Molecular Psychiatry最新文献

{"title":"Correction: Central-peripheral neuroimmune dynamics in psychological stress and depression: insights from current research.","authors":"Xiao Feng, Min Jia, Meng Cai, Tong Zhu, Kenji Hashimoto, Jian-Jun Yang","doi":"10.1038/s41380-025-03121-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03121-x","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070077","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":"Cerebral glutamate levels over two years in initially antipsychotic-naïve first-episode patients with psychosis are related to clinical symptoms and cognition","authors":"Kirsten Borup Bojesen, Cecilie Koldbæk Lemvigh, Anne Korning Sigvard, Mark Bitsch Vestergaard, Henrik Bo Wiberg Larsson, Egill Rostrup, Bjørn Hylsebeck Ebdrup, Birte Glenthøj","doi":"10.1038/s41380-025-03234-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03234-3","url":null,"abstract":"<p>Although emerging evidence supports glutamatergic dysfunction in schizophrenia, clinical trials with glutamatergic compounds have overall been negative. This may be due to changes in glutamate levels during the course of illness. To address this, we measured glutamate levels in dorsal anterior cingulate cortex (dACC) and left thalamus in 57 initially antipsychotic-naïve patients with first-episode psychosis (FEP) aged 22.6 ± 5.0 years (58% females) and 55 healthy controls (HC) on a 3T MR scanner at baseline, after six weeks (48 FEP and 53 HC), six months (37 FEP and 49 HC), and two years (35 FEP and 45 HC). Positive and negative symptoms and cognitive function in tests of attention and spatial working memory were assessed at all visits. Linear mixed models were used in statistical analyses. We found lower glutamate levels in dACC in FEP (p = 0.03) that was associated with deficits in attention at all visits (p &lt; 0.05). Thalamic glutamate levels did not differ between groups, but higher levels were related to more pronounced positive symptoms at all visits (p = 0.02). The relation between thalamic glutamate levels and negative symptoms was altered over time (negative symptoms*time: p = 0.003) due to a significant positive association after two years (p = 0.04) but not at other visits. For other metabolites, thalamic NAA were lower in FEP (p = 0.04) and total creatine was increased after 6 weeks treatment (p = 0.01), whereas dACC glx levels were lower after two years (p = 0.02). The results suggest that greater positive symptom severity is related to higher thalamic glutamate levels and cognitive deficits to lower dACC glutamate levels during the first two years of illness. Furthermore, higher thalamic glutamate levels after two years are associated with more severe negative symptomatology. Findings imply that glutamatergic compounds decreasing thalamic and increasing dACC glutamate levels may be beneficial in FEP over the first two years of illness.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"19 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068090","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 China Brain Multi-omics Atlas Project (CBMAP)","authors":"Dan Zhou, Yuan Zhou, Zeyu Sun, Feiyang Ji, Dandan Zhang, Quan Wang, Yijun Ruan, Yongcheng Wang, Yimin Zhu, Xiaohui Sun, Mulin Jun Li, Changzheng Yuan, Kefu Liu, Lingyun Sun, Wenli Zhai, Jiayao Fan, Keqing Zhu, Wenying Qiu, Xiaoxin Yan, Chao Ma, Yi Shen, Aimin Bao, Weihua Yue, Yongyong Shi, Chao Chen, Jian Yang, Shumin Duan, Jing Zhang","doi":"10.1038/s41380-025-03250-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03250-3","url":null,"abstract":"<p>The China Brain Multi-omics Atlas Project (CBMAP) aims to generate a comprehensive molecular reference map of over 1000 human brains (Phase I), spanning a broad age range and multiple regions in China, to address the underrepresentation of East Asian populations in brain research. By integrating genome, epigenome, transcriptome, proteome (including multiple post-translational modifications), and metabolome data, CBMAP is set to provide a rich and invaluable resource for investigating the molecular underpinnings of aging-related brain phenotypes and neuropsychiatric disorders. Leveraging high-throughput omics data and advanced technologies, such as spatial transcriptomics, proteomics, and single-nucleus 3D chromatin structure analysis, this atlas will serve as a crucial resource for the brain science community, illuminating disease mechanisms and enhancing the utility of data from genome-wide association studies (GWAS). CBMAP is also poised to accelerate drug discovery and precision medicine for brain disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"36 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067980","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 to: Elevated maternal C-reactive protein and autism in a national