Non-suicidal self-injury (NSSI) in adolescents is a common clinical condition among young people, often associated with adolescent depression or bipolar disorder. The clinical diagnosis and treatment remain challending, leading to issues such as diagnostic inconsistency and poor therapeutic outcomes. We invited a panel of Chinese experts from the fields of psychiatry, clinical psychology, traditional Chinese medicine (TCM) for emotional disorders, integrated traditional Chinese and Western medicine, and evidence-based medicine. Based on clinical practice, particularly in relation to adolescent depression and bipolar disorder, we have developed a clinical pathway for the integrated management of adolescent NSSI in China. Guided by principles of practicality, scientific validity, cost-effectiveness, and ease of memorization, this clinical pathway is named “DIARY.” It offers a constructive approach for the comprehensive, in-depth, and effective treatment of adolescent NSSI. This is the first clinical pathway for NSSI, and it is a combination of traditional Chinese and Western medicine. There may be shortcomings, but it provides a foundation for developing more comprehensive clinical pathway in treatments for NSSI in the future.

BackgroundAdolescent depression is associated by substantial cognitive impairment and poor treatment response, yet its neurobiological underpinnings remain insufficiently understood. Resting-state functional near-infrared spectroscopy (fNIRS) offers a portable and developmentally sensitive tool to examine intrinsic prefrontal activity and network properties.MethodsSeventy-nine adolescents with depressive disorder (DD) and age-matched healthy controls (HC) underwent 6-min resting-state fNIRS recording over the prefrontal cortex. We extracted fractional amplitude of low-frequency fluctuations (fALFF) and resting-state functional connectivity were computed, and graph-theoretical metrics, including clustering coefficient, local/global efficiency, path length, and small-worldness were derived. Depressive and anxiety symptoms was assessed using the 17 - item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA), and cognitive performance was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS).ResultsCompared with HC, the DD group exhibited elevated prefrontal fALFF in multiple channels (e.g., ch11, ch26, ch31), reduced average functional connectivity within and between bilateral frontal regions (including FPA and Broca’s area), and lower clustering coefficient, local efficiency, and global efficiency relative to healthy controls, whereas path length and small-worldness were preserved. Region-specific associations with cognition were observed: fALFF in ch11 positively correlated with verbal fluency, whereas fALFF in ch31 negatively correlated with executive functioning, these associations remained significant after controlling for depressive and anxiety symptom severity. Conclusions: Adolescents with depression show elevated prefrontal fALFF and reduced network efficiency, with region-specific associations with cognitive performance. These findings suggest that resting-state fNIRS is a developmentally suitable method for probing prefrontal neurocognitive alterations in youth depression.

BACKGROUND:The anorectic peptide nesfatin-1 has been identified as a potential mood regulator. Abnormal nesfatin-1 expression has been observed in both depression animal models and clinical cohorts, but its exact role in depression pathogenesis remains unclear. AIM:This study aimed to detect peripheral and central nesfatin-1 alterations in rats with chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors, and explore their correlations with hypothalamic-pituitary-adrenal (HPA) axis activity and brainstem monoamine synthesis. METHODS:Rats were subjected to 5-week CUMS. Enzyme-linked immunosorbent assay (ELISA) quantified plasma mature nesfatin-1 peptide, and Western blot (WB) detected full-length nucleobindin 2 (NUCB2)/nesfatin-1 in the hypothalamus and brainstem. Spearman's rank correlation was performed solely within the CUMS group (n = 6); these exploratory correlational findings require cautious interpretation due to small sample size. RESULTS:CUMS significantly increased plasma nesfatin-1 as well as hypothalamic and brainstem NUCB2/nesfatin-1. In CUMS rats, plasma nesfatin-1 was positively correlated with corticosterone and forced swim test (FST) immobility time, and negatively correlated with sucrose preference index(SPT) and weight gain. Brainstem NUCB2/nesfatin-1 showed a positive correlation with tryptophan hydroxylase (TPH), while no significant correlation was found between hypothalamic NUCB2/nesfatin-1 and all measured parameters. CONCLUSION:Chronic stress-induced nesfatin-1 elevation accompanies peripheral HPA hyperactivation and aggravated depressive-like behaviors. Brainstem NUCB2/nesfatin-1 positively correlates with TPH, suggesting NUCB2/nesfatin-1 may link neuroendocrine activity and serotonergic plasticity with the brainstem as a core site. This study provides preliminary correlational evidence for coordinated NUCB2/nesfatin-1 changes across peripheral and central systems under stress-induced depression.

