Molecular Psychiatry最新文献

{"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}

{"title":"Several methodological issues in the systematic review \"PD-1/PD-L1 blockade in Alzheimer's disease\".","authors":"Junwen Wang, Peng Pan, Jing Zhang, Yiming Wang","doi":"10.1038/s41380-026-03842-7","DOIUrl":"https://doi.org/10.1038/s41380-026-03842-7","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":"148990686","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":"Reconciling the neurogenic hypothesis of depression with recent advances in adult hippocampal neurogenesis research in humans.","authors":"Sophie Simard, Naguib Mechawar","doi":"10.1038/s41380-026-03896-7","DOIUrl":"https://doi.org/10.1038/s41380-026-03896-7","url":null,"abstract":"<p><p>Depression is a highly prevalent mood disorder with a complex etiology that has yet to be fully characterized. Alterations in the generation of new granule neurons in the hippocampal dentate gyrus have been hypothesized to contribute to the pathophysiology of depression and recovery from this mood disorder, a theory coined the \"neurogenic hypothesis of depression\". This article revisits current evidence of this hypothesis in humans, which reveals varying perspectives from post-mortem studies. Drawing on recent findings in the field of human adult hippocampal neurogenesis, we also offer here potential research directions regarding how immature granule neurons, which have been so far understudied in this context, may be affected in the pathogenesis of depression. Finally, this review explores to what extent immature granule neurons are involved in the neurobiological basis of this mood disorder and how their properties may increase their vulnerability to stress-mediated changes in the hippocampus. Together, this review provides crucial insight into immature granule neurons as a particularly interesting therapeutic target to mitigate stress-related behavioural impairments.</p>","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":"148990755","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":"Psilocybin restores social novelty investigation in male SAPAP3 knockout mice and engages prefrontal-hippocampal circuitry.","authors":"James J Gattuso, Bilgenur Bezcioglu, Jenna Hendey, Jennyfer M Payet, Zoe J Phelan, Matthew W Hale, Anthony J Hannan, Thibault Renoir","doi":"10.1038/s41380-026-03879-8","DOIUrl":"https://doi.org/10.1038/s41380-026-03879-8","url":null,"abstract":"<p><p>Obsessive-compulsive disorder (OCD) remains difficult to treat, and evidence indicates that social dysfunction, common across obsessive-compulsive and related disorders, is an under-recognized clinical burden. SAPAP3 knockout (KO) mice, a well-established model of compulsive behavior, exhibit social abnormalities, suggesting broader disruptions in circuits relevant to social cognition. Here, we investigated whether psilocybin, a serotonergic psychedelic with emerging therapeutic potential, can restore social behavior in SAPAP3 KO mice and whether behavioral rescue is associated with modulation of neural activity. Male and female SAPAP3 KO mice and wild-type littermates received a 1 mg/kg psilocybin intraperitoneal injection, and social behavior was assessed seven days later using the three-chamber social interaction test. Psilocybin produced a male-specific, enduring restoration of novel-mouse-directed investigation during social recognition/novelty testing. Immunohistochemical quantification of c-Fos revealed that psilocybin increased neural activation in the medial prefrontal cortex and hippocampus regardless of genotype. Only infralimbic c-Fos levels correlated with improved social recognition/novelty behavior in male SAPAP3 KO mice, identifying infralimbic recruitment as a key correlate of therapeutic rescue. Psilocybin did not alter c-Fos in the nucleus accumbens, basolateral amygdala, or dorsal striatum. These findings demonstrate that psilocybin exerts domain-specific, enduring effects on social cognition in an established model of compulsive-like behavior, potentially involving prefrontal plasticity-related mechanisms. Given the lack of pharmacological treatments targeting social dysfunction in OCD and associated neuropsychiatric disorders, these results highlight psilocybin as a promising candidate for improving social-cognitive outcomes in disorders characterized by repetitive behaviors and social impairment.