Molecular Psychiatry最新文献

{"title":"Resilience beyond diagnosis: prospective neural correlates of better-than-expected outcomes in depression","authors":"Vincent Hammes,Katharina Brosch,Paula Usemann,Friederike S. David,Hannah Scherer,Christina Schmitter,Jochen Bauer,Tiana Borgers,Kira Flinkenflügel,Dominik Grotegerd,Elisabeth J. Leehr,Susanne Meinert,Frederike Stein,Lea Teutenberg,Florian Thomas-Odenthal,Udo Dannlowski,Tim Hahn,Hamidreza Jamalabadi,Andreas Jansen,Robert Miller,Igor Nenadić,Benjamin Straube,Albrecht Stroh,Tilo Kircher,Nina Alexander","doi":"10.1038/s41380-026-03897-6","DOIUrl":"https://doi.org/10.1038/s41380-026-03897-6","url":null,"abstract":"Abstract Resilience, the ability to adapt positively in the face of adversity, is shaped by combined influences of risk and protective factors. Previous neuroimaging studies on resilience have predominantly focused on single factors, often operationalizing resilience dichotomously as the absence of psychiatric disorders despite adversity. In this prospective magnetic resonance imaging study, we defined resilience as “better-than-expected” depressive symptom severity (Hamilton Depression Rating Scale) relative to cumulative risk across 22 risk and protective variables. Using ridge-regularized regression in N  = 1804 participants (955 healthy, 849 depressed) from the Marburg-Münster Affective Disorders Cohort Study, we predicted symptom severity and derived residuals as measures of resilience. Residuals were then used to predict gray matter volume (GMV) and cortical thickness at baseline (T1) and two-year follow-up (T2; N = 808). This approach was complemented by extreme-group comparisons of resilient (better-than-expected outcome) and vulnerable (worse-than-expected outcome) individuals. Cumulative risk explained 49.6% of variance in depressive symptoms at T1 and 40.1% at T2. Residual scores showed moderate temporal stability ( r  = 0.32, p  < 0.001). Region-of-interest and whole-brain analyses revealed no morphometric associations with resilience at T1. In contrast, higher resilience at T1 predicted lower GMV in the left inferior orbitofrontal gyrus (IOFG) and temporal pole at T2 (ROI, p FWE(peak) <0.001, r partial  = 0.18), with no changes in cortical thickness. Taken together, resilience to cumulative risk, defined as better-than-expected depressive symptom severity, was not associated with immediate brain structural differences. However, prospective analyses revealed smaller GMV in the IOFG and temporal pole over time, potentially reflecting greater neural efficiency or delayed biological costs.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"63 1 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020396","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":"Hippocampal AdipoR1 regulates the microglial response and delays disease progression in a mouse model of Alzheimer’s disease","authors":"Jing Li,Lin Jiang,Fenglei Chao,Lei Zhang,Chunnian Hu,Yuning Zhou,Shun Wang,Qing Pan,Yanmin Luo,Jing Tang,Xin Liang,Yue Li,Peilin Zhu,Yuhui Deng,Shan Liu,Yingqiang Qi,Qian Xiao,Yong Tang,Chunni Zhou","doi":"10.1038/s41380-026-03907-7","DOIUrl":"https://doi.org/10.1038/s41380-026-03907-7","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"47 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020549","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":"A thioredoxin-Serinc2-lipid signaling axis modulates mood-related behaviors in mice.","authors":"Chong-Lei Fu, Ying-Han Wang, Ya-Ni Zhang, Hong-Zuo Liu, Si-Yao Lu, Xin-Yu She, Dan Li, Bo-Cheng Dong, Xi Jiang, Zhen-Liang Yuan, Li-Lo Geng, Yi-Ming Yang, Ke-Bing Yang, Jun Yao","doi":"10.1038/s41380-026-03901-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03901-z","url":null,"abstract":"<p><p>Bipolar disorder (BD) shows strong heritability and distinct symptomatic subtypes. However, the molecular basis underlying subtype-specific features remains poorly understood. Here, we identified Serinc2, a BD susceptibility gene encoding a L-serine transporter that regulates membrane lipid synthesis, as a regulator of mood-related behavioral phenotypes. Using patient plasma samples, BD iPSC-derived forebrain organoids, and Serinc2 knockout/overexpression mouse models, we found that Serinc2 expression was increased in bipolar I (BDI) but decreased in bipolar II (BDII); bi-directional manipulation of Serinc2 induced opposite changes in synaptic transmission and depression-related behaviors, accomplied by alterations in PS/SM-dependent redistribution of NMDAR subunits in postsynaptic membranes. Mechanistically, we found that thioredoxin (Txn) bound to the Serinc2 regulatory region and negatively regulate its transcription, and that differential chromatin accessibility of Txn contributed to subtype-associated expression patterns. Together, our results demonstrated a Txn-Serinc2-lipid signaling axis that linked membrane lipid composition to synaptic function and