Translational Psychiatry最新文献

{"title":"Capturing trial-by-trial variability in behaviour: people with Parkinson's disease exhibit a greater rate of short-term fluctuations in response times.","authors":"Hayley J MacDonald, Ole Bernt Fasmer, Olav T Jønsi, Lin Sørensen","doi":"10.1038/s41398-025-03516-y","DOIUrl":"https://doi.org/10.1038/s41398-025-03516-y","url":null,"abstract":"<p><p>Average response time is frequently used to reflect executive function. Less often studied is intra-individual variability in response times (IIVRT) which reflects within-person consistency. Higher IIVRT in Parkinson's disease (PD) has been associated with poor executive function but almost exclusively studied using standard deviation (SD). SD provides a standardised measure of inconsistency in RTs but is necessarily calculated as an average measure, precluding any trial-level investigation. Such linear measures cannot capture rapid and spontaneous changes in biological systems such as dopaminergic bursting activity. Therefore, nonlinear measures provide important complementary insights into dopamine-related neurocognition. The nonlinear method of graph theory is one viable approach to capture the complex biological changes in PD and their effect on behaviour. Our primary aim was to increase the understanding of RT fluctuations in PD beyond the use of SD by investigating nonlinear IIVRT measures using graph theory, constituting the first use of this approach on RT data. As hypothesized, PD was associated with a greater rate of trial-by-trial IIVRT compared to healthy older adults. The difference between groups could not be explained simply by worse overall RT performance, as average RT was comparable between groups. Instead, the IIVRT findings reflected impaired consistency in performance for people with PD and specifically a greater rate of short-term fluctuations in behaviour. These novel results indicate that a similarity graph algorithm may be a sensitive tool to capture the rapidly varying changes in behaviour that result from dysfunctional dopamine bursting activity in PD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"300"},"PeriodicalIF":6.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12368238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970622","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 impact of blood MCP-1 levels on Alzheimer's disease with genetic variation at the NAV3 and UNC5C loci.","authors":"Jinghan Huang, Yixuan Wang, Thor D Stein, Ting Fang Alvin Ang, Yibo Zhu, Qiushan Tao, Kathryn L Lunetta, Jesse Mez, Rhoda Au, Lindsay A Farrer, Wei Qiao Qiu, Xiaoling Zhang","doi":"10.1038/s41398-025-03542-w","DOIUrl":"10.1038/s41398-025-03542-w","url":null,"abstract":"<p><p>Monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in peripheral inflammation, has been shown to modulate established Alzheimer's disease (AD) loci. In this study, we hypothesized that blood MCP-1 levels may impact the associations of other genetic variants with AD risk beyond the well-established AD loci. We performed a genome-wide association study (GWAS) using logistic regression with the generalized estimating equation (GEE) and Cox proportional hazards models to examine the combined effects of single nucleotide polymorphisms (SNPs) and blood MCP-1 levels on AD. Three datasets were used: the Framingham Heart Study (FHS), Religious Orders Study/Memory and Aging Project (ROSMAP), and Alzheimer's Disease Neuroimaging Initiative (ADNI). We identified SNPs in two genes in the meta-analysis, namely, neuron navigator 3 (NAV3, also named unc-53 homolog 3, rs696468) (p < 7.55 × 10^-9) and the homolog unc-5 netrin receptor c (UNC5C rs72659964) (p < 1.07 × 10^-8), which are modified by blood MCP-1 concentration for AD risk. Elevated blood MCP-1 concentrations increased AD risk and brain AD pathology in individuals with NAV3 (rs696468-CC) and UNC5C (rs72659964-AT + TT) genotypes. Given that NAV3 and UNC5C are involved in regulating neurite outgrowth and guidance, increased MCP-1 levels may disturb the functions of vulnerable gene carriers to increase AD risk.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"296"},"PeriodicalIF":6.