Molecular Psychiatry最新文献

{"title":"Kappa opioid receptor antagonism restores phosphorylation, trafficking and behavior induced by a disease-associated dopamine transporter variant","authors":"Felix P. Mayer, Adele Stewart, Durairaj Ragu Varman, Amy E. Moritz, James D. Foster, Anthony W. Owens, Lorena B. Areal, Raajaram Gowrishankar, Michelle Velez, Kyria Wickham, Hannah Phelps, Rania Katamish, Maximilian Rabil, Lankupalle D. Jayanthi, Roxanne A. Vaughan, Lynette C. Daws, Randy D. Blakely, Sammanda Ramamoorthy","doi":"10.1038/s41380-025-03055-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03055-4","url":null,"abstract":"<p>Aberrant dopamine (DA) signaling is implicated in schizophrenia, bipolar disorder (BPD), autism spectrum disorder (ASD), substance use disorder, and attention-deficit/hyperactivity disorder (ADHD). Treatment of these disorders remains inadequate, as exemplified by the therapeutic use of d-amphetamine and methylphenidate for the treatment of ADHD, agents with high abuse liability. In search for an improved and non-addictive therapeutic approach for the treatment of DA-linked disorders, we utilized a preclinical mouse model expressing the human DA transporter (DAT) coding variant DAT Val559, previously identified in individuals with ADHD, ASD, or BPD. DAT Val559, like several other disease-associated variants of DAT, exhibits anomalous DA efflux (ADE) that can be blocked by d-amphetamine and methylphenidate. Kappa opioid receptors (KORs) are expressed by DA neurons and modulate DA release and clearance, suggesting that targeting KORs might also provide an alternative approach to normalizing DA-signaling disrupted by perturbed DAT function. Here we demonstrate that KOR stimulation leads to enhanced surface trafficking and phosphorylation of Thr53 in wildtype DAT, effects achieved constitutively by the Val559 mutant. Moreover, these effects can be rescued by KOR antagonism of DAT Val559 in ex vivo preparations. Importantly, KOR antagonism also corrected in vivo DA release as well as sex-dependent behavioral abnormalities observed in DAT Val559 mice. Given their low abuse liability, our studies with a construct valid model of human DA associated disorders reinforce considerations of KOR antagonism as a pharmacological strategy to treat DA associated brain disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"36 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176621","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":"Single-molecule DNA analysis implicates brain mitochondria pathology in bipolar disorder","authors":"Hiroki Ohtani, Ryuya Ichikawa, Kanako Mori, Tadafumi Kato, Masaki Nishioka","doi":"10.1038/s41380-025-03071-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03071-4","url":null,"abstract":"<p>Bipolar disorder (BD), characterized by recurrent manic and depressive episodes, is a global medical challenge. Based on its high heritability, various genomic studies have elucidated the genetic architecture of BD. Nonetheless, the specific genomic mechanisms underpinning BD pathogenesis remain elusive. Among under-investigated genomic factors, mitochondrial variants—particularly brain heteroplasmic variants—are of particular interest, given the critical role of mitochondria in neural function and the frequent psychiatric symptoms observed in mitochondrial diseases. In this study, we analyzed 163 brain DNA samples from 54 BD patients, 54 controls, and 55 schizophrenia patients to investigate the association between BD and mitochondrial heteroplasmic variants. Duplex molecular barcoding sequencing was employed for single-molecule resolution. We found an enrichment of ultra-rare heteroplasmic variants with allele fractions exceeding 1% in BD. Among them, potentially pathogenic variants, including m.3243A&gt;G, loss-of-function variants, and rRNA variants, were particularly enriched in BD. In contrast, single-molecule analysis did not reveal a general trend of increases in low-level heteroplasmic variants in BD, in terms of per-base mutation frequency and heteroplasmic fractions. Thus, a subset of BD patients may be stratified according to the presence of ultra-rare mitochondrial variants. Our findings provide a foundation for future research into targeted therapeutic strategies for BD, grounded in genomic stratification by mitochondrial variants.