Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with sex differences, possibly linked to testosterone; however, the relationship remains unclear. This study aimed to clarify the genetic correlation and polygenic overlap between ADHD and testosterone traits, identify shared genomic loci, and investigate the underlying biological mechanisms through functional annotation. Genomic data on ADHD and three testosterone traits (total testosterone [TT], bioavailable testosterone [BT], and sex hormone-binding globulin [SHBG]) were obtained from publicly accessible genome-wide association studies. Employing the MiXeR bivariate causal mixture model, we quantified the polygenic overlap between ADHD and these testosterone traits. Subsequently, we applied the conjunctional false discovery rate (conjFDR) method to identify genomic loci and performed functional annotation with the Functional Mapping and Annotation tool to aid biological interpretation. Using MiXeR, we found negative correlations between TT and ADHD, and SHBG and ADHD, but a positive correlation between BT and ADHD. Over one-third of testosterone-associated variants were predicted to affect ADHD. Using the conjFDR approach, we identified 22-51 genomic loci shared between testosterone traits and ADHD, including MCM9 and MANBA. Functional enrichment analysis highlighted the predominant involvement of these mapped genes in signal transduction pathways, synapses, cell differentiation, and neurogenesis. In conclusion, we reported a substantial polygenic overlap between ADHD and testosterone traits, identified multiple shared genomic loci implicating common biological mechanisms, and highlighted the association of glutamatergic synapses and neurogenesis with ADHD and testosterone levels.

Studies on schizophrenia-associated rare copy number variants (CNVs) have predominantly focused on people of European (EUR) ancestry. Here we present a rare CNV study of schizophrenia in East Asian (EAS) populations, comprising 20,903 cases and 23,258 controls. We observed a significantly elevated genome-wide rare CNV burden in EAS cases compared with controls. Cross-population comparisons showed largely consistent rare CNV effects on schizophrenia risk. In the EAS sample, we identified nine genome-wide-significant schizophrenia-associated rare CNV loci. Meta-analysis with EUR data yielded 14 significant loci, including 8 that reached genome-wide significance for the first time. Genes within these 14 loci were significantly less tolerant to loss-of-function variants than genes in other CNV loci. The new rare CNVs associated with schizophrenia in EAS populations showed higher carrier frequencies in EAS than in EUR populations (0.38% versus 0.0017%). Overall, this study underscores the importance of increasing population diversity to fully capture the genetic underpinnings of schizophrenia. Genomic analyses in populations of East Asian ancestry identify rare copy number variants associated with schizophrenia. Meta-analyses with populations of European ancestry identify additional risk loci enriched in genes less tolerant to loss-of-function variants.

BACKGROUND:Suicidal ideation (SI) represents a severe consequence of major depressive disorder (MDD). While sleep disorders and immune dysregulation are associated with SI, the precise associations and complex mediating pathways involving sleep disturbances, inflammatory biomarkers, and anxiety and depression severity remain poorly understood. METHODS:A total of 157 patients suffering from MDD were enrolled. Based on Item 3 of the 17-item Hamilton Depression Rating Scale (HAMD), participants were categorized into SI and non-suicidal ideation (NSI) groups. Sleep disorders were assessed using the Pittsburgh Sleep Quality Index (PSQI). Peripheral inflammatory markers were from complete blood counts. Spearman correlation analysis and multiple logistic regression methods were employed to analyze the associations of sleep disorders, emotional symptoms, and inflammatory markers with SI. Additionally, a bidirectional mediation analysis was conducted to explore the association of these variables with SI. RESULTS:Patients with SI exhibited poorer sleep quality and altered inflammatory profiles. Significant correlations were observed among affective symptoms, sleep measures, and immune markers. The results showed that in models excluding emotional symptoms, the global PSQI score and sleep disturbances component were associated with SI. Mediation analysis indicates that the percentage of lymphocytes was indirectly associated with SI via the sleep disturbances and daytime dysfunction components. The daytime dysfunction component and HAMA score were associated with SI through bidirectional mediating pathways. CONCLUSIONS:Sleep disorders, inflammatory dysregulation, and anxiety symptoms constitute an interconnected network associated with SI in MDD. These findings highlight the importance of comprehensive, integrated interventions.

