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.

The primary focus of sepsis therapy is to alleviate organ dysfunction. Sepsis-associated liver injury (SALI) occurs in about 40 % of sepsis patients, yet targeted therapeutic strategies remain unavailable. Electroacupuncture (EA) has emerged as a potential adjunctive therapy for sepsis, owing to its capacity to modulate the neuroendocrine-immune network. This study aims to investigate whether EA can alleviate SALI and its potential mechanisms. A murine model of sepsis was established via cecal ligation and puncture (CLP). The Zusanli (ST36) and Neiguan (PC6) acupoints, known for their anti-inflammatory properties, were selected for EA intervention. Following CLP, mice received EA stimulation at ST36 and PC6 for 20 min daily over two consecutive days. The results showed that EA significantly improved survival and attenuated SALI. Transcriptomic profiling via mRNA-seq uncovered immune cell gene expression changes in response to EA. Bioinformatics analysis indicated that EA downregulated genes involved in proinflammatory responses and leukocyte migration, which were enriched in Toll-like receptors and NOD-like receptors signaling pathways. Further research confirmed that EA significantly reduced serum levels of the proinflammatory cytokines IL-6, TNF-α, and IL-1β in septic mice. Mechanistically, EA suppressed activation of the proinflammatory signaling pathway IκBα/NF-κB and concurrently attenuated pyroptosis by inhibiting the NLRP3/caspase-1/GSDMD axis in immune cells.

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/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.

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.

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.

The growing popularity of internet gaming among adolescents and young adults has driven an increase in both casual and excessive gaming behavior. Nevertheless, it remains unclear how progressive increases in internet gaming engagement led to changes within and between brain networks. This study aims to investigate these connectivity alterations across varying levels of gaming involvement. In this cross-sectional study, 231 participants were recruited and classified into three groups according to Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for Internet Gaming Disorder (IGD): IGD group, highly engaged gaming(HEG) group, and lowly engaged gaming (LEG) group. Resting-state fMRI data from 217 participants (143 males, 74 females) were included in the final analysis. Independent component analysis was used to examine differences in intra- and inter-network functional connectivity (FC)across the three groups. No significant differences were found in intra-network FC across the three groups. However, significant inter-network differences between the dorsal attention network(dAN)and the visual network (VN) among the three groups were observed. The HEG group exhibited significantly higher dAN-VN functional network connectivity (FNC) compared to the LEG group. Linear correlation analyses showed no significant correlation between the dAN-VN FNC values and IGD-20T scores. Throughout the development of IGD, increasing levels of engagement are associated with a rise and subsequent decline in FNC of DAN-VN. This pattern may reflect top-down attentional regulation in the early stages of addiction, followed by attentional bias as addiction progresses.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cerebral amyloid-β deposition, neurofibrillary tangles of hyperphosphorylated tau, and chronic neuroinflammation. Growing evidence underscores the role of the gut-brain axis in mediating bidirectional communication between the gut and the central nervous system. Postbiotics, non-viable microorganisms and/or ingredients that are beneficial to the host's health, have emerged as promising modulators of brain function via this axis. Herein, we evaluated the neuroprotective effects of three postbiotics derived from Bifidobacterium animalis subsp. lactis IOBL07, Lactiplantibacillus plantarum IOB602 and Lactobacillus paracasei IOB413 in a D-galactose/AlCl3-induced AD rats. These postbiotics ameliorated cognitive deficits and anxiety-like behaviors, reduced neuronal degeneration and Aβ accumulation, and suppressed microglial activation and neuroinflammation via the TLR4/MyD88/NLRP3 signaling pathway. 16S rDNA sequencing revealed that postbiotics intervention induced substantial gut microbiota remodeling, selectively enriching Lachnospiraceae, Ruminococcus and Lactobacillus, while depleting Muribaculaceae. Postbiotic administration also elevated fecal short-chain fatty acid levels. Metabolomics analysis identified 11 metabolites, including indole derivatives, cholinergics and niacinamides, that were uniquely enriched in the IOB602 group. These metabolites may underlie its anti-AD effects by attenuating oxidative stress, modulating neuroinflammation, and enhancing mitochondrial function. Together, these findings provide a foundation for developing postbiotic-based adjuvant therapies against AD pathogenesis.