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"244 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165595","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":"Whole-blood transcriptomic analysis reveals preoperative complement inhibitor deficiencies linked to postoperative delirium","authors":"Occam Kelly Graves, Jiayi Kang, Haobo Li, Serkan Erdin, Matthew Smith, Ariel Mueller, Christopher Simon, Kwame Wiredu, Varun Bhave, Celine De Esch, John Lemanski, Michael E. Talkowski, James Rhee, Jason Qu, Tina B. McKay, Oluwaseun Akeju","doi":"10.1038/s41380-025-03063-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03063-4","url":null,"abstract":"<p>Postoperative delirium is a type of acute cognitive dysfunction characterized by inattention, disorganized thinking, and altered levels of consciousness that commonly develops after major surgery. Efforts to reduce the incidence of delirium have focused primarily on optimizing perioperative care, however the development of prophylactic interventions have been hindered by a limited understanding of the underlying mechanisms involved in delirium. In this secondary analysis of the Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) trial, a nested case-control study (<i>n</i> = 51) was conducted using total RNA-sequencing analysis of whole-blood to investigate genes associated with delirium risk and development. Transcriptomic analysis revealed significantly lower expression of a key complement pathway inhibitor, <i>C4BPA</i>, in participants who experienced postoperative delirium. This finding was confirmed by quantitative PCR in the MINDDS cohort (<i>n</i> = 319) in adjusted logistic models. Furthermore, complement inhibitor <i>CD55</i> was also found to be under-expressed in participants who developed delirium. Dexmedetomidine treatment modified associations between <i>C4BPA</i> and <i>CD55</i> expression and the incidence of postoperative delirium by decreasing incidence in participants with low <i>C4BPA</i> and <i>CD55</i> expression. This study revealed key complement regulators as risk biomarkers of postoperative delirium. Importantly, our findings suggest postoperative delirium risk is modifiable. Unlike previous research that has mainly focused on proteomics, this study underscores the effectiveness of whole-blood transcriptomics in identifying biomarkers and underlying biological mechanisms of postoperative delirium.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"48 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145890","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":"Efficacy and mechanisms of repeated closed-loop auditory exposure during slow-wave sleep for internet gaming disorder","authors":"Xiaoqin Yang, Yixuan Song, Wangyue Liu, Yuchen Huang, Tianye Jia, Jianfeng Liu, Lin Lu, Yan Sun, Jie Shi","doi":"10.1038/s41380-025-02995-1","DOIUrl":"https://doi.org/10.1038/s41380-025-02995-1","url":null,"abstract":"<p>Internet Gaming Disorder (IGD) is marked by impaired psychological and social functioning but remains without effective treatments. Cue exposure therapy (CET) is typically administered during wakefulness to help extinguish addictive memories. However, recent studies suggest that sleep may be an optimal state for memory modulation. This study aimed to assess the efficacy of repeated closed-loop exposure to game sounds during UP-state of slow-wave sleep (SWS) on IGD. 84 participants meeting DSM-5 criteria for IGD were randomly assigned to sleep intervention/control groups (SIG/SCG) or awake intervention/control groups (AIG/ACG) with two consecutive days of intervention. During SWS of two intervention nights, around 300 sounds were exposed at slow-wave UP-state. While the awake groups received similar auditory cue exposure during the awake state for two consecutive days. Cravings, playtime, and P300 amplitude in the cue reactivity task were recorded at baseline, post-intervention, and follow-up intervals (1, 2, 3, weeks, and 1 month). Results showed that the SIG significantly reduced cravings (<i>p</i> &lt; 0.001), and playtime (<i>p</i> = 0.009) at post-intervention and follow-up, whereas awake CET showed no effect. The SIG exhibited higher low-frequency and early spindle power, along with lower late spindle power after sound exposure. Notably, the linear increase in sound-elicited late spindle power across the 20 intervention blocks over two experiment nights was positively correlated with reduced cravings post-intervention (<i>r</i> = 0.54, <i>p</i> = 0.015), especially among participants achieving a craving reduction greater than 30% after one month. Our findings suggest that closed-loop auditory exposure during SWS presents a promising, non-invasive intervention strategy for treating IGD, potentially exerting its effects by modulating late spindle power.