Molecular Psychiatry最新文献

{"title":"Translational research approach to social orienting deficits in autism: the role of superior colliculus-ventral tegmental pathway","authors":"Alessandro Contestabile, Nada Kojovic, Giulia Casarotto, Farnaz Delavari, Patric Hagmann, Marie Schaer, Camilla Bellone","doi":"10.1038/s41380-025-02962-w","DOIUrl":"https://doi.org/10.1038/s41380-025-02962-w","url":null,"abstract":"<p>Autism Spectrum Disorder (ASD) is characterized by impairments in social interaction and repetitive behaviors. A key characteristic of ASD is a decreased interest in social interactions, which affects individuals’ ability to engage with their social environment. This study explores the neurobiological basis of these social deficits, focusing on the pathway between the Superior Colliculus (SC) and the Ventral Tegmental Area (VTA). Adopting a translational approach, our research used Shank3 knockout mice (<i>Shank3</i>^{<i>−/</i>−}), which parallel a clinical cohort of young children with ASD, to investigate these mechanisms. We observed consistent deficits in social orienting across species. In children with ASD, fMRI analyses revealed a significant decrease in connectivity between the SC and VTA. Additionally, using miniscopes in mice, we identified a reduction in the frequency of calcium transients in SC neurons projecting to the VTA, accompanied by changes in neuronal correlation and intrinsic cellular properties. Notably, the interneuronal correlation in <i>Shank3</i>^{<i>−/</i>−} mice and the functional connectivity of the SC to VTA pathway in children with ASD correlated with the severity of social deficits. Our findings underscore the potential of the SC-VTA pathway as a biomarker for ASD and open new avenues for therapeutic interventions, highlighting the importance of early detection and targeted treatment strategies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"34 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782540","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":"PsycGM: a comprehensive database for associations between gut microbiota and psychiatric disorders","authors":"Dongfang Wang, Siwen Gui, Juncai Pu, Xiaogang Zhong, Li Yan, Zhuocan Li, Xiangkun Tao, Dan Yang, Haipeng Zhou, Renjie Qiao, Hanping Zhang, Xiangyu Cheng, Yi Ren, Weiyi Chen, Xiaopeng Chen, Wei Tao, Yue Chen, Xiang Chen, Yiyun Liu, Peng Xie","doi":"10.1038/s41380-025-03000-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03000-5","url":null,"abstract":"<p>Psychiatric disorders pose substantial global burdens on public health, yet therapeutic options remain limited. Recently, gut microbiota is in the spotlight of new research on psychiatric disorders, as emerging discoveries have highlighted the importance of gut microbiome in the regulation of central nervous system via mediating the gut-brain-axis bidirectional communication. While metagenomics studies have accumulated for psychiatric disorders, few systematic efforts were dedicated to integrating these high-throughput data across diverse phenotypes, interventions, geographical regions, and biological species. To present a panoramic view of global data and provide a comprehensive resource for investigating the gut microbiota dysbiosis in psychiatric disorders, we developed the PsycGM, a manually curated and well-annotated database that provides the literature-supported associations between gut microbiota and psychiatric disorders or intervention measures. In total, PsycGM incorporated 559 studies from 31 countries worldwide, encompassing research involving humans, rats, mice, and non-human primates. PsycGM documented 8907 curated associations between 1514 gut microbial taxa and 11 psychiatric disorders, as well as 4050 associations between 869 taxa and 232 microbiota-based and non-microbiota-based interventions. Moreover, PsycGM provided a user-friendly web interface with comprehensive information, enabling browsing, retrieving and downloading of all entries. In the application of PsycGM, we panoramically depicted the intestinal microecological imbalance in depression. Additionally, we identified 9 microbial taxa consistently