Molecular Psychiatry最新文献

{"title":"Quantitative trait loci mapping of circulating metabolites in cerebrospinal fluid to uncover biological mechanisms involved in brain-related phenotypes","authors":"Lianne M. Reus, Toni Boltz, Marcelo Francia, Merel Bot, Naren Ramesh, Maria Koromina, Yolande A. L. Pijnenburg, Anouk den Braber, Wiesje M. van der Flier, Pieter Jelle Visser, Sven J. van der Lee, Betty M. Tijms, Charlotte E. Teunissen, Loes Olde Loohuis, Roel A. Ophoff","doi":"10.1038/s41380-025-02934-0","DOIUrl":"https://doi.org/10.1038/s41380-025-02934-0","url":null,"abstract":"<p>Genomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological mechanisms in vivo, measuring 5543 CSF metabolites, the largest panel in CSF to date, in 977 individuals of European ancestry. Individuals originated from two separate cohorts including cognitively healthy subjects (n = 490) and a well-characterized memory clinic sample, the Amsterdam Dementia Cohort (ADC, n = 487). We performed metabolite quantitative trait loci (mQTL) mapping on CSF metabolomics and found 126 significant mQTLs, representing 65 unique CSF metabolites across 51 independent loci. To better understand the role of CSF mQTLs in brain-related disorders we integrated our CSF mQTL results with pre-existing summary statistics on brain traits, identifying 34 genetic associations between CSF metabolites and brain traits. Over 90% of significant mQTLs demonstrated colocalized associations with brain-specific gene expression, unveiling potential neurobiological pathways.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"28 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518656","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":"Investigating dopaminergic abnormalities in schizophrenia and first-episode psychosis with normative modelling and multisite molecular neuroimaging","authors":"Alessio Giacomel, Daniel Martins, Giovanna Nordio, Rubaida Easmin, Oliver Howes, Pierluigi Selvaggi, Steven C. R. Williams, Federico Turkheimer, Marius De Groot, Ottavia Dipasquale, Mattia Veronese","doi":"10.1038/s41380-025-02938-w","DOIUrl":"https://doi.org/10.1038/s41380-025-02938-w","url":null,"abstract":"<p>Molecular neuroimaging techniques, like PET and SPECT, offer invaluable insights into the brain’s in-vivo biology and its dysfunction in neuropsychiatric patients. However, the transition of molecular neuroimaging into diagnostics and precision medicine has been limited to a few clinical applications, hindered by issues like practical feasibility, high costs, and high between-subject heterogeneity of neuroimaging measures. In this study, we explore the use of normative modelling (NM) to identify individual patient alterations by describing the physiological variability of molecular functions. NM potentially addresses challenges such as small sample sizes and diverse acquisition protocols typical of molecular neuroimaging studies. We applied NM to two PET radiotracers targeting the dopaminergic system ([¹¹C]-(+)-PHNO and [¹⁸F]FDOPA) to create a reference-cohort model of healthy controls. The models were subsequently utilized on different independent cohorts of patients with psychosis in different disease stages and treatment outcomes. Our results showed that patients with psychosis exhibited a higher degree of extreme deviations (~3-fold increase) than controls, although this pattern was heterogeneous, with minimal overlap of extreme deviations topology (max 20%). We also confirmed that striatal [¹⁸F]FDOPA signal, when referenced to a normative distribution, can predict treatment response (striatal AUC ROC: 0.77–0.83). In conclusion, our results indicate that normative modelling can be effectively applied to molecular neuroimaging after proper harmonization, enabling insights into disease mechanisms and advancing precision medicine. In addition, the method is valuable in understanding the heterogeneity of patient populations and can contribute to maximising cost efficiency in studies aimed at comparing cases and controls.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"12 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526236","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 case for hemispheric lateralization of the human amygdala in fear processing","authors":"Tao Xie, Sanne J. H. van Rooij, Cory S. Inman, Shuo Wang, Peter Brunner, Jon T. Willie","doi":"10.1038/s41380-025-02940-2","DOIUrl":"https://doi.org/10.1038/s41380-025-02940-2","url":null,"abstract":"The amygdala has increasingly been proposed as a therapeutic target for patients with post-traumatic stress disorder (PTSD). However, the distinct contributions of the left and right amygdala to various aspects of fear processing remain inadequately understood. Here, we critically re-evaluate key findings from human functional neuroimaging and lesion studies on fear conditioning and extinction. We propose that while both amygdalae likely make critical contributions to fear processing, the right is more associated with sensory-mediated fear expression, and the left is associated with cognitive-mediated fear acquisition and extinction. With accumulating evidence from human lesion studies, we suggest that differentially targeting the right versus left amygdala for ablative or neuromodulatory therapies can be crucial for optimizing PTSD treatment.