Translational Psychiatry最新文献

{"title":"Amygdala-hippocampus connectivity and childhood depressive symptoms: subnuclei insights and self-concept roles.","authors":"Lizhu Luo, Pei Huang, Shi Yu Chan, Aisleen Mariz Arellano Manahan, Jasmine Chuah, Zhen Ming Ngoh, Helen Chen, Marielle V Fortier, Michael J Meaney, Ai Peng Tan","doi":"10.1038/s41398-025-03524-y","DOIUrl":"10.1038/s41398-025-03524-y","url":null,"abstract":"<p><p>Amygdala-hippocampal connectivity is a promising area of study for an understanding of the neurobiological mechanisms of depression. In this study, we examined the association between amygdala-hippocampal connectivity and depressive symptoms in children with a specific focus on the subnuclei level. We then examined whether self-concept mediated brain-behavior associations. Resting-state functional magnetic resonance imaging (fMRI) was performed at age 7.5 years (N = 319), followed by self-reported depressive symptoms and self-concept between ages 8.5 and 10.5 years, using the Children's Depression Inventory (CDI-2) and Piers-Harris Children's Self-Concept Scale (PHCSC) respectively. We conducted multiple regression analyses to examine the associations between the amygdala-hippocampus resting-state functional connectivity (RSFC) and CDI scores, first at the whole-region level and subsequently at the subnuclear level. Mediation analyses were then performed to explore the mediating role of self-concept in these brain-behavior associations. We observed a significant association between left amygdala-anterior hippocampus connectivity and CDI total scores, primarily driven by the left superficial amygdala. Further exploration at sub-symptomatic levels highlighted an association with negative cognition. Finally, self-concept mediated the association between left amygdala-anterior hippocampus connectivity and depressive symptoms in children. This study provided valuable insights into the associations among amygdala-hippocampal subnuclei connectivity, childhood depressive symptoms, and self-concept. Diminished left superficial amygdala-anterior hippocampus connectivity may serve as an early biomarker to identify depressive symptoms, particularly in children with negative cognition problems.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"293"},"PeriodicalIF":6.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875398","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":"Multivariate genome-wide association analysis of dyslexia and quantitative reading skill improves gene discovery.","authors":"Hayley S Mountford, Else Eising, Pierre Fontanillas, Adam Auton, Evan K Irving-Pease, Catherine Doust, Timothy C Bates, Nicholas G Martin, Simon E Fisher, Michelle Luciano","doi":"10.1038/s41398-025-03514-0","DOIUrl":"10.1038/s41398-025-03514-0","url":null,"abstract":"<p><p>The ability to read is an important life skill and a major route to education. Dyslexia, characterized by difficulties with accurate/ fluent word reading, and poor spelling is influenced by genetic variation, with a twin study heritability estimate of 0.4-0.6. Until recently, genomic investigations were limited by modest sample size. We used a multivariate genome-wide association study (GWAS) method, MTAG, to leverage summary statistics from two independent GWAS efforts, boosting power for analyses of dyslexia; the GenLang meta-analysis of word reading (N = 27,180) and the 23andMe, Inc., study of dyslexia (N_cases = 51,800, N_controls = 1,087,070). We increased the effective sample size to 1,228,832 participants, representing the largest genetic study of reading-related phenotypes to date. Our analyses identified 80 independent genome-wide significant loci, including 36 regions which were not previously reported as significant. Of these 36 loci, 13 were novel regions with no prior association with dyslexia. We observed clear genetic correlations with cognitive and educational measures. Gene-set analyses revealed significant enrichment of dyslexia-associated genes in four neuronal biological process pathways, and findings were further supported by enrichment of neuronally expressed genes in the developing embryonic brain. Polygenic index analysis of our multivariate results predicted between 2.34-4.73% of variance in reading traits in an independent sample, the National Child Development Study cohort (N = 6410). Polygenic adaptation was examined using a large panel of ancient genomes spanning the last ~15 k years. We did not find evidence of selection, suggesting that dyslexia has not been subject to recent selection pressure in Europeans. By combining existing datasets to improve statistical power, these results provide novel insights into the biology of dyslexia.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"289"},"PeriodicalIF":6.