altered in patients with depression, with the most common dysregulations observed for <i>Parabacteroides</i>, <i>Alistipes</i>, and <i>Faecalibacterium</i>; in animal models of depression, consistent changes were observed in 21 microbial taxa, most frequently reported as <i>Helicobacter</i>, <i>Lactobacillus</i>, <i>Roseburia</i>, and the ratio of Firmicutes/Bacteroidetes. PsycGM is a comprehensive resource for future investigations on the role of gut microbiota in mental and brain health, and for therapeutic target innovations based on modifications of gut microbiota. PsycGM is freely accessed at http://psycgmomics.info.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"59 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782541","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 large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations","authors":"Pavithra Nagarajan, Thomas W. Winkler, Amy R. Bentley, Clint L. Miller, Aldi T. Kraja, Karen Schwander, Songmi Lee, Wenyi Wang, Michael R. Brown, John L. Morrison, Ayush Giri, Jeffrey R. O’Connell, Traci M. Bartz, Lisa de las Fuentes, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E. Harris, Zhijie Huang, Mart Kals, Minjung Kho, Christophe Lefevre, Jian’an Luan, Leo-Pekka Lyytikäinen, Massimo Mangino, Yuri Milaneschi, Nicholette D. Palmer, Varun Rao, Rainer Rauramaa, Botong Shen, Stefan Stadler, Quan Sun, Jingxian Tang, Sébastien Thériault, Adriaan van der Graaf, Peter J. van der Most, Yujie Wang, Stefan Weiss, Kenneth E. Westerman, Qian Yang, Tabara Yasuharu, Wei Zhao, Wanying Zhu, Drew Altschul, Md Abu Yusuf Ansari, Pramod Anugu, Anna D. Argoty-Pantoja, Michael Arzt, Hugues Aschard, John R. Attia, Lydia Bazzanno, Max A. Breyer, Jennifer A. Brody, Brian E. Cade, Hung-hsin Chen, Yii-Der Ida Chen, Zekai Chen, Paul S. de Vries, Latchezar M. Dimitrov, Anh Do, Jiawen Du, Charles T. Dupont, Todd L. Edwards, Michele K. Evans, Tariq Faquih, Stephan B. Felix, Susan P. Fisher-Hoch, James S. Floyd, Mariaelisa Graff, Charles Gu, Dongfeng Gu, Kristen G. Hairston, Anthony J. Hanley, Iris M. Heid, Sami Heikkinen, Heather M. Highland, Michelle M. Hood, Mika Kähönen, Carrie A. Karvonen-Gutierrez, Takahisa Kawaguchi, Setoh Kazuya, Tanika N. Kelly, Pirjo Komulainen, Daniel Levy, Henry J. Lin, Peter Y. Liu, Pedro Marques-Vidal, Joseph B. McCormick, Hao Mei, James B. Meigs, Cristina Menni, Kisung Nam, Ilja M. Nolte, Natasha L. Pacheco, Lauren E. Petty, Hannah G. Polikowsky, Michael A. Province, Bruce M. Psaty, Laura M. Raffield, Olli T. Raitakari, Stephen S. Rich, Renata L. Riha, Lorenz Risch, Martin Risch, Edward A. Ruiz-Narvaez, Rodney J. Scott, Colleen M. Sitlani, Jennifer A. Smith, Tamar Sofer, Maris Teder-Laving, Uwe Völker, Peter Vollenweider, Guanchao Wang, Ko Willems van Dijk, Otis D. Wilson, Rui Xia, Jie Yao, Kristin L. Young, Ruiyuan Zhang, Xiaofeng Zhu, Jennifer E. Below, Carsten A. Böger, David Conen, Simon R. Cox, Marcus Dörr, Mary F. Feitosa, Ervin R. Fox, Nora Franceschini, Sina A. Gharib, Vilmundur Gudnason, Sioban D. Harlow, Jiang He, Elizabeth G. Holliday, Zoltan Kutalik, Timo A. Lakka, Deborah A. Lawlor, Seunggeun Lee, Terho Lehtimäki, Changwei Li, Ching-Ti Liu, Reedik Mägi, Fumihiko Matsuda, Alanna C. Morrison, Brenda WJH Penninx, Patricia A. Peyser, Jerome I. Rotter, Harold Snieder, Tim D. Spector, Lynne E. Wagenknecht, Nicholas J. Wareham, Alan B. Zonderman, Kari E. North, Myriam Fornage, Adriana M. Hung, Alisa K. Manning, James Gauderman, Han Chen, Patricia B. Munroe, Dabeeru C. Rao, Diana van Heemst, Susan Redline, Raymond Noordam, Heming Wang","doi":"10.1038/s41380-025-02954-w","DOIUrl":"https://doi.org/10.1038/s41380-025-02954-w","url":null,"abstract":"<p>Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes’ functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"24 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775630","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":"Impaired synaptosome phagocytosis in macrophages of individuals with autism spectrum disorder","authors":"Yuki Nishi, Michihiro Toritsuka, Ryohei Takada, Mitsuru Ishikawa, Rio Ishida, Yoshinori Kayashima, Takahira Yamauchi, Kazuki