Major depressive disorder (MDD) is pathologically associated with inflammatory-immune dysregulation. While regulatory T cells (Tregs) are essential for immune homeostasis, clinical evidence have reported paradoxical dynamics (deficiency vs. expansion) of peripheral Tregs in MDD patients. The plasticity of Tregs and microenvironmental reprogramming mechanisms remain elusive, highlighting the need for pathology-driven biomarkers and targeted interventions. In this study, we integrated mass cytometry (CyTOF; n = 37), single-cell RNA/T cell receptor sequencing (n = 10), and flow cytometry (n = 123) to systematically profile Tregs in MDD. Functional assays were conducted to evaluate suppressive capacity, interleukin-6/interferon-γ (IL-6/IFN-γ)-driven plasticity, and diagnostic utility via receiver operating characteristic (ROC) analysis. Results showed that MDD patients exhibit significant peripheral immune dysregulation, notably expanded peripheral Tregs (1.2-fold increase, p = 0.001). Single-cell analysis revealed that these were predominantly T-bet+ Th1-like subpopulations (1.5-fold increase, p = 0.01) displaying mitochondrial dysfunction, elevated IFN-γ response (NES = 1.51), and impaired suppression (16.7 vs. 62.8% inhibition, p < 0.001). IL-6 signaling drove this aberrant differentiation, and IL-6 blockade reversed the inflammatory phenotype (1.8-fold reduction, p < 0.001). Clinically, T-bet+ Th1-like Tregs effectively discriminated drug-naïve MDD patients (area under the curve [AUC] = 0.776, 95% confience interval (CI): 0.668–0.884) and correlated with symptom severity (HAMD score: r = 0.49, p < 0.001). These findings demonstrate that MDD-associated IL-6-driven Th1-like Treg polarization underlies MDD immunopathology, linking metabolic dysregulation with inflammatory conversion, and positions this subset as dual diagnostic biomarkers and therapeutic targets for modulating the IL-6/IFN-γ axis in depression.

Anxiety disorders pose a considerable burden on public health. While exercise has been increasingly established as a viable strategy for preventing and alleviating anxiety symptoms, the underlying molecular mechanisms of this action remain elusive. We previously conducted an 8-week randomized controlled trial which suggested that exercise not only significantly reduced anxiety levels but also triggered the release of acidic ribosomal protein P2 (RPLP2) from peripheral tissues into the bloodstream. These elevated circulating RPLP2 levels showed an inverse association with anxiety severity in patients, suggesting a potential therapeutic role for the protein. Further experiments in mice confirmed that skeletal muscle-derived RPLP2 exerts its anxiolytic effects by facilitating hippocampal neurogenesis. Mechanistically, RPLP2 facilitates ribosomal localization and increases the efficiency of ribosomal subunit assembly, thereby increasing local protein synthesis and supporting the development and maturation of newly generated neurons. The successful maturation of these neurons, in turn, promotes morphological and functional synaptic plasticity, which is crucial for the integration and functional maturation of newborn neurons into hippocampal circuits. Collectively, our findings reveal a previously unknown muscle-brain axis mediated by RPLP2, offering mechanistic evidence for exercise-induced stress resistance.

