Molecular Psychiatry最新文献

{"title":"Correction: Cardiovascular diseases and depression: A meta-analysis and Mendelian randomization analysis.","authors":"Jun Zeng, Yuting Qiu, Chengying Yang, Xinrong Fan, Xiangyu Zhou, Chunxiang Zhang, Sui Zhu, Yang Long, Kenji Hashimoto, Lijia Chang, Yan Wei","doi":"10.1038/s41380-025-03049-2","DOIUrl":"https://doi.org/10.1038/s41380-025-03049-2","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079137","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":"Association between autism and dementia across generations: evidence from a family study of the Swedish population","authors":"Zheng Chang, Honghui Yao, Shihua Sun, Le Zhang, Shengxin Liu, Isabell Brikell, Brian M. D’Onofrio, Henrik Larsson, Paul Lichtenstein, Ralf Kuja-Halkola, Sara Hägg, Francesca Happé, Mark J. Taylor","doi":"10.1038/s41380-025-03045-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03045-6","url":null,"abstract":"<p>There is emerging evidence to suggest that autistic individuals are at an increased risk for cognitive decline or dementia. It is unknown whether this association is due to shared familial influences between autism and dementia. The main purpose of this study was, thus, to investigate the risk of dementia in relatives of autistic individuals. We conducted a family study based on linking Swedish registers. We identified all individuals born in Sweden from 1980–2013, followed until 2020, and clinical diagnoses of autism among these individuals. We linked these index individuals with their parents, grandparents, and aunts/uncles. The risk of dementia (including any type of dementia, Alzheimer’s disease, and other types of dementia) in relatives of autistic individuals was estimated using Cox proportional hazards models. Analyses were then stratified by sex of the relatives and intellectual disability in autistic individuals. Relatives of autistic individuals were at an increased risk of dementia. The risk was strongest in parents (hazards ratio [HR] = 1.36, 95% confidence intervals = 1.25–1.49), and weaker in grandparents (HR = 1.08, 1.06–1.10) and aunts/uncles (HR = 1.15, 0.96–1.38). Furthermore, there were indications of a stronger association between autism in index individuals and dementia in mothers (HR = 1.51, 1.29–1.77) compared to dementia in fathers (HR = 1.30, 1.16–1.45). There was only a small difference in relatives of autistic individuals with and without intellectual disability. Our results provide evidence of familial co-aggregation between autism and different types of dementia, and a potential genetic link. Future research now needs to clarify the risk of dementia in autistic individuals.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"43 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979454","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 history of metaphorical brain talk in psychiatry","authors":"Kenneth S. Kendler","doi":"10.1038/s41380-025-03053-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03053-6","url":null,"abstract":"<p>From the very beginnings of our field in the late 18th century, psychiatrists have engaged, often extensively, in “metaphorical brain talk” – rephrasing descriptions of mental processes in unconfirmed brain metaphors (e.g., “diseased working of the brain convolutions”). In the late 19th century, Kraepelin criticized the later developments of such approaches, termed “brain mythology” by the philosopher/psychiatrist Jaspers in 1913. In this essay, I review the history, meaning, and significance of this phenomenon and reach four conclusions. First, this trend has continued to the present day in metaphors such as the “broken brain” and the use of simplistic and empirically poorly supported explanations of psychiatric illness, such as depression being “due to an imbalance of serotonin in the brain.” Second, our language stems from the tension in our profession that seeks to be a part of medicine yet declares our main focus as treatment of the mental. We feel more comfortable with the reductionist approach of brain metaphors, which, even though at times self-deceptive, reinforce our commitment to and membership in a brain-based medical specialty. Third, metaphorical brain talk can also be seen as the “promissory note” of our profession, a pledge that the day will come when we can indeed explain accurately to ourselves and to our patients the brain basis of the psychiatric disorders from which they suffer. Finally, moving away from metaphorical brain talk would reflect an increasing maturity of both the research and clinical aspects of our profession.