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875401","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":"Dysbiosis and depression: A study of gut microbiota alterations and functional pathways in antidepressant-naïve mood disorder patients.","authors":"Shih-Kai Kevin Lin, Hsi-Chung Chen, I-Ming Chen, Cheng-Dien Hsu, Ming-Chyi Huang, Chih-Min Liu, Shu-I Wu, Po-Yu Chen, Chun-Hsin Chen, Po-Hsiu Kuo","doi":"10.1038/s41398-025-03521-1","DOIUrl":"10.1038/s41398-025-03521-1","url":null,"abstract":"<p><p>Depression, a common mood disorder, has been associated with gut microbiota alterations, though the underlying microbial mechanisms remain unclear. This study investigated potential gut microbiota biomarkers and functional pathways in 106 antidepressant-naïve depressive patients and 151 healthy controls, with careful of confounding factors. Stool samples were analyzed using 16S rRNA sequencing, revealing significantly lower alpha diversity and distinct beta diversity in depressive patients. Eleven taxa with differential abundance were identified, including Dialister and Lactococcus (decreased) and Hungatella, Sellimonas, and Lachnoclostridium (elevated), which may relate to gut inflammation and depressive symptom severity. Functional pathway analysis highlighted 36 altered pathways, including those involved in purine degradation, lipopolysaccharide biosynthesis, and amino acid metabolism. A random forest classification model built using the identified taxa achieved moderate accuracy (~0.72) in distinguishing depressive patients from controls. Additionally, we developed a novel Depression Dysbiosis Index (DDI), which positively correlated with depression severity and effectively differentiated between groups. The DDI was robust across analyses, emphasizing its potential clinical value. Future research should incorporate longitudinal designs, advanced sequencing techniques, and additional clinical factors to deepen our understanding of the gut-brain axis in depression and improve diagnostic and therapeutic strategies.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"290"},"PeriodicalIF":6.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875399","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":"NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy.","authors":"Ye Sun, Liya Li, Xianglong Yang, Shengming Yin, Zhaoyang Xiao","doi":"10.1038/s41398-025-03502-4","DOIUrl":"10.1038/s41398-025-03502-4","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is characterized by persistent low mood and anhedonia. Mitochondrial dysfunction is linked to MDD, but the mechanisms are unclear. In this study, transcriptomic analysis of MDD patients' peripheral blood found three key genes: TFAM, SURF1, and NDUFB9. Single-cell transcriptomic analysis of the prefrontal cortex (PFC) in MDD patients identified seven cell types. Analysis showed strong interactions between excitatory and inhibitory neurons in the PFC, with the three genes mainly in inhibitory neurons and NDUFB9 having the highest expression. We then established a chronic unpredictable mild stress (CUMS) mouse model. CUMS exposure induced depressive-like behaviors in mice, as evidenced by decreased sucrose preference, increased immobility time in the forced swim, and reduced activity and frequency of entries into the central area in the open field. Moreover, CUMS-exposed mice exhibited mitochondrial dysfunction in the prefrontal cortex (PFC). Notably, the expressions of TFAM, SURF1, and NDUFB9 were decreased in the PFC of CUMS mice, with the most significant decrease observed in NDUFB9. Subsequently, the overexpression of NDUFB9 in CUMS-treated mice significantly alleviated depressive-like behaviors, restored mitochondrial function and reduced the death of inhibitory neurons. It also enhanced mitophagy by PINK1/Parkin pathway. Inhibiting autophagy and mitophagy confirmed mitophagy's pivotal role in NDUFB9-mediated restoration. Co-IP and protein half-life assays revealed that NDUFB9 stabilizes PINK1, thereby promoting mitophagy. In conclusion, our findings reveal a novel role of NDUFB9 on alleviating depression-like behavior by enhancing mitophagy, suggesting that targeting NDUFB9 could offer a promising therapeutic strategy for MDD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"292"},"PeriodicalIF":6.