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"68 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153349","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 neural substrate of comorbid depressive symptoms in alcohol use","authors":"Zhenlei Chen, Shangchen Yang, Lige Leng, Jinjun Ding, Ziqi Yuan, Kai Zhuang, Dan Can, Tingting Zou, Ya Wang, Huifang Li, Ti-Fei Yuan, Jie Zhang","doi":"10.1038/s41380-025-03061-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03061-6","url":null,"abstract":"<p>Alcohol use disorder (AUD) is commonly associated with depression, which may exacerbate the clinical outcome and increase treatment difficulty. The neural substrates underlying such comorbid symptoms are unclear. Here, we identify the regulatory role of amygdala Menin (multiple endocrine neoplasia type 1) signaling in orchestrating local GABAergic inhibition, which modulates the emotional state following alcohol use. Alcohol intake reduces Menin expression in the amygdala, decreasing GAT1 transcription. Restoring Menin signaling or overexpressing GAT1 in the amygdala could suppress alcohol preference and prevent depressive-like behaviors in these animals. Notably, knocking-in mice expressing a human <i>MEN1</i> variant (Menin-G503D) that associates with MDD exhibit strong alcohol preference. These findings uncover a previously unknown mechanism for a common clinical element of alcohol addiction and point to a novel candidate therapeutic target against depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"57 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145891","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 ensembles regulate circuit-induced relapse of extinguished fear","authors":"James E. Hassell, Angel D. Arellano Perez, Krithika Vasudevan, Reed L. Ressler, Gabriela M. Garcia, Madison Parr, Valerie M. Vierkant, Hugo Bayer, Stephen Maren","doi":"10.1038/s41380-025-03064-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03064-3","url":null,"abstract":"<p>Extinction learning is central to behavioral therapies for post-traumatic stress disorder (PTSD), but relapse poses a major challenge to this approach. Recent work has revealed a critical role for the thalamic nucleus reuniens (RE) in the suppression of extinguished fear memories. Silencing the RE yields a relapse of extinguished fear (i.e., “circuit-induced relapse”). Considerable work suggests that RE may contribute to extinction by inhibiting the retrieval of hippocampal (HPC)-dependent fear memories. To test this hypothesis, we first examined whether undermining the formation of contextual fear memories in the HPC would prevent circuit-induced relapse. Intra-hippocampal infusions of the NMDA receptor antagonist, APV, prior to auditory fear conditioning eliminated contextual fear memory and prevented the subsequent relapse of extinguished fear to the auditory conditioned stimulus (CS). In a second experiment, we used an activity-dependent labeling system (AAV-cFos-tTA; AAV-TRE-hM3Dq-mCherry) to express excitatory DREADDs in HPC neurons during fear conditioning. Chemogenetic reactivation of these ensembles after extinction was sufficient to drive relapse of fear to the extinguished CS. Lastly, in a third experiment, we expressed excitatory DREADDs in HPC ensembles captured during extinction learning and found that chemogenetic reactivation of this ensemble was sufficient to inhibit circuit-induced relapse. These results reveal that HPC-dependent ensembles play a critical role in regulating the expression and relapse of extinguished fear.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"34 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137142","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":"Deep learning algorithms reveal genomic markers for anxiety disorder in a large cohort of children with down syndrome","authors":"Yichuan Liu, Hui-Qi Qu, Xiao Chang, Frank D. Mentch, Haijun Qiu, Shahram Torkamandi, Kenny Nguyen, Kayleigh Ostberg, Tiancheng Wang, Joseph Glessner, Hakon Hakonarson","doi":"10.1038/s41380-025-03065-2","DOIUrl":"https://doi.org/10.1038/s41380-025-03065-2","url":null,"abstract":"<p>Despite a significant burden of neurobehavioral and psychiatric comorbidities in children with Down syndrome (DS), and the general increased risk for anxiety in individuals with intellectual disabilities (ID), children with DS have significantly lower odds of anxiety. Understanding the specific mechanisms of anxiety in DS could inform the development of new treatments. This study performed a comprehensive investigation of genomic variants that contribute to anxiety disorders in DS, as well as variants shared in other mental disorders. We employed deep learning algorithms using neural network models in combination with one of the largest whole-genome sequencing (WGS) cohorts of 1479 DS individuals and family members, including 255 DS probands diagnosed with at least one type of mental disorder, of whom 74 had confirmed anxiety disorders. We found that only a fraction (19%) of anxiety-specific corresponding gene variants previously reported overlap with those