Panic attacks (PA), characterized by acute psychophysiological symptoms, affect 28% of adults globally. In China, with 1.04 billion short video users, Douyin plays a pivotal role in disseminating health information; however, the quality of PA-related content on this platform remains unassessed. To evaluate the quality and reliability of PA-related videos on Douyin and to propose evidence-based improvements for digital mental health communication. We conducted a systematic search using the Chinese keyword for "panic attacks (Jingkong Fazuo, (sic)(sic)(sic)(sic))" on Douyin, China's premier short video platform, and selected the top 150 most viewed videos (as of February 2025). After excluding 24 ineligible videos, the remaining 126 were analyzed through a combination of manual content coding and validated assessment tools, including the JAMA Benchmark Criteria, Global Quality Scale (GQS), and modified DISCERN (mDISCERN). Health professionals produced 60.32% of content, yet critical gaps persisted: 65.87% omitted definitions, 78.57% excluded risk factors, and 85.72% lacked outcome/evolution. Median scores for quality and reliability were suboptimal (JAMA: 2/4; GQS: 2/5; mDISCERN: 2/5). Engagement metrics including likes, comments, collections and shares showed strong positive intercorrelations (r > 0.7, P < 0.050), but no significant association with quality and reliability indices (|r| < 0.1). Health professionals' videos outperformed others in GQS (P = 0.031) and mDISCERN (P = 0.001) but not JAMA. The quality of PA-related content on Douyin remains unsatisfactory, although health professionals provide comparatively reliable materials. Rigorous vetting and standardization of health-related social media content are imperative. Health information seekers should exercise cautious evaluation regarding Douyin's credibility as an information source.

Given the global prevalence of schizophrenia (SCZ), it is urgent to elucidate and quantify its burden and clarify its environmental and social influencing factors. This study aimed to quantify the global disease burden of SCZ. It also investigated the causes of regional disparities and the impact of environmental and social factors. This study conducted an extensive analysis of the global, regional and national incidence, prevalence, and disability-adjusted life years (DALYs) of SCZ. In 2021, there were 1.22 million incident cases, 23.18 million prevalent cases and 14.82 million DALYs. From 1990 to 2021, the global incidence, prevalence, and DALYs of SCZ exhibited consistent upward trends, whereas the age-standardized rates remained stable. The prevalence of SCZ was found to be higher in males and exhibited age-related fluctuations. The highest incidence risk was observed in the 20–24 age group, while the highest DALYs risk was in the 35–39 age group. The highest disease burden of DALYs was observed in East Asia. The study delivered an analysis of the distribution of disease burden at the socio-demographic index level and investigated the impact of environmental factors on regional disparities. Projection analyses indicated a continued escalation in the incidence, prevalence, and DALYs attributable to SCZ by 2040. The disease burden of SCZ has increased since 1990. To mitigate the future impact of SCZ, these findings call for a multi-pronged approach: targeted service planning informed by disease burden, environmental emission reduction, and a renewed clinical focus on early intervention and functional recovery.

The neural mechanisms coordinating social behavior and attentional control are often disrupted together in individuals with neuropsychiatric disorders such as autism spectrum disorder (ASD); however, how distinct circuits within a shared brain region separately regulate these functions remains unclear. Here, we identified two functionally distinct subpopulations of glutamatergic neurons in the anterior cingulate cortex (ACC) that project to different downstream targets: the zona incerta (ZI) and the limbic sector of the thalamic reticular nucleus (lTRN). These two ACC subpopulations differentially mediate social interaction and attentional allocation. Deficits in both behaviors were observed in Shank3b mutant ASD model mice. Optogenetic activation of the ACC→ZI circuit rescued social impairments, whereas activation of the ACC→lTRN pathway restored attentional performance. Our findings reveal dissociable ACC subpopulations and their downstream circuits for social and attentional behaviors, providing circuit-level insights that may inform future research on modulating related symptoms in patients with psychiatric disorders.