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"22 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518657","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":"Suspected autoimmune-mediated dissociative symptoms","authors":"Dominique Endres, Elena Reinhold, Christian Klesse, Katharina Domschke, Harald Prüss, Ludger Tebartz van Elst","doi":"10.1038/s41380-025-02926-0","DOIUrl":"https://doi.org/10.1038/s41380-025-02926-0","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"40 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495385","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":"Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats","authors":"Brittany N. Kuhn, Nazzareno Cannella, Apurva S. Chitre, Khai-Minh H. Nguyen, Katarina Cohen, Denghui Chen, Beverly Peng, Kendra S. Ziegler, Bonnie Lin, Benjamin B. Johnson, Thiago Missfeldt Sanches, Ayteria D. Crow, Veronica Lunerti, Arkobrato Gupta, Eric Dereschewitz, Laura Soverchia, Jordan L. Hopkins, Analyse T. Roberts, Massimo Ubaldi, Sarah Abdulmalek, Analia Kinen, Gary Hardiman, Dongjun Chung, Oksana Polesskaya, Leah C. Solberg Woods, Roberto Ciccocioppo, Peter W. Kalivas, Abraham A. Palmer","doi":"10.1038/s41380-025-02922-4","DOIUrl":"https://doi.org/10.1038/s41380-025-02922-4","url":null,"abstract":"<p>The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing to vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified. <i>Tom1</i>, a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, including <i>Brwd1</i>, <i>Pcp4, Phb1l2</i> and <i>Mmp15</i> were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"22 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486451","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":"Dual recombinase-mediated intersectional genetics defines the functional heterogeneity of neural stem cells in adult hippocampus","authors":"Ziqi Liang, Zhimin Li, Dan Zhang, Xing Luo, Qiang Liu, Dezhe Qin, Min Wang, Zhiheng Xu, Jin Feng, Jinting He, Weixiang Guo","doi":"10.1038/s41380-025-02937-x","DOIUrl":"https://doi.org/10.1038/s41380-025-02937-x","url":null,"abstract":"<p>The Cre-lox site-specific recombinase system is one of the most powerful and versatile technology platforms for studying neural stem cells (NSCs) in adult brain, which is now challenged due to the complex and dynamic nature of in vivo gene expression. In this study, we develop an inducible dual recombinase-mediated intersectional genetics by combining Dre-rox and Cre-lox recombination technologies to specifically target two subpopulations of NSCs (α- and β-NSCs). By visiting their cell lineage and functionality, we find that α- and β-NSCs display distinct self-renewal and differentiation potential, as well as differential responses to external stimuli. Notably, in contrast to α-NSCs, the number of β-NSCs is not affected in aged mice and an APP/PS1 mouse model of Alzeimer’s disease. Single cell transcriptome analysis reveals divergent molecular signatures between type α- and β-NSCs and identifies PRMT1 as an important regulatory element to differentially regulate the neurogenic potential of α- and β-NSCs. Inhibition of PRMT1 specifically enhances the neurogenic capacity of β-NSCs and promotes the cognition functions in aged mice. Importantly, PRMT1 inhibition combined with increased BDNF levels pharmacologically ameliorates the cognitive impairments in APP/PS1 mice. Together, our study suggests that understanding the functional heterogeneity of NSCs might pave the way for harnessing the specific subpopulation of NSCs to treat brain disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"5 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486454","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":"Childhood trauma cortisol and immune cell glucocorticoid transcript levels are associated with increased risk for suicidality in adolescence","authors":"Tanya Goltser-Dubner, Fortu Benarroch, Michal Lavon, Reaan Amer, Laura Canetti, Ruth Giesser, Ella Kianski, Josef Martin, Dalya Pevzner, Pnina Blum Weinberg, Amichai Ben-Ari, Moriah Bar-Nitsan, Shaked Alon, Shai Yshai, Amit Lotan, Esti Galili-Weisstub, Ronen Segman, Amit Shalev","doi":"10.1038/s41380-025-02923-3","DOIUrl":"https://doi.org/10.1038/s41380-025-02923-3","url":null,"abstract":"<p>Rising adolescent suicide rates present a growing unmet need. Childhood trauma (CT) has been associated with altered cortisol dynamics and immune cell glucocorticoid reactivity, yet their additive longer-term contributions to later suicide outcomes are less clear. The current study compared CT scores, resting salivary free cortisol and mononuclear cell gene expression levels of the nuclear receptor, subfamily 3, member 1 (NR3C1) coding the glucocorticoid receptor, and its co-chaperons FKBP prolyl isomerase 5 (FKBP5) and KIT Ligand (KITLG), between a cohort of adolescents presenting with a suicidal crisis requiring hospital treatment, and matched healthy controls. Childhood trauma scores and glucocorticoid measures were significantly altered among suicidal adolescents, and CT scores correlated with mononuclear cell glucocorticoid transcripts. Both CT scores and glucocorticoid measures explained substantial additive portions of the variance in adolescent suicidality. Long-term perturbations in cortisol dynamics and immune cell glucocorticoid response elements denote dysregulated immune stress reactivity, and may possess value in prediction and point to modifiable-risk factors in prevention of clinically significant suicidality during the brittle period of adolescence, years after childhood trauma exposure.