</p>","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":"148990760","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":"Altered function of peripheral organ systems in first-episode drug naïve mental illnesses: a systematic review and meta-analysis.","authors":"Jetro E Ang, Yangqi Xu, Vanessa Cropley, Andrew Zalesky, Ye Ella Tian","doi":"10.1038/s41380-026-03891-y","DOIUrl":"10.1038/s41380-026-03891-y","url":null,"abstract":"<p><strong>Background: </strong>Although mental illness is primarily regarded as a disorder of the brain, body system dysfunction is increasingly recognized as a salient biomarker in psychiatry, often emerging before the onset of overt symptoms. Here, we systematically review studies on peripheral organ systems (cardiovascular, metabolic, immune, liver, kidneys, lungs and muskeloskeletal) in schizophrenia, major depressive disorder (MDD), bipolar disorder (BD) and generalized anxiety disorder (GAD), aiming to synthesize findings on the function of multiple body systems in the early stages of mental illness.</p><p><strong>Methods: </strong>EMBASE, MEDLINE and PsycINFO were searched from inception until 19 November 2024, identifying case-control studies comparing physiological markers of peripheral organ systems (i.e., cardiovascular, metabolic, immune, liver, kidney, lung and muskeloskeletal) in adults with one of the four mental illnesses at first-episode and drug naive, with healthy controls. We followed the PRISMA 2020 guidelines (PROSPERO: CRD42023408594).</p><p><strong>Results: </strong>Of 2637 citations retrieved, 138 studies met inclusion criteria for review with 52 markers of immune (n = 32), metabolic (n = 11), cardiovascular (n = 6), liver (n = 2) and musculoskeletal (n = 1) function identified. 105 studies were eligible for meta-analysis, including 80, 26, 4 and 0 studies on schizophrenia, MDD, BD and GAD respectively. Meta-analysis revealed increased waist-hip-circumference ratio, triglycerides, insulin, insulin resistance, 2-hr glucose, neutrophil, monocyte, white blood cell, IL-4 and systolic blood pressure, and reduced albumin in schizophrenia; increased TNF-α and IL-10 in MDD; and increased IL-6 and IFN-γ in both schizophrenia and MDD. Other results were narratively discussed.</p><p><strong>Conclusions: </strong>Alterations in peripheral organ function across multiple systems characterizes the onset of psychiatric disorders. However, research on peripheral organ function in psychiatry is limited and primarily focusses on the immune and metabolic systems.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983247","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":"De novo variants in the poly(rC)-binding protein gene PCBP1 cause a neurodevelopmental disorder.","authors":"Wallid Deb, Thomas Besnard, Florence Desprez, Benjamin Cogné, Laura Do Souto Ferreira, Virginie Vignard, Sylviane Marouillat, Louis Januel, Svetlana Gorokhova, Tiffany Busa, Victor Morel, Benjamin Dauriat, Vincent Des Portes, Eyyüp Üçtepe, Özlem Akgün Doğan, Ahmet Yeşilyurt, Yasemin Alanay, Anne M Slavotinek, Yu An, Hane Lee, Jessy Hary, Peter Kannu, Taryn B Athey, Ingrid M B H van de Laar, Marjon A van Slegtenhorst, Patricia Dickson, Rachel Slaugh, Fadi F Hamdan, Jean-François Soucy, Jacques L Michaud, Alison M Muir, Rebecca Buchert, Tobias B Haack, Dominic Imort, Sérgio B Sousa, Belinda Campos-Xavier, Pedro M Almeida, Borut Peterlin, Sophie Kaspar, Christian Netzer, Hans Zempel, Meghan C Towne, Roger L Ladda, Susan L Sell, Lina Quteineh, Romane Meurs, Stylianos E Antonarakis, Pawel Gawlinski, Xiaofei Song, Wojciech Wiszniewski, Daniel G Calame, Jennifer E Posey, Frederic Ebstein, James R Lupski, Bertrand Isidor, Stéphane Bézieau, Frédéric Laumonnier, Sébastien Küry","doi":"10.1038/s41380-026-03877-w","DOIUrl":"10.1038/s41380-026-03877-w","url":null,"abstract":"<p><p>Poly(rC)-binding protein 1 (PCBP1), a splicing factor and key member of the hnRNP E family, was initially characterized for its tumor suppressive properties. More recently, its role in gene regulation in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 16 de novo pathogenic variants in PCBP1 across 17 subjects from 16 unrelated families. All affected individuals exhibited intellectual disability (ID), with autism spectrum disorder (ASD) as a prominent feature. Functional analysis in primary hippocampal mouse neuron cultures indicated that PCBP1 variants impair dendritic arborization, underscoring their deleterious effects. Transcriptomic profiling by RNA sequencing of subject-derived T cells showed a distinctive signature characterized by significantly increased exon skipping. These results highlight the