Molecular Psychiatry最新文献

Migraine is a neurovascular disorder that poses a high burden to Veterans, who face a greater risk than sex-matched individuals in the general population. Genetic research on migraine in Veterans and its link to psychiatric comorbidities is limited. We present a meta-analysis of a genome-wide association study (GWAS) of migraine in a predominantly male sample of over 433,000 Veterans, including 87,859 cases, from the Million Veteran Program (MVP), identifying 49 genome-wide significant loci, with 36 novel to this study, of which 7 replicated in an independent prior GWAS (after Bonferroni correction for number of loci tested). Our analyses revealed 283 genes, including some newly associated with migraine: MAML3, CELF4, IRX1, ASXL1, SPOCD1, CXCL, and TLR4. In silico analyses showed enrichment in brain and uterine tissues, which may reflect broader hormonal or neuroendocrine pathways. Compared to previous migraine GWAS, our results show minimal vascular tissue enrichment, potentially reflecting the sample composition, which was predominantly men and Veterans. Migraine SNP-based heritability was 10% for men and 16% for women, and several sex-specific loci were identified through sex-stratified analyses. Despite high genetic correlations with neuropsychiatric disorders - including post-traumatic stress disorder, depression, and traumatic brain injury - Mendelian randomization analyses found no causal links. Finally, we prioritized potential migraine drug targets, including losmapimod (which reduces production of toxic DUX4 protein) and TLR4 antagonists.

The transcranial alternating current stimulation (tACS) has been reported to improve attention-related neurophysiological measures in individuals with attention deficit hyperactivity disorder (ADHD); however, robust clinical evidence remains limited. This randomized, double-blind, sham-controlled trial aimed to explore the clinical efficacy, safety, and underlying neural mechanisms of tACS in adults with ADHD. A total of 56 adults with ADHD were randomly assigned in a 1:1 ratio to receive either active tACS or sham stimulation across 20 sessions over four consecutive weeks, with follow-up assessments conducted at week 8 and week 16. Clinical symptoms and resting-state magnetoencephalography (MEG) data were collected before and after the intervention. The tACS group showed significantly greater improvement in inattention symptoms compared to the sham group at week 4, as measured by the Adult ADHD Self-Report Scale - inattention subscale (ASRS-IA) (-10.1 vs. -5.5, p < 0.001, Cohen's d = 1.02). This improvement was sustained at week 8 but attenuated at week 16. Safety profiles were comparable between the two groups. Furthermore, the reduction in ASRS-IA scores was positively correlated with decreased gamma-band connectivity between the orbitofrontal cortex and the precuneus, indicating a desynchronization of neural activity in these brain regions. These findings suggest that tACS may serve as a promising neuromodulation intervention for adult ADHD, demonstrating both clinical benefits and specific neurophysiological mechanisms. TRIAL REGISTRATION: ChiCTR Identifier: ChiCTR2400081121.

Prenatal exposure to a heightened maternal immune response, such as that triggered by viral infection in the mother, can alter fetal brain development and increase risk of neurodevelopmental disorders in offspring, including autism (ASD) and schizophrenia. However, the cellular and molecular mechanisms linking early inflammatory signals to long-term changes in brain function remain unclear. While rodent models of maternal immune activation (MIA) display brain and behavioral disruptions, their translational relevance to humans is limited. To address this gap, we utilized a nonhuman primate (NHP) MIA model to examine how transient maternal immune responses in early gestation alter gene expression in the amygdala-a brain region essential for socioemotional behavior and implicated many neurodevelopmental disorders. Pregnant macaques were administered the viral mimic Poly(I:C) during the late first trimester, and amygdala samples were collected from 4-year-old male offspring for single-nucleus RNA sequencing (>71,000 nuclei). We identified 2768 unique differentially expressed genes (DEGs), concentrated in excitatory and inhibitory neurons of the lateral nucleus and microglia of the central nucleus. These DEGs converge on synaptic structure, neurotransmission, and neuroimmune signaling-core processes in circuit assembly and behavioral regulation. MIA-associated DEGs significantly overlap with high-confidence ASD- and psychosis-risk gene sets, directly linking prenatal immune events to human disease pathways. This study provides the first region- and cell-type-specific evidence in a primate model that transient prenatal maternal immune responses lead to lasting transcriptomic dysregulation. These findings reveal how early immune insults may alter neurodevelopment and offer a translational framework for identifying molecular targets for early intervention.

Mental and substance use disorders profoundly affect global population health, while there is a notable absence of systematic studies focusing on their burden in the Chinese population. We estimated the burden of Global Burden of Diseases (GBD) 2021 for 10 mental disorders and two types of substance use disorders in China from 1990 to 2021. We presented the numbers and rates of prevalence, disability-adjusted life years (DALYs), years of life lost (YLL) and years lived with disability (YLDs), from national and 33 province-level administrative units in China. In 2021, China contributed 174.4 million prevalent cases (95% uncertainty interval [UI] 162.4-188.4 million) of mental disorders and 27.0 million prevalent cases (23.8-30.7 million) of substance use disorders. The age-standardized DALY rate for mental and substance disorders in China was lower than that in countries with high Socio-demographic Index (SDI) and middle SDI, as well as lower than global level. Depressive disorder and anxiety disorder being the two leading causes, accounting for 61.1% of mental disorder YLDs, and were most prevalent among individuals aged 15 and over. Population growth was an important contributor to the 62.0% increases in DALYs for mental disorder. Regionally, the age-standardized prevalence rates for mental disorders were higher in Eastern China, while substance use disorders were more prevalent in Western regions. These findings showed the burden of mental disorders in China has increased mainly due to the population growth and population aging. The comprehensive prevention and early intervention strategies is urgent to mitigate the burden and the impact for the public.