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12365253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883833","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":"Pharmacogenetic study of antipsychotic-induced lipid and BMI changes in Chinese schizophrenia patients: A Genome-Wide Association Study.","authors":"Kenneth Chi-Yin Wong, Perry Bok-Man Leung, Benedict Ka-Wa Lee, Zoe Zi-Yu Zheng, Emily Man-Wah Tsang, Meng-Hui Liu, Kelly Wing-Kwan Lee, Shi-Tao Rao, Pak-Chung Sham, Simon Sai-Yu Lui, Hon-Cheong So","doi":"10.1038/s41398-025-03499-w","DOIUrl":"10.1038/s41398-025-03499-w","url":null,"abstract":"<p><p>Second-generation antipsychotics (SGAs) are widely used to treat schizophrenia (SCZ), but they often induce metabolic side effects like dyslipidemia and obesity. We conducted genome-wide association studies (GWASs) to identify genetic variants associated with SGA-induced lipid and BMI changes in Chinese SCZ patients. A longitudinal cohort of Chinese SCZ receiving SGAs was followed for up to 18.7 years (mean = 5.7 years, SD = 3.3 years). We analysed the patients' genotypes (N = 669), lipid profiles, and BMI using 19 316 prescription records and 3 917 to 7 596 metabolic measurements per outcome. Linear mixed models were employed to evaluate seven SGAs' random effects on metabolic changes for each patient, followed by GWAS and gene set analyses with Bonferroni and FDR correction. Five SNPs achieved p-value < 5 × 10^-08 before multiple testing correction: rs6532055 (ABCG2) linked to olanzapine-induced LDL changes, rs2644520 (near SORCS1) linked to aripiprazole-induced triglyceride changes, rs115843863 (near UPP2) linked to clozapine-induced HDL changes, rs2514895 (near KIRREL3) linked to paliperidone-induced LDL changes, and rs188405603 (SLC2A9) linked to quetiapine-induced triglyceride changes. These five SNPs passed FDR correction at 0.2 but not Bonferroni-corrected genome-wide significance threshold (p-value < 3.125 × 10^-10) for 160 GWAS analyses. Gene-based analysis revealed six genome-wide significant genes after Bonferroni correction (p-value < 2.73 × 10^-6): ABCG2, APOA5, ZPR1, GCNT4, MAST2, and CRTAC1. Four gene sets were significantly associated with SGA-induced metabolic side effects. In summary, this pharmacogenetic GWAS identified several genetic variants potentially associated with SGA-induced metabolic side effects, potentially informing personalized treatment strategies to minimize metabolic risk in SCZ patients. Given our limited sample size, further replications are required to confirm the findings.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"295"},"PeriodicalIF":6.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12365156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883832","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 maternal HFD exposure impairs cognition via a hippocampal NMDA mechanism.","authors":"Kuan-Ru Chen, Yu-Cheng Ho, Chih-Wei Huang, Lung Yu, Pao-Lin Kuo","doi":"10.1038/s41398-025-03520-2","DOIUrl":"10.1038/s41398-025-03520-2","url":null,"abstract":"<p><p>Maternal obesity increases the risk of neurodevelopmental disorders and cognitive impairments in offspring later in life. Most animal studies investigated the effects of maternal high-fat diet (HFD) from pre-mating to lactation on offspring neurodevelopment and cognitive function. However, the specific impact of in-utero exposure to maternal HFD on the cognitive function in offspring remains limited. In this study, female dams were fed laboratory chow or HFD for 11 weeks: 8 weeks before conception and during gestation. To isolate the prenatal effects, newborns were reared by foster mothers under control-diet conditions during lactation. Behavioral tests were conducted between postnatal days 42 and 56. Our results demonstrate that maternal HFD exposure in utero impaired spatial working memory and spatial memory, and also caused depression-like behavior in offspring. These behavioral abnormalities were associated with reduced hippocampal NMDA receptor expression, diminished neurogenesis, and deficits in hippocampal long-term potentiation (LTP). In addition, intrahippocampal microinjection of NMDA receptor antagonists that block NMDA ion channels or compete for glutamate binding effectively reduces hippocampal long-term potentiation (LTP), resulting in deficits in spatial learning and memory. Furthermore, microinjection of NMDA into the hippocampus bilaterally activated NMDA receptor signaling, leading to the amelioration of behavioral abnormalities in HFD offspring. In summary, alteration of hippocampal NMDA receptors induced by prenatal maternal HFD exposure is associated with spatial learning and memory deficits in offspring.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"294"},"PeriodicalIF":6.