BackgroundChildhood maltreatment plays an important role for developing major depressive disorder (MDD), and many studies have suggested brain structural alterations related to this psychological factor. However, the specific impact of childhood maltreatment on rich club organization in structural brain networks in MDD remains unclear. The aim of this study was to investigate whether childhood maltreatment was related to the disruption of rich club organization in structural networks in MDD.MethodsIn this cross-sectional study, we recruited 130 first-episode, drug-naïve MDD patients and 122 healthy controls (HCs). The structural brain networks were reconstructed for all participants based on diffusion imaging data. Subsequently, the rich club organization was determined, and the connectivity measures (strength and density) in different connection classes were calculated and compared. The relationships between connectivity measures and clinical scores were evaluated.ResultsThe MDD patients with childhood maltreatment showed significant decreased connectivity strength and density in rich club connections, as well as increased connectivity density in feeder connections, as compared to those patients without childhood maltreatment. Besides, HCs with childhood maltreatment had lower connectivity strength and density in feeder connections than that of HCs without childhood maltreatment. Moreover, the correlations between scores of childhood maltreatment and connectivity density in feeder connections were significantly positive in MDD, whereas these correlations exhibited negative in HCs.ConclusionOur results may reflect the associations between the disrupted rich club organization and childhood maltreatment in MDD. Furthermore, with exposure to childhood maltreatment, the distinct connection patterns in depressed and healthy populations may indicate neuroimaging features associated with individual vulnerability or resilience to developing MDD in context of early life stress.

BACKGROUND:Depression is a major global health problem, the pathogenesis of which remains to be elucidated, and current antidepressants exhibit limited efficacy. FK506-binding protein 51 (FKBP51) has been identified as a key modulator of stress-related psychiatric disorders, yet further research is required in depression. METHODS:We investigated the role of hippocampal FKBP51 using a chronic unpredictable mild stress rat model and stereotaxic FKBP5 overexpression. The antidepressant effect of the FKBP51 inhibitor, selective antagonist of FKBP51 by induced fit 2 (SAFit2), was evaluated in corticosterone-induced depression model both in vivo and in vitro. Molecular and structural changes were analyzed using quantitative polymerase chain reaction, Western blotting, Golgi-Cox staining, transmission electron microscopy, and immunofluorescence. SH-SY5Y cells were utilized to examine autophagic flux and dissect downstream pathways. RESULTS:Hippocampal FKBP51 was upregulated in chronic unpredictable mild stress-susceptible rats and correlated with depressive-like behaviors. Functionally, FKBP5 overexpression mimicked stress pathologies, inducing autophagic hyperactivation and suppressing AKT/mTOR signaling. Mechanistically, corticosterone enhanced the recruitment of the phosphatase PHLPP to FKBP51, thereby inhibiting the AKT/mTOR pathway. SAFit2 treatment disrupted the FKBP51-PHLPP interaction, reactivated the AKT/mTOR pathway, normalized autophagic flux, restored neuroplasticity, and attenuated depressive-like behaviors. CONCLUSIONS:Stress-induced FKBP51 upregulation drives depressive-like behaviors in male rats by impairing neuroplasticity and inducing autophagic hyperactivation via the PHLPP-AKT-mTOR pathway. SAFit2 exhibited antidepressant-like effects by targeting this axis, highlighting FKBP51 as a potential target for depression.