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875313","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":"The role of reward-related brain activity in response to treatment and later depression severity: data from a randomized controlled trial in early adolescents with anxiety disorders.","authors":"Cecilia A Westbrook, Michael Schlund, Jennifer S Silk, Erika E Forbes, Neal D Ryan, Ronald E Dahl, Dana L McMakin, Philip C Kendall, Anthony Mannarino, Cecile D Ladouceur","doi":"10.1038/s41398-025-03388-2","DOIUrl":"10.1038/s41398-025-03388-2","url":null,"abstract":"<p><p>Alterations in reward-related brain activity have been linked to response to psychological treatment in adolescents with anxiety disorders. However, it remains unknown whether these effects are driven by reward anticipation or feedback, which reflect different functional roles in motivated behavior, or whether brain activity changes as a function of treatment response. The current study investigated these questions in the context of a randomized controlled trial of cognitive-behavioral therapy (CBT) for anxiety disorders in adolescents. This study used an fMRI paradigm to investigate reward-related brain activity in youth aged 9-14 with anxiety disorders (ANX; N = 133; 57 female) before and after 16 weeks of CBT or an active comparison (child-centered therapy, CCT). Age- and sex-matched healthy comparison (HC) youth (N = 38; 17 female) completed scans on a similar timeline. A subset of ANX youth completed a 2-year follow-up assessment of depressive symptoms. At pretreatment, ANX compared to HC youth demonstrated reduced brain activity in reward-related regions (e.g. dorsal striatum, thalamus) during reward anticipation, and elevated activity in angular gyrus, PCC and inferior frontal gyrus during reward feedback. Reduced pretreatment activation in the precuneus/cuneus and pre-to-post reductions in left angular gyrus corresponded with treatment response. Finally, pre-to-post increases in posterior cingulate cortex (PCC) corresponded with increased depressive symptoms at 2 years. Our results suggest that reward-related brain activity outside of striatal reward regions, including PCC, precuneus and angular gyrus, plays a role in treatment response in youth with anxiety disorders. Trial registration: ClinicalTrials.gov NCT00774150.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"286"},"PeriodicalIF":6.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862492","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":"Neural transmission in the wired brain, new insights into an encoding-decoding-based neuronal communication model.","authors":"Sivan Kinreich","doi":"10.1038/s41398-025-03506-0","DOIUrl":"10.1038/s41398-025-03506-0","url":null,"abstract":"<p><p>Brain activity is known to be rife with oscillatory activity in different frequencies, which are suggested to be associated with intra-brain communication. However, the specific role of frequencies in neuronal information transfer is still an open question. To this end, we utilized EEG resting state recordings from 5 public datasets. Overall, data from 1668 participants, including people with MDD, ADHD, OCD, Parkinson's, Schizophrenia, and healthy controls aged 5-89, were part of the study. We conducted a running window of Spearman correlation between the two frontal hemispheres' Alpha envelopes. The results of this analysis revealed a unique pattern of correlation states alternating between fully synchronized and desynchronized several times per second, likely due to the interference pattern between two signals of slightly different frequencies, also named \"Beating\". Subsequent analysis showed this unique pattern in every pair of ipsilateral/contralateral, across frequencies, either in eyes closed or open, and across all ages, underscoring its inherent significance. Biomarker analysis revealed significantly lower synchronization and higher desynchronization for people older than 50 compared to younger ones and lower ADHD desynchronization compared to age-matched controls. Importantly, we propose a new brain communication model in which frequency modulation creates a binary message encoded and decoded by brain regions for information transfer. We suggest that the binary-like pattern allows the neural information to be coded according to certain physiological and biological rules known to both the sender and recipient. This digital-like scheme has the potential to be exploited in brain-computer interaction and applied technologies such as robotics.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"288"},"PeriodicalIF":6.