contribution of PCBP1 in neurogenesis and neuritogenesis, which is impacted by loss-of-function variants expressed in neuronal cells, thereby supporting the link between splicing defects and neurodevelopmental disorders. Collectively, our findings demonstrate the prominent role of PCBP1 in neurodevelopment, reaffirming the importance of splicing regulation in mammalian neurodevelopment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983232","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 genetic overlap between schizophrenia and major depression with cognitive function.","authors":"Qiao Su, Meijuan Li, Yuying Qiu, Xiaoxiao Sun, Zhenning Feng, Ying Xu, Boxuan Zhou, Jie Li","doi":"10.1038/s41380-026-03887-8","DOIUrl":"https://doi.org/10.1038/s41380-026-03887-8","url":null,"abstract":"<p><p>This study aimed to systematically dissect the shared genetic basis of schizophrenia (SCZ) and major depression (MD) with cognitive function. To investigate this, we integrated large-scale genome-wide association studies (GWAS) summary statistics for SCZ (N = 175,799, [cases, 74,776; controls, 101,023]), MD (N = 2,622,273 [cases, 550,355; controls, 2,071,918]) and four cognitive traits (reaction time, N = 330,069; memory, N = 112,067; verbal-numerical reasoning, N = 36,035; educational attainment, N = 111,114). Linkage disequilibrium (LD) score regression analysis revealed that SCZ showed significant negative genetic correlations with reaction time, memory, and verbal-numerical reasoning. MD showed negative genetic correlations with memory, verbal-numerical reasoning, and educational attainment. Bayesian colocalization analysis identified seven genomic regions with strong or supportive evidence between SCZ and cognitive function, and two genomic regions with supportive evidence between MD and cognitive function. Gene mapping and over representation analysis (ORA) indicated that SCZ-associated genes were primarily involved in pathways related to transport processes, and MD-associated genes were significantly enriched in pathways related to neural development. Through genetic correlation and colocalization analysis, this study elucidates the genetic overlap between SCZ and MD with cognitive function, providing a new perspective for related research.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983256","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 C/EBPβ/ Calbindin 1 pathway bolsters the neural resilience to tau pathology and improves tau-impaired episodic memory.","authors":"Jiale Liu, Fuqiang Zhang, Tongkai Zhong, Jianhao Wang, Huiyang Lei, Junning Zhao, Feng Lin, Tiancen Fan, Ting He, Rui Xiong, Xin Wang, Linyu Wei, Fei Sun, Yue Xiao, Guilin Pi, Dongkun Kang, Yanjun Bian, Honglian Li, Qun Wang, Dan Ke, Jian-Zhi Wang, Xifei Yang, Zhi-Hao Wang, Ying Yang","doi":"10.1038/s41380-026-03876-x","DOIUrl":"https://doi.org/10.1038/s41380-026-03876-x","url":null,"abstract":"<p><p>Intracellular accumulation of tau protein is a defining feature of Alzheimer's disease (AD) and is closely associated with episodic memory loss. In our previous report, we highlighted the high susceptibility of ventral hippocampal Calbindin1^- neurons in the dorsal part of ventral hippocampal CA1 (dvCA1^Calb1- neurons) to tau pathology in AD. However, it remains unclear whether and how dvCA1^Calb1+ neurons are also vulnerable during the chronic and progressive process of AD. In this study, we characterized dvCA1^Calb1+ neurons in terms of circuit connections and behavioral phenotypes under physiological conditions. Postmortem examination of AD patients' brains and P301L mice revealed a preferential reduction of Calb1 in the dvCA1, accompanied by heightened susceptibility of the dvCA1^Calb1+ neurons to phospho-tau mislocalization. Mechanistically, C/EBPβ was found to bind to the promoter regions of CALB1, resulting in the inhibition of CALB1 transcription. Knockdown of Calb1 accelerated, while overexpression of Calb1 impeded the AD-like tau pathology in dvCA1^Calb1+ neurons. As tau accumulated, dvCA1^Calb1+ neurons lost their firing patterns, leading to contextual social memory deficits. Ursolic acid, by promoting the degradation of C/EBPβ, modified the C/EBPβ-Calb1 pathway, ultimately enhancing the resilience of dvCA1^Calb1+ neurons against tau pathology and improving contextual social memory in AD. Our findings underscore the critical role of the C/EBPβ-Calb1 pathway in controlling the susceptibility of dvCA1^Calb1+ neurons to tau pathology. Furthermore, targeting the C/EBPβ-Calb1 pathway and UA administration could be promising strategies for treating AD in the future.