Cognitive impairment in schizophrenia occurs in the early stages of the disease and is closely associated with prognosis. Alleviation of cognitive impairment in schizophrenia faces major challenges owing to the lack of preventive and therapeutic drugs that are novel and effective. Urolithin A (UA) is a gut microbial metabolite of ellagic acid that has demonstrated neuroprotective effects in multiple neurological disease models. Nonetheless, the neuromodulatory role of UA in schizophrenia is yet to be elucidated. Wistar rat pups were separated from their mothers for 24 h on postnatal days (PNDs) 9–10 to establish an early-life stress model. The pups were pretreated with UA at different administration times (2, 4, and 6 weeks) and doses (50, 100, and 150 mg/kg) from adolescence (PND29). Behavioral tests were performed after the end of the administration. Subsequently, hippocampal samples were collected for histopathological and molecular evaluations. Male offspring rats subjected to maternal separation exhibited increased sensitivity to prepulse inhibition and cognitive impairment, accompanied by severe neuroinflammation and impaired neurogenesis. However, UA attenuated maternal separation-induced prepulse inhibition deficits and cognitive impairments and restored hippocampal neurogenesis in a dose-dependent manner. Furthermore, UA pretreatment preserved dendritic spine density, synapses, and presynaptic vesicles. In addition, it exerted anti-inflammatory effects by inhibiting microglial activation and expression of the proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1β. Potential mechanisms included upregulation of brain-derived neurotrophic factor protein expression and activation of the extracellular signal-regulated kinase signaling pathway. This study is the first preclinical evaluation of the effects of UA on cognitive impairment in schizophrenia. The findings suggest that changes in cognitive function linked to schizophrenia are driven by the interaction among neuroinflammation, neurogenesis, and synaptic plasticity and that UA has the potential to reverse these processes. These observations provide evidence for future clinical trials of UA as a dietary supplement for preventing schizophrenia.

BACKGROUND:Resveratrol, a natural bitter polyphenol, exhibits significant antidepressant property. Numerous studies have linked its antidepressant effect to neuroplasticity enhancement or mitochondrial regulation. However, the interplay between these two mechanisms remains unclear. This study aims to elucidate the relationship among resveratrol's antidepressant effect, its regulatory impact on neuroplasticity and mitochondrial function, and to investigate the potential role of the type 2 bitter taste receptors (Tas2rs) in these processes. METHODS:A chronic unpredictable mild stress (CUMS) model was used to induce depressive-like behaviors, while resveratrol was administered as an intervention. Following CUMS and resveratrol treatment, proteomic analysis combined with bioinformatics predicted significantly altered biological pathways in the hippocampus. The aforementioned predictions were validated using Western blotting (WB), Golgi staining, Nissl staining, and electron microscopy. Additionally, Tas2rs expression and calcium (Ca2 +) levels in the hippocampus were quantified using quantitative PCR, WB, and calcium assay kit. Finally, immunofluorescence (IF) colocalization was used to examine the association of Tas2r123 with mitochondrial outer membrane in hippocampus. RESULTS:Resveratrol significantly alleviated depressive-like behaviors induced by CUMS. Proteomic analysis revealed that resveratrol's therapeutic effects are associated with neuroplasticity-related and metabolic pathways, particularly with differentially expressed proteins (DEPs) predominantly localized in the mitochondria. Gene Ontology analysis of mitochondrial DEPs further revealed substantial changes in mitochondrial organization. Furthermore, molecular biology experiments validated these proteomics findings. Additionally, resveratrol also reversed the CUMS-induced downregulation of Tas2r123 mRNA and protein expression. Moreover, IF colocalization demonstrated a strong association between Tas2r123 and mitochondria. CONCLUSIONS:Our findings suggest that resveratrol may exert antidepressant property by modulating neuroplasticity through the Tas2r123-mitochondrial organization pathway. This study introduces a novel perspective linking Tas2rs to resveratrol's antidepressant mechanisms, potentially pave the way for future antidepressant therapies.

Major depressive disorder (MDD) is common, and successful treatment remains challenging. Resveratrol, a naturally occurring polyphenol, has been shown to alleviate depression-like behaviors, but the underlying mechanisms remain unclear. We previously developed a new model of depression by inducing hippocampal ferroptosis in rats, suggesting that ferroptosis may be involved in the development of MDD. Here, we further explored the antidepressant-like effect of resveratrol and its association with ferroptosis. Male rats were exposed to chronic unpredictable mild stress (CUMS), with or without resveratrol, followed by comprehensive behavioral testing. In PC12 cells in vitro, LY294002 (an AKT inhibitor) and ML385 (an NRF2 inhibitor) were used to elucidate the involvement of AKT/NRF2 signaling in resveratrol-mediated ferroptosis. mRNA and protein levels of AKT/NRF2 pathway and ferroptosis-related targets were measured. Ferroptosis was quantified by measuring malondialdehyde (MDA), glutathione (GSH), and Fe2+ content and superoxide dismutase (SOD) activity. Resveratrol ameliorated depression-like behaviors in rats, simultaneously restoring AKT/NRF2 pathway and ferroptosis-related targets in the hippocampus downregulated by CUMS. Elevated markers of oxidative stress in plasma were attenuated by resveratrol. Furthermore, erastin induced ferroptosis and inhibited AKT/NRF2 signaling in PC12 cells, which was counteracted by resveratrol. Additionally, the impact of resveratrol on erastin-induced ferroptosis was reversed by LY294002 and ML385. This study demonstrates that resveratrol ameliorates depression-like behaviors by inhibiting ferroptosis via the AKT/NRF2 pathway.