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862491","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":"iPSC-modelling reveals genetic associations and morphological alterations of oligodendrocytes in schizophrenia.","authors":"Man-Hsin Chang, Jan Benedikt Waldeck, Marius Stephan, Nirmal Kannaiyan, Valéria de Almeida, Emanuel Boudriot, Temmuz Karali, Lukas Röll, Laura Fischer, Damianos Demetriou, Nadia Gabellini, Sabrina Galinski, Andrea Schmitt, Sergi Papiol, Daniel Keeser, Peter Falkai, Moritz J Rossner, Florian J Raabe","doi":"10.1038/s41398-025-03509-x","DOIUrl":"10.1038/s41398-025-03509-x","url":null,"abstract":"<p><p>There is strong evidence for a genetically driven neuronal contribution in schizophrenia (SCZ). Although imaging and postmortem studies also provide evidence for white matter alterations with implications of the oligodendroglial lineage in SCZ, it is unclear whether these disturbances are a secondary consequence of neuronal deficits or also, at least in parts, genetically driven and cell-autonomous. Using human induced pluripotent stem cells (hiPSCs) in combination with gene set enrichment analysis, we investigated the cellular impact of SCZ genetics on the oligodendroglial lineage. We performed unsupervised clustering analysis of hiPSC-differentiated neural cells including oligodendrocytes (iOLs) and their precursor cells (iOPCs) with corresponding human postmortem cell types from single-cell RNA sequencing (scRNAseq) data and conducted a comparative gene set enrichment analysis. Subsequently, we stratified individuals based on white matter alteration using diffusion tensor imaging (DTI) within a translational cohort (N = 112) and then explored the cellular effects of SCZ risk with hiPSC modelling in a subset of SCZ patients (N = 8) with disturbed white matter integrity and unaffected healthy controls (N = 7). hiPSC-iOPCs/iOLs expression profiles strongly correlated with human postmortem OPCs/OLs based on scRNAseq, and their transcriptional signatures were highly enriched in the genetic associations of SCZ. The cellular assessment of patient-derived iOPCs/iOLs revealed morphological alterations, including significantly increased branch length and elevated junction number in mature iOLs from SCZ. Moreover, transcriptomic profiling revealed a dysregulation in oligodendroglial cell signaling and proliferation. In sum, hiPSC-modelling shows an impact of SCZ genetics on dedicated features of the oligodendroglial lineage.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"287"},"PeriodicalIF":6.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862490","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":"The association between prenatal maternal anxiety, infant brain volumes, and temperament during the COVID-19 pandemic.","authors":"Amber-Lee Di Paolo, Emily S Nichols, Lianne Tomfohr-Madsen, Gerald F Giesbrecht, Kathryn Y Manning, Catherine A Lebel, Emma G Duerden","doi":"10.1038/s41398-025-03527-9","DOIUrl":"10.1038/s41398-025-03527-9","url":null,"abstract":"<p><p>Prenatal maternal stress (PNMS), anxiety, and depression are associated with altered trajectories of infant socio-emotional and brain development, including the amygdala and prefrontal cortex (PFC). During the COVID-19 pandemic, prenatal anxiety and depression was significantly elevated, yet the impact on infant neurodevelopment remains uncertain. The objective of this study was to determine whether PNMS and mental health during the pandemic was associated with infant amygdala and PFC volumes as well as temperament. Participants were enrolled in the Canadian 'Pregnancy during the COVID-19 Pandemic' cohort study. Pregnant individuals had their perceived stress, pandemic-related objective hardship, and mental health measured via questionnaires. Infant magnetic resonance imaging (MRI) scans (n = 100) were conducted at 3 months of age, and parents reported on infant temperament at 6 months of age. General linear models were used to examine the associations among PNMS, mental health, brain volumes, and developmental outcomes. Prenatal maternal anxiety negatively predicted 3-month left infant amygdala volumes (B = -5.919; p = 0.016; 95% CI, -10.748 to -1.089). Smaller left amygdala volumes were associated with greater infant 6-month negative affectivity (B = -0.003; p = 0.002; 95% CI, -0.006--0.001). This study provides evidence for infant brain alterations related to prenatal maternal anxiety, indicating that the impact of anxiety on infant development during the COVID-19 pandemic may have long-lasting implications for children's health. Our findings suggest that prenatal anxiety may be a key area for screening and intervention during pregnancy to best support healthy infant development.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"283"},"PeriodicalIF":6.