Disturbances in energy metabolism are a key pathophysiological feature of major depressive disorder (MDD). The gut microbiota, as a critical regulator of host metabolism, may influence systemic energy homeostasis and contribute to depression. To investigate this, we performed a multi-omics analysis integrating targeted metabolomics and shotgun metagenomics on samples from 100 MDD patients and 68 healthy controls. MDD patients exhibited significant disruptions in central energy pathways (glycolysis, TCA cycle, and ornithine cycle), which correlated with symptom severity and cognitive impairment. We identified 36 bacterial species whose abundances were linked to mitochondrial fatty acid synthesis, ketogenesis, and amino acid metabolism, and were associated with altered levels of core metabolites like lactate and L-glutamic acid. Mediation analysis established a "gut microbiota-energy metabolites-depressive phenotype" axis, where metabolites mediated the effects of specific bacteria (e.g., Dorea_formicigenerans) on symptoms. To validate causality, we used a chronic social defeat stress mouse model with simultaneous autologous fecal microbiota transplantation (FMT). FMT effectively reshaped the gut microbiota, ameliorated depression-like behaviors, and reversed the stress-induced shift toward anaerobic glycolysis in serum and the central nervous system. Critically, FMT restored mitochondrial morphology and structural integrity in the prefrontal cortex and hippocampus, renormalizing the relationship between metabolism and behavior. Our findings elucidate the gut microbiota's role in MDD pathogenesis via host energy metabolism regulation and posit early autologous FMT as a novel strategy to correct central energy imbalances.

Emerging evidence underscores bidirectional communication along the microbiota-gut-brain axis in neuropsychiatric disorders. However, the field lacks dedicated metagenomic resources with standardized phenotyping for these conditions. Existing single-cohort studies face inherent limitations due to restricted sample sizes, confounding heterogeneity, and methodological fragmentation, compromising reproducibility and mechanistic insights. To overcome these challenges, we constructed the Gut Microbiome in Multinational Integrated Neuropsychiatric Disorders (GutMIND) database, a comprehensive resource integrating shotgun metagenomic data with harmonized metadata. Adhering to a standardized preprocessing protocol and rigorous quality control workflow, this dataset represents the largest gut-brain microbiome repository to date, encompassing 31 studies across 12 countries (n = 3,492) spanning 14 neuropsychiatric conditions. Utilizing this dataset, we characterized microbial community heterogeneity, which was significantly elevated in patients compared to healthy controls. Subsequently, we developed a computational framework, MetaClassifier, enabling the diagnosis of neuropsychiatric disorders and the identification of microbial biomarkers. Employing a comprehensive two-stage validation strategy, we first assessed the model utilizing taxonomic abundance profiles via nested cross-validation in the high-quality discovery cohort (n = 2,734), achieving a mean AUROC of 0.69 (range: 0.55-0.78) across 8 disorders. Its robustness was further confirmed in an independent platform-extended validation cohort (n = 400), yielding a mean AUROC of 0.71 (range: 0.60-0.76). We also developed the Microbial Gut-Brain Axis Health Index (MGBA-HI), which effectively distinguished neuropsychiatric status in both the high-quality cohort and the platform-extended cohort. Furthermore, integrative analysis of health-abundant species, index-derived biomarkers, and ecological prevalence, we identified 9 core neuropsychiatric-protective microbiota. These species predominantly exhibited metabolic capacities linked to glutamate synthesis and acetate production. Building upon this, the GutMIND framework ensures robust cross-cohort comparability while minimizing technical heterogeneity, thereby enhancing inferential rigor in gut microbiome-neuropsychiatry research. Notably, the MetaClassifier, MGBA-HI, and core microbiota hold translational potential for developing microbiome-based prognostic tools and personalized therapeutic strategies in neuropsychiatric disorders. The source code and usage instructions for MetaClassifier are accessible at https://github.com/juyanmei/MetaClassifier.