The management of cognitive impairments in schizophrenia presents a considerable challenge, with a strong association between neuroinflammation and its progression. Urolithin A (UA) demonstrates important antiinflammatory properties in multiple neurological disease models, contributing to the enhancement of cognitive deficits. However, it remains uncertain if UA can produce comparable neuroregulatory effects in female rat models of schizophrenia. Eight-week-old female Sprague Dawley rats received either 0.1 mg/kg of MK801 or volume-matched saline via intraperitoneal injection for 5 consecutive days. Furthermore, they were administered 150 mg/kg of UA through oral gavage for 4 weeks. Behavioral assessments were performed to evaluate cognitive function and behavior after UA treatment. Immunofluorescence staining was employed to assess microglial activity in the hippocampus, while Western blot analysis was conducted to investigate the expression of neuroinflammation-associated proteins. Prolonged exposure to MK801 induces schizophrenia-like behaviors and cognitive deficits in female rats. It also elevates the expression of NLRP3, Caspase-1, IL-1(3, and IL-18 proteins in the hippocampus, accompanied by the activation of microglial cells. However, UA treatment can reverse the expression of these inflammatory proteins and the activation of microglial cells induced by MK801. This is the first study to evaluate the effects of UA on behavior and cognition in a female rat model of schizophrenia. The findings indicate that UA mitigates MK-801-induced cognitive deficits in female rats by inhibiting neuroinflammation and microglial activation via modulation of the NLRP3 signaling pathway. These findings offer preclinical data endorsing the possible application of UA as a dietary supplement to prevent cognitive deficits in schizophrenia.

The rapid development of modern society and heightened competitiveness have led to increased expectations from parents, educators, and society regarding college students. This environment, coupled with academic pressures and employment challenges, significantly affects students’ physical and mental health. This paper employs big data analysis to explore the intrinsic connections between physical activity and mental health, incorporating biomechanical insights into the discussion. Biomechanics examines the mechanical aspects of human movement, providing a deeper understanding of how physical activity influences mental well-being. Engaging in regular physical activity enhances physiological responses, such as improved circulation, increased endorphin release, and reduced stress hormones, all of which contribute to better mental health outcomes. In our study, we utilized the SCL-90 for mental health assessment and conducted a survey on cognitive characteristics related to sports participation. A sample of 500 university students was analyzed to establish a behavioral cognitive model of sports activity participation. Correlation coefficients revealed that the intensity (0.1354) and duration (0.2455) of physical activity correlate positively with mental health scores. Furthermore, factors such as frequency and total volume of physical activity demonstrated varying degrees of correlation across five mental health dimensions. Regression analysis yielded a standardized coefficient of 0.6154, indicating that physical activity participation significantly positively influences mental health scores. By integrating biomechanical principles, this research highlights the importance of movement efficiency and physical engagement in promoting mental health, suggesting that enhancing physical activity can serve as a vital strategy for improving overall well-being among college students.

Appetite decrease is a common symptom in major depressive disorder (MDD). However, published research discussing the cognitive process to food stimuli in MDD patients with decreased appetite is lacking, as are objective indicators to assess their degree of appetitive loss. The current study evaluated the disparities in food-related cognition between healthy controls and MDD patients, explored the brain regions contributing to these changes, and evaluated the potential of event-related potentials for assessing appetite loss severity. A total of 149 subjects (healthy controls, n = 50; MDD patients with decreased appetite, n = 52; MDD patients without appetite change, n = 47) were included in this study. We used the Dimensional Anhedonia Rating Scale (DARS) to measure the degree of appetite decrease, and assessed their alterations in food-related cognition with the late positive potential (LPP). The standardized low-resolution brain electromagnetic tomography (sLORETA) method was used to explore the source activity of the LPP. We found the two groups of MDD patients did not differ in the disease severity, while those with appetite decrease got the lowest DARS food/drink score. And MDD patients with decreased appetite allocated fewer attentional resources to food stimuli with significantly lower LPP amplitude evoked by food in this group. Within depressed patients, LPP source activations were reduced in lingual gyrus, cuneus, inferior and middle occipital lobe, and inferior occipital gyrus in appetite-decreased patients, indicating altered occipital activity may be associated with attentional processing in MDD patients with decreased appetite. And correlation analysis revealed a moderate, positive correlation between LPP amplitude and DARS food/drink score. This study demonstrates the cognitive differences between MDD patients with appetite decrease and without appetite change, and provides a potential biomarker for evaluating the degree of appetite loss in MDD patients experiencing decreased appetite.