Molecular Psychiatry最新文献

{"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}

{"title":"Targeting the dopaminergic midbrain with precision 7-Tesla biofeedback training in depression: A proof-of-principle randomized controlled trial.","authors":"Laurel S Morris, Jacqueline M Beltrán, Timo L Kvamme, Avijit Chowdhury, Grace Butler, Abigail Adams, Tanvi Patel, Emerald Obie, Samantha Fontaine, Morgan Corniquel, Marishka M Mehta, Derek A Smith, Lazar Fleysher, Priti Balchandani, Yael Jacob, James W Murrough","doi":"10.1038/s41380-026-03911-x","DOIUrl":"https://doi.org/10.1038/s41380-026-03911-x","url":null,"abstract":"<p><p>The significant heterogeneity of major depressive disorder (MDD) requires the development of interventions that directly target underlying cognitive or neurobiological mechanisms. This work tested the efficacy of self-modulation of the dopaminergic midbrain with high-field 7-Tesla functional MRI biofeedback in a randomized, controlled, proof-of-principle trial that targeted motivation regulation. A total of N = 62 unmedicated participants (MDD and healthy controls) were randomized to receive either Active or Sham 7-Tesla functional MRI biofeedback and completed clinical assessments pre- and up to 30-days post-training. Factor analysis of clinical symptom change revealed a single latent clinical improvement factor that was significantly improved in the Active MDD compared to the Sham MDD group, immediately post-training (β = 15.85, t = 2.31, p = 0.03), and at 24-hours post-training (β = 22.84, t = 2.45, p = 0.02); effects were diminished and no longer significant at 7-day and 30-day follow-ups. Results of specific phenotypic clinical analysis revealed that depressed mood (F = 5.04, p = 0.029) and negative affect (F = 5.21, p = 0.027), but not positive affect, were most improved by the Active biofeedback intervention. Active biofeedback training engaged functional coupling over time between the VTA and the lateral frontal cortex in the MDD group (F = 6.03, p = 0.017), and greater overall VTA regulation was associated with clinical improvement (R = 0.268, p = 0.048). Together, these results indicate the potential utility of dopaminergic midbrain-based biofeedback training for improvement of mood and negative affect in MDD.</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":"149008623","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":"Histamine H₂ receptor in substantia nigra pars reticulata parvalbumin positive neurons mediates risk-taking behavior.","authors":"Dadao An, Lingyan Zheng, Jinjin Zhu, Zonghan Liu, Zhengyi Xu, Yanrong Zheng, Li Cheng, Yi Wang, Weiwei Hu, Zhong Chen","doi":"10.1038/s41380-026-03892-x","DOIUrl":"https://doi.org/10.1038/s41380-026-03892-x","url":null,"abstract":"<p><p>Risk-taking is frequently observed in psychiatric conditions such as attention-deficit hyperactivity disorder, yet the neuronal mechanisms underlying this behavior remain unclear. Here, we show that histamine H₂ receptor (H₂R) in parvalbumin-positive neurons (PV⁺) of the substantia nigra pars reticulata (SNr) bidirectionally regulates risk-taking behaviors. Dysfunction of superior colliculus-projecting SNr PV⁺ neurons contributes to the increased risk-taking caused by H₂R deficiency. Moreover, H₂R deficiency promotes risk-taking behavior by altering PV⁺ neuronal dynamics during risk assessment in an H₂R-dependent manner. Pharmacological activation of H₂R in the SNr rescues excessive risky exploration in dopamine transporter heterozygous mutant mice (DAT^+/-), a well-established mouse model of attention deficit hyperactivity disorder (ADHD)-like phenotypes with increased risk-taking behavior. Collectively, these findings demonstrate that H₂R deficiency in SNr PV⁺ neurons drives risk-taking execution by disrupting the function of PV⁺ neurons and their downstream projections in mice. It may enhance the understanding of the neural mechanism underlying threat-related risk-taking and highlight H₂R as a potential therapeutic target for pathological risk-taking behavior.</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":"149008791","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":"An mPFC-DMV cortical-autonomic-immune axis governs stress-induced immune dysregulation in sepsis.","authors":"Lu Yin, Fuhong Liu, Mengyun Li, Ye Wang, Lei Liu, Xinxin Zhang, Zhongmin Fan, Tingting Gu, Yaru Guo, Dan Wang, Guangchao Zhao, Yongxin Guo, Hongwei Ma, Jing Han, Xijing Zhang","doi":"10.1038/s41380-026-03913-9","DOIUrl":"https://doi.org/10.1038/s41380-026-03913-9","url":null,"abstract":"<p><p>Chronic psychological stress is a major predisposing factor that worsens sepsis outcomes, yet the neural mechanisms linking stress exposure to immune dysregulation remain poorly understood. Here, using a mouse model of chronic restraint stress (CRS) followed by endotoxemia, we show that prior stress markedly aggravates mortality, systemic inflammation, and immune imbalance during sepsis. Mechanistically, we identify a stress-sensitive medial prefrontal cortex (mPFC)-dorsal motor nucleus of the vagus (DMV) circuit that functions as a central regulator of peripheral neuroimmune homeostasis. Chronic stress is associated with impaired mPFC-DMV circuit function, accompanied by reduced splenic nerve activity, disrupted splenic norepinephrine (NE) and acetylcholine (ACh) signaling, heightened inflammatory responses, and diminished regulatory T cell (Treg) activity. Chemogenetic activation of the mPFC-to-DMV pathway restores splenic autonomic output, normalizes neurotransmitter homeostasis, attenuates systemic inflammation, improves survival, and rescues stress-associated Treg dysfunction. Importantly, chemical sympathectomy with 6-hydroxydopamine (6-OHDA) largely attenuates the protective effects of circuit activation, including its regulation of splenic NE/ACh balance, inflammatory cytokine production, and Treg responses, indicating that intact splenic sympathetic neuroimmune signaling is required for mPFC-DMV-mediated immunomodulation. Furthermore, in vitro experiments reveal that exogenous ACh promotes macrophage-mediated Treg activation through α7 nicotinic acetylcholine receptors (α7nAChRs), providing a cellular mechanism through which autonomic neurotransmitter signaling regulates peripheral immune homeostasis. Together, these findings define a functional cortical-autonomic-immune axis through which chronic stress disrupts neuroimmune homeostasis during sepsis. Our findings further identify autonomic neurotransmitter signaling and α7nAChR-dependent macrophage-Treg communication as key mechanisms linking cortical circuit dysfunction to peripheral immune dysregulation, highlighting cortical-autonomic neuromodulation as a potential therapeutic strategy for stress-associated immune dysfunction in sepsis.</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":"149008844","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 eye as a canary in the coal mine: oculomics for psychiatry.","authors":"Halide Bilge Türközer, Siegfried K Wagner, Paulo Lizano, Steven M Silverstein","doi":"10.1038/s41380-026-03905-9","DOIUrl":"https://doi.org/10.1038/s41380-026-03905-9","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990679","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":"Limitations of registry proxies: Why the search for a better cardiovascular disease risk model in bipolar disorder must continue.","authors":"Yu Xiao","doi":"10.1038/s41380-026-03860-5","DOIUrl":"https://doi.org/10.1038/s41380-026-03860-5","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990752","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}