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983271","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":"Persistent tic disorders are associated with 17q12 duplications.","authors":"Matthew W Halvorsen, Sheng Wang, Tyne W Miller-Fleming, Dongmei Yu, Apostolia Topaloudi, Elles de Schipper, Julia Bäckman, David Mataix-Cols, Christian Rück, Behrang Mahjani, Joseph D Buxbaum, Dorothy E Grice, Larisa H Cavallari, Dominick J Angiolillo, Francesco Franchi, Lea K Davis, Lide Han, Douglas M Ruderfer, Andrea Dietrich, Pieter J Hoekstra, Manuel Mattheisen, Luz M Porras, Paola Giusti-Rodriguez, Carol A Mathews, Peristera Paschou, Jeremiah M Scharf, A Jeremy Willsey, James J Crowley","doi":"10.1038/s41380-026-03849-0","DOIUrl":"10.1038/s41380-026-03849-0","url":null,"abstract":"<p><p>Tourette Syndrome (TS) and Persistent Tic Disorder (PTD) are childhood-onset neuropsychiatric conditions with high heritability. Due to current sample size limitations, identifying TS/PTD risk genes has been challenging. This study addressed this issue by conducting a meta-analysis of microarray copy number variant (CNV) studies from three TS/PTD genomics consortia, supplemented with new data from 3291 cases. This approach more than doubled the sample size of previous TS/PTD CNV studies, with CNV calls generated from 5725 TS/PTD cases and 10,982 matched controls. The results confirmed that TS/PTD cases 1) have a higher burden of ultra-rare deletions overlapping loss-of-function intolerant genes (OR = 1.68, P = 9.3×10^-5) and 2) are more likely to carry established neurodevelopmental CNVs (OR = 1.42, P = 3.9×10^-2) compared to controls. Additionally, a novel, genome-wide significant CNV locus for TS/PTD was discovered, involving duplications at 17q12 (hg19 chr17:34.8 - 36.2 Mb). This locus is associated with a known duplication syndrome associated with variable neuropsychiatric traits, but has not been previously linked to tic disorders. Eight cases and one control carried the canonical ~1.4 Mb duplication at chr17:34.8-36.2 Mb, while one additional case had a smaller 110 kb duplication within this known CNV that included only one gene, ACACA (acetyl-CoA carboxylase, OR = 26.7, P = 5.69×10^-7). Overall, this study provides further evidence that rare, genic CNVs play a substantial role in the genetic architecture of TS/PTD and identifies a new genome-wide significant association with this neurodevelopmental disorder.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983263","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":"Transcranial photobiomodulation to enhance sleep by elevating adenosine signaling: a translational study.","authors":"Jieun Jung, Chanyoung Cheong, Yoonho Oh, Youngjoo Lee, Khanh Van Do, Xiaohui Zhu, Jinhong Kim, Chaebeom Yeo, Hansang Cho, Jae Gwan Kim, Tae Kim","doi":"10.1038/s41380-026-03875-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03875-y","url":null,"abstract":"<p><p>Sleep disturbances are a significant health concern in modern society, with prevalent treatments often leading to limited efficacy and unwanted side effects. Adenosine, a sleep-promoting molecule in the brain, presents a promising target for innovative therapies, yet strategies to augment intracerebral adenosine have remained largely unexamined. This study explores transcranial photobiomodulation (tPBM) as a potential intervention, employing near-infrared (NIR) light to enhance mitochondrial adenosine triphosphate (ATP) synthesis and facilitate adenosine release. Utilizing fiberoptic cannula and electroencephalographic electrodes implanted in mice, we found that tPBM significantly increased non-rapid eye movement (NREM) sleep during and after stimulation compared to sham controls. Enhanced NREM delta power and elevated adenosine concentration in the frontal cortex were confirmed. In vitro experiments further demonstrated that NIR PBM increased cellular ATP production without inducing cytotoxicity. Additionally, a double-blind randomized controlled trial with 40 subjects demonstrated significant reductions in insomnia severity, sleep disturbances, and sleep latency. These findings provide preliminary clinical and translational evidence that tPBM may represent a promising non-pharmacological approach for short-term improvement of sleep disturbances through increased homeostatic pressure.</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":"148977298","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}