Obesity and depression as chronic diseases increase the burden on society, and they often co-exist, interacting to worsen prognosis. However, the long-term trends in obesity prevalence specifically among the growing population of individuals with depression remain unclear. Investigating these trends is crucial for informing targeted treatment and public health strategies. Clinical data on adults aged ≥ 20 years with depression were extracted from the National Health and Nutrition Examination Survey 2005–2023. The primary outcome was obesity prevalence [body mass index (BMI) ≥ 30 kg/m2]. Trends in the prevalence of obesity among depressed adults in the US were assessed by a trend test. The study included 4035 adults aged ≥ 20 years with depression in the United States population, with an average age of 46.9 (± 16.3). The age-standardized prevalence of obesity among depressed Americans increased from 42.8

Background and Hypothesis Schizophrenia is linked to hippocampal dysfunction and microglial inflammatory activation. Our prior clinical findings revealed significantly reduced transient receptor potential vanilloid 1 (TRPV1) expression in both first-episode and recurrent schizophrenia patients, with levels inversely correlating with symptom severity, implicating TRPV1 dysfunction in disease progression. Preclinical maternal separation (MS) models recapitulate schizophrenia-like behavioral and synaptic deficits, paralleled by hippocampal microglial TRPV1 downregulation. We hypothesize that early-life stress-induced TRPV1 deficiency in microglia disrupts the calmodulin-dependent protein kinase II (CaMKII)/nuclear factor-erythroid 2-related factor 2 (NRF2)/Sirtuin 3 (SIRT3) signaling axis, thereby amplifying microglial inflammatory responses and synaptic dysfunction underlying cognitive and behavioral impairments.Study Design Using a 24-h acute MS model in postnatal day 9 rats, we assessed hippocampal microglial TRPV1 expression, synaptic plasticity, and schizophrenia-like behaviors. Pharmacological (capsaicin, CAP) and genetic (adeno-associated virus (AAV)-mediated overexpression/knockdown (KD)) TRPV1 manipulations were applied. Co-cultures of TRPV1-knockout (KO) microglia and neurons were used to dissect cell-specific effects.Study Results MS reduced microglial TRPV1, increased pro-inflammatory cytokines, and induced hyperlocomotion, cognitive deficits, and impaired sensory gating. CAP or microglial TRPV1 overexpression restored synaptic plasticity and reversed behavioral deficits. Conversely, TRPV1 KD worsened neuronal dysfunction. TRPV1-KO microglia, but not neurons, promoted inflammation and neuronal damage via CaMKII/NRF2/SIRT3 downregulation.Conclusions These findings provided novel insights into the role of microglial TRPV1 in schizophrenia pathogenesis, establishing it as an upstream regulator of the CaMKII/NRF2/SIRT3 signaling axis-a pathway not previously linked to TRPV1 in neuroinflammation. Our work identifies microglia-specific TRPV1 modulation as a new therapeutic strategy for schizophrenia, highlighting its therapeutic potential for cognitive and negative symptoms in schizophrenia.

Background/Objectives: Apigenin, a naturally occurring flavonoid, has shown promising antidepressant-like effects in previous studies. However, its precise mechanisms remain unclear. This study aims to investigate the underlying neurobiological mechanisms mediating the antidepressant effects of apigenin in chronic unpredictable mild stress (CUMS)-induced mice. Methods: The male mice were subjected to 4-week CUMS, with or without treatment, followed by behavioral testing. Network pharmacology analysis was employed to predict relevant signaling pathways. The mRNA and protein expression levels of the PI3K/AKT/NRF2 pathway were measured. Oxidative stress was assessed through the measurement of malondialdehyde, glutathione, and superoxide dismutase levels. Results: Apigenin significantly ameliorated CUMS-induced depression-like behaviors. The PI3K/AKT pathway may mediate the antidepressant properties of apigenin with both PI3K and AKT emerging as core target molecules. Apigenin restored the activity of the PI3K/AKT/NRF2 pathway and oxidative stress in the hippocampus downregulated by CUMS. Conclusions: The present study demonstrates that apigenin ameliorates depression-like behaviors in mice exposed to CUMS and mitigates oxidative stress in the hippocampus, which is associated with the PI3K/AKT/NRF2 signaling pathway.

