Molecular Psychiatry最新文献

{"title":"Highly demarcated structural alterations in the brain and impaired social incentive learning in Tbx1 heterozygous mice.","authors":"Takeshi Hiramoto, Akira Sumiyoshi, Risa Kato, Takahira Yamauchi, Takeshi Takano, Gina Kang, Marisa Esparza, Bailey Matsumura, Lucas J Stevens, Yukiko J Hiroi, Takaki Tanifuji, Rie Ryoke, Hiroi Nonaka, Akihiro Machida, Kensaku Nomoto, Kazutaka Mogi, Takefumi Kikusui, Ryuta Kawashima, Noboru Hiroi","doi":"10.1038/s41380-024-02797-x","DOIUrl":"10.1038/s41380-024-02797-x","url":null,"abstract":"<p><p>Copy number variants (CNVs) are robustly associated with psychiatric disorders and changes in brain structures. However, because CNVs contain many genes, the precise gene-phenotype relationship remains unclear. Although various volumetric alterations in the brains of 22q11.2 CNV carriers have been identified in humans and mouse models, it is unknown how each gene encoded in the 22q11.2 region contributes to structural alterations, associated mental illnesses, and their dimensions. Our previous studies identified Tbx1, a T-box family transcription factor encoded in the 22q11.2 CNV, as a driver gene for social interaction and communication, spatial and working memory, and cognitive flexibility. However, it remains unclear how TBX1 impacts the volumes of various brain regions and their functionally linked behavioral dimensions. In this study, we used volumetric magnetic resonance imaging analysis to comprehensively evaluate brain region volumes and behavioral alterations relevant to affected structures in congenic Tbx1 heterozygous mice. Our data showed that the volumes of the anterior and posterior portions of the amygdaloid complex and its surrounding cortical regions were most robustly reduced in Tbx1 heterozygous mice. In an amygdala-dependent task, Tbx1 heterozygous mice were impaired in their ability to learn the incentive value of a social partner. The volumes of the primary and secondary auditory cortexes were increased, and acoustic, but not non-acoustic, sensorimotor gating was impaired in Tbx1 heterozygous mice. Our findings identify the brain's regional volume alterations and their relevant behavioral dimensions associated with Tbx1 heterozygosity.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"1876-1886"},"PeriodicalIF":9.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12014486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal and early childhood infections requiring hospitalization and risk of neurodevelopmental disorders in offspring: a population-based birth cohort study in Taiwan.","authors":"Mei-Chen Lin, Yi-Jiun Pan, Chi-Shin Wu, Chia-Lin Liu, Pei-Chun Chen, Wesley K Thompson, Chun-Chieh Fan, Shi-Heng Wang","doi":"10.1038/s41380-024-02787-z","DOIUrl":"10.1038/s41380-024-02787-z","url":null,"abstract":"<p><p>In utero and early childhood infections have been associated with an increased risk of neurodevelopmental disorders; however, the observed associations may be confounded by familial predispositions. This study examined the neurodevelopmental disorders attributable to maternal infections during pregnancy and early childhood infections during the first year of life, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), tic disorders, and mental retardation (MR). We performed population and sibling comparison analyses to account for unmeasured familial confounding factors. We conducted a register-based cohort study with 2,885,662 individuals (comprising 1,864,660 full siblings) born in Taiwan between 2001 and 2018 and followed up until 2021. We employed Cox regression analysis to assess the association between in utero and early childhood infections requiring hospitalization and the subsequent risk of neurodevelopmental disorders. In the population analyses, an offspring exposed to maternal infection had an increased risk for ASD (hazard ratio (HR) = 1.19, 95% confidence interval (CI): 1.13-1.26), ADHD (HR = 1.14, 95% CI: 1.11-1.18), and MR (HR = 1.21, 95% CI: 1.13-1.30). These associations attenuated toward null in the sibling analyses. Individuals exposed to early childhood infection had an increased risk for ASD (HR = 1.13, 95% CI: 1.10-1.16), ADHD (HR = 1.16, 95% CI: 1.15-1.18), tic disorders (HR = 1.12, 95% CI: 1.09-1.15), and MR (HR = 1.64, 95% CI: 1.60-1.69) in the population analyses; these associations were also significant for ASD (HR = 1.14, 95% CI: 1.07-1.21) and MR (HR = 1.52, 95% CI: 1.44-1.62) in the sibling analyses. The association between maternal infection during pregnancy and offspring neurodevelopmental risk is largely due to familial confounding factors. Conversely, infection in early childhood may be attributable to it being a sensitive period and may play a role in the subsequent risk of ASD and MR.