mood-related behaviors, and indicated a potential molecular framework contributing to subtype-specific features of BD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016846","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":"Lifetime substance use disorder and suicidal behaviour: a population-based familial co-aggregation register study","authors":"Lotfi Khemiri,Ralf Kuja-Halkola,Henrik Larsson,Isabell Brikell,Zheng Chang,Brian M. D’Onofrio,Antti Latvala,Paul Lichtenstein","doi":"10.1038/s41380-026-03866-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03866-z","url":null,"abstract":"Abstract Substance use disorders (SUD) are associated with suicidal behaviour, but less is known regarding the extent to which familial factors influence these associations across different types of SUD. We performed a national register study including 4,209,615 individuals born in Sweden 1958–1999 and followed 1973–2020. Exposure was life-time SUD diagnosis, including alcohol use disorder (AUD), drug use disorder (DUD) or dual diagnosis (AUD + DUD). DUD was further classified into substance type (e.g., cannabis, opioids, sedatives or stimulants). Outcome was life-time suicidal event, operationalized as either suicide attempt or death by suicide. Log-linear regression models estimating risk ratios (RR) were fitted with adjustment for sex, birth year, socioeconomic factors and psychiatric co-morbidity. Of 258,046 individuals with SUD, 23.0% ( n  = 59,436) had any life-time suicidal event compared to 1.5% ( n  = 59,784) in 3,951,569 persons without SUD. SUD was associated with increased risk of any suicidal event (Adjusted RR: 6.4 [6.3–6.5]), suicide attempt (6.9 [6.8–7.0]) and suicide death (3.3 [3.2–3.5]). Elevated suicide risk was observed across all SUD, with greatest risk in those with AUD + DUD. Larger RR suicidal events were observed in relatives of individuals with SUD as genetic similarity increased (e.g., full siblings: 2.6 [2.6–2.7]; half siblings: 1.5 [1.5–1.6]). This pattern was observed for all types of SUD, with highest RR in individuals with AUD + DUD relatives (e.g., full siblings: 3.5 [3.4–3.6]; half siblings: 1.7 [1.7–1.8]). Our results suggest that SUD of all substances and suicidality share familial factors, with the clinical implication that family history of SUD constitutes a risk factor for suicidal behaviour.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"7 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020551","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":"Higher peripheral blood homocysteine levels are associated with schizophrenia: evidence from a case-control study and a meta-analysis","authors":"Yuxiao Bi,Lili Zhu,Li Li,Nicha Wareesawetsuwan,Na Wang,Chunjing Li,Jianyue Pang,Jin He,Qian Liu,Xiaofeng Zhao","doi":"10.1038/s41380-026-03910-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03910-y","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"47 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020552","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":"Neurostimulation in the treatment of psychiatric disorders: Underlying mechanisms and critical analysis of circuit-based interventions.","authors":"F R Bambico, A Nicoglou, J Relente, A Surget, C Belzung","doi":"10.1038/s41380-026-03872-1","DOIUrl":"https://doi.org/10.1038/s41380-026-03872-1","url":null,"abstract":"<p><p>Neurostimulation of targeted brain regions has emerged as a novel therapeutic approach to induce remission in patients with various psychiatric disorders. This strategy encompasses several modalities, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and transcranial focused ultrasound neurostimulation (tFUS), all of which aim to modulate dysfunctional neural circuits and restore activity toward physiological ranges. While the clinical efficacy of these techniques is increasingly documented, the mechanisms underlying their effects-beyond immediate changes in regional excitability-remain incompletely understood. Further, neurostimulation represents not only a technical advance, but also a conceptual shift in psychiatry, moving from interventions aimed at modulating neurotransmission or cognition toward circuit-based models of mental illness. This review surveys the current literature to clarify the mechanisms of action of neurostimulation across multiple levels of biological integration, ranging from large-scale neural circuits to cellular and subcellular processes. Subsequently, it explores innovative targets and emerging modalities that expand the scope of circuit-based interventions beyond traditional approaches. Finally, it engages in a critical epistemological reflection, addressing the conceptual challenges that accompany the translation of circuit-based models from neuroscience to clinical psychiatry.