Molecular Psychiatry最新文献

{"title":"Early-childhood temperament trajectories map onto transdiagnostic psychiatric risk","authors":"J. Kopal,N. R. Bakken,P. Parekh,A. A. Shadrin,P. Jaholkowski,L. A. R. Ystaas,N. Parker,O. B. Smeland,E. P. Tissink,I. E. Sønderby,K. S. O’Connell,O. Frei,A. M. Dale,O. A. Andreassen","doi":"10.1038/s41380-026-03881-0","DOIUrl":"https://doi.org/10.1038/s41380-026-03881-0","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923251","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":"Corticotropin-releasing hormone neurons in the bed nucleus of the stria terminalis control wakefulness in physiological and stressful conditions in mice.","authors":"Kai-Lin Zhang, Wei Xu, Pan Sun, Heng-Yu Liu, Lv-Ming Wang, Mieradili Aimaiti, Ke-Xin Wang, Wei-Min Qu, Zhi-Li Huang, Lu Wang","doi":"10.1038/s41380-026-03885-w","DOIUrl":"https://doi.org/10.1038/s41380-026-03885-w","url":null,"abstract":"<p><p>Stressful and emotionally salient stimuli often trigger heightened wakefulness that can predispose to sleep disorders such as insomnia. The bed nucleus of the stria terminalis (BNST), a center for emotional information processing and anxiety-related behaviors, contains diverse neuropeptide-enriched neuronal subpopulations that may respond to and drive opposing emotional states. Although recently implicated in arousal regulation, the mechanisms by which BNST neuronal subpopulations control sleep-wake states remain unclear. Here, we show that optogenetic activation of corticotropin-releasing hormone (CRH)-expressing neurons, but not cholecystokinin- or somatostatin-expressing neurons, in the BNST triggers a rapid shift from non-rapid eye movement sleep to wakefulness in male mice. BNST CRH neurons are active during both wakefulness and rapid eye movement (REM) sleep, and their optogenetic activation also triggers wakefulness from REM sleep. Chemogenetic activation of BNST CRH neurons significantly increases the amount and alpha (8-13 Hz) power of wakefulness, whereas their inhibition decreases wakefulness. Moreover, inhibition of BNST CRH neurons alleviates stress-induced heightened wakefulness. These results identify BNST CRH neurons as key regulators of wakefulness under physiological and stressful conditions and suggest them as potential targets for stress-induced heightened wakefulness and insomnia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930649","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":"Psychedelic 4-AcO-DMT attenuated looming-induced freezing behaviors by activating PrL ^CaMKIIα neurons in mice.","authors":"Ke Xia, Yuanyuan Wang, Junhong Liu, Yishan Yao, Ruibin Su, Haitao Yan","doi":"10.1038/s41380-026-03894-9","DOIUrl":"https://doi.org/10.1038/s41380-026-03894-9","url":null,"abstract":"<p><p>Psychedelics modulate emotion and cognition, yet the underlying mechanisms remain unclear. Given the ability of psychedelics to induce visual hallucinations, we employed the looming model-a visual threat assay that combines visual stimulation with innate fear-to investigate the effects of psychedelics. Unexpectedly, 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), a psychedelic compound that acts as a prodrug of psilocin and exhibits comparable central nervous system effects to psilocybin, significantly reduced looming-induced freezing behavior compared to R/S-MDMA, without eliciting overt hallucinogen-like effects under the current experimental conditions. This anti-fear effect was independent of β-arrestin 2 signaling and visual function, but associated with decreased innate fear emotion. We identified that 4-AcO-DMT activates CaMKIIα neurons in the prelimbic cortex (PrL) via 5-HT_2A receptors, and the PrL ^CaMKIIα-MD ^CaMKIIα circuit mediates this response. Our findings reveal that despite being designed from a visual hallucination perspective, the looming model unexpectedly uncovers a robust anti-innate fear effect of psychedelics, providing new insights into their emotional modulation and therapeutic potential.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920729","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":"Novel insight into the effects of the metabolites from gut microbiota in both unmedicated depressive adolescents and mice: key roles of indole derivatives-aryl hydrocarbon receptor signaling in neurogenesis and microglial homeostasis.","authors":"Xi Wang, Miaoyang Hu, Weilan Wu, Jing Liu, Zhiru Tang, A Yiguzaili Manglike, Jin Wei, S Thameem Dheen, Yuan Lin, Gang Liu, Jie Cheng, Wenjuan Wang, Rong Gao, Xufeng Chen, Jun Wang","doi":"10.1038/s41380-026-03895-8","DOIUrl":"https://doi.org/10.1038/s41380-026-03895-8","url":null,"abstract":"<p><p>Adolescent depression is undergoing a rapid surge and has become a severe global public health challenge. However, current therapeutic approaches are limited and often accompanied by significant side effects primarily due to the elusive underlying mechanisms. The gut-brain axis has recently gained growing attention for its pivotal roles in neuropsychiatric disorders, particularly the tryptophan (Trp) metabolism by the microbiota. With the 16S rRNA gene sequencing, the abundance of Bacteroidetes, a microbiota phylum that includes several taxa involved in tryptophan metabolism and indole derivative production was significantly reduced in unmedicated adolescents with depression. The in-depth analysis showed that levels of key indole derivatives, including IAA, IPA and IAld, were markedly decreased in depressed patients; crucially, these