Translational Psychiatry最新文献

{"title":"Primary sensory neuron dysfunction underlying mechanical itch hypersensitivity in a Shank3 mouse model of autism.","authors":"Damien Huzard, Giulia Oliva, Mélanie Marias, Chloé Granat, Vanessa Soubeyre, Glaécia do Nascimento Pereira, Ahmed Negm, Gawain Grellier, Jérôme Devaux, Emmanuel Bourinet, Amaury François","doi":"10.1038/s41398-025-03461-w","DOIUrl":"10.1038/s41398-025-03461-w","url":null,"abstract":"<p><p>Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder marked by social deficits, repetitive behaviors and atypical sensory perception. The link between ASD and skin abnormalities, inducing itchiness, has never been investigated in depth. This study explores mechanical itch sensitivity in the Shank3^ΔC/ΔC mouse model. Key observations include heightened scratching in response to skin deformation and hypersensitivity to mechanical itch (i.e. alloknesis) in Shank3^ΔC/ΔC mice. In Shank3^ΔC/ΔC mice, ex vivo electrophysiological experiments revealed that C-fiber low-threshold mechanoreceptors (C-LTMRs) were hyporesponsive and transcriptomic analysis showed a downregulation of TAFA4, a protein secreted by C-LMTRs. Interestingly, pharmacologically inhibiting Aβ-LTMR, important in mechanical itch initiation, abolished the itch hypersensitivity. Also, TAFA4 injections reduced the spontaneous scratching response to skin deformation but failed to restore itch sensitivity. Our data suggest that somatosensory deficits in Shank3^ΔC/ΔC mice lead to a hypersensitivity to itchiness and indicate that two pathways might be regulating mechanical itchiness, dependent or not on TAFA4.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"259"},"PeriodicalIF":6.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733387","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":"Decoding the striatum of drug-naive patients with obsessive-compulsive disorder: a transcriptome and longitudinal functional magnetic resonance imaging study.","authors":"Yiding Han, Haohao Yan, Xiaoxiao Shan, Huabing Li, Feng Liu, Ping Li, Dongsheng Lv, Jingping Zhao, Wenbin Guo","doi":"10.1038/s41398-025-03475-4","DOIUrl":"10.1038/s41398-025-03475-4","url":null,"abstract":"<p><p>The striatum's role in obsessive-compulsive disorder (OCD) pathology is recognized. However, the specific contributions of individual striatal subregions (SSs) to OCD pathology are underexplored. We recruited 49 drug-naive OCD patients and 53 healthy controls, conducting clinical assessments and resting-state functional magnetic resonance imaging (rs-fMRI) scans pre- and post-4-week paroxetine treatment. Inter-group comparisons were conducted to investigate baseline and treatment-related changes in the patients' striatum using several fMRI metrics, including amplitude of low-frequency fluctuation, regional homogeneity, and degree centrality (DC). Furthermore, these metrics, along with functional connectivity (FC), and effective connectivity (EC) of SSs, were analyzed. Associations between gene expression patterns and altered information flow patterns in SSs were examined, where information flow was measured using EC, followed by enrichment analysis of relevant genes. While no significant alterations were observed in the patients' striata in whole-brain statistical analyses, significant changes in DC, FC, and EC were identified in SSs pre- and post-treatment. In particular, the EC analysis unveiled an enhanced top-down control and diminished bottom-up regulation in drug-naive OCD patients. Following treatment, bottom-up EC improved, along with an improvement in clinical symptoms. Additionally, information flow alteration-related genes were enriched in various biological processes and pathways. They substantially overlapped between bidirectional information flows among SSs and the rest of brain and between information flows among homotopical SSs and the rest of brain. This study highlights the diverse contributions of each striatal subregion to OCD pathology. Paroxetine may alleviate OCD symptoms by enhancing bottom-up regulation, specifically the normalization of aberrant connectivity. Furthermore, integrating transcriptomic and rs-fMRI findings offer novel insights into the biological substrates underlying the altered EC of SSs in OCD patients.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"258"},"PeriodicalIF":6.