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016918","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":"Single cell RNA-sequencing reveals neuron type-specific vulnerabilities in a model of STXBP1-related disorder.","authors":"A Roig Adam, A A van Berkel, M Vanheusden, L Bast, A B Smit, P F Sullivan, J Hjerling-Leffler, M Verhage","doi":"10.1038/s41380-026-03869-w","DOIUrl":"https://doi.org/10.1038/s41380-026-03869-w","url":null,"abstract":"<p><p>STXBP1-related disorder (STXBP1-RD) is a severe neurodevelopmental disorder caused by de novo heterozygous mutations that lead to STXBP1 haploinsufficiency. STXBP1-RD is characterised by developmental delay, intellectual disability, early-onset seizures and autistic features. EEG analysis suggests excitation-inhibition (E/I) disbalance. However, STXBP1 is ubiquitously expressed in all neuron types studied so far, and it remains unknown how haploinsufficiency leads to E/I disbalance and STXBP1-RD symptoms. Here, we used single-cell RNA-sequencing to characterize the effect of Stxbp1 haploinsufficiency across all brain cell types in the somatosensory cortex of a validated mouse model. We observed that the relative abundance of cell types was normal. The most prominent transcriptomic changes occurred in GABAergic and glutamatergic neurons, especially Sncg interneurons and deep-layer pyramidal neurons. Astrocytes exhibited substantial changes despite not expressing STXBP1, suggesting a non-cell autonomous response. Differentially expressed genes showed little overlap between neuronal types but accumulated in synaptic and translation-related GO terms. This was accompanied by a strong trend towards reduced protein translation as measured by puromycin incorporation. Excitatory neurons showed greater synaptic dysregulation than inhibitory neurons. Notably, neuronal transcriptome changes greatly overlapped with prior proteomics STXBP1-RD data but differed radically from other disorders. Seizure burden correlated negatively in astrocytes and neurons to expression of translation-related genes. These findings identify cell-type specific vulnerabilities to STXBP1 haploinsufficiency which may explain hyperexcitability, network dysfunction and cognition deficits in STXBP1-RD. Overall, our study provides a cellular-resolution map of the transcriptomic changes in STXBP1-related disorders, providing potential new therapeutic targets.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017160","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":"Exploring the shared genetic architecture and causal relationship between childhood maltreatment and psychiatric disorders","authors":"Nanxi Li, Sihao Chen, Juan Wang, Tao Li","doi":"10.1038/s41380-026-03912-w","DOIUrl":"https://doi.org/10.1038/s41380-026-03912-w","url":null,"abstract":"Childhood maltreatment (CM) is a major risk factor for psychiatric disorders, yet the shared genetic etiology, potential causal effects, and mediating pathways underlying these associations remain incompletely understood. We investigated the shared genetic architecture, potential causal relationships, and candidate mediating pathways linking genetically proxied reported CM with major psychiatric disorders. Summary statistics were obtained from large-scale genome-wide association studies of CM and 10 psychiatric disorders. Genetic correlations were estimated using linkage disequilibrium score regression and genetic covariance analysis. Shared loci were identified using pleiotropy analysis under the composite null hypothesis. Causal effects and mediation pathways were evaluated using two-sample and two-step Mendelian randomization analyses. CM showed significant positive genetic correlations with 10 psychiatric disorders, with the strongest association observed for post-traumatic stress disorder (rg = 0.71). Mendelian randomization supported potential effects of CM on increased risk for major depressive disorder (OR = 1.61), bipolar disorder (OR = 1.70), schizophrenia (OR = 2.33), attention-deficit/hyperactivity disorder (OR = 2.40), obsessive-compulsive disorder (OR = 1.76), and post-traumatic stress disorder (OR = 1.24). Pleiotropy analysis identified 4113 shared single nucleotide polymorphisms mapped to 167 unique genes. Multi-omics integration prioritized 12 pleiotropic genes enriched in neurodevelopmental, immune, and neuronal signaling pathways. Several candidate mediators were implicated, including lifestyle and behavioral factors (e.g., number of sexual partners, smoking, religious involvement, and leisure screen time), psychosocial traits (loneliness and neuroticism), and physical health indicators. These shared loci and mediation findings should be interpreted as hypothesis-generating candidates for future mechanistic and intervention studies rather than as direct clinical targets.