BACKGROUND:Sleep deprivation (SD) is a potent trigger of anxiety and poses a substantial threat to mental health. Although accumulating evidence suggests that disrupted intestinal function contributes to abnormal behaviors associated with SD, the specific mechanisms by which gut-derived signals modulate SD-related anxiety remain poorly understood. METHODS:Combining behavioral analysis, chemogenetic manipulation, and neuropharmacological approaches in a male mouse model of SD, we investigated the circuit mechanism from colonic enterochromaffin (EC) cells to hippocampal neurogenesis. The involvement of vagal afferent signaling was further probed by pharmacological blockade of 5-HT3 receptors. RESULTS:We identified colonic EC cells as critical early responders to SD, whose dysfunction temporally precedes the emergence of anxiety phenotypes. Chemogenetic inhibition of EC cells mimicked the behavioral and neurogenic deficits observed after SD. Conversely, chemogenetic activation of EC cells during SD normalized 5-HT levels, rescued hippocampal neurogenesis, and alleviated anxiety-like behaviors. Mechanistically, 5-HT derived from EC cells activated vagal afferents via 5-HT3 receptors, thereby promoting hippocampal neurogenesis and reducing anxiety-like behaviors. CONCLUSIONS:Our findings reveal a key role for colonic EC cells in regulating emotional homeostasis during SD. These results provide novel insights into the mechanisms underlying SD-induced anxiety and highlight potential therapeutic targets for preventing anxiety related to sleep loss.

While Western dietary patterns are increasingly linked to neuropsychiatric disorders, the causal mechanisms by which chronic high-fat diet (HFD) contributes to depression remain elusive. Here, we demonstrate that prolonged ( ≥ 10 weeks) HFD exposure in mice robustly induces depressive-like behaviors, phenocopying chronic stress models. Integrating multi-omics and targeted lipidomics, we reveal that HFD-induced behavioral deficits are underpinned by gut microbiota dysbiosis and a profound disruption of polyunsaturated fatty acid (PUFA) homeostasis. This disruption is characterized by a surge in pro-inflammatory ω-6 metabolites, particularly arachidonic acid (AA), alongside a concomitant reduction in anti-inflammatory ω-3 metabolites. These lipid perturbations strongly correlate with marked microglial activation and elevated pro-inflammatory cytokine levels (IL-6, TNF-α, CCL2) in the prefrontal cortex and hippocampus. Functionally, AA supplementation alone was sufficient to recapitulate depressive-like behaviors in vivo and, through neuron-microglia co-culture assays, directly induce pro-inflammatory microglial activation, NF-κB pathway upregulation, and subsequent synaptic impairment in vitro. Critically, therapeutic intervention with aspirin, a dual COX-1/COX-2 inhibitor, effectively reversed HFD-induced behavioral deficits. This protection was mediated by a dual mechanism: directly inhibiting microglial hyperactivation and normalizing the neuroinflammatory milieu by suppressing the biosynthesis of pro-inflammatory ω-6-derived prostanoids, including AA and 12-HETE. Collectively, our findings identify AA as a critical etiological link between HFD and neuroinflammation, establishing a mechanistic framework for "metabolic depression." The profound therapeutic efficacy of aspirin validates the AA metabolic pathway, specifically COX-1/COX-2, as a promising and targetable node for intervention, offering translational insights for the burgeoning field of nutritional psychiatry.

Brain diseases such as ischaemic stroke, Alzheimer's disease (AD), and glioma were characterized by high mortality and disability rate, and oxidative stress remains a major obstacle in treatment. Plasma-nanomedicine synergistic treatment technology provides a very attractive treatment strategy based on complementarity. This technology integrates cold atmospheric plasma (CAP) with nanomedicine. CAP produces active substances that regulate oxidative stress, while nanomedicine is specially designed for targeted delivery, controlled release, and microenvironmentally responsive activation of therapeutic agents. This integration generates new therapeutic functions and significantly improves the overall therapeutic effect. Despite the broad prospects of this emerging technology, researchers in the fields of medicine, physics, or pharmacy have not yet paid much attention to it. To fill this research gap, this review describes the physicochemical properties and biological effects of CAP and summarizes the latest advances in plasma nanomedicine strategies in the field of brain disease intervention, and reviews the four major nanomedical categories-metal-based, inorganic non-metallic, polymer-based and hydrogel systems-and their clinical applications in the treatment of brain tumors, strokes and neurodegenerative diseases in conjunction with CAP. Finally, we highlight a number of key challenges-limited resources of special CAP equipment, incomplete understanding of the mechanism, obstacles to transformation application-and put forward the future research direction to promote the development of accurate, safe, and clinical transformation value plasma-nanomedicine therapy for brain diseases.