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733386","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":"Exploring the capabilities of repetitive transcranial magnetic stimulation in major depressive disorder: Dynamic causal modeling of the neural network.","authors":"Akira Kita, Takuya Ishida, Natsuko Kita, Michiyo Tabata, Atsushi Tamaki, Shinya Uenishi, Kasumi Yasuda, Shun Takahashi, Hiroki Matsuura, Shinichi Yamada, Sohei Kimoto","doi":"10.1038/s41398-025-03480-7","DOIUrl":"10.1038/s41398-025-03480-7","url":null,"abstract":"<p><p>Repetitive transcranial magnetic stimulation (rTMS) of the left dorsal prefrontal cortex (DLPFC) has been utilized to manage treatment-resistant major depressive disorder (MDD). Understanding the biological basis of rTMS treatment in MDD is crucial for enhancing its clinical efficacy. Numerous brain regions functionally connected to the left DLPFC have been identified as a critical role in the pathophysiology of MDD, highlighting the significance of alterations in these neural circuits. We employed a dynamic causal modeling to estimate the causal relationships among depression-related regions functionally linked to the left DLPFC using a large-sample, multi-site resting-state functional magnetic resonance imaging dataset, comprising 270 healthy controls and 175 patients with MDD. We revealed aberrant causal connections from the left DLPFC, amygdala (AMY), nucleus accumbens (NAC), and thalamus (Thal) to the visual cortex (VIS) in MDD. We also found negative associations between depression severities and NAC-to-VIS connections, indicating that VIS plays an essential role in MDD. Furthermore, we identified aberrant causal connections between the ventromedial prefrontal cortex (VMPFC) and subcortical regions including, AMY, NAC, and subgenual anterior cingulate cortex (sgACC), and positive correlation between the depression severities and AMY-to-sgACC connection, suggesting the disruption in corticostriatal circuit is related to the aberrant emotional regulation in MDD. These aberrant connections may support the neural mechanisms of MDD and indicate rTMS may modulate these areas, potentially improving the disrupted function in MDD. Our study provides deeper insights into the pathophysiological mechanisms of MDD and the potential mechanisms of rTMS treatment.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"257"},"PeriodicalIF":6.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718670","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":"Polygenic risk scores for severe psychiatric disorders in bipolar disorders: associations with the clinical and dimensional expression, interactions with childhood maltreatment and mediation models.","authors":"Bruno Etain, Mohamed Lajnef, Ophélia Godin, Cynthia Marie-Claire, Frank Bellivier, Elisa Courtois, Violaine Latapie, Sébastien Gard, Raoul Belzeaux, Philippe Courtet, Caroline Dubertret, Emmanuel Haffen, Antoine Lefrere, Emilie Olie, Mircea Polosan, Paul Roux, Ludovic Samalin, Raymund Schwan, Marion Leboyer, Stéphane Jamain","doi":"10.1038/s41398-025-03466-5","DOIUrl":"10.1038/s41398-025-03466-5","url":null,"abstract":"<p><p>Polygenic risk scores (PRSs) for several psychiatric disorders have been associated with the clinical presentation of bipolar disorder (BD). PRSs have also been suggested to moderate the associations between childhood maltreatment and BD severity. In this study, we investigated how PRSs for BD, schizophrenia, major depressive disorders (MDD) and attention-deficit/hyperactivity disorder (ADHD) might disentangle the clinical and dimensional heterogeneity of BD in a sample of 852 affected individuals. We used logistic and linear regressions, moderation and mediation models to test the associations between PRSs, dimensions in childhood/adulthood and clinical indicators of severity of BD. All models were adjusted for age, sex, BD type and depressive symptoms. None of the PRSs were significantly associated with the clinical expression of BD when considered in terms of mode of onset, course, or psychiatric comorbidities. Nevertheless, the PRS-ADHD significantly and positively correlated with the levels of childhood maltreatment, childhood ADHD symptoms, and of some adulthood measures (affective lability, impulsivity and hostility) with p values ranging from 3.10^-8-4.10^-4. None of the PRSs moderated the effects of childhood maltreatment on the clinical or dimensional variables. Mediation model suggested paths from both PRS-ADHD and PRS-MDD to childhood ADHD symptoms and childhood maltreatment. The links between PRS-ADHD to all adulthood dimensions were mediated by childhood ADHD symptoms (p < 0.002). In turn, some adulthood dimensions (mainly affect intensity and affective lability) were associated with the clinical severity of BD, as defined by rapid cycling, suicide attempts and anxiety disorders. In conclusion, this study disentangles the associations between the genetic liability for four psychiatric disorders and the clinical/dimensional heterogeneity of BD. We suggest a continuum from the genetic risk for ADHD and MDD through dimensions in childhood/adulthood to a severe/complex clinical expression of BD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"256"},"PeriodicalIF":6.