Okumura, Tsutomu Takeda, Kazuhiko Yamamuro, Minobu Ikehara, Yuki Noriyama, Kohei Kamikawa, Shuhei Murayama, Osamu Ichikawa, Hidetaka Nagata, Hideyuki Okano, Nakao Iwata, Manabu Makinodan","doi":"10.1038/s41380-025-03002-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03002-3","url":null,"abstract":"<p>Dendritic spine abnormalities are believed to be one of the critical etiologies of autism spectrum disorder (ASD). Over the past decade, the importance of microglia in brain development, particularly in synaptic elimination, has become evident. Thus, microglial abnormalities may lead to synaptic dysfunction, which may underlie the pathogenesis of ASD. Several human studies have demonstrated aberrant microglial activation in the brains of individuals with ASD, and studies in animal models of ASD have also shown a relationship between microglial dysfunction and synaptic abnormalities. However, there are very few methods available to directly assess whether phagocytosis by human microglia is abnormal. Microglia are tissue-resident macrophages with phenotypic similarities to monocyte-derived macrophages, both of which consistently exhibit pathological phenotypes in individuals with ASD. Therefore, in this study, we examined the phagocytosis capacity of human macrophages derived from peripheral blood monocytes. These macrophages were polarized into two types: those induced by granulocyte-macrophage colony-stimulating factor (GM-CSF MΦ, traditionally referred to as “M1 MΦ”) and those induced by macrophage colony-stimulating factor (M-CSF MΦ, traditionally referred to as “M2 MΦ”). Synaptosomes purified from human induced pluripotent stem cell-derived neuron were used to assess phagocytosis capacity. Our results revealed that M-CSF MΦ exhibited higher phagocytosis capacity compared to GM-CSF MΦ, whereas ASD-M-CSF MΦ showed a marked impairment in phagocytosis. Additionally, we found a positive correlation between phagocytosis capacity and <i>cluster of differentiation 209</i> expression. This research contributes to a deeper understanding of the pathobiology of ASD and offers new insights into potential therapeutic targets for the disorder.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"108 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775631","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":"Stress-induced dysfunction of neurovascular astrocytes in the prefrontal cortex contributes to sex-dependent deficits in cognition and behavior","authors":"Justin L. Bollinger, Shobha Johnsamuel, Lauren L. Vollmer, Alexander M. Kuhn, Eric S. Wohleb","doi":"10.1038/s41380-025-02993-3","DOIUrl":"https://doi.org/10.1038/s41380-025-02993-3","url":null,"abstract":"<p>Astrocytes form an integral component of the neurovascular unit, ensheathing brain blood vessels with endfeet high in aquaporin-4 (AQP4) expression. These AQP4-rich endfeet facilitate interaction between the vascular endothelium, astrocytes, and neurons, and help stabilize vascular morphology. Studies using preclinical models of psychological stress and post-mortem tissue from patients with major depressive disorder (MDD) have reported reductions in AQP4, loss of astrocytic structures, and vascular impairment in the prefrontal cortex (PFC). Though compelling, the role of AQP4 in mediating stress-induced alterations in neurovascular function and behavior remains unclear. Here, we address this, alongside potential sex differences in chronic unpredictable stress (CUS) effects on astrocyte phenotype, blood-brain barrier integrity, and behavior. CUS led to more pronounced shifts in stress-coping behavior and working memory deficits in male- as compared to female mice. Following behavioral testing, astrocytes from the frontal cortex were isolated for gene expression analyses. We found that CUS increased transcripts associated with blood vessel maintenance in males, but either had no effect on- or decreased- these transcripts in females. Furthermore, CUS caused a reduction in vascular-localized AQP4 and elevated extravasation of a small fluorescent reporter (Dextran) in the PFC in males but not females. Studies showed that knockdown of AQP4 in the PFC is sufficient to disrupt astrocyte phenotype and increase behavioral susceptibility to a sub-chronic stressor in males yet has little effect on stress susceptibility in females. Our findings provide evidence that sex-specific alterations in astrocyte phenotype and neurovascular integrity in the PFC contribute to cognitive-behavioral consequences following stress.