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"1791-1800"},"PeriodicalIF":9.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400809","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":"ErbB inhibition rescues nigral dopamine neuron hyperactivity and repetitive behaviors in a mouse model of fragile X syndrome.","authors":"Sebastian L D'Addario, Eleonora Rosina, Mariangela Massaro Cenere, Claudia Bagni, Nicola B Mercuri, Ada Ledonne","doi":"10.1038/s41380-024-02831-y","DOIUrl":"10.1038/s41380-024-02831-y","url":null,"abstract":"<p><p>Repetitive stereotyped behaviors are core symptoms of autism spectrum disorders (ASD) and fragile X syndrome (FXS), the prevalent genetic cause of intellectual disability and autism. The nigrostriatal dopamine (DA) circuit rules movement and creation of habits and sequential behaviors; therefore, its dysregulation could promote autistic repetitive behaviors. Nevertheless, inspection of substantia nigra pars compacta (SNpc) DA neurons in ASD models has been overlooked and specific evidence of their altered activity in ASD and FXS is absent. Here, we show that hyperactivity of SNpc DA neurons is an early feature of FXS. The underlying mechanism relies on an interplay between metabotropic glutamate receptor 1 (mGluR1) and ErbB tyrosine kinases, receptors for the neurotrophic and differentiation factors known as neuregulins. Up-regulation of ErbB4 and ErbB2 in nigral DA neurons drives neuronal hyperactivity and repetitive behaviors of the FXS mouse, concurrently rescued by ErbB inhibition. In conclusion, beyond providing the first evidence that nigral DA neuron hyperactivity is a signature of FXS and nigral mGluR1 and ErbB4/2 play a relevant role in FXS etiology, we demonstrate that inhibiting ErbB is a valuable pharmacological approach to attenuate stereotyped repetitive behaviors, thus opening an avenue toward innovative therapies for ASD and FXS treatment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"2183-2196"},"PeriodicalIF":9.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12014506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-dose-dependent reduction of Fshr expression improves spatial memory deficits in Alzheimer's mice.","authors":"Funda Korkmaz, Steven Sims, Fazilet Sen, Farhath Sultana, Victoria Laurencin, Liam Cullen, Anusha Pallapati, Avi Liu, Ronald Chen, Satish Rojekar, Georgii Pevnev, Uliana Cheliadinova, Darya Vasilyeva, Guzel Burganova, Anne Macdonald, Mansi Saxena, Ki Goosens, Clifford J Rosen, Orly Barak, Daria Lizneva, Anisa Gumerova, Keqiang Ye, Vitaly Ryu, Tony Yuen, Tal Frolinger, Mone Zaidi","doi":"10.1038/s41380-024-02824-x","DOIUrl":"10.1038/s41380-024-02824-x","url":null,"abstract":"<p><p>High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of Alzheimer's disease (AD). We have shown recently that FSH directly activates the hippocampal FSH receptors (FSHRs) to drive AD-like pathology and memory loss in mice. To unequivocally establish a role for FSH in memory loss, we depleted the Fshr on a 3xTg background and utilized Morris Water Maze to study deficits in spatial memory. 3xTg;Fshr^+/+ mice displayed impaired spatial memory at 5 months of age. The loss of memory acquisition and retrieval were both rescued in 3xTg;Fshr^-/- mice and, to a lesser extent, in 3xTg;Fshr^+/- mice-documenting clear gene-dose-dependent prevention of spatial memory loss. Furthermore, at 5 and 8 months, sham-operated 3xTg;Fshr^-/- mice showed better memory performance during the learning and/or retrieval phases, further suggesting that Fshr deletion prevents age-related progression of memory deficits. This prevention was not seen when mice were ovariectomized, except in the 8-month-old 3xTg;Fshr^-/- mice. There was also a gene-dose-dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial memory deficits in mice and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of memory loss in post-menopausal women.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"2119-2126"},"PeriodicalIF":9.