Molecular Psychiatry最新文献

{"title":"Consortium profile: the methylation, imaging and NeuroDevelopment (MIND) consortium","authors":"Isabel K. Schuurmans, Rosa H. Mulder, Vilte Baltramonaityte, Alexandra Lahtinen, Fan Qiuyu, Leonardo Melo Rothmann, Marlene Staginnus, Jetro J. Tuulari, S. Alexandra Burt, Claudia Buss, Jeffrey M. Craig, Kirsten A. Donald, Johan G. Eriksson, Janine F. Felix, Tom P. Freeman, Rodrigo Grassi-Oliveira, Anke Huels, Luke W. Hyde, Scott A. Jones, Hasse Karlsson, Linnea Karlsson, Nastassja Koen, Will Lawn, Colter Mitchell, Christopher S. Monk, Michael A. Mooney, Ryan Muetzel, Joel T. Nigg, Síntia Iole Nogueira Belangero, Daniel Notterman, Yi Ying Ong, Tom O’Connor, Kieran J. O’Donnell, Pedro Mario Pan, Tiina Paunio, Peter Ryabinin, Richard Saffery, Giovanni A. Salum, Marc Seal, Tim J. Silk, Dan J. Stein, Ai Peng Tan, Ai Ling Teh, Dennis Wang, Heather Zar, Esther Walton, Charlotte A. M. Cecil","doi":"10.1038/s41380-025-03203-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03203-w","url":null,"abstract":"<p>Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults. To bridge this gap, we established the Methylation, Imaging and NeuroDevelopment (MIND) Consortium, which aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies. MIND currently integrates 16 cohorts worldwide, comprising (repeated) measures of DNA methylation in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging across up to five time points over a period of up to 21 years (N_{pooled DNAm} = 12,877; N_{pooled neuroimaging} = 10,899; N_{pooled combined} = 6074). By triangulating associations across multiple developmental time points and study types, we hope to generate new insights into the dynamic relationships between peripheral DNA methylation and the brain, and how these ultimately relate to neurodevelopmental and psychiatric phenotypes.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"40 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002995","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":"GABAA receptor availability in clinical high-risk and first-episode psychosis: a [11C]Ro15-4513 positron emission tomography study","authors":"Paulina B. Lukow, Julia J. Schubert, Mario Severino, Samuel R. Knight, Amanda Kiemes, Nicholas R. Livingston, James Davies, Andrea de Micheli, Thomas J. Spencer, Paolo Fusar-Poli, Beate Haege, Natasha Vorontsova, Jacek Donocik, Eugenii A. Rabiner, Anthony A. Grace, Steven C. Williams, Philip McGuire, Mattia Veronese, Federico E. Turkheimer, Gemma Modinos","doi":"10.1038/s41380-025-03204-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03204-9","url":null,"abstract":"<p>Disrupted gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of schizophrenia. Reductions in hippocampal GABAergic neurons have been found in schizophrenia, and increased hippocampal perfusion has been described in schizophrenia and in people at clinical high-risk for psychosis (CHRp). We have also found decreases in hippocampal GABA_A receptors containing the α5 subunit (GABA_ARα5) in a well-validated neurodevelopmental rat model of relevance for schizophrenia. Positive allosteric modulation of these receptors in the hippocampus using a specific compound was shown to reverse the behavioural and neurophysiological phenotypes of this model. However, whether GABA_ARα5 availability is dysregulated in the psychosis spectrum at the regional or network levels is unknown. We addressed this issue by using [¹¹C]Ro15-4513 and positron emission tomography (PET) in 22 individuals at CHRp, 10 people with a first-episode psychosis (FEP) and 23 healthy controls (HC). We quantified GABA_ARα5 availability in the hippocampus and across the brain, and employed a perturbation covariance method to assess individual molecular covariance deviations in CHRp and FEP groups compared to the HC group. Hippocampal GABA_ARα5 availability was not significantly different between groups (<i>F</i>(2,50) = 0.25, p = 0.78). However, network analysis identified significant deviations in GABA_ARα5 covariance between groups, both across all regions (all p &lt; 0.001, pairwise Cohen’s d = 0.07–0.5) and relative to the hippocampus (all p &lt; 0.001, pairwise Cohen’s d = 0.01–0.67). These findings suggest that individuals at clinical high-risk for psychosis and people with early psychosis may show alterations to the brain-wide organisation of the GABA_ARα5 system, rather than changes at a regional level.