Background and Hypothesis A subset of patients with schizophrenia (SCZ) exhibit subclinical immune activation. However, the gut microbial features of this subgroup and their interplay with the immune function remain poorly understood. This study aimed to identify the gut microbiome signature of immune-activated SCZ and elucidate the role of short-chain fatty acids (SCFAs) in the gut-immune crosstalk.Study Design In this study, 297 patients with SCZ and 301 healthy controls (HCs) were assessed for 4 serum immune mediators. Immune-activated subgroups were classified based on these biomarkers. Fecal metagenomic sequencing, SCFA metabolomics, and in vitro peripheral blood mononuclear cells (PBMCs) stimulation experiments were performed to analyze the microbial composition, SCFA levels, and immune responses.Study Results We found that 46.5% of the patients with SCZ exhibited elevated immune activation biomarker levels, which displayed unique bacterial signatures. Microbiome-based machine learning classifiers demonstrated robustness in SCZ and immune activation classification. Notably, microbial species abundance, functional metagenomics, and SCFA levels have confirmed an elevated capacity for SCFA production in patients with immune activation. Furthermore, in vitro PBMC stimulation experiments revealed a diminished anti-inflammatory effect of SCFAs in immune-activated patients when exposed to lipopolysaccharide-induced inflammation.Conclusions This study delineates the gut microbiome and SCFA metabolic profiles of immune-activated SCZ patients, revealing an association between gut microbiota dysbiosis, enhanced SCFA production capacity, and diminished anti-inflammatory effect of SCFA. These findings provide new insights into the underlying mechanisms and potential targeted treatments for SCZ patients with immune activation.

BACKGROUND:Adolescent depression shows clear sex differences, with females having higher prevalence and more severe symptoms than males. The biological basis of these differences, particularly involving inflammation and the gut-brain axis, remains poorly understood. This study investigated sex-specific clinical and biological features and their value in predicting non-suicidal self-injury (NSSI) in adolescents with major depressive disorder (MDD). METHODS:Ninety-two adolescents with MDD were assessed using the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale. Serum levels of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-4, IL-8), gut barrier markers (iFABP, LBP), and blood-brain barrier (BBB) markers (S100β, claudin-5) were measured. Associations were examined using Spearman correlation, and logistic regression was applied to identify predictors of NSSI in females. RESULTS:Female patients had more severe depressive and anxiety symptoms and higher TNF-α levels than males. Gut and BBB markers were positively correlated, indicating gut-brain axis involvement. Logistic regression showed that younger age (OR < 1) and higher S100β levels (OR > 1) significantly predicted NSSI in females. The gut-brain biomarker model showed the best predictive performance (AUC = 0.844). CONCLUSION:Adolescents with MDD exhibit sex-specific clinical and biological profiles. Younger age and increased BBB permeability, reflected by elevated S100β, are key predictors of NSSI in females. Gut-brain axis biomarkers may aid early risk identification and targeted intervention in adolescent depression.