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"114 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945759","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":"Deciphering the influence of socioeconomic status on brain structure: insights from Mendelian randomization","authors":"Charley Xia, Yuechen Lu, Zhuzhuoyu Zhou, Mattia Marchi, Hyeokmoon Kweon, Yuchen Ning, David C. M. Liewald, Emma L. Anderson, Philipp D. Koellinger, Simon R. Cox, Marco P. Boks, W. David Hill","doi":"10.1038/s41380-025-03047-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03047-4","url":null,"abstract":"<p>Socioeconomic status (SES) influences physical and mental health, however its relation with brain structure is less well documented. Here, we examine the role of SES on brain structure using Mendelian randomisation. First, we conduct a multivariate genome-wide association study of SES using educational attainment, household income, occupational prestige, and area-based social deprivation, with an effective sample size of <i>N</i> = 947,466. We identify 554 loci associated with SES and distil these loci into those that are common across those four traits. Second, using an independent sample of ~35,000 we provide evidence to suggest that SES is protective against white matter hyperintensities as a proportion of intracranial volume (WMHicv). Third, we find that differences in SES still afford a protective effect against WMHicv, independent of that made by cognitive ability. Our results suggest that SES is a modifiable risk factor, causal in the maintenance of cognitive ability in older-age.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"8 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940632","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":"Implications of neurogenesis in depression through BDNF: rodent models, regulatory pathways, gut microbiota, and potential therapy","authors":"Haijun Han, Jianhua Yao, Jinhan Wu, Shiqi Mao, Hongyi Pan, Lingling Qv, Guanqi Zhu, Juntian Ren, Yaning Yu, Feiyang Xuan, Linghui Zeng, Yunlong Ma, Zhongli Yang, Zhijing Zhu, Feng Zhu, Ming D. Li","doi":"10.1038/s41380-025-03044-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03044-7","url":null,"abstract":"<p>Major Depressive Disorder (MDD) is a prevalent psychiatric disorder with a profound impact on global health, necessitating a deeper understanding of its pathophysiology. This review synthesizes current evidence linking neurogenesis, particularly in the hippocampal region, with MDD. Accumulating data showed a significant reduction of neurogenesis in the hippocampal region of both MDD patients and various MDD rodent models. We highlight the role of brain-derived neurotrophic factor (BDNF) and its associated signaling pathways in regulating neurogenesis and depressive symptoms. Additionally, the influence of gut microbiota on the neurogenesis in depression is presented, offering a novel perspective on environmental modulation of neurogenesis. This review also underscores the potential antidepressant interventions targeting neurogenesis and BDNF’s regulation, such as therapeutic benefits of environmental enrichment, physical activity, and pharmacological agents in enhancing neurogenesis and alleviating depressive symptoms. Together, this systemic review provides a foundation for future research aiming at developing personalized treatments by targeting neurogenesis in MDD, potentially leading to novel biomarkers and therapeutic strategies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"8 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927272","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":"CLN5 deficiency impairs glucose uptake and uncovers PHGDH as a potential biomarker in Batten disease","authors":"Maria Marchese, Sara Bernardi, Rachele Vivarelli, Stefano Doccini, Lorenzo Santucci, Asahi Ogi, Rosario Licitra, Jingjing Zang, Rabah Soliymani, Serena Mero, Stephan CF Neuhauss, Lea Ciarmoli, Giovanni Signore, Maciej M. Lalowski, Filippo M. Santorelli","doi":"10.1038/s41380-025-03043-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03043-8","url":null,"abstract":"<p>CLN5 disease, a form of juvenile dementia within the neuronal ceroid lipofuscinosis (NCL), is associated with mutations in the <i>CLN5</i> gene encoding the lysosomal bis(monoacylglycero)phosphate (BMP) synthase, essential for BMP production and lysosomal function. Limited knowledge of cellular mechanisms and unclear drug targets hinder translating this to children’s treatment, which remains symptomatic. We developed and characterized a new <i>cln5</i> knock-out zebrafish model that replicates key features and molecular signatures of