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"28 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002994","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":"Astrocytic Mettl14 depletion enhances cognitive function by attenuating astrogliosis via the DUSP1/MAPK pathway in APP/PS1 mice: targeting neuroinflammation in Alzheimer's disease.","authors":"Yan Teng, Jianli Xu, Shu He, Jin Yi, Manjun Li, Qin Tang, Xingmin Chen, Fan Wei, Yanzhuo Liu, Haisong Jiang, Yang Xiang, Jia-Ling Zhao, Jing Yang, Weidong Le, Min Zheng, Lu Yang","doi":"10.1038/s41380-025-03211-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03211-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD), a leading cause of dementia, represents a critical unmet global medical need. While the precise mechanisms underlying AD pathogenesis remain elusive, increasing evidence underscores the pivotal role of neuroinflammation in driving cognitive impairment. N6-methyladenosine (m6A), an epigenetic modification regulating RNA metabolism, has been found to be dysregulated in AD. In this study, we used a Mettl14 conditional knockout APP/PS1 mouse model (AD-cKO mice) to investigate the effects of modulating astrocytic m6A levels on AD progression. Our comprehensive histological, biochemical, and transcriptomic analyses revealed that AD-cKO mice exhibited enhanced cognitive function, along with decreased astrogliosis and reduced neuroinflammation when compared to APP/PS1 control mice. Based on the conjoint analysis of MeRIP-seq and RNA-seq data, our mechanistic studies further demonstrated that the loss of Mettl14 in astrocytes significantly affected the expression of DUSP1, a negative regulator of inflammation, to mitigate MAPK signaling. These findings suggest that targeting m6A regulators, such as Mettl14, may represent a promising therapeutic strategy to control neuroinflammation in AD progression. This study also highlights the broader potential of epigenetic modulation as a novel approach for treating AD. This graphic abstract illustrates the impact of Mettl14-mediated m6A modification on Alzheimer's disease (AD) pathogenesis. Alzheimer's disease, a leading cause of dementia, involves significant neuroinflammation. The study utilizes a Mettl14 conditional knockout APP/PS1 mouse model (AD-cKO mice) to investigate the role of m6A modification in astrocytes, the findings suggest that targeting m6A regulators like Mettl14 offers potential therapeutic benefits for controlling neuroinflammation in AD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008391","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":"Transdiagnostic reduction in cortical choline-containing compounds in anxiety disorders: a 1H-magnetic resonance spectroscopy meta-analysis","authors":"Richard J. Maddock, Jason Smucny","doi":"10.1038/s41380-025-03206-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03206-7","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Anxiety disorders (AnxDs) are highly prevalent and often untreated or unresponsive to treatment. Although proton magnetic resonance spectroscopy (1H-MRS) studies of AnxDs have been conducted for over 25 years, a consensus regarding neurometabolic abnormalities in these conditions is lacking.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A systematic review and meta-analysis of 1H-MRS studies of AnxDs (social anxiety disorder, generalized anxiety disorder, and panic disorder) identified 25 published datasets meeting inclusion criteria. These compared neurometabolites between 370 patients and 342 controls, including n-acetlyaspartate (NAA), total creatine, total choline (tCho), myo-inositol, glutamate, glutamate+glutamine, GABA, and lactate.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Across AnxDs, tCho was significantly reduced in prefrontal cortex and across all cortical regions. Effect sizes for cortical tCho were significantly more negative in studies with better measurement quality, with Hedges’ <i>g</i> = −0.64 and an 8% mean reduction. NAA was unchanged in prefrontal cortex but reduced across all cortical regions (after exclusions). These abnormalities did not differ between the three disorders. No other neurometabolites differed significantly.