birth cohort.","authors":"A S Brown, A Sourander, S Hinkka-Yli-Salomäki, I W McKeague, J Sundvall, H-M Surcel","doi":"10.1038/s41380-025-03262-z","DOIUrl":"https://doi.org/10.1038/s41380-025-03262-z","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070058","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":"Thalamo-frontal functional connectivity patterns in Tourette Syndrome: Insights from combined intracranial DBS and EEG recordings","authors":"Laura Wehmeyer, Juan Carlos Baldermann, Alek Pogosyan, Fernando Rodriguez Plazas, Philipp A. Loehrer, Leonardo Bonetti, Sahar Yassine, Katharina zur Mühlen, Thomas Schüller, Jens Kuhn, Veerle Visser-Vandewalle, Huiling Tan, Pablo Andrade","doi":"10.1038/s41380-025-03220-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03220-9","url":null,"abstract":"<p>Thalamic deep brain stimulation (DBS) has shown clinical improvement for patients with treatment-refractory Tourette Syndrome (TS). Advancing DBS for TS requires identifying reliable electrophysiological markers. Recognising TS as a network disorder, we investigated thalamo-cortical oscillatory connectivity by combining local field potential (LFP) recordings from the DBS thalamic target region using the Percept^TM PC neurostimulator with high-density EEG in eight male TS patients (aged 27–38) while stimulation was off. We identified a spatially and spectrally distinct oscillatory network connecting the medial thalamus and frontal regions in the alpha band (8–12 Hz), with functional connectivity strength negatively correlated with TS symptom severity. Moreover, reduced thalamo-frontal alpha functional connectivity before tic onset, localised in sensorimotor regions and the inferior parietal cortex, suggests its direct role in tic generation. Importantly, associations with symptoms and pre-tic dynamics were specific to functional connectivity patterns and not evident in the pure power spectra. These findings underscore the importance of investigating electrophysiological oscillatory connectivity to characterise pathological network connections in TS, potentially guiding stimulation-based interventions and future research on closed-loop DBS for TS.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"66 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043030","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":"Glucagon-like Peptide-1 receptor agonists as emerging therapeutics in bipolar disorder: a narrative review of preclinical and clinical evidence","authors":"Cristian-Daniel Llach, Sebastian Badulescu, Aniqa Tabassum, Hiya Shah, Hartej Gill, Gia Han Le, Eduard Vieta, Roger S. McIntyre, Joshua D. Rosenblat, Rodrigo B. Mansur","doi":"10.1038/s41380-025-03261-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03261-0","url":null,"abstract":"<p>Bipolar disorder (BD) is a chronic and disabling psychiatric illness characterized by complex pathophysiological mechanisms. Traditional treatments often fail to address these multidimensional processes, highlighting the need for novel therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for metabolic disorders, have emerged as promising candidates for a range of neuropsychiatric conditions due to their broad neurobiological effects. This narrative review synthesizes preclinical, clinical, and real-world evidence evaluating the therapeutic potential of GLP-1RAs in BD. These agents modulate neurotransmission, reduce neuroinflammation and oxidative stress, enhance mitochondrial and neurotrophic function, and improve insulin sensitivity and hypothalamic-pituitary-adrenal (HPA) axis regulation. These mechanisms are implicated in the neurobiology of BD, and preliminary findings suggest benefits across core psychopathological domains and common comorbidities, including depression, anxiety, mania, cognitive dysfunction, weight gain, and substance use disorders. While human data—particularly in BD populations—remain limited, evidence points to potential adjunctive benefits, especially in individuals with metabolic or cognitive vulnerabilities. Given their pleiotropic actions and established safety profile, GLP-1RAs represent compelling candidates for drug repurposing in BD. Well-powered, controlled trials are needed to confirm efficacy and safety, identify optimal subgroups, and evaluate long-term outcomes.