the human disease. Loss of Cln5 function in vivo altered axonal growth of retinal ON-bipolar cells and disrupted calcium homeostasis in the cerebellum, revealing new disease features. Additionally, multi-omic analyses at different developmental stages revealed an impaired glucose metabolism as an original finding in NCL. A novel biomarker, PHGDH, was validated in zebrafish and human skin fibroblasts harboring pathogenic variants in <i>CLN5</i>, and in <i>CLN7</i>. We also tested metformin which improved the expression of PHGDH in patient-derived cells, and rescued zebrafish behavior. This work demonstrates the profound metabolic impact of CLN5 dysfunction, offering a promising avenue toward targeted therapies for juvenile dementia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"49 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930757","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":"40Hz transcranial alternating current stimulation enhance insomnia treatment efficacy: a pilot study","authors":"Qi Zhou, Xiaoqian Guo, Xiaolin Zheng, Qicheng Tao, Chang Li, Yafang Tang, Zhiwang Liu, Guolin Jin, Dongsheng Zhou","doi":"10.1038/s41380-025-03001-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03001-4","url":null,"abstract":"<p>Insomnia is a prevalent clinical condition characterized by difficulty for patients to initiate and/or stay in sleep along with common comorbidities such as irritability or fatigue during wakefulness [1]. Study found that insomnia patients show declines in cognitive abilities such as working memory and aspects of execution [2]. Currently, pharmacotherapy and cognitive-behavioral therapy for insomnia (CBT-I) are the primary treatment methods in clinical practice, but the effects of drug tolerance, dependence, and side effects, as well as CBT-I in terms of compliance, treatment professionalism, and their efficacy appears to vary among individuals [3]. Therefore, various neuromodulation techniques, such as magnetic stimulation, electrical stimulation, and light stimulation, strive to provide innovative therapeutic alternatives.</p><p>Flickering light stimulation is a non-invasive neuromodulation technique that has promising futures in alleviating pathological changes in insomnia [4]. Current research hypothesized that the therapeutic effect of light flickering stands on the fundamentals of brain entrainment, such as repetitive and regular stimulation of light, sound or other electrical and magnetic signals could prompt the brain to produce brain waves in the matching frequency, and 40 Hz light induce the strongest gamma oscillation [5, 6]. Even though studies conducted specifically on light flickering and insomnia is yet limited, we are going to introduce a new study below that demonstrates the specific neurochemical basis for 40 Hz flickering and how its therapeutic effect on insomnia was achieved [7].</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"54 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920250","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":"MMP-2/9 inhibition modulates sharp wave abundance, inhibitory proteoglycan sulfation, and fear memory in juvenile zebrafish: relevance to affective disorders","authors":"Ismary Blanco, Samantha Deasy, Matthew Amontree, Miranda Gabriel, Adam Caccavano, Stefano Vicini, Eric Glasgow, Katherine Conant","doi":"10.1038/s41380-025-03007-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03007-y","url":null,"abstract":"<p>Sharp wave ripple (SWR) events, present in diverse species, spontaneously occur in the hippocampus during quiescent restfulness and slow-wave sleep. SWRs comprise a negative deflection, the sharp wave (SW) event with an often-superimposed ripple (R) and are the neural correlates of memory consolidation and recall. The Anterodorsolateral lobe (ADL) (zebrafish hippocampal homolog) exhibits SW and SWR events, and since SWs initiate SWRs, their abundance typically shows the same directionality. In previous work, we observed matrix metalloproteinase-9 (MMP-9)-dependent effects on depression-relevant behaviors, perineuronal net (PNN) levels, and SWR abundance in the adult rodent hippocampus. Here, we investigate MMP-2/9-dependent effects on biochemical, behavioral, and neurophysiological endpoints in juvenile zebrafish and zebrafish at the transition from the late juvenile period to early adulthood. With MMP-2/9 inhibition, juvenile zebrafish showed reduced SW amplitude and abundance together with increased fear memory retention and decreased sociability. Juvenile zebrafish also showed an increased percentage of longer-duration SW events. Except for a reduction in SW amplitude, these changes were not observed at the transition from late juvenile to early adulthood. These changes were accompanied by increased levels of chondroitin sulfate (CS) proteoglycan 4-<i>O</i>-sulfation, which modulates PNNs and excitatory-to-inhibitory (E/I) balance. Discontinuation of MMP-2/9 inhibition in juvenile zebrafish normalized deficits in ADL SW abundance and sociability. Together, these findings show that MMP-2/9 significantly influences E/I balance and learning and memory during the highly plastic juvenile period. Findings also have relevance to an emerging appreciation of PNN changes that may contribute to altered neuronal oscillations and mood or cognition.