Depression is a prevalent mental disorder with poorly understood pathogenesis and often exhibits limited treatment response. Transient receptor potential vanilloid 1 (TRPV1) regulates glial activation and inflammatory responses, but its role in stress-related depressive pathophysiology remains elusive. Here, we investigated the effects of TRPV1 modulation on neuroinflammation and the impairment of neurogenesis underlying depression-like behaviors. Using a chronic social defeat stress (CSDS) mouse model, we evaluated the antidepressant potential of the TRPV1 antagonist capsazepine (CPZ) and agonist capsaicin (CAP) through behavioral assays. Then, hippocampal microglial activation, pro-inflammatory cytokine levels, neurogenesis, and the JAK2/STAT3 signaling pathway were assessed via Western blotting, ELISA, and immunofluorescence. The JAK2 agonist coumermycin A1 (CMA1) and viral-mediated TRPV1 knockdown were used to verify pathway involvement and target specificity. Our results showed that CPZ, but not CAP, effectively alleviated depression-like behaviors in CSDS mice. In CSDS-susceptible mice, TRPV1 and p-CaMKIIα levels were elevated, and CPZ treatment normalized their expression. CPZ also reduced microglial numbers and restored microglial morphology in the hippocampus, accompanied by decreased IL-6 and IL-1β production. Moreover, CPZ promoted neurogenesis in the dentate gyrus, as indicated by increased BrdU+ and DCX+ cells. Additionally, knockdown of TRPV1 enhanced stress resilience. Mechanistically, CPZ exerted these effects via inhibition of the JAK2/STAT3 signaling pathway, and CMA1-mediated activation of JAK2 reversed CPZ’s neuroprotective effects. Collectively, these findings reveal a microglia-mediated mechanism through which TRPV1 modulation ameliorates stress-induced neuroinflammation and impaired neurogenesis, identifying TRPV1 as a potential therapeutic target for depression.

Cognitive impairment in schizophrenia is inadequately treated. The molecular link between oxidative stress and neuroinflammation in its pathophysiology remains unclear. We measured CB2R in circulating microglia‑derived exosomes from schizophrenia patients and healthy controls. In a maternal separation rat model, we assessed brain reactive oxygen species, microglial activation, and the 2‑AG/CB2R signaling axis. A microglia‑targeted hydrogen‑releasing nanoplatform (PdH0.12@CM) was administered to maternal separation rats, followed by behavioural, histological and transcriptomic analyses. In primary microglia, we examined the effects of hydrogen peroxide on CB2R, 2‑AG and inflammatory responses, and tested rescue with a CB2R agonist or exogenous 2‑AG. CB2R was reduced in patient-derived microglia exosomes and correlated with cognitive performance and symptom severity. Maternal separation rats showed elevated brain reactive oxygen species, microglial activation, and selective decreases in microglial 2-AG and CB2R, with reduced CB2R expression observed in the hippocampal CA1 region. PdH0.12@CM treatment scavenged reactive oxygen species, restored 2‑AG/CB2R signaling, suppressed pro‑inflammatory cytokines, and rescued cognitive and sensorimotor deficits. In vitro, hydrogen peroxide directly reduced CB2R and 2‑AG levels, increased CD86 and cytokine release; these effects were reversed by a CB2R agonist or 2‑AG. Elevated oxidative stress is associated with disruption of the microglial 2‑AG/CB2R axis, which correlates with neuroinflammation and cognitive deficits. Targeted ROS scavenging restores this pathway, identifying the 2‑AG/CB2R axis as a potential therapeutic target in schizophrenia.