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718671","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":"Transcription of GABA_A receptor subunits in circulating monocytes and association to emotional brain function in premenstrual dysphoric disorder.","authors":"Louise Stiernman, Erika Comasco, Maja Johansson, Marie Bixo","doi":"10.1038/s41398-025-03465-6","DOIUrl":"10.1038/s41398-025-03465-6","url":null,"abstract":"<p><p>Premenstrual dysphoric disorder (PMDD) has been hypothesized to be related to an altered sensitivity of the γ-aminobutyric acid type A (GABA_A) receptor to progesterone-derived neurosteroids. GABA_A receptor sensitivity to neurosteroid-modulation is dependent on its subunit composition. In the present study, we used quantitative reverse transcription polymerase chain reactions (RT-qPCR) to compare messenger ribonucleic acid (mRNA) expression of GABA_A receptor subunits in peripheral mononuclear cells (PBMCs) across the menstrual cycle in 29 women with PMDD and 27 controls. We related mRNA subunit expression to serum levels of neurosteroids and to functional activation of the amygdala, a key brain region involved in emotion generation, measured using functional magnetic resonance imaging (fMRI). Women with PMDD had lower mRNA expression of the delta GABA_A receptor subunit during the symptomatic, luteal phase (compared to the asymptomatic, follicular phase) of the menstrual cycle. Lower delta mRNA expression was related to higher amygdala activation in PMDD women. GABA_A receptors incorporating the delta subunit are especially sensitive to neurosteroid modulation. It is possible that the mood symptoms of PMDD are mediated by an inability to effectively adjust the expression of this receptor type in response to neurosteroid fluctuations, leading to dysregulation GABAergic tone and increased activity in emotion-generating brain circuits.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"255"},"PeriodicalIF":5.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699644","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":"Pharmacologic and genetic evidence converge on mechanisms of psychotic illness.","authors":"Brian Fennessy, Liam Cotter, Nicole W Simons, Lora E Liharska, Girish N Nadkarni, Douglas M Ruderfer, Alexander W Charney","doi":"10.1038/s41398-025-03456-7","DOIUrl":"10.1038/s41398-025-03456-7","url":null,"abstract":"<p><p>Idiopathic and substance-induced forms of psychotic illness afflict millions of people worldwide, and it is largely unknown whether these two forms emerge through the same molecular mechanisms. Though genetic studies have implicated thousands of genes in idiopathic psychotic illnesses (e.g., schizophrenia), consensus is lacking regarding which of these genes are most likely to treat psychotic illness when modulated pharmacologically and, as a result, antipsychotic medications targeting these genes have yet to be developed. Previous studies suggest that one way to determine if a candidate target gene is likely to lead to an effective treatment for a given illness is if the gene is implicated by multiple lines of evidence (e.g., genetic, pharmacologic). Here, pharmacologic, genetic, and clinical data were leveraged to determine if the idiopathic and substance-induced forms of psychotic illness are related to one another through a common set of genes. A set of medications that cause psychotic illness as a side effect (\"propsychotics\") were identified by analyzing 15 million medication side effects reports from over 100 countries. Gene products targeted by propsychotics overlapped significantly with those targeted by antipsychotics and for many of the overlapping targets propsychotics act through a mechanism that was qualitatively the opposite of the mechanism through which antipsychotics act (e.g., activation vs. inhibition). Propsychotic and antipsychotic target genes were significantly enriched for genes implicated in schizophrenia by rare loss-of-function genetic variation but not for genes implicated in schizophrenia by common genetic variation. Only one gene - GRIN2A, encoding the GluN2A subunit of the NMDA glutamate receptor - was implicated in psychotic illness by propsychotics, rare loss-of-function genetic variation, and common genetic variation. Mining genetic data from a diverse cohort of 30,000 adults treated in a New York City health system, a carrier of a rare loss-of-function variant in GRIN2A with severe psychotic illness was identified with a clinical course notable for psychotic symptoms and cognitive deficits that are not targeted by current antipsychotics. Altogether, this report shows how integrating pharmacologic, genetic, and clinical data from large cohorts can prioritize target genes for novel drug development and align the prioritized targets with specific clinical presentations.