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"37 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782542","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":"Brain overlapping system-level architecture influenced by external magnetic stimulation and internal gene expression in AD-spectrum patients","authors":"Weina Yao, Xinle Hou, Wenao Zheng, Xian Shi, JunJian Zhang, Feng Bai","doi":"10.1038/s41380-025-02991-5","DOIUrl":"https://doi.org/10.1038/s41380-025-02991-5","url":null,"abstract":"<p>The brain overlapping system-level architecture is associated with functional information integration in the multiple roles of the same region, and it has been developed as an underlying novel biomarker of brain disease and may characterise the indicators for the treatment of Alzheimer’s disease (AD). However, it remains uncertain whether these changes are influenced by external magnetic stimulation and internal gene expression. A total of 73 AD-spectrum patients (52 with true stimulation and 21 with sham stimulation) were underwent four-week neuronavigated transcranial magnetic stimulation (rTMS). Shannon-entropy diversity coefficient analysis was used to explore the brain overlapping system of the neuroimaging data in these pre- and posttreatment patients. Transcription-neuroimaging association analysis was further performed via gene expression data from the Allen Human Brain Atlas. Compared with the rTMS_sham stimulation group, the rTMS_true stimulation group achieved the goal of cognitive improvement through the reconstruction of functional information integration in the multiple roles of 27 regions associated with the brain overlapping system, involving the attentional network, sensorimotor network, default mode network and limbic network. Furthermore, these overlapping regions were closely linked to gene expression on cellular homeostasis and immune inflammation, and support vector regression analysis revealed that the baseline diversity coefficients of the attentional and sensorimotor networks can effectively predict memory improvement after rTMS treatment. These findings highlight the brain overlapping system associated with cognitive improvement, and provide the first evidence that external magnetic stimulation and internal gene expression could influence these overlapping regions in AD-spectrum patients.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"33 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782570","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":"Joint contribution of polygenic scores for depression and attention-deficit/hyperactivity disorder to youth suicidal ideation and attempt","authors":"Massimiliano Orri, Genevieve Morneau-Vaillancourt, Isabelle Ouellet-Morin, Samuele Cortese, Cedric Galera, Ivan Voronin, Frank Vitaro, Mara R. Brendgen, Ginette Dionne, Stephane Paquin, Alberto Forte, Gustavo Turecki, Richard E. Tremblay, Sylvana M. Côté, Marie-Claude Geoffroy, Michel Boivin","doi":"10.1038/s41380-025-02989-z","DOIUrl":"https://doi.org/10.1038/s41380-025-02989-z","url":null,"abstract":"<p>Children presenting comorbid attention-deficit/hyperactivity disorder (ADHD) and depression symptoms have higher risks of later suicidal ideation and attempt. However, it is unclear to what extent this risk stems from individual differences in the genetic predisposition for ADHD and/or depression. We investigated the unique and combined contribution of genetic predisposition to ADHD and depression to suicidal ideation and attempt by early adulthood. Data were from two longitudinal population-based birth cohorts, the Quebec Longitudinal Study of Child Development and the Quebec Newborn Twin Study (total <i>N</i> = 1207). Genetic predisposition for ADHD and depression were measured using