Modern psychiatry is shifting from unitary diagnostic models toward identifying biologically distinct depression subtypes. Despite the potential of multi-omics and AI, the field is hindered by non-standardized pipelines and poor reproducibility. We propose a four-pillar computational framework to standardize the subtyping process: (1) standardized preprocessing and feature embedding to ensure data integrity; (2) integrative multi-omics modeling strategies tailored to diverse sample sizes; (3) robust subtype identification and Explainable Artificial Intelligence (XAI) interpretation, where we propose the Minimum Reporting Standards for Computational Psychiatry Subtyping (MiR-CPS) to ensure methodological transparency; and (4) hierarchical clinical validation to benchmark subtype stability and utility. Beyond this core trajectory, we extend the framework to longitudinal trajectories and cross-diagnostic approaches to address temporal and diagnostic heterogeneity. This framework provides a reproducible roadmap for transitioning from raw high-dimensional data to clinically actionable subtypes, advancing evidence-based precision psychiatry.

Women are twice as likely to suffer from major depressive disorder (MDD). The underlying mechanism between estrogen and depression is still unknown. We used ovariectomized rats to simulate menopausal status and established a depression model of chronic and acute stress. The therapeutic effects of estrogen were systematically studied through behavioral testing, Western blotting, ELISA, LC-MS, and cell experiments. In chronic stress, OVX rats showed depressive-like behaviors, and elevated hippocampal ER, BDNF, IL-1β/IL-18, and body weight. ERT reduced depression-like behavior by 64% to 76% in the behavioral test. ERT also reversed the molecules without affecting GPR30. In acute stress, ERT reduced depression-like behavior by 20% to 58% in the behavioral test. OVX decreased ER, BDNF, P2X7, IL-1β/IL-18, spine density, and microglia and increased the expression of GPR30. ERT reversed all the above. ERT normalized metabolic abnormalities caused by CUMS. Our study demonstrates that estrogen deficiency contributes to the onset and progression of depression in a rat model of menopause-like estrogen deficiency. Estrogen replacement therapy appears to alleviate depressive-like behaviors by reducing brain inflammation and supporting the brain’s adaptive capacities through ER. Furthermore, the dual function positions GPR30 as a promising potential target for future treatments of menopausal depression, and GPR30 regulates neuroinflammation and neuroplasticity through the NLRP3/P2X7/IL-1β pathway.

BACKGROUND:Bitter substances, such as resveratrol, alleviate depression by curbing inflammation, yet the mechanisms involved are obscure, not to mention a unified mechanism. Our previous research implies that the type 2 bitter taste receptors (Tas2rs) signaling pathway is crucial for the anti-inflammatory effect of resveratrol, potentially driving its antidepressant action. This study aims to illustrate the possible antidepressant mechanism of resveratrol via Tas2rs-mediated anti-inflammatory pathways which may reveal a common thread in therapeutic action of the bitter. METHOD:Firstly, resveratrol, a typical bitter polyphenol, was selected as a representative of bitter compounds. Then, a phylogenetic analysis and agarose gel electrophoresis of 35 Tas2rs in rats' brain was performed. Subsequently, we established a chronic unpredictable mild stress (CUMS) model with administering resveratrol to evaluate impact of this polyphenol on depressive-like behaviors and the expression of Tas2rs. Meanwhile, inflammation-related proteins were measured within the hippocampus and prefrontal cortex (PFC) using qPCR and western blotting (WB). Further, we utilized qPCR, WB, and calcium (Ca2+) assay kit to scrutinize the expression of Tas2rs downstream signaling pathway in the aforementioned brain areas. Ultimately, proteomics analysis of hippocampus has been employed to speculated the holistic changes post-resveratrol intervention. RESULT:Our investigation has unveiled the considerable heterogeneity and pronounced cerebral expression of Tas2rs. It shows that depressive-like behaviors are induced by CUMS, with 2 Tas2rs in hippocampus and 1 Tas2r in PFC decreasing. Nevertheless, resveratrol exerts its antidepressant effect with 14 Tas2rs increasing in hippocampus but only 1 Tas2r in the PFC. During this process, among the Tas2rs that declined in the hippocampus and PFC following CUMS, only Tas2r123 in hippocampus exhibited a notable increase after resveratrol treatment. Meanwhile, we observe that resveratrol ameliorates the hippocampal inflammation incited by CUMS, an effect not observed in the PFC. Additionally, the Tas2rs downstream signaling pathway is highly involved in the anti-inflammatory property of resveratrol with the context of its antidepressant effect and our previous proteomics have supported these findings. CONCLUSION:The Tas2rs-mediated anti-inflammatory pathway in the hippocampus plays a pivotal role in the antidepressant effect of resveratrol. Concurrently, a Tas2rs mediated anti-inflammatory pathway paradigm has been provide for exploring the common mechanisms underlying the antidepressant and anti-inflammatory properties of bitter substances, offering a novel perspective on the pathophysiology of depression and promising avenues for innovative antidepressant therapies.