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"35 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901269","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":"Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving","authors":"Eun-Kyung Hwang, Amanda M. Wunsch, Marina E. Wolf","doi":"10.1038/s41380-025-03026-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03026-9","url":null,"abstract":"<p>Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca²⁺-permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca²⁺ at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naïve rats rapidly upregulates CP-AMPARs. This is observed only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, we observe CP-AMPAR upregulation in D1 MSN (but not D2 MSN) and the effect of exogenous RA application is occluded in these D1 MSN. Instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of ‘incubated rats’ normalizes elevated cue-induced cocaine seeking back to non-incubated levels. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"44 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901272","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 emergence of chronic diseases of adulthood and middle age in the young: the COIDS (chronic inflammation, obesity, insulin resistance/type 2 diabetes, and depressive syndromes) noxious quartet of pro-inflammatory stress outcomes","authors":"Julio Licinio, Alice W. Licinio, João Vicente Busnello, Luciana Ribeiro, Philip W. Gold, Stefan R. Bornstein, Ma-Li Wong","doi":"10.1038/s41380-025-03034-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03034-9","url":null,"abstract":"<p>Major depression, type 2 diabetes, and essential (primary) hypertension are chronic medical and psychiatric disorders that have traditionally affected primarily adults and middle-aged individuals. However, recent decades have witnessed an increasing prevalence of these conditions among children and adolescents. For diseases that typically require prolonged exposure to risk factors to emerge in childhood and adolescence, the amount of exposure to a single risk factor would have to be exceptionally high. We advance the alternative hypothesis of multiple factors acting synergistically. Biological mechanisms underlying the response to ongoing (chronic) stress are logical candidates for being a shared pathway. In the context of persistent and synergistic psychological, social, and economic pressures, unremitting stress can lead to such disease outcomes, exerting a direct influence on the emergence of chronic disorders, and it can also contribute to obesity. Depression follows the same trajectory; therefore, we should examine it as an entity whose consequences are directly reflected in behavioral outcomes, including (over-) eating. Other contributing pathways include chronic sleep deprivation, epigenetic modifications, telomere shortening, the physical environment, pathogens, and the microbiome. We introduce here the concept of the Chronic inflammation, Obesity, Insulin resistance/type 2 diabetes, and Depressive Syndromes (COIDS) noxious quartet of pro-inflammatory stress outcomes, as an increasingly common pathophysiologic state, representing a distinct presentation of type 2 allostatic overload, with direct implications for the current chronic disease epidemic. The compounded effects of a pro-inflammatory state that is fueled by four different and co-existing sources may contribute to explain the emergence of chronic diseases of adulthood and middle age in the young. PPARγ might represent a potential translational therapeutic target for those with COIDS. We propose that highly adverse environments sustain sufficient chronic stress to bring about in the young diseases that had been previously confined to adults.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"34 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901312","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}