polygenic scores. Suicidal ideation and attempt by age 20 years were self-reported via questionnaires. Across the two cohorts, suicidal ideation and attempt were reported by 99 (8.2%) and 75 (6.1%) individuals, respectively. A higher polygenic score for depression was associated with significantly higher risk of suicidal ideation and attempt, while no significant associations were found for ADHD polygenic score. However, we found an interaction between polygenic scores for depression and ADHD in the association with suicide attempt (<i>P</i> = 0.012), but not suicidal ideation (<i>P</i> = 0.897). The association between polygenic score for depression and suicide attempt was significantly stronger for individuals with a higher polygenic score for ADHD. Individuals scoring ≥ 1-SD above the mean for both polygenic scores were at increased risk for suicide attempt compared to individuals with lower scores (OR 4.03, CI 1.64–9.90), as well as compared to individuals scoring ≥ 1-SD above the mean in only depression (OR 2.92, CI 1.01–8.50) or only ADHD (OR 4.88, CI 1.56–15.26) polygenic scores. Our findings suggest that genetic predisposition for ADHD and depression contributes to increase the risk of suicide attempt in a multiplicative, rather that additive, way. Our results contribute to our understanding of the etiology of suicide risk and may inform screening and risk stratification.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"73 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782569","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":"17β-estradiol status alters NMDAR function and antipsychotic-like activity in female rats","authors":"Kimberly M. Holter, McKenna G. Klausner, Mary Hunter Hite, Carson T. Moriarty, Samuel H. Barth, Bethany E. Pierce, Alexandria N. Iannucci, Douglas J. Sheffler, Nicholas D. P. Cosford, Heather A. Bimonte-Nelson, Kimberly F. Raab-Graham, Robert W. Gould","doi":"10.1038/s41380-025-02996-0","DOIUrl":"https://doi.org/10.1038/s41380-025-02996-0","url":null,"abstract":"<p>Low 17β-estradiol (E2) in females of reproductive age, and marked E2 decline with menopause, contributes to heightened symptom severity in schizophrenia (i.e. cognitive dysfunction) and diminished response to antipsychotic medications. However, the underlying mechanisms are unknown. <i>N</i>-methyl-D-aspartate receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia, yet impact of E2 depletion on NMDAR function is not well characterized. Quantitative electroencephalography (qEEG), specifically gamma power, is a well-established functional readout of cortical activity that is elevated in patients with schizophrenia and is sensitive to alterations in NMDAR function. Using qEEG and touchscreen cognitive assessments, present studies investigated the effects of E2 on NMDAR function by administering MK-801 (NMDAR antagonist) to ovariectomized rats with or without E2 implants (Ovx+E and Ovx, respectively). Ovx rats were more sensitive to MK-801-induced elevations in gamma power and attentional impairments compared to Ovx+E rats. Further investigation revealed these effects were mediated by reduced synaptic GluN2A expression. Consistent with clinical reports, olanzapine (second-generation antipsychotic) was less effective in mitigating MK-801-induced elevations in gamma power in Ovx rats. Lastly, we examined antipsychotic-like activity of a Group II metabotropic glutamate receptor (mGlu_2/3) positive allosteric modulator (PAM), SBI-0646535, as a novel therapeutic in E2-deprived conditions. SBI-0646535 reversed MK-801-induced elevations in gamma power regardless of E2 status. Collectively, these studies established a relationship between E2 deprivation and NMDAR function that is in part GluN2A-dependent, supporting the notion that E2 deprivation increases susceptibility to NMDAR hypofunction. This highlights the need to examine age/hormone-specific factors when considering antipsychotic response and designing novel pharmacotherapies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782543","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":"Genetic and neural mechanisms shared by