Postpartum period being a critical phase affecting women's health recovery, and stressful events during this period are major risk factors for postpartum depression. Pup separation (PS) serves as a natural model of postpartum maternal care. However, the effects of different PS (no separation, NPS; 15 min/day, PS15, brief PS; 180 min/day, PS180, long PS) during lactation on stress-induced behavioral deficits in dams, along with the underlying mechanisms of resilience remain unclear. In this study, we assessed cognitive and emotional behaviors in lactating C57BL/6 J dams subjected to different PS from postnatal day 1 to day 21, along with chronic restraint stress (CRS). Subsequently, hippocampal samples were collected to analyze the expression of NLRP3, IL-18, and IL-1β, along with microglial activation and adult hippocampal neurogenesis (AHN) in the hippocampal dentate gyrus. We further modulated AHN using viral and examined the effects of AHN overexpression or inhibition on behavior and hippocampal neuroinflammation. Dams subjected to brief PS exhibited reduced anxiety and depressive-like behaviors and improved cognitive function. Additionally, PS15 dams showed decreased hippocampal expression of NLRP3, IL-18, and IL-1β, reduced microglia activation, and increased AHN. Overexpression of AHN can significantly improved cognitive function, but no significant changes in emotional behaviors were observed. Besides, AHN-mediated cognitive behavior participates in resilience to anxiety and depression-like behaviors of dams after CRS. Similarly, inhibition of hippocampal NLRP3 expression enhanced AHN-related cognitive behavior and promoted stress resilience in adult female mice. Brief PS resulted in resilience to anxiety and depressive-like behaviors in dams and mitigated memory impairments induced by CRS. This study confirmed AHN-mediated cognitive behavior participates in stress resilience to anxiety and depression-like behaviors in postpartum dams after CRS.

Background The global burden of major depressive disorder (MDD) is rising, with current diagnostic methods hindered by significant subjectivity and low inter-rater reliability. Several studies have implied underlying link between coagulation-related proteins, such as kininogen (KNG) and coagulation factor VIII (FVIII), and depressive symptoms, offering new insights into the exploration of depression biomarkers. This study aims to elucidate the roles of KNG and FVIII in depression, potentially providing a foundational basis for biomarker research in this field. Methods A three-part experiment was conducted: (1) we measured serum levels of KNG and FVIII in the chronic unpredictable mild stress (CUMS) model; (2) KNG adeno-associated-virus overexpression (KNG-AAV-OE) model was constructed to further investigate the roles of KNG and FVIII. Meanwhile, quantity PCR, western blotting and immunofluorescence staining detected the KNG-FVIII pathway. (3) Peripheral blood samples were gathered from healthy control (HC, N = 21), as well as first-episode drug-naive patients with MDD (FEDN-MDD, N = 21), to further confirm the association between KNG, FVIII and depression. Results Firstly, serum KNG and FVIII levels were significantly elevated in the CUMS model. Then, the rats exhibited pronounced depressive-like behaviors in the KNG-AAV-OE model, with corresponding increases in serum KNG and FVIII. Lastly, clinical data showed increased KNG and FVIII levels in FEDN-MDD compared to HC. Furthermore, KNG and FVIII levels exhibited a strong positive correlation with the scores of the 24-item Hamilton Depression Scale and the 14-item Hamilton Anxiety Scale. Conclusion To sum up, this study highlights critical roles of serum KNG and FVIII in depression and the KNG-AAV-OE may lead the augment of FVIII in serum. Consequently, our research may offer new evidence and foundation for depression biomarkers research in the future.