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639377","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":"Npbwr1 signaling mediates fast antidepressant action.","authors":"Gregor Stein, Janine S Aly, Lisa Lange, Annamaria Manzolillo, Konstantin Riege, Anna Brancato, Christian A Hübner, Gustavo Turecki, Steve Hoffmann, Olivia Engmann","doi":"10.1038/s41380-024-02790-4","DOIUrl":"10.1038/s41380-024-02790-4","url":null,"abstract":"<p><p>Chronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we identify the receptor for neuropeptides B and W, Npbwr1, as a key regulator of depressive-like symptoms. Npbwr1 is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link between Npbwr1, dendritic spine morphology, the biomarker Bdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist of Npbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and alters Bdnf levels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"1828-1835"},"PeriodicalIF":9.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE deficiency inhibits amyloid-facilitated (A) tau pathology (T) and neurodegeneration (N), halting progressive ATN pathology in a preclinical model","authors":"Sarah Vanherle, Art Janssen, Manuel Gutiérrez de Ravé, Bieke Janssen, Chritica Lodder, Pablo Botella Lucena, Sofie Kessels, Jana Hardy, Eline Vandeput, Yanyan Wang, Ilie-Cosmin Stancu, Andrei Segal, Markus Kleinewietfeld, Thomas Voets, Bert Brône, Suresh Poovathingal, Yeranddy A. Alpizar, Ilse Dewachter","doi":"10.1038/s41380-025-03036-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03036-7","url":null,"abstract":"<p>In AD, amyloid pathology (A) precedes progressive development of tau pathology (T) and neurodegeneration (N), with the latter (T/N) processes associated with symptom progression. Recent anti-amyloid beta (Aβ) clinical trials raise hope but indicate the need for multi-targeted therapies, to effectively halt clinical AD and ATN pathology progression. <i>APOE</i>-related putative protective mutations (including <i>APOE3Christchurch</i>, <i>RELN-COLBOS</i>) were recently identified in case reports with exceptionally high resilience to autosomal dominant AD. In these cases, Nature provided proof of concept for halting autosomal dominant AD and ATN progression in humans, despite a high amyloid load, and pointing to the APOE pathway as a potential target. This is further supported by the recent identification of <i>APOE4</i> homozygosity as genetic AD. Here we studied the role of APOE in a preclinical model that robustly mimics amyloid-facilitated (A) tau pathology (T) and subsequent neurodegeneration (N), denoted as ATN model, generated by crossing 5xFAD (<i>F</i> ^<i>+</i>) and TauP301S (<i>T</i> ^<i>+</i>) mice. We show that APOE deficiency, markedly inhibited progression to tau pathology and tau-induced neurodegeneration in this ATN model, despite a high Aβ load, reminiscent of the high resilience ADAD case reports. Further study identified, despite increased Aβ load (W02 stained), a significant decrease in compacted, dense core plaques stained by ThioS in APOE deficient ATN mice. Furthermore, single-cell RNA sequencing (scRNA-seq) showed a crucial role of APOE in microglial conversion beyond homeostatic microglia to reactive and disease associated microglia (DAM) in this ATN preclinical model. Microglial elimination significantly decreased amyloid-driven tau pathology, in the presence of APOE, but not in APOE deficient mice. Together the data demonstrate that APOE deficiency inhibits amyloid-driven tau pathology and subsequent neurodegeneration, by pleiotropic effects including prevention of dense core plaque formation and halting conversion of homeostatic microglia. We here present a model recapitulating inhibition of amyloid-facilitated tau pathology by APOE deficiency despite high Aβ load, important for understanding the role of APOE, and APOE-dependent processes in ATN progression and its therapeutic exploitation in AD.</p><figure></figure>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"11 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893398","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: N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells.","authors":"Jiang-Zhou Yu, Jennifer Wang, Steven D Sheridan, Roy H Perlis, Mark M Rasenick","doi":"10.1038/s41380-025-03039-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03039-4","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010644","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":"Response to: \"Circular reasoning concerning red flags for predicting rituximab response in OCD\".","authors":"Maike Gallwitz, Isa Lindqvist, Annica J Rasmusson, Simon Cervenka, Joachim