</p><h3 data-test=\"abstract-sub-heading\">Discussion</h3><p>Reduced choline-containing compounds in cortical regions is a consistent, transdiagnostic abnormality in AnxDs. Notably, arousal-related neuromodulators, including norepinephrine, alter membrane phospholipid homeostasis and methylation reactions, which influence brain tCho levels. This suggests that chronically elevated arousal in AnxDs may increase neurometabolic demand for choline compounds without a proportionate increase in brain uptake, leading to reduced tCho levels. Reduced cortical NAA suggests compromised neuronal function in AnxDs. Future studies may clarify the clinical significance of reduced cortical tCho and the possibility that appropriate choline supplementation could have therapeutic benefit in anxiety disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"136 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003154","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":"Impulsivity and neuroticism share distinct functional connectivity signatures with alcohol-use risk in youth","authors":"Annie Cheng, Sarah Lichenstein, Bader Chaarani, Qinghao Liang, Marzieh Babaeianjelodar, Steven J. Riley, Wenjing Luo, Corey Horien, Abigail S. Greene, Tobias Banaschewski, Arun L. W. Bokde, Sylvane Desrivières, Herta Flor, Antoine Grigis, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Luise Poustka, Sarah Hohmann, Nathalie Holz, Christian Baeuchl, Michael N. Smolka, Nilakshi Vaidya, Henrik Walter, Robert Whelan, Gunter Schumann, R. Todd Constable, Godfrey Pearlson, Hugh Garavan, Sarah W. Yip","doi":"10.1038/s41380-025-03196-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03196-6","url":null,"abstract":"<p>Increases in impulsivity and negative affect (e.g., neuroticism) are common during adolescence and are both associated with risk for alcohol-use initiation and other risk behaviors. Whole-brain functional connectivity approaches—when coupled with appropriate cross-validation—enable identification of complex neural networks subserving individual differences in dimensional traits (hereafter referred to as ‘neural signatures’). Here, we analyzed functional connectivity data acquired at age 19 from individuals enrolled in a multisite European study of adolescent development (N ~ 1100) using connectome-based predictive modeling. Network anatomies of these dimensional phenotypes were compared with one another and with a previously identified alcohol-use risk network to identify shared and unique neural mechanisms. Models accurately predicted both impulsivity and neuroticism (r’s ~ 0.17-0.19, p’s &lt; 0.05), and successfully generalized to an external sample. The impulsivity network was predominantly characterized by motor/sensory-related connections. By contrast, the neural signature of neuroticism was relatively more distributed across multiple canonical networks, including motor/sensory, default mode, subcortical, frontoparietal and cerebellar networks. Very few connections were common to both impulsivity and neuroticism networks. Moreover, while ~10-20% of the connections from each trait overlapped with the alcohol-use risk network, these connections were distinct between the two traits. This study for the first time identifies functional connectivity signatures of two common risk factors for alcohol-use in youth—impulsivity and neuroticism. Consistent with current equifinality-based conceptions of development, few connections predicted both impulsivity and neuroticism, indicating that the neural signatures of these two traits are relatively distinct despite both being implicated in alcohol-use risk and a wide array of behaviors.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"18 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995348","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 role of low subcortical iron, white matter myelin, and oligodendrocytes in schizophrenia: a quantitative susceptibility mapping and diffusion tensor imaging study","authors":"Luke J. Vano, Robert A. McCutcheon, Jan Sedlacik, Grazia Rutigliano, Stephen J. Kaar, Valeria Finelli, Maria C. Lobo, Alaine Berry, Ben Statton, Amir Fazlollahi, Ian P. Everall, Oliver D. Howes","doi":"10.1038/s41380-025-03195-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03195-7","url":null,"abstract":"<p>Iron—the most abundant