Background: Maternal separation (MS) in rodents is a paradigm of early life events that affects neurological development in depression. Adolescence is a time of dramatic increases in psychological vulnerability, and being female is a depression risk factor. However, data on whether different MS scenarios affect behavioral deficits and the potential mechanisms in adolescent female mice are limited. Methods: C57BL/6 J female pups were exposed to different MS (no MS, NMS; MS for 15 min/day, MS15; or 180 min/day, MS180) from postnatal day (PND)1 to PND21 and subjected for behavioral tests during adolescence. Behavioural tests, specifically the open field test (OFT), novel object recognition test (NOR) test and tail suspension test (TST), were performed. The expression of proinflammatory cytokines, hippocampal neurogenesis, neuroinflammation, and gut microbiota were also assessed. Results: The results showed that MS180 induced emotional behavioral deficits and object recognition memory impairment; however, MS15 promoted object recognition memory in adolescent females. MS180 decreased hippocampal neurogenesis of adolescent females, induced an increase in microgliosis, and increased certain inflammatory factors in the hippocampus, including TNF-alpha, IL-1 beta, and IL-6. Furthermore, different MS altered gut microbiota diversity, and alpha diversity in the Shannon index was negatively correlated with the peripheral inflammatory factors TNF-alpha, IL-1 beta, and IL-6. Species difference analysis showed that the gut microbiota composition of the phyla Desulfobacterota and Proteobacteria was affected by the MS. Limitations: The sex differences in adolescent animal and causality of hippocampal neurogenesis and gut microbiota under different MS need to be further analyzed in depression. Conclusion: This study indicates different MS affect recognition memory and emotional behaviors in adolescent females, and gut microbiota-neuroinflammation and hippocampal neurogenesis may be a potential site of early neurodevelopmental impairment in depression.

Objectives: The transient receptor potential vanilloid type 1 (TRPV1) is a factor that mediates glial cell response with effects on mitochondrial function. It may affect the occurrence and development of schizophrenia. The aim of this study is to further explore schizophrenia biomarkers by analyzing TRPV1 and oxidative stress in astrocyte-derived extracellular vesicles (ADEs) and peripheral blood mononuclear cells (PBMCs). Methods: A case–control study was conducted. The Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia (BACS) clinical data were obtained from 50 symptomatic patients with schizophrenia and 50 controls, and fasting peripheral blood samples were collected for the isolation of PBMCs and ADEs. Western blotting was used to assess TRPV1, Sirtuin3 (Sirt3), SOD2, and acetyl-SOD2. Results: The patient group exhibited significantly reduced TRPV1 and Sirt3 expression levels in PBMCs and ADEs compared with the control group. In addition, there was a marked increase in SOD2 and acetyl-SOD2 levels. TRPV1 was negatively correlated with the negative symptom score in the patient PBMCs and ADEs. SOD2 showed positive correlations with the general psychopathology symptom score, and acetyl-SOD2 was positively correlated with the negative symptom score. The BACS total score was positively correlated with TRPV1 levels and negatively correlated with acetyl-SOD2 levels in the patient group. Conclusion: TRPV1 expressions in PBMCs and ADEs were reduced and closely correlated, and TRPV1 levels were associated with psychiatric symptoms and cognitive function in patients with schizophrenia. It was indicated that TRPV1 could be a biomarker for schizophrenia and reflect the disease severity.