Inflammatory bowel diseases (IBDs) are frequently accompanied by anxiety and depression, largely driven by perturbed gut-brain axis signaling. However, current oral therapies remain constrained by the spatial and functional separation between intestinal inflammation and central nervous system dysfunction. Here, we present a comprehensive gut-brain dual region integrated therapeutic strategy based on functionalized Bifidobacterium longum hydrogel (INPs@BL@Gel), in which baicalin and tyrosine are coordinated with Fe(III) to form infinite coordination polymers (ICPs), coated with inulin, assembled onto Bifidobacterium longum (BL), and subsequently encapsulated within a pH- and matrix metalloproteinase-responsive silk fibroin-gelatin hydrogel. INPs@BL@Gel exhibits high drug-loading, effective gastric protection, inflammation-triggered release, and long-term intestinal colonization. Within the inflamed intestine, BL and components synergistically suppress inflammatory responses, restore gut microbiota homeostasis, and promote intestinal barrier repair through multi-target integrated therapy. Importantly, BL combined with components markedly enhances the production of beneficial neuroactive metabolites such as homovanillic acid and short-chain fatty acids, which integratedly regulate neuroinflammation, preserve synaptic function, and facilitate blood-brain barrier repair via the gut-brain axis. In vivo studies demonstrate that INPs@BL@Gel not only exerts potent therapeutic efficacy against colitis and effectively alleviates associated depression, but also reshapes the gut microbiota and restores barrier integrity, achieving a remarkable comprehensive therapeutic effect.

Background Major Depressive Disorder (MDD) and obesity are prevalent and burdensome public health issues linked by a complex, bidirectional association potentially driven by systemic inflammation. Nevertheless, this relationship remains poorly understood in adolescents with MDD. Methods We enrolled 339 adolescents with MDD and stratified them by body mass index (BMI) into underweight, normal weight, overweight, and obese groups. Depression and anxiety severity were evaluated using the Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) Rating Scales. Hematological inflammatory markers, including neutrophils, monocytes, lymphocyte, platelets, white blood cells, high-sensitivity C-Reactive Protein (hs-CRP), derived ratios, and systemic immune-inflammation index (SII), were assessed across groups. Linear regression and mediation analyses evaluated associations among clinical symptoms, BMI, and inflammatory markers. Results The association between BMI and depressive symptoms differed significantly by sex. Among females, the abnormal BMI group had significantly higher total HAMD scores than the normal-weight group, with the obese group demonstrating a higher score on the cognitive impairment factor of HAMD. Inflammatory markers increased progressively across ascending BMI categories. BMI and blood inflammatory markers were associated with depression severity in adolescents. Neutrophil count and monocyte-to-lymphocyte ratio (MLR) showed significant positive indirect effects, accounting for part of the association between obesity and depressive symptoms. Conclusions High BMI correlates with more severe depressive symptoms and increased inflammatory status in adolescents with MDD, especially among females. Systemic inflammation partially accounts for the association between high BMI and depression, suggesting that interventions targeting immune and metabolic pathways may offer additional therapeutic benefits.

This study aimed to characterize the alterations in both oral and gut microbiota in a mouse model of depression and to explore their potential role in the pathogenesis of major depressive disorder (MDD) through the oral-gut-brain axis. A depression model was established in male C57BL/6J mice using chronic social defeat stress (CSDS) paradigm. Depressive phenotypes were confirmed through social interaction, sucrose preference, open field, tail suspension, and forced swim tests. The microbial composition of oral and gut samples was analyzed using 16S rRNA sequencing, with Linear Discriminant Analysis Effect Size (LEfSe) employed to identify differentially abundant taxa and Spearman correlation analysis to examine microbiota-behavior relationships. CSDS successfully induced robust depression-like behaviors, including social avoidance, anhedonia, and behavioral despair. Beta-diversity analysis revealed significant separation in oral microbiota between CSDS and control groups. LEfSe analysis identified distinct microbial signatures: control mice were enriched in oral Streptococcus and gut commensals including Lachnospiraceae, Bacteroides and Oscillospiraceae, whereas CSDS mice showed expansion of oral Muribacter and Rodentibacter and gut Alloprevotella, Helicobacter and Colidextribacter. Correlation analyses demonstrated significant associations between specific microbial patterns and depression-like behaviors, with control-enriched taxa negatively correlating with behavioral deficits. Furthermore, significant cross-habitat microbial correlations were observed between oral and gut differential taxa. Our findings demonstrate that CSDS induces divergent microbial alterations in both oral and gut ecosystems, which are systematically associated with depression-like behaviors. These results provide compelling evidence for the involvement of the oral-gut-brain axis in depression pathophysiology and suggest that modulating these microbial ecosystems may represent a potential therapeutic strategy for MDD.