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"254"},"PeriodicalIF":5.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699643","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":"Exosomes from high-altitude cerebral edema patients induce cognitive dysfunction by altering oxidative stress responses in mice.","authors":"Qiang Fu, Rui Qiu, Quan Tang, Xiaodong Li, Yaobo Li, Yuxiang Qin, Qiaosheng Li, Jia Yao, Zhongyong Jiang, Huan Xu, Yong Cheng","doi":"10.1038/s41398-025-03469-2","DOIUrl":"10.1038/s41398-025-03469-2","url":null,"abstract":"<p><p>The impact of exosomes derived from patients with High Altitude Cerebral Edema (HACE) on cognitive function in mice was investigated, along with the underlying mechanisms. Exosomes were extracted from HACE patients and injected into the dentate gyrus (DG) of mice. A series of behavioral tests assessed cognitive abilities. Results indicated that mice injected with HACE patient exosomes exhibited significant declines in exploratory behavior and object recognition, suggesting notable cognitive impairments. Additionally, these exosomes induced oxidative stress responses and abnormal activation of microglia, closely associated with neuronal death. Proteomic analysis revealed that the differentially expressed protein STAMBP, which is closely linked to neurodevelopment, may play a key role. In conclusion, our findings highlight the potential impact of exosomes from HACE patients on cognitive dysfunction in mice, providing new insights into the pathophysiological mechanisms of HACE.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"253"},"PeriodicalIF":6.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12284110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691652","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":"Examining the genetic links between clusters of immune-mediated diseases and psychiatric disorders.","authors":"Sophie Breunig, Younga Heather Lee, Elizabeth W Karlson, Arjun Krishnan, Jeremy M Lawrence, Lukas S Schaffer, Andrew D Grotzinger","doi":"10.1038/s41398-025-03470-9","DOIUrl":"10.1038/s41398-025-03470-9","url":null,"abstract":"<p><p>Extant phenotypic and genetic literature has established consistent relationships between autoimmune, autoinflammatory, and psychiatric disorders. However, a comprehensive model investigating the association between a broad range of psychiatric disorders and immune-mediated disease in a multivariate framework is lacking. We utilized Genomic Structural Equation Modeling (Genomic SEM) to establish a factor structure across 11 immune-mediated diseases. Genetic correlations between these immune factors were examined with five established factors across 13 psychiatric disorders. We develop and validate a new heterogeneity metric, Q_Factor, that quantifies the degree to which factor correlations are driven by more specific pairwise associations, which were further investigated in the form of residual genetic correlations. A four-factor model of immune-mediated diseases fit the data well and described a continuum from autoimmune to autoinflammatory diseases, reflecting autoimmune, celiac, mixed pattern, and autoinflammatory diseases. Analyses revealed six significant factor correlations between the immune and psychiatric factors, including autoimmune and mixed pattern diseases with the substance use factors, autoinflammatory diseases and mixed pattern diseases with the internalizing factor, autoinflammatory diseases with the compulsive disorders factor, and autoinflammatory diseases with the schizophrenia/bipolar factor. Additionally, we find evidence of divergence in associations within factors as indicated by Q_Factor and 10 significant residual genetic correlations between individual psychiatric disorders and immune-mediated diseases. The results suggest that previously described relationships between specific psychiatric disorders and immune-mediated diseases often capture broader pathways of risk sharing indexed by our genomic factors yet are more specific than a general association across all psychiatric disorders and immune-mediated diseases.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"252"},"PeriodicalIF":6.