Cardiovascular disease (CVD) risk prediction models for the general population may not provide accurate predictions in individuals with bipolar disorder (BD) who have elevated risks of cardiometabolic conditions and premature mortality. Therefore, we aimed to: 1) develop a five-year CVD risk prediction model in this population by using nationwide register data from Sweden, 2) investigate whether the performance improved when we considered additional risk factors, including psychiatric comorbidity, psychotropic medication, and socio-demographic variables, compared to using established CVD risk factors only, and 3) whether machine learning approach provided improvements compared to standard logistic regression models. We followed 33,933 persons with BD aged 30-82 years old, without previous CVD, from the date of BD diagnosis registered between 2007-2014, for up to five years. The logistic regression model containing only established risk factors yielded an area under the receiver operating characteristic curve (AUC) of 0.76 (95% confidence interval 0.74-0.78) in the test dataset, while the logistic regression model and the best performing machine learning model including additional predictors yielded similar results (AUC was 0.77 (0.75, 0.79) in both models). The performance of logistic regression models slightly improved with additional predictors when continuous risk scores were used. In conclusion, standard logistic regression and established CVD risk factors may be sufficient to predict CVD in individuals with BD when using population register-based data from Sweden. External validation across diverse healthcare settings and rigorous assessment of clinical impact will be crucial next steps before implementing these models in clinical practice.

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of gene expression, particularly in complex neuropsychiatric disorders such as major depressive disorder (MDD). This study investigates the expression of lncRNAs in the dorsolateral prefrontal cortex (dlPFC) of MDD subjects and their potential roles in chromatin remodeling and gene silencing. Following the 8×60 K microarray platform, we profiled the expression of 35,003 lncRNAs in 59 MDD and 41 control subjects, identifying 1625 upregulated and 1439 downregulated lncRNAs in the MDD group. Co-expression network analysis revealed a complex and interconnected lncRNA network in MDD, suggesting intricate regulatory mechanisms. Furthermore, by employing the PIRCh-seq technique, we found that a subset of 60 upregulated lncRNAs in the MDD brain interacts with heterochromatic regions marked by the H3K27me3 modification, thereby silencing gene expression. These lncRNAs were associated with 24 downregulated protein-coding genes linked to neuronal functions, including synaptic vesicle exocytosis and neurotransmitter release. Gene ontology and pathway analyses highlighted disruptions in critical neurobiological functions, with particular emphasis on synaptic and neuronal signaling pathways. Our findings underscore the role of lncRNA-mediated heterochromatization in the pathophysiology of MDD, offering novel insights into the epigenetic regulation of brain function and behavior.

Epidemiologic evidence links follicle-stimulating hormone (FSH), a pituitary glycoprotein that rises during menopause, to memory loss, fat accumulation, and bone loss. We and others have shown that the attenuation of FSH signaling, either genetically or pharmacologically, prevents memory loss, fat accrual, and bone loss in multiple mouse models. Here, we investigated whether the genetic depletion of the FSH receptor (Fshr) affects recognition memory, body composition, and bone mineral density (BMD) in two AD mouse models. We generated male and female 3xTg and APP-KI mice carrying the Fshr^+/+, Fshr^+/-, and Fshr^-/- genotypes. Recognition memory was evaluated using the Novel Object Recognition (NOR) test. Body composition (fat, lean, and total mass) and site-specific bone mineral density (femur, tibia, L3-L5 spine) measurements were made using quantitative nuclear magnetic resonance (qNMR) and dual-energy X-ray absorptiometry (DXA), respectively, at two time points. Given that female Fshr^-/- genotypes are otherwise hypogonadal, they were implanted with 17β-estradiol pellets at 8-12 weeks of age to normalize serum estrogen. At the early time point, the deficit in recognition memory was rescued in female 3xTg;Fshr^-/- and APP-KI;Fshr^-/- mice, but not in male mice. Likewise, female, but not male 3xTg;Fshr^-/- mice showed reduced fat mass at both the early and later time points, but without changes in total body mass. In contrast, in the APP-KI cohort, both female and male Fshr^-/- mice showed reduced fat mass at the early, but not the late time point. DXA revealed that female, but not male APP-KI;Fshr^-/- mice showed progressive increases with time in BMDs in tibiae, femora, and vertebrae, which were either statistically significant or approached significance. This phenotype was not observed on the 3xTg background. These studies constitute the first report for time- and strain-dependent effects of global Fshr depletion in the same mouse, setting the stage for the simultaneous prevention, using a single therapeutic, of three disorders of public health magnitude-Alzheimer's disease, obesity and osteoporosis.