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"51 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486452","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":"Polygenic scores for autism are associated with reduced neurite density in adults and children from the general population","authors":"Yuanjun Gu, Eva Maria-Stauffer, Saashi A. Bedford, Rafael Romero-Garcia, Jakob Grove, Anders D. Børglum, Hilary Martin, Simon Baron-Cohen, Richard A. I. Bethlehem, Varun Warrier","doi":"10.1038/s41380-025-02927-z","DOIUrl":"https://doi.org/10.1038/s41380-025-02927-z","url":null,"abstract":"<p>Genetic variants linked to autism are thought to change cognition and behaviour by altering the structure and function of the brain. Although a substantial body of literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic variants are linked to changes in cortical macro- and micro-structure. We investigated this using neuroimaging and genetic data from adults (UK Biobank, N = 31,748) and children (ABCD, N = 4928). Using polygenic scores and genetic correlations we observe a robust negative association between common variants for autism and a magnetic resonance imaging derived phenotype for neurite density (intracellular volume fraction) in the general population. This result is consistent across both children and adults, in both the cortex and in white matter tracts, and confirmed using polygenic scores and genetic correlations. There were no sex differences in this association. Mendelian randomisation analyses provide no evidence for a causal relationship between autism and intracellular volume fraction, although this should be revisited using better powered instruments. Overall, this study provides evidence for shared common variant genetics between autism and cortical neurite density.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"90 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486453","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":"YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs","authors":"Marlene F. Pereira, Veronica Finazzi, Ludovico Rizzuti, Davide Aprile, Vittorio Aiello, Luca Mollica, Matteo Riva, Chiara Soriani, Francesco Dossena, Reinald Shyti, Davide Castaldi, Erika Tenderini, Maria Teresa Carminho-Rodrigues, Julien F. Bally, Bert B. A. de Vries, Michele Gabriele, Alessandro Vitriolo, Giuseppe Testa","doi":"10.1038/s41380-025-02929-x","DOIUrl":"https://doi.org/10.1038/s41380-025-02929-x","url":null,"abstract":"<p>Germline mutations of YY1 cause Gabriele-de Vries syndrome (GADEVS), a neurodevelopmental disorder featuring intellectual disability and a wide range of systemic manifestations. To dissect the cellular and molecular mechanisms underlying GADEVS, we combined large-scale imaging, single-cell multiomics and gene regulatory network reconstruction in 2D and 3D patient-derived physiopathologically relevant cell lineages. YY1 haploinsufficiency causes a pervasive alteration of cell type specific transcriptional networks, disrupting corticogenesis at the level of neural progenitors and terminally differentiated neurons, including cytoarchitectural defects reminiscent of GADEVS clinical features. Transcriptional alterations in neurons propagated to neighboring astrocytes through a major non-cell autonomous pro-inflammatory effect that grounds the rationale for modulatory interventions. Together, neurodevelopmental trajectories, synaptic formation and neuronal-astrocyte cross talk emerged as salient domains of YY1 dosage-dependent vulnerability. Mechanistically, cell type resolved reconstruction of gene regulatory networks uncovered the regulatory interplay between YY1, NEUROG2 and ETV5 and its aberrant rewiring in GADEVS. Our findings underscore the reach of advanced in vitro models in capturing developmental antecedents of clinical features and exposing their underlying mechanisms to guide the search for targeted interventions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"30 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470667","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":"Coding principles and mechanisms of serotonergic transmission modes","authors":"Yajun Zhang, Peng Zhang, Mimi Shin, Yuanyu Chang, Stephen B. G. Abbott, B. Jill Venton, J. Julius Zhu","doi":"10.1038/s41380-025-02930-4","DOIUrl":"https://doi.org/10.1038/s41380-025-02930-4","url":null,"abstract":"<p>Serotonin-mediated intercellular communication has been implicated in myriad human behaviors and diseases, yet how serotonin communicates and how the communication is regulated remain unclear due to limitations of available monitoring tools. Here, we report a method multiplexing genetically encoded sensor-based imaging and fast-scan cyclic voltammetry, enabling simultaneous recordings of synaptic, perisynaptic, proximate and distal extrasynaptic serotonergic transmission. Employing this method alongside a genetically encoded sensor-based image analysis program (GESIAP), we discovered that heterogeneous firing patterns of serotonergic neurons create various transmission modes in the mouse raphe nucleus and amygdala, encoding information of firing pulse frequency, number, and synchrony using neurotransmitter quantity, releasing synapse count, and synaptic and/or volume transmission. During tonic and low-frequency phasic activities, serotonin is confined within synaptic clefts due to efficient retrieval by perisynaptic transporters, mediating synaptic transmission modes. Conversely, during high-frequency, especially synchronized phasic activities, or when transporter inhibition, serotonin may surpass transporter capacity, and escape synaptic clefts through 1‒3 outlet channels, leading to volume transmission modes. Our results elucidate a mechanism of how channeled synaptic enclosures, synaptic properties, and transporters collaborate to define the coding principles of activity pattern-dependent serotonergic transmission modes.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"31 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473453","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}