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"11 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149010523","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":"A circuit dissection of perception-action decoupling in S-ketamine-induced hallucination-like states.","authors":"Dijia Wang, Junnan Xu, Zhaoran Wang, Zhirui Liu, Ziqing He, Tianjie Xu, Bin Mei, Jiqian Zhang, Hu Liu, Zhilai Yang, Xiang Ren, Junda Ni, Yi Li, Wei Gong, Gaolin Qiu, Xuesheng Liu","doi":"10.1038/s41380-026-03893-w","DOIUrl":"https://doi.org/10.1038/s41380-026-03893-w","url":null,"abstract":"<p><p>Hallucinations are a core feature of several psychiatric disorders, but the circuit mechanisms that separate perception from behavioral output remain poorly defined. Here, we combined an auditory discrimination task with AI-based pose analysis to quantify S-ketamine-induced false auditory threat responses and behavioral disorganization in mice. Control assays, including sucrose preference, loss of righting reflex, and prepulse inhibition, indicated that these effects were not explained by anhedonia, anesthesia, or basic auditory deficits. Using in vivo fiber photometry, single-cell miniscope calcium imaging, and pathway-specific chemogenetic and optogenetic manipulations, we identified dissociable circuit contributions within convergent striatal pathways. The basolateral amygdala to caudal striatum pathway (BLA→TS) supported salience-weighted perceptual decisions and, when aberrantly recruited by S-ketamine, promoted auditory false alarms. In contrast, the medial prefrontal cortex to caudal striatum pathway (mPFC→TS) primarily shaped behavioral expression and, when dysregulated, generated disorganized action patterns. At the network level, S-ketamine shifted TS activity from a sparse, high-contrast state to a high-frequency, low-amplitude, diffusely coupled state, consistent with reduced integrative precision. Auditory cortex to TS inputs were not broadly suppressed, supporting pathway specificity. Bidirectional chemogenetic manipulation of BLA→TS and mPFC→TS pathways in drug-naive mice further supported the TS as an integrative node linking perceptual evaluation to behavioral output. Dexmedetomidine co-administration restored pathway-level temporal dynamics and reorganized TS network coupling without simply suppressing activity. Together, these findings define a circuit framework for NMDAR-antagonist-induced hallucination-like states and provide a mechanistic rationale for dexmedetomidine-mediated mitigation of S-ketamine-associated perceptual and behavioral disruption.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008831","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":"Nociceptin orphanin F/Q Pathways are dysregulated by stress and modulate reward responsiveness and motivated behavior across species.","authors":"Diego A Pizzagalli, Meghan Gallo, Michael T Treadway, Brian D Kangas, Jocelyn Breton, Michael R Bruchas, Ann M Graybiel, Emily Hueske, Kevin G Bath","doi":"10.1038/s41380-026-03898-5","DOIUrl":"10.1038/s41380-026-03898-5","url":null,"abstract":"<p><p>Nociceptin orphanin F/Q has been implicated in stress-related depressive phenotypes. Specifically, exposure to chronic stressors upregulates nociceptin receptors (NOPR), whereas NOPR antagonism has antidepressant/anti-anhedonic effects. However, the mechanisms underlying reward-related effects remain unclear. Here, we investigated the role of NOPR in a broad spectrum of reward-related phenotypes (reward consumption, reward learning, motivated behavior) alongside potentially prohedonic effects of NOPR antagonism across species. Study 1 evaluated whether exposure to early-life adversity upregulated ventral tegmental area (VTA) and striatal prepronociceptin (Pnoc) gene expression in adult mice. Study 2 assessed whether NOPR antagonism boosted reward learning in rats using the touchscreen-based Probabilistic Reward Task. Finally, Study 3 tested whether NOPR antagonism modulated decision about motivated behavior using the Effort Expenditure for Reward Task among depressed humans. In Study 1, early-life adversity induced reduced sucrose preference and produced enduring and sex-dependent alterations in effort-related reward behavior, and increased Pnoc expression in the VTA; in females (but not males), early-life adversity increased Pnoc expression in the dorsal striatum. In Study 2, acute administration of 30 mg/kg (but not lower doses) of a NOPR antagonist (BTRX-246040) enhanced reward learning in rats. Finally, in Study 3, relative to placebo, 8-week treatment with BTRX-246040 modulated choice consistency during a motivated task in depressed humans. Collectively, our findings indicate that chronic stress alters Pnoc and mRNA levels of Pnoc-expressing cells in a sex-selective and region-specific manner impacting reward structures, and that NOPR antagonism shows promising efficacy in increasing reward-related behaviors in rodents and humans. Future studies using similar manipulations and outcome measures across species are warranted.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008471","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}