schizophrenia and depression","authors":"Yingying Xie, Jilian Fu, Liping Liu, Xijin Wang, Feng Liu, Meng Liang, Hesheng Liu, Wen Qin, Chunshui Yu","doi":"10.1038/s41380-025-02975-5","DOIUrl":"https://doi.org/10.1038/s41380-025-02975-5","url":null,"abstract":"<p>Schizophrenia (SCZ) and depression are two prevalent mental disorders characterized by comorbidity and overlapping symptoms, yet the underlying genetic and neural mechanisms remain largely elusive. Here, we investigated the genetic variants and neuroimaging changes shared by SCZ and depression in Europeans and then extended our investigation to cross-ancestry (Europeans and East Asians) populations. Using conditional and conjunctional analyses, we found 213 genetic variants shared by SCZ and depression in Europeans, of which 82.6% were replicated in the cross-ancestry population. The shared risk variants exhibited a higher degree of deleteriousness than random and were enriched for synapse-related functions, among which fewer than 3% of shared variants showed horizontal pleiotropy between the two disorders. Mendelian randomization analyses indicated reciprocal causal effects between SCZ and depression. Using multiple trait genetic colocalization analyses, we pinpointed 13 volume phenotypes shared by SCZ and depression. Particularly noteworthy were the shared volume reductions in the left insula and planum polare, which were validated through large-scale meta-analyses of previous studies and independent neuroimaging datasets of first-episode drug-naïve patients. These findings suggest that the shared genetic risk variants, synapse dysfunction, and brain structural changes may underlie the comorbidity and symptom overlap between SCZ and depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766628","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":"Temporal interactions between neural proxies for memory recall, negative affect, and emotion regulation in major depression","authors":"Christina A. Michel, Mike Schmidt, J. John Mann, Sarah Herzog, Kevin N. Ochsner, Lila Davachi, Noam Schneck","doi":"10.1038/s41380-025-02982-6","DOIUrl":"https://doi.org/10.1038/s41380-025-02982-6","url":null,"abstract":"<p>Dysfunction in emotion regulation (ER) and autobiographical memory are components of major depressive disorder (MDD). However, little is known about how they mechanistically interact with mood disturbances in real time. Using machine learning-based neural signatures, we can quantify negative affect (NA), ER, and memory continuously to evaluate how these processes dynamically interact in MDD. Unmedicated individuals with MDD (<i>N</i> = 45) and healthy volunteers (HV; <i>N</i> = 38) completed a negative autobiographical memory functional magnetic resonance imaging task wherein they recalled, distanced from (an ER strategy), and immersed into memories. We used a negative affect signature (PINES) and an emotion regulation signature (ERS) to quantify moment-to-moment NA and ER. We then examined whether memory engagement, indexed by hippocampal activity, predicted subsequent change in PINES and ERS over time. During memory recall and immersion, greater hippocampal activity predicted increased PINES across groups. During distancing, greater hippocampal activity in HVs predicted increased ERS but not PINES. In MDD, greater hippocampal activity predicted increased PINES but not ERS. Findings suggest abnormalities in the real-time relationship between memory, NA, and ER in MDD. During distancing, as predicted, HVs showed an attenuation of the linkage between memory engagement and NA, and they had subsequent increases in ER following memory reactivation. In contrast, MDD was characterized by continued linkage between memory engagement and NA, without subsequent increases in ER. Deficits in engagement of ER and ineffective modulation of NA following negative memory recall may contribute to the mood disturbances in MDD and are potential targets for clinical intervention.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"236 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775644","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}