,Osama A. Arshad,Ran Tao,Joel E. Kleinman,Daniel R. Weinberger,Thomas M. Hyde,Paul J. Harrison,Wilfried Haerty,Elizabeth M. Tunbridge","doi":"10.1038/s41380-026-03890-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03890-z","url":null,"abstract":"Abstract CACNA1C is a risk gene for multiple psychiatric disorders and the Ca V 1.2 protein it encodes is a potential target for their treatment. It is known that alternative start exon usage and splicing of CACNA1C RNA results in multiple transcript isoforms. However, the identity of full-length isoforms, and their relative abundance between tissues, remains unknown. Such information is important for understanding the molecular mechanisms of illness associations and to advance the potential for Ca V 1.2 isoform-selective drugs. In this study we compared full-length isoforms expressed in human brain with those expressed in heart and aorta using PCR-targeted long-read nanopore amplicon sequencing. We also performed 5’-RACE to profile which CACNA1C transcription start exons are used. CACNA1C RNA splicing revealed distinct tissue-enriched isoforms in brain, heart and aorta, with the results corroborated by publicly available short-read RNA-seq data. For example, splicing of mutually exclusive exons 21 and 22 differentiated isoforms expressed in the brain from those in the heart and aorta. 5’-RACE identified a novel start exon, exon 1d, which was detected in brain and aorta but not heart, and which predicts channels with a truncated N-terminus. The full-length isoforms identified here, from both the previously known start exons and the novel start exon, are likely to impact on the function and the pharmacology of the encoded Ca V 1.2 channel. Identification of brain-enriched isoforms provides the possibility of designing drugs preferentially targeting Ca V 1.2 for psychiatric indications.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"81 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923253","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":"The contribution of common and rare genetic variation to emotional and behavioural symptoms in childhood and adolescence","authors":"Olivia Wootton,Emma E. Wade,Daniel S. Malawsky,Mahmoud Koko,Wei Huang,Qin Qin Huang,Varun Warrier,Matthew E. Hurles,Hilary C. Martin","doi":"10.1038/s41380-026-03851-6","DOIUrl":"https://doi.org/10.1038/s41380-026-03851-6","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"54 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923254","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}