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875314","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":"Dose-response relationship between accelerometer-measured physical activity and depression: evidence from the UK Biobank.","authors":"Shuangfa Qu, Zhenhua Xing","doi":"10.1038/s41398-025-03543-9","DOIUrl":"10.1038/s41398-025-03543-9","url":null,"abstract":"<p><p>Studies on the relationship between physical activity (PA) and depression often rely on self-reported data, with a predominant focus on moderate-to-vigorous physical activity (MVPA). However, research examining accelerometer-measured PA, particularly light physical activity (LPA), and its impact on depression risk in the general population remains limited. This study explores the dose-response relationship between accelerometer-measured PA and depression, with a particular focus on varying PA intensities and high-risk groups for depression, including women and individuals with obesity. This prospective cohort study involved 90,585 participants with accelerometer-measured PA data from the UK Biobank Study. Total PA volume was assessed using the average overall acceleration (ACC). Weekly minutes of LPA, moderate PA (MPA), and vigorous PA (VPA) were recorded. Incident cases of clinical depression were identified through diagnostic codes linked to hospital records and death certificates. Cox proportional hazards models with restricted cubic splines were used to analyze the associations. During an average follow-up period of 8.35 ± 0.97 years, 1,641 participants (2.2 per 1,000 person-years) developed depression. Depression risk decreased as total ACC reached 30 mg and as time spent in LPA, MPA, and VPA increased to 2000, 500, and 50 min per week, respectively, beyond which no further reduction in risk was observed. Higher-intensity PA, particularly VPA, did not provide additional benefits for depression when total PA volume was comparable. The relationship between LPA and depression risk was moderated by gender and obesity status, with no significant risk reduction observed in women and individuals with obesity engaging in LPA. Device-measured PA across all intensities, including LPA, MPA, and VPA, was associated with a reduced risk of depression, though the reduction was more dependent on PA volume than intensity. A threshold effect was observed, beyond which additional benefits diminished. Nonetheless, MVPA remains recommended for women and individuals with obesity.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"297"},"PeriodicalIF":6.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12365289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883831","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":"Interaction of daytime and nighttime light exposure on objective sleep quality in patients with bipolar disorder: a cross-sectional analysis of the APPLE cohort.","authors":"Yuichi Esaki, Kenji Obayashi, Keigo Saeki, Kiyoshi Fujita, Nakao Iwata, Jamie M Zeitzer, Tsuyoshi Kitajima","doi":"10.1038/s41398-025-03549-3","DOIUrl":"10.1038/s41398-025-03549-3","url":null,"abstract":"<p><p>Light plays a crucial role in regulating nocturnal sleep patterns. This cross-sectional study evaluated the potential association between levels of light exposure in real-life settings and sleep parameters in individuals with bipolar disorder. We included 204 ambulatory individuals with bipolar disorder who participated in the APPLE (Association between Pathology of Bipolar Disorder and Light Exposure in Daily Life) cohort study. Daytime illuminance and sleep were assessed using actigraphy over a seven-day period. In addition, a portable light meter was used to evaluate the illuminance levels in the bedroom during nighttime. The median values of daytime illuminance and nighttime illuminance were 221.8 lux (interquartile range: 150.9-306.9 lux) and 2.3 lux (0.3-9.6 lux), respectively. Multivariable linear regression analyses, adjusting for potential confounders, revealed a significant association between greater daytime illuminance and higher sleep efficiency as well as shorter sleep onset latency and wake after sleep onset. Moreover, the interaction term of daytime and nighttime illuminance demonstrated a significant correlation with sleep efficiency (95% confidence interval [CI], -10.45 to -2.17; P = 0.003), sleep onset latency (95% CI, 0.18 to 0.91; P = 0.004), and wake after sleep onset (95% CI, 13.47 to 50.1; P < 0.001). Our findings indicate the existence of a significant positive correlation between daytime light exposure and sleep parameters in individuals with bipolar disorder. The interaction of increased daytime light and decreased nighttime light appears to be positively associated with sleep quality.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"291"},"PeriodicalIF":6.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875400","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":"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}