reductions showed a significant negative correlation with depression severity scores. Consistent with the clinical findings, a similar decline in IAA, IPA, and IAld levels was observed in adolescent mice with depression induced by chronic restraint stress (CRS). Notably, depression-like behaviors in these mice were substantially ameliorated by a high-Trp diet (CRS + 1.19% Trp) and direct supplementation with indole derivatives. In a reciprocal experiment, a low-Trp diet (0.09% Trp) was found to de novo induce depressive behaviors in otherwise healthy mice. Morphological analysis of brain tissue uncovered another critical insight, the microglial cells in CRS mice exhibited hallmark features of overactivation. Remarkably, both the high-Trp diet and indole derivative supplementation exerted consistent protective effects, shown as restored microglial morphology and neurogenesis. Mechanistically, the indole derivatives were shown to activate AhR signaling, which in turn balanced the expression of anti-inflammatory factors (e.g., IL-10, TGF-β) and pro-inflammatory factors (e.g., IL-1β, CD68), thereby remodeling microglial morphology and promoting neurogenesis in hippocampus. A series of loss-of-function and gain-of-function experiments further confirmed AhR's essential role: the salutary effects of indole derivatives on anti-depression were substantially attenuated in AhR^-/- mice; reciprocally, conditional microglia-specific overexpression of AhR in the hippocampus of CRS mice significantly ameliorated CRS-induced depressive-like changes, accompanied by suppression of microglial activation and upregulation of anti-inflammatory factors. Collectively, the present study revealed a previously unrecognized the microbiota-derived indole derivatives ameliorated CRS-induced adolescent depression via the AhR signaling pathway. These findings highlight that targeting the indole derivative-AhR signaling axis may represent a novel therapeutic strategy for adolescent depression, one with the potential to minimize side effects and address the unmet clinical needs of this vulnerable population.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920737","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":"Distinct depressive-like behavioural phenotypes in mice exhibit unique patterns of transcriptional perturbations across habenular cell subtypes.","authors":"Priyam Narain, Marko Šušić, Aleksa Petković, Giuseppe Antonio-Saldi, Marc Arnoux, Mehar Sultana, Beemnet Andualem Belete, Dipesh Chaudhury","doi":"10.1038/s41380-026-03843-6","DOIUrl":"https://doi.org/10.1038/s41380-026-03843-6","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is characterized by substantial heterogeneity, which hinders attempts to associate distinct symptoms with specific neural mechanisms. The lateral habenula (LHb) is a key brain region involved in negative affect and reward processing, but the molecular changes in the LHb that lead to mood disorders remain unclear. Here, we combined chronic social defeat stress (CSDS), behavioural phenotyping, and single-cell RNA sequencing to examine cell-type and subregion-specific transcriptional changes in the mouse habenula. Mice were classified into behavioural phenotypes reflecting social avoidance, anhedonia, passive coping, resilience, or susceptibility. We identified nine major habenular cell classes and found distinct phenotype-associated transcriptional signatures across both neurons and glia. Distinct transcriptional signatures were observed in LHb neurons of susceptible animals and in oligodendrocytes of resilient animals. Subregional analysis revealed that the oval-medial LHb accounted for most stress-related transcriptional changes, while the HbX subregion displayed a unique molecular signature associated with passive coping behaviour. These findings highlight the cellular heterogeneity of stress responses within the habenula and will pave the way for identifying potential targets for precision psychiatry approaches in depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912889","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":"Mapping the dual functional organization of the substantia nigra.","authors":"Dániel Veréb, Blanca Zufiria-Gerbolés, Massimiliano Passaretti, Mite Mijalkov, Mattia Veronese, Joana B Pereira","doi":"10.1038/s41380-026-03803-0","DOIUrl":"https://doi.org/10.1038/s41380-026-03803-0","url":null,"abstract":"<p><p>The human substantia nigra (SN) is a central hub for dopaminergic signalling and a key site of pathology in Parkinson's disease (PD). However, its internal functional organization in human individuals is not well understood. To fill this knowledge gap, here we applied connectopic mapping to the SN in more than 1000 participants from four independent datasets. We identified two main gradients or axes of functional organization within the SN-a mediolateral and a posteroanterior-each showing distinct transcriptomic, behavioural, and pathological associations. Specifically, the mediolateral gradient was related to motor and executive functions, aging and α-synuclein pathology in both PD and Alzheimer's disease (AD). In contrast, the posteroanterior gradient was linked to memory, anxiety, depression and other neuropsychiatric symptoms in all cohorts. We found gradient-specific associations with gene expression profiles, neurotransmitter maps and cerebrospinal fluid biomarkers that further supported their neurobiological differences. Together, these results reveal a dual-gradient architecture that