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"132 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043092","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":"Maternal depression and offspring neurodevelopmental impairments in wild rodents induced by ecologically relevant prenatal stress","authors":"Jinyue Pang, Jinmei Hao, Xin Gu, Lanlan Zhang, Wei Wang, Zhicheng Qin, Qiyan Feng, Chang Liu, Hongxiang Xie, Shengmei Yang, Wanhong Wei, Ruiyong Wu","doi":"10.1038/s41380-025-03258-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03258-9","url":null,"abstract":"<p>Prenatal maternal stress negatively impacts maternal mental health and mother-child interaction, potentially increasing the risk of developmental outcomes in offspring. While studies in humans and lab animals have established these associations, the underlying mechanisms in naturalistic settings, where stressors are dynamic and interspecies differences may emerge, remain poorly characterized. This study introduced a novel model system using wild Brandt’s voles (<i>Lasiopodomys brandtii</i>) to investigate the effects of maternal depression-like psychopathology on offspring mood, cognition, and brain development. This model involves the repeated exposure of pregnant voles to predator odors, a natural stressor, which induces a depression-like state from late pregnancy to the early postpartum period. This model integrates ecologically relevant stressors with neurobehavioral assessments in a wild-derived species, allowing for a mechanistic investigation in a biologically meaningful context. We found that while exposure to predator odor stress during pregnancy induced maternal depressive-like states, it did not alter the level of postnatal parent-offspring interaction. Offspring born to mothers exposed to predator odor during pregnancy exhibited increased anxiety- and depression-like behaviors, impaired spatial and social cognition, and reduced sociability compared to offspring of mothers exposed to distilled water. These offspring also showed reduced neurogenesis in the hippocampal dentate gyrus, along with decreased dendrite branching and spine density. Our findings suggest that the effects of depression-like states during pregnancy and postpartum in female Brandt’s voles on offspring brain and behavioral functions occur independently of parent-offspring interactions, with hippocampal structural and functional abnormalities potentially mediating behavioral deficits. Importantly, this work establishes Brandt’s voles as a new, ecologically valid animal model for studying gestational depression and its intergenerational outcomes, bridging the gap between laboratory rodent studies and natural behavioral contexts.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"142 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056777","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":"Interrelations between dopaminergic-, gabaergic- and glutamatergic neurotransmitters in antipsychotic-naïve psychosis patients and the association to initial treatment response","authors":"Kirsten Borup Bojesen, Karen S. Ambrosen, Anne Korning Sigvard, Mette Ødegaard Nielsen, Albert Gjedde, Yoshitaka Kumakura, Lars Thorbjørn Jensen, Dan Fuglø, Bjørn Hylsebeck Ebdrup, Egill Rostrup, Birte Yding Glenthøj","doi":"10.1038/s41380-025-03229-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03229-0","url":null,"abstract":"<p>Preclinical evidence points to disturbances in neural networks in psychosis involving interrelations between dopaminergic-, GABAergic- and glutamatergic neurotransmitter systems. In support, we have previously shown that aberrant interrelations between these neurotransmitters, in contrast to individual transmitter systems, can separate antipsychotic-naïve first-episode psychotic patients (AN-FEP) from healthy controls (HC). Here, we characterized neurotransmitter interrelations, examined their association with treatment response, and explored the effect of treatment on the interrelations. Sixty participants (29 AN-FEP and 31 HC) underwent dynamic [18F]-DOPA PET with arterial blood sampling to measure dopamine synthesis (DS) (k₃) in nucleus accumbens (NAcc) and magnetic resonance spectroscopy (MRS) to estimate levels of glutamate (Glu) in anterior cingulate cortex (ACC) and thalamus, and gamma-aminobutyric-acid (GABA) in ACC. A subgroup of the patients was re-scanned after six weeks antipsychotic monotherapy with aripiprazole (PET: 10 AN-FEP; MRS: 27 AN-FEP; 30 HC). Psychopathology was assessed at both visits. Multiple linear regression models and linear mixed models were used to analyze data. We found a negative association between k₃ (dependent variable) and GABA in HC (β = −0.15, p = 0.03) and a positive association in patients (β = 0.15, p = 0.04). The aberrant relationship between k₃ and GABA was driven by the group-GABA interaction (p = 0.002) and related to treatment response (p = 0.02). No significant group interactions were found for the interrelations between k₃ and Glu, but a positive association was found between k₃ and Glu in thalamus (p = 0.04) in both groups and the association decreased after treatment in AN-FEP (p = 0.01). The data show that DS in NAcc and GABA levels in ACC are inversely interrelated in AN-FEP, and that the degree of abnormality predicts treatment effect. Moreover, antipsychotic treatment alters the relationship between dopaminergic activity in NAcc and Glu levels in thalamus. The findings suggest that combined instead of single neurotransmitter disturbances should be considered when novel therapeutics are developed for schizophrenia. Clinical trial registration: The Pan European Collaboration on Antipsychotic Naïve Schizophrenia II (PECANSII) study, ClinicalTrials.gov Identifier: NCT02339844. https://www.clinicaltrials.gov/study/NCT02339844.