Converging evidence indicates that dysregulated cortico-subcortical connectivity underpins core cognitive impairment in schizophrenia (SCZ). However, the mechanistic basis linking this disrupted brain function to cognitive deficits remains elusive. We hypothesized that dysfunction within the hippocampal-thalamocortical circuitry mediates the impact of peripheral inflammation on cognitive deficits in SCZ. We recruited 62 drug-native patients with SCZ and 44 age and sex-matched healthy controls (HCs), assessing: serum levels of cytokines, cognition using the MATRICS Consensus Cognitive Battery, and resting-state functional connectivity (FC) and functional connectivity network (FCN) features. Correlation and mediation analyses were employed to examine relationships among peripheral inflammation, brain functional alterations, and cognitive deficits. The findings revealed reduced FC in SCZ between the right subiculum of the hippocampus and the anterior division of the right parahippocampal gyrus (aPaHC), as well as the entorhinal cortex and the left lingual gyrus/precuneus. Conversely, the thalamus exhibited aberrant hyperconnectivity with widespread areas, including the Cornu Ammonis of the hippocampus, right lateral occipital cortex, intraparietal sulcus (IPS), and sensorimotor areas. Conjunction analysis identified distinct disruptions within hippocampal-thalamo-visual circuitry, suggesting that an imbalance in thalamo-visual and intra-hippocampal connectivity may mediate the relationship between peripheral inflammation (e.g., IL-4, CCL-2) and working memory dysfunction. This study advances our understanding of the role of peripheral inflammation in SCZ, revealing complex cross-domain interactions between pathophysiological changes (e.g., dysregulated peripheral immunity and circuit-specific dysfunction) and behavioral features. Our findings highlight a novel combinatorial therapeutic strategy—integrating cytokine-specific agents (e.g., for CCL-2 and IL-4) with circuit-directed neuromodulation of the dysfunctional hippocampal-thalamic-visual circuitry, thereby ameliorating cognitive deficits in SCZ.

BackgroundEmerging evidence supports the role of immune-mediated neuroinflammatory processes and disrupted sleep patterns in elevating susceptibility to major depressive disorder (MDD). Sleep disturbances, a hallmark clinical feature of MDD, have further been linked to changes in lymphocyte profiles. Nevertheless, the potential relationship between sleep disturbance and lymphocyte subpopulations characteristic in patients with MDD remains underexplored.MethodsIn this study, flow cytometry was used to measure the proportion of peripheral blood CD4+ T-helper cells in 63 patients with MDD and 60 age- and sex-matched healthy controls (HCs). The relationship between self-reported sleep disturbances and the proportion of these cells was evaluated using Pearson’s correlation coefficient.ResultsBaseline scores on the Hamilton Depression Rating Scale (HAMD) and Self-Rating Depression Scale (SDS) in patients with MDD were significantly higher than those in HCs. Regardless of antidepressant medication use, patients with MDD exhibited elevated proportions of CD4+ regulatory T cells (Tregs), IFN-γ+-Tregs, IL-4+-Tregs and Th1 (IFN-γ+-CD4+ T) cells compared to HCs. Furthermore, the Pittsburgh Sleep Quality Index (PSQI) scores in patients with MDD showed a positive correlation with CD4+ T cell frequency. Notably, MDD patients with self-reported sleep disturbance had a higher CD4+ T cell percentage than those without such disturbance.ConclusionsOur findings demonstrate that patients with MDD comorbid with sleep disturbances exhibit elevated proportions of CD4+ T cells compared to those without such disturbance. These results suggest that targeted interventions addressing sleep disruption may contribute to restoring CD4+ T cell homeostasis, potentially offering a novel therapeutic strategy for MDD management.