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683184","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":"Translating medication effects for alcohol use disorder across preclinical, human laboratory, and clinical trial outcomes using meta-analysis.","authors":"Steven J Nieto, Suzanna Donato, Han Du, Lindsay R Meredith, Wave-Ananda Baskerville, Kaitlin R McManus, Molly Magill, Marcelo F Lopez, Howard C Becker, Lara A Ray","doi":"10.1038/s41398-025-03473-6","DOIUrl":"10.1038/s41398-025-03473-6","url":null,"abstract":"<p><p>Animal models are used for preliminary testing of novel compounds for alcohol use disorder (AUD). However, it is unclear whether early efficacy in preclinical models reliably predicts efficacy in human laboratory and clinical trials. We searched the literature for medications tested for AUD in preclinical models (i.e., two-bottle choice [2-BC] and operant reinstatement), human laboratory cue-reactivity, and randomized clinical trials (RCTs). For preclinical models, we computed medication effects on 2-BC alcohol preference and consumption (k = 77 studies, 14 medications) as well as operant reinstatement (k = 18 studies, 8 medications). For human laboratory studies, we computed medication effects on alcohol cue-induced craving (k = 36 studies, 15 medications). For RCTs, we computed medication effects on RCT endpoints including return to any drinking and return to heavy drinking (k = 139 studies, 19 medications). We used medication as the unit of analysis and applied the Williamson-York bivariate weighted least squares estimation to preserve the errors in both the independent and dependent variables. Medication effects on 2-BC alcohol preference ( <math> <mover><mrow><mi>β</mi></mrow> <mo>ˆ</mo></mover> </math>  = 0.04, p = 0.004) and reinstatement ( <math> <mover><mrow><mi>β</mi></mrow> <mo>ˆ</mo></mover> </math>  = 0.20, p = 0.05) were positively associated with medication effects on return to any drinking in human clinical trials but no associations were found on other RCT outcomes tested. Preclinical medications findings were not associated with medication effects on cue-induced craving in the human laboratory. Medication findings on 2-BC alcohol preference and operant reinstatement track medication effects on select clinical trial outcomes, specifically return to any drinking. This study provides empirical support for the association between medication effects across species and experimental models, a critical, yet untested, premise of preclinical studies in medications development.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"250"},"PeriodicalIF":5.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683186","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":"Sex-specific cortical networks drive social behavior differences in an autism spectrum disorder model.","authors":"Mariana Lapo Pais, José Sereno, Vanessa A Tomé, Carla Fonseca, Camila Seco, Inês Ribeiro, João Martins, Ana Fortuna, Antero Abrunhosa, Luísa Pinto, Miguel Castelo-Branco, Joana Gonçalves","doi":"10.1038/s41398-025-03464-7","DOIUrl":"10.1038/s41398-025-03464-7","url":null,"abstract":"<p><p>Social behavior is highly sensitive to brain network dysfunction caused by neuropsychiatric conditions like autism spectrum disorders (ASDs). Some studies suggest that autistic females show fewer social skill impairments than autistic males. However, the relationship between sex differences in social behavior and sexually dimorphic brain neurophysiology in ASD remains unclear. We hypothesize that sex-specific changes in cortical neurophysiology drive the sexual dimorphism observed in social behavior for ASD. To test this, we used male and female Tsc2^+/- mice, a genetic ASD model, to examine cortical neuron morphology, the serotonergic system, E/I balance, structural connectivity, and social behavior. At the cellular level, transgenic males had shorter and less complex cortical basal dendrites, while transgenic females showed the opposite in apical dendrites. Notably, only Tsc2^+/- females exhibited changes in the serotonergic system and E/I balance, with reduced cortical 5-HT_1A receptor density and increased excitability. Additionally, activation of these serotonin receptors in transgenic animals correlated with E/I imbalance, highlighting inherent sexual dimorphisms in neuronal connectivity. In parallel, the TSC2 mouse model displayed sex-dependent changes in the structural connectivity of the cortex-amygdala-hippocampus circuit and social behavior: females showed a reduced number of axonal fiber pathways and reduced sociability, while males exhibited a loss of tissue density and deficits in social novelty. Moreover, in our ASD mouse model, better social performance correlated with the cortical serotonergic system. Our findings suggest that sex-dependent alterations in cortical neurophysiology, particularly in the serotonergic system, may contribute to the sexually dimorphic social behaviors observed in ASD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"251"},"PeriodicalIF":5.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683185","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}