magnetic brain substance—is essential for many biological processes, including dopamine and myelin synthesis. Quantitative susceptibility mapping (QSM) MRI has recently linked altered subcortical magnetic susceptibility (χ) to schizophrenia. Since χ is increased by iron and decreased by myelin, abnormal levels of either could underlie these QSM differences. In white matter tracts, magnetic susceptibility anisotropy (δχ) serves as a myelin-specific marker that is insensitive to iron content. To clarify the origin of case-control χ differences, we employed QSM in 85 individuals with schizophrenia, from first-episode mental health teams, and 86 healthy controls. A subset also underwent diffusion tensor imaging (DTI) to calculate subcortical tissue mean diffusivity, which inversely correlates with myelin concentration and fractional anisotropy. White matter δχ was calculated by combining QSM and DTI. Schizophrenia was associated with lower subcortical χ (d = −0.36, p = 0.023). This was significant in the caudate nucleus (d = −0.37, p = 0.037), putamen (d = −0.36, p = 0.037), globus pallidus (d = −0.57, p = 0.001), and SN-VTA (as previously reported). Additionally, schizophrenia was linked to higher subcortical mean diffusivity (d = 0.44, p = 0.018), and lower white matter δχ (d = −0.37, p = 0.047). These findings suggest that both subcortical iron and brain myelin levels are lower in schizophrenia. By comparing our voxelwise χ maps with postmortem gene expression data, we reveal that regions with lower subcortical χ in schizophrenia are enriched for oligodendrocyte-related genes (p &lt; 0.001). As oligodendrocytes are both the most iron-rich brain cells and essential for myelin synthesis, our results implicate oligodendrocyte dysfunction in schizophrenia pathophysiology.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"48 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002993","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 striosome-matrix distribution and activity of striatal cholinergic interneurons in a model of autism-linked repetitive behaviors","authors":"Jordan Molitor, Juliette Graniou, Pascal Salin, Francis Castets, Ahmed Fatmi, Lydia Kerkerian-Le Goff, Laurent Fasano, Xavier Caubit, Paolo Gubellini","doi":"10.1038/s41380-025-03208-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03208-5","url":null,"abstract":"<p>Repetitive behaviors are cardinal features of many brain disorders, including autism spectrum disorder (ASD). We previously associated dysfunction of striatal cholinergic interneurons (SCINs) with repetitive behaviors in a mouse model based on conditional deletion of the ASD-related gene <i>Tshz3</i> in cholinergic neurons (<i>Chat-cKO</i>). Here, we provide evidence linking SCIN abnormalities to the unique organization of the striatum into striosome and matrix compartments, whose imbalances are implicated in several pathological conditions. <i>Chat-cKO</i> mice exhibit an altered relationship between the embryonic birthdate of SCINs and their adult striosome-matrix distribution, leading to an increased proportion of striosomal SCINs. In addition, the ratio of striosomal SCINs with slow-irregular <i>vs</i>. sustained-regular firing is increased, which translates into decreased activity, further stressing the striosome-matrix imbalance. These findings provide novel insights into the pathogenesis of ASD-related stereotyped behaviors by pointing to abnormal developmental compartmentalization and activity of SCINs as a substrate.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"104 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995502","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":"Estrogen receptor beta in lateral habenula mediates antidepressant effects of estrogen in postpartum-hormone-withdrawal-induced depression","authors":"Chenchi Duan, Shuangshuang Ma, Min Chen, Junying Wang, Yihao Jiang, Mingliang Ye, Yi Tan, Songxia Cheng, Xuexuan Yang, Hailan Hu, Yan Yang, He-Feng Huang","doi":"10.1038/s41380-025-03215-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03215-6","url":null,"abstract":"<p>Dramatic drop in reproductive hormone, especially estrogen level, from pregnancy to postpartum period is known to contribute to postpartum depression (PPD), but the underlying mechanism and the role of the estrogen receptors (ERs) in this process were unclear. Here, we used an estrogen-withdrawal-induced PPD model following hormone simulated pregnancy (HSP) in female Sprague-Dawley rats to induce depressive-like behaviors. After estrogen withdrawal, we observe an up-regulation of astrocyte-specific potassium channel (Kir4.1) in the brain’s anti-reward center lateral habenula (LHb), along with enhanced bursting and excitability of LHb neurons. Among all 3 subtypes of ERs in the LHb, only ERβ shows an HSP-correlated expression temporal dynamics. Systemic administration of selective ERβ agonist, but not agonists of other subtypes of ERs, inhibits neuronal bursting activities and blocks up-regulation of Kir4.1 in the LHb, as well as decreases estrogen-withdrawal-induced depressive-like behavior. Importantly, intra-LHb injection of ERβ agonist is sufficient to rescue depressive-like behaviors induced by estrogen withdrawal. Conversely, local knock-down of ERβ in the LHb suppresses the antidepressant-like effect of estrogen. Our results reveal a critical role of LHb in the pathogenesis of hormone-sensitive PPD and ERβ as a critical mediator of estrogen’s antidepressant effects on PPD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"15 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002992","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":"Correction: Short- and long-term modulation of rat prefrontal cortical activity following single doses of psilocybin.","authors":"Ross J Purple, Rahul Gupta, Christopher W Thomas, Caroline T Golden, Nicola Palomero-Gallagher, Robin Carhart-Harris, Seán Froudist-Walsh, Matthew W Jones","doi":"10.1038/s41380-025-03231-6","DOIUrl":"10.1038/s41380-025-03231-6","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006377","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":"Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models","authors":"Yusuke Shintani, Atsuko Hayata-Takano, Ichiro Takasaki, Takashi Kurihara, Atsuro Miyata, Yui Yamano, Manato Ikuta, Rei Takeshita, Kenichiro Murata, Taisei Oguri, Chiaki Asaka, Kazuto Nunomura, Bangzhong Lin, Shinsaku Nakagawa, Takuya Okada, Naoki Toyooka, Toru Takumi, Yukio Ago, Kazuhiro Takuma, Hitoshi Hashimoto","doi":"10.1038/s41380-025-03209-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03209-4","url":null,"abstract":"<p>Stress-related disorders, such as depression and anxiety, have been one of the most important medical issues. Accumulating evidence suggests that the activation of the pituitary adenylate cyclase-activating polypeptide and its receptor PAC1 are involved in the stress axis and the development of stress-related disorders. We recently developed PA-915, a small-molecule, non-peptide, high-affinity PAC1 antagonist, and demonstrated that it significantly suppresses anxiety-like behavior in acute stress-induced mice. In this study, we aimed to investigate the behavioral effects of PA-915 in chronic stress-induced mouse models of depression, which included repeated social defeat stress, repeated corticosterone administration, and social isolation rearing. PA-915 ameliorated the increased immobility time in the forced swim test in these stress-induced mice. In repeated social defeat stress mice, PA-915 improved anxiety-like and depression-like behaviors and cognitive dysfunction, as assessed by the light-dark, open field, elevated plus maze, sucrose preference, forced swim, Y-maze, and novel object recognition tests. In addition, we evaluated the usefulness of PA-915 as an antidepressant and compared it with ketamine and fluoxetine. In the sucrose preference test, an antidepressant-like effect was observed for 8 weeks in mice that received a single dose of PA-915, which was a similar effect observed with ketamine. In non-stressed control mice, PA-915 did not induce behavioral abnormalities, such as hyperlocomotion, cognitive dysfunction, or dependency. The present results show that PA-915 improves anxiety-like behaviors and cognitive impairment and exerts rapid and long-lasting antidepressant effects in chronic stress-induced mouse models of anxiety and depression, proposing a promising treatment option for stress-related disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"61 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987280","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}