shared in anxiety in DS patients, suggesting distinct molecular mechanisms for anxiety in DS individuals. Functional overrepresentation analysis suggested that anxiety results from a complex interplay of genetic and environmental factors. Additionally, non-coding variants, particularly those proximal to splicing sites, play significant roles. Moreover, the variants associated with anxiety and other mental disorders are not uniquely distributed genome wide. Several loci, including 17q25, 16q23, 21q22, and 22q13, show greater weight in DS patients. Furthermore, 29 biomarkers containing recurrent anxiety-specific variants were identified to assist in the diagnosis of anxiety in the DS population. This pioneering study represents the first comprehensive exploration of anxiety disorders in DS utilizing WGS cohorts and advanced deep-learning AI models. The results indicate that anxiety disorder in DS patients has distinct molecular patterns from other mental disorders. The insights gained from our research offer valuable understanding of underlying mechanisms and hold promise for enhancing clinical diagnosis and potentially guiding more effective intervention strategies in this vulnerable population.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"12 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133586","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":"Unfolding neural diversity: how dynamic three-dimensional genome architecture regulates brain function and disease.","authors":"Brandon L Logeman, Steven F Grieco, Todd C Holmes, Xiangmin Xu","doi":"10.1038/s41380-025-03056-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03056-3","url":null,"abstract":"<p><p>The advent of single cell multi-omic technologies has ushered in a revolution in how we study the impact of three-dimensional genome organization on brain cellular composition and function. Transcriptomic and epigenomic studies reveal enormous cellular diversity that is present in mammalian nervous systems, raising the question, \"how does this diversity arise and for what is its use?\" Advances in the field of three-dimensional nuclear architecture have illuminated our understanding of how genome folding gives rise to dynamic gene expression programs important in healthy brain function and in disease. In this review we highlight recent work defining how neuronal identity, maturation, and plasticity are shaped by genome architecture. We discuss how newly identified genetic variations influence genome architecture and contribute to the evolution of species-unique neuronal and behavioral functional traits. We include examples for both humans and model organisms in which maladaptive genomic architecture is a causal agent in disease. Finally, we make conclusions and address future perspectives of dynamic three-dimensional genome (4D nucelome) research.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131894","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":"An ace in the hole? Opportunities and limits of using mice to understand schizophrenia neurobiology","authors":"Joseph M. Villarin, Christoph Kellendonk","doi":"10.1038/s41380-025-03060-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03060-7","url":null,"abstract":"<p>In applying model organisms to study the neurobiology of mental disorders, rodents offer unique potential for probing, with high spatiotemporal resolution, the neural and molecular mechanisms underlying behavior in a mammalian system. Furthermore, investigators can wield exceptional power to manipulate genes, molecules, and circuits in mice to pin down causal relationships. While these advantages have allowed us to understand much more deeply than ever before the brain mechanisms regulating complex behaviors, the impact of rodent models on developing therapeutic strategies for psychiatric disorders has remained thus far limited. Herein, we will discuss the opportunities and limits of using mouse models in the context of schizophrenia, a complex psychiatric disorder with strong genetic basis that poses various unmet clinical needs calling out for basic science research. We review approaches for employing behavioral, genetic, and circuit-based methods in rodents to inform schizophrenia symptomatology, pathophysiology, and, ultimately, treatment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"1 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting FSHR is a highly promising strategy for improving cognitive impairment in postmenopausal women.","authors":"Da Peng Wang, Zhe Bao Wu","doi":"10.1038/s41380-025-03048-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03048-3","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120352","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}