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"25 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035258","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":"Psychedelic studies in nonhuman primates: Past and future","authors":"Jamie C. Masthay, Alex C. Kwan, Steve W. C. Chang","doi":"10.1038/s41380-025-03240-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03240-5","url":null,"abstract":"<p>Studies of serotonergic or ‘classic’ psychedelics in nonhuman primates (NHPs) have provided valuable information about the drugs’ effects on the brain and behavior in closely related species to humans. Psychedelics induce characteristic changes to both spontaneous and operant behaviors in NHPs, though variability exists in the different effects reported by different studies; this variability could be due to factors like differences across drugs, differences in dose ranges across studies, and inter-individual variability in drug responsiveness. Several effects of psychedelics in NHPs mirror those in humans, including development of tolerance to psychedelic effects and low abuse liability, though evidence is mixed on whether psychedelics cause visual hallucinations in NHPs. NHP studies have also examined psychedelic mechanisms of action, supporting and connecting existing findings from human and rodent studies. Here we review the knowledge gained from psychedelic research in NHPs encompassing multiple psychedelic compounds in several NHP species. We conclude by highlighting NHPs’ potential to serve as preclinical models of psychedelic effects on psychiatric conditions and suggesting several directions for future research to ensure the accuracy and effectiveness of an NHP psychedelic model.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"106 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043094","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":"Hippocampal Cofilin and CFL1 gene variants are linked to Alcohol Use Disorder phenotypes","authors":"Ahmad Salamian, Roberto Pagano, Edyta Skonieczna, Liubov S. Kalinichenko, Monika Puchalska, G. Yiğit Ünlü, Olga Gajewska-Woźniak, Lali Kruashvili, Małgorzata Grochowicz, Bartosz Wojtas, Bartek Gielniewski, Zofia Harda, Anna Cały, Christiane Mühle, Bernd Lenz, Johannes Kornhuber, Anbarasu Lourdusamy, Robbert Havekes, Ted Abel, Christian P. Müller, Kasia Radwanska","doi":"10.1038/s41380-025-03226-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03226-3","url":null,"abstract":"<p>Alcohol use disorder (AUD) is characterized by pathological motivation to consume alcohol and cognitive inflexibility, leading to excessive alcohol seeking and use. In this study, we investigated the molecular correlates of impaired extinction of alcohol seeking during forced abstinence using a mouse model of AUD in the automated IntelliCage social system. This model distinguished AUD-prone and AUD-resistant animals based on the presence of ≥2 or &lt;2 criteria of AUD, respectively. We used RNA sequencing to identify genes differentially expressed in the hippocampus, a brain region implicated in alcohol motivation, seeking during abstinence, and cognitive inflexibility. Our findings revealed differences in the hippocampal genes linked to the actin cytoskeleton and synaptic function, including cofilin (Cfl), and impaired synaptic transmission in the molecular layer of the hippocampal dentate gyrus (ML-DG) in ≥2 criteria mice as compared to &lt;2 crit animals. To complement this data, we conducted local genetic manipulations in DG. Overexpression of Cfl in the polymorphic layer of the hippocampal dentate gyrus (PoDG) inhibited ML-DG synapses, increased motivation to seek alcohol and sucrose rewards, impaired extinction of seeking, and decreased reward consumption during relapse. Reducing Cfl levels had opposite effects. We also identified three SNPs in the human CFL1 gene (rs369270402, rs2376005, rs36124259) associated with increased AUD risk and found CFL1 mRNA blood levels correlated with alcohol-related hospital admissions. Overall, our study uncovers a novel mechanism linking hippocampal Cfl expression with AUD phenotypes and identifies CFL1 polymorphisms as AUD risk factor in humans.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"308 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032160","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}