Resveratrol, a plant-derived polyphenol, exhibits significant antidepressant effects and notably enhances neuroplasticity in neurological diseases. However, whether the antidepressant function of resveratrol is related to neuroplasticity remains uncertain, and the underlying mechanisms is poorly understood. This study aims to investigate the role and mechanism of resveratrol in neuroplasticity in depression. Here, we adopted the chronic unpredictable mild stress (CUMS) model and resveratrol intervention by oral gavage. Thereafter, behavioral tests confirmed resveratrol’s antidepressant effect, and Nissl staining, Golgi staining, and Western blotting (WB) were employed to assess the neuronal plasticity. Moreover, proteomic analysis and WB were used to screen and identify the key proteins. To investigate the downstream target of ELAV-like RNA-binding protein 4 (ELAVL4) (one of candidate genes), the RNA Interactome Database and the National Center for Biotechnology Information databases were utilized to predict the targets of ELAVL4. Finally, Quantitative PCR, WB, and Immunofluorescence were used to verify the prediction. Our results indicate that resveratrol alleviates CUMS-induced depressive-like behaviors accompanied by the restoration of impaired hippocampal neuroplasticity. Then, proteomic analysis shows that 351 differentially expressed proteins (DEPs) decrease after CUMS, while 24 DEPs increase remarkably with the resveratrol treatment. Among which, ELAVL4 is downregulated by CUMS, simultaneously increasing after resveratrol intervention, which acts as a protective protein in this process. Finally, brain-derived neurotrophic factor (Bdnf) mRNA is predicted to be the potential target of ELAVL4 and validated by molecular technologies. In conclusion, our findings demonstrate that resveratrol’s antidepressant efficacy is closely associated with ELAVL4, an RNA-binding protein, a mediated neuroplasticity pathway, potentially intersecting with the Bdnf mRNA. Overall, this research sheds light on the role of the ELAVL4-Bdnf mRNA pathway through neuroplasticity in resveratrol’s antidepressant action, which provides an mRNA regulation perspective for the development of novel antidepressants and understanding depression pathology.

Maternal separation (MS) during early life can induce behaviors in adult animals that resemble those seen in schizophrenia, manifesting cognitive deficits. These cognitive deficits may be indicative of oxidative stress linked to mitochondrial dysfunction. However, there is limited understanding of the molecular mechanisms regulating mitochondria in neural circuits that govern cognitive impairment relevant to schizophrenia, and their impact on neuronal structure and function. A 24-h MS rat model was utilized to simulate features associated with schizophrenia. Schizophrenia-associated behaviors and cognitive impairment were assessed using the open field test, pre-pulse inhibition, novel object recognition test, and Barnes maze test. The levels of mitochondrial proteins were measured using western blot analysis. Additionally, alterations in mitochondrial morphology, reduced hippocampal neuronal spine density, and impaired LTP in the hippocampus were observed. Nicotinamide (NAM) supplementation, administration of honokiol (HNK) (a SIRT3 activator), or overexpression of SIRT3 could inhibit cognitive deficits and cellular dysfunction. Conversely, administration of 3-TYP (a SIRT3 inhibitor) or knocking down SIRT3 expression in control rats led to deficits in behavioral and hippocampal neuronal phenotype. Our results suggest a causal role for the NAD+/SIRT3 axis in modulating cognitive behaviors via effects on hippocampal neuronal synaptic plasticity. The NAD+/SIRT3 axis could be a promising therapeutic target for addressing cognitive dysfunctions, such as those seen in schizophrenia.

BackgroundMiddle-aged and older adult men are at a heightened risk of depression. Green tea, as a popular beverage, has drawn widespread attention for its health benefits. However, there remains controversy over the effects of green tea on combating depression and regulating hormones.ObjectiveThis study aimed to investigate the effects of long-term green tea consumption on depression levels, hormones, and brain structure in, middle-aged and older adult men.MethodsA total of 280 volunteers participated in the study, divided into a tea-drinking group and a control group. Basic demographic information and biological marker data, as well as MRI data from some of the volunteers, were collected. A controlled study was conducted to explore the effects of long-term tea drinking on them.ResultsBMI (p = 0.002), depression level (p = 0.003), insomnia severity (p = 0.008), and systemic inflammation index (p = 0.009) were significantly lower in the tea drinking group, and their testosterone levels were significantly higher than those in the control group (p = 0.001). Moreover, GM volume in the right precuneus in the control group was significantly reduced compared with that in the tea drinking group.ConclusionLong-term tea consumption helps reduce BMI and increase testosterone levels in middle-aged and older adult men, and it can also reduce their risk of depression by lowering inflammation and improving sleep quality. Additionally, long-term tea consumption may have the potential to delay brain aging in middle-aged and older adult men.