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859661","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":"Lipidomic and proteomic insights from extracellular vesicles in the postmortem dorsolateral prefrontal cortex reveal substance use disorder-induced brain changes.","authors":"Chioma M Okeoma, Wasifa Naushad, Bryson C Okeoma, Carlos Gartner, Yulica Santos-Ortega, Calvin Vary, Savio Lima-Bastos, Victor Corasolla Carregari, Martin R Larsen, Alessio Noghero, Consuelo Walss-Bass, Rodrigo Grassi-Oliveira","doi":"10.1038/s41398-025-03512-2","DOIUrl":"10.1038/s41398-025-03512-2","url":null,"abstract":"<p><p>Substance use disorder (SUD) significantly increases the risk of neurotoxicity, inflammation, oxidative stress, and impaired neuroplasticity. The activation of inflammatory pathways by substances may lead to reactive astrogliosis and chronic neuroinflammation, potentially mediated by the release of extracellular particles (EPs), such as extracellular condensates (ECs) and extracellular vesicles (EVs). These particles, which reflect the physiological, pathophysiological, and metabolic states of their cells of origin, might carry molecular signatures indicative of SUD. In particular, our study investigated neuroinflammatory signatures in SUD patients by isolating EVs from the dorsolateral prefrontal cortex (dlPFC) Brodmann's area 9 (BA9) from postmortem subjects. We isolated BA9-derived EVs from postmortem brain tissues of eight individuals (controls: n = 4, SUD: n = 4). The physical properties (concentration, size, zeta potential, morphology) of the EVs were analyzed, and the EVs were subjected to integrative multiomics analysis to profile the lipidomic and proteomic characteristics. We assessed the interactions and bioactivity of EVs by evaluating their uptake by glial cells. We further assessed the effects of EVs on complement mRNA expression in glial cells and on microglial migration. No significant differences in EV concentration, size, zeta potential, or surface markers were observed between the SUD group and the control group. However, lipidomic analysis revealed significant enrichment of glycerophosphoinositol bisphosphate (PIP2) in SUD-derived EVs. Proteomic analysis revealed the downregulation of SERPINB12, ACYP2, CAMK1D, DSC1, and FLNB and the upregulation of C4A, C3, and ALB in SUD-derived EVs. Gene Ontology (GO) and protein‒protein interactome analyses revealed functions associated with the identified proteins, such as cell motility, focal adhesion, and acute phase response signaling. Both control and SUD-derived EVs increased C3 and C4 mRNA expression in microglia, but only SUD-derived EVs upregulated these genes in astrocytes. SUD-EVs also significantly enhanced microglial migration in a wound healing assay. This study successfully isolated EVs from postmortem brains and used a multiomics approach to identify EV-associated lipids and proteins in SUD. Elevated C3 and C4 in SUD-derived EVs and the distinct effects of EVs on glial cells suggest a crucial role for these cells in acute phase response signaling and neuroinflammation.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"284"},"PeriodicalIF":6.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859659","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":"Microglia-mediated inflammation and synaptic pruning contribute to sleep deprivation-induced mania in a sex-specific manner.","authors":"Rong-Jun Ni, Wei-Jun Yuan, Yi-Yan Wang, Xiao Yang, Jin-Xue Wei, Lian-Sheng Zhao, Qiang Wang, Xiang-Dong Tang, Xiao-Hong Ma","doi":"10.1038/s41398-025-03525-x","DOIUrl":"10.1038/s41398-025-03525-x","url":null,"abstract":"<p><p>Sleep loss is a key trigger for a manic episode of bipolar disorder (BD), but the underlying microglial and molecular mechanisms remain unclear. Sleep loss induces microglial and inflammatory responses. Microglia, resident macrophages in the central nervous system, regulate synaptic pruning by engulfing dendritic spines. Here, we introduce a modified paradoxical sleep deprivation (SD) paradigm as a BD mouse model. After intermittent 16-h daily SD for 4 days, the mice showed mania-like behavior, reduced cytokine/chemokine production, mitochondrial damage, microglial loss, decreased synaptic engulfment by microglia, and synaptic gain. Single-nucleus RNA sequencing (snRNA-seq) revealed cell-type-specific inflammation- and synapse-related gene expression profiles in the prefrontal cortex (PFC) and hippocampus of SD-treated male mice. Interestingly, much more differentially expressed genes were observed in SD-treated female versus male mouse brain, especially in the PFC. Pharmacological depletion of microglia by colony stimulating factor-1 receptor (CSF1R) inhibitor PLX3397 blocked SD-induced inflammation-related and senescence-associated abnormalities in a sex-specific manner. Microglial elimination reversed SD-induced synapse gain and mania-like behavior in males but not in females. However, microglial inhibition by minocycline had no effect on SD-induced behaviors in a sex-independent manner. These findings demonstrate that microglia-mediated neuroinflammation and synaptic pruning contribute to SD-induced mania-like behavior in a mouse model of BD in a sex-specific manner.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"285"},"PeriodicalIF":6.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859660","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}