Burman, Janet L Cunningham","doi":"10.1038/s41380-025-03012-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03012-1","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008637","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":"Nutritional interventions to counteract the detrimental consequences of early-life stress","authors":"Jorine Geertsema, Hannah G. Juncker, Lars Wilmes, George L. Burchell, Susanne R. de Rooij, J. B. van Goudoever, Kenneth J. O’Riordan, Gerard Clarke, John F. Cryan, Aniko Korosi","doi":"10.1038/s41380-025-03020-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03020-1","url":null,"abstract":"<p>Exposure to stress during sensitive developmental periods comes with long term consequences for neurobehavioral outcomes and increases vulnerability to psychopathology later in life. While we have advanced our understanding of the mechanisms underlying the programming effects of early-life stress (ES), these are not yet fully understood and often hard to target, making the development of effective interventions challenging. In recent years, we and others have suggested that nutrition might be instrumental in modulating and possibly combatting the ES-induced increased risk to psychopathologies and neurobehavioral impairments. Nutritional strategies are very promising as they might be relatively safe, cheap and easy to implement. Here, we set out to comprehensively review the existing literature on nutritional interventions aimed at counteracting the effects of ES on neurobehavioral outcomes in preclinical and clinical settings. We identified eighty six rodent and ten human studies investigating a nutritional intervention to ameliorate ES-induced impairments. The human evidence to date, is too few and heterogeneous in terms of interventions, thus not allowing hard conclusions, however the preclinical studies, despite their heterogeneity in terms of designs, interventions used, and outcomes measured, showed nutritional interventions to be promising in combatting ES-induced impairments. Furthermore, we discuss the possible mechanisms involved in the beneficial effects of nutrition on the brain after ES, including neuroinflammation, oxidative stress, hypothalamus-pituitary-adrenal axis regulation and the microbiome-gut-brain axis. Lastly, we highlight the critical gaps in our current knowledge and make recommendations for future research to move the field forward.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"41 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878118","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 circuits that regulate social behavior","authors":"Hao Li, Zhe Zhao, Shaofei Jiang, Haitao Wu","doi":"10.1038/s41380-025-03037-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03037-6","url":null,"abstract":"<p>Social interactions are essential for the survival of individuals and the reproduction of populations. Social stressors, such as social defeat and isolation, can lead to emotional disorders and cognitive impairments. Furthermore, dysfunctional social behaviors are hallmark symptoms of various neuropsychiatric disorders, including autism spectrum disorder (ASD) and post-traumatic stress disorder (PTSD). Consequently, understanding the neural circuit mechanisms underlying social behaviors has become a major focus in neuroscience. Social behaviors, which encompass a wide range of expressions and phases, are regulated by complex neural networks. In this review, we summarize recent progress in identifying the circuits involved in different types of social behaviors, including general social investigation, social preference, mating, aggression, parenting, prosocial behaviors, and dominance behaviors. We also outline the circuit mechanisms associated with social deficits in neuropsychiatric disorders, such as ASD, schizophrenia, and PTSD. Given the pivotal role of rodents in social behavior research, our review primarily focuses on neural circuits in these animals. Finally, we propose future research directions, including the development of specific behavioral paradigms, the identification of circuits involved in motor output, the integration of activity, transcriptome, and connectome data, the multifunctional roles of neurons with multiple targets, and the interactions among multiple brain regions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"17 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878119","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}