reflects the functional heterogeneity of the SN and offers new markers, grounded in behaviour and pathology, for stratifying neurodegenerative disease risk in aging, PD and AD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912850","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":"Dynamic, differentiated clinical trajectories and prediction in clinical high risk for psychosis.","authors":"Yuxuan Xiong, Guisen Wu, Xiaochen Tang, Yiyi Yang, Dan Zhang, Wensi Zheng, Yanyan Wei, Lihua Xu, Huiru Cui, Haichun Liu, Yingying Tang, Chunbo Li, Jijun Wang, Tianhong Zhang","doi":"10.1038/s41380-026-03870-3","DOIUrl":"https://doi.org/10.1038/s41380-026-03870-3","url":null,"abstract":"<p><p>Clinical subtypes of individuals at clinical high risk for psychosis (CHR), classified by baseline symptoms and cognitive performance, may follow distinct trajectories of symptom progression and functional outcomes. Baseline symptom, cognitive and EEG data were collected from 204 CHR individuals aged 13-38 years, who subsequently completed clinical assessments at 2 months, 1 year, and 2 years. Although baseline positive symptom scores and highest past-year global functioning did not differ significantly, the subtypes demonstrated divergent progression patterns across follow-ups. Baseline cognitive performance exerted sustained influence over subsequent assessments, with visuospatial learning and working memory showing significant long-term effects on positive symptoms or global functioning, highlighting them as core cognitive domains with longitudinal, cross-subtype impact on CHR progression. Brain network features also contributed to long-term outcomes. The involvement of microstate D was sustained over time, with its occurrence linked to functional outcomes in the most impaired subtype and its coverage associated with positive symptom trajectories in the moderately impaired subtype. We further constructed a predictive model incorporating the interaction between microstate D and subtype that effectively identified individuals who converted to psychosis, underscoring its potential as a dynamic biomarker for more precise CHR clinical profiles.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912815","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":"Natural anti–NMDAR1 autoantibodies are associated with lower risk for depression and PTSD symptoms after traumatic brain injury","authors":"Melonie N. Vaughn, Dean T. Acheson, Susan B. Powell, Jenna M. DeWit, Kate A. Yurgil, Caroline M. Nievergelt, Dewleen Baker, Victoria B. Risbrough, Xianjin Zhou","doi":"10.1038/s41380-026-03883-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03883-y","url":null,"abstract":"Exposure to a traumatic brain injury (TBI) increases risk of developing psychiatric symptoms including depression, anxiety, and post‑traumatic stress disorder (PTSD). However, biological risk and resiliency factors that help explain the heterogeneity in outcomes are limited. Although ~10% of the population was reported to carry natural autoantibodies to the NMDA receptor, it remains unknown whether carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI. Plasma anti-NMDAR1 autoantibody levels were quantified in male active-duty service members before a combat deployment. Outcome measures included post-deployment PTSD (Clinician Administered PTSD Scale-IV), depression (Beck Depression Inventory-2) and anxiety symptoms (Beck Anxiety Inventory). Lifetime TBI was associated with increased predicted depression, PTSD and anxiety symptoms after a combat deployment (N = 606 with TBI, N = 419 without TBI). Higher pre-deployment plasma levels of natural anti-NMDAR1 autoantibodies were modestly but significantly associated with lower predicted post-deployment depression (p = 0.0008) and PTSD symptoms (p = 0.0075), but not anxiety, among individuals with TBI. Within the TBI group, high autoantibody group membership (top quartile) lowered predicted post-deployment CAPS-IV and BDI-II scores by 22% ( ~ 4 points) and 25% ( ~ 2 points), respectively and overall prevalence of psychotropic medication use (p = 0.006). High autoantibody group membership predicted lower odds of reporting post‑deployment moderate-severe depression symptoms (BDI-II > 19) (OR = 0.14, 95% CI 0.01–0.69, p = 0.014). Natural anti-NMDAR1 autoantibodies may be a “resiliency” factor for TBI-associated risk for depression and PTSD symptoms, suggesting potential neuroprotective effects. Future studies should determine if anti-NMDAR1 autoantibodies reach the CNS to suppress glutamate excitotoxicity associated with TBI and if these results generalize across different populations.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"32 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899559","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: The transformational power of psychedelics: catalysts for creativity, consciousness, and mental health.","authors":"Xiubo Du, Jiantao Liu, Xiaohui Wang","doi":"10.1038/s41380-026-03863-2","DOIUrl":"10.1038/s41380-026-03863-2","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912793","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":"Is (S)-norketamine an active mediator of esketamine's antidepressant effects?","authors":"Kenji Hashimoto, Chun Yang","doi":"10.1038/s41380-026-03867-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03867-y","url":null,"abstract":"","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":"148906590","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}