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To investigate the role of PINK1/Parkin-mediated mitophagy in regulating synaptic remodeling of neuronal cells in depression-like behaviors induced by nonylphenol (NP). In vitro experiments: HT-22 neuronal cells were exposed to NP, and mitophagy and Parkin expression were inhibited using specific inhibitors. The cells were categorized into the following groups: (1) control (C) and low-dose NP group (L: 2.5 µM), medium-dose NP group (M: 50 µM), and high-dose NP groups (H: 100 µM); (2) control (C), NP (100 µM), Mdivi-1 (5 µM), and Mdivi-1 + NP (5 µM Mdivi-1 +100 µM NP) groups; (3) control (C), NP (100 µM), AC220 (2 nM), and AC220 + NP (2 nM AC220 +100 µM NP) groups. In vivo experiments: a total of 48 mice, including 24 C57BL/6 wild-type mice and 24 PKRK2 gene-knockout mice, were randomly assigned to the following four groups: control (C), NP (100 mg/kg/day), PKRK2-knockout (KO), and PKRK2-knockout + NP (100 mg/kg/day, KH) groups, with 12 mice in each group. In vitro: With increasing NP concentration, the ATP content reduced and the expressions of synaptic remodeling-related proteins (i.e., PSD-95, BDNF, SYN) decreased. In contrast, the expressions of mitophagy-related proteins and those involved in the PINK1/Parkin-signaling pathway (such as p62, Beclin1, PINK1, Parkin) increased (P < 0.05). Inhibition of mitophagy with Mdivi-1 alleviated the NP-induced changes in synaptic, mitophagy-related, and PINK1/Parkin pathway-related proteins. Similarly, the inhibition of Parkin with AC220 mitigated NP-induced effects on synaptic, mitophagy-related, and PINK1/Parkin-signaling pathway-related proteins and mRNA expression. In vivo: PKRK2 gene-knockout mice exhibited improved NP-induced depression-like behaviors and decreased NP-induced synaptic morphology and mitochondrial ultrastructure changes. Moreover, the gene knockout alleviated the downregulation of synaptic remodeling-related proteins and inhibited the PINK1/Parkin-signaling pathway-mediated mitophagy activated by NP. Mitophagy inhibition or PKRK2 knockout can alleviate NP-induced downregulation of synaptic remodeling-related proteins, protect synaptic morphology and ultrastructure, and improve NP-induced depression-like behaviors. Show less

Maternal physical activity during pregnancy has been shown to confer benefits on the brain functions of offspring. This study investigated the positive effects of maternal exercise during pregnancy on enhancing hippocampal synaptic plasticity and resilience to stress-induced depressive behavior in adult murine offspring. Using a mouse model with mother mice engaged in voluntary wheel running during pregnancy, we assessed changes in long-term potentiation (LTP) in the hippocampal dentate gyrus, synaptic protein expression, and behavioral responses to chronic stress in adult male and female offspring from exercised dams compared with those from sedentary dams. We found that maternal exercise enhanced LTP in offspring of both sexes. Western blot analysis of hippocampal synaptoneurosome extractions revealed significant main effects of maternal exercise on increasing the expression of brain-derived neurotrophic factor (BDNF), PSD-95, synaptophysin, and phosphorylation of N-methyl-D-aspartate receptor subunit GluN2A and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA1. Maternal exercise significantly increased synaptophysin levels in both male and female offspring, with sex-specific effects on increasing PSD-95 levels in male offspring and increased p-GluN2A levels in female offspring from exercised dams. Golgi staining revealed a significant increase in hippocampal dendritic spine density in female offspring only. Maternal exercise-induced improvements in hippocampal synaptic plasticity were associated with reduced depression-like behaviors in both male and female offspring exposed to chronic unpredictable stress. Additionally, male offspring displayed reduced anxiety-like behavior, while female offspring showed no significant anxiolytic changes. These findings elucidate the sex-specific effects of maternal exercise on enhancing hippocampal synaptic plasticity, which may contribute to increased resilience against stress-induced depressive behaviors in adult offspring. Show less

Neural circuit formation through synaptogenesis plays a crucial role in learning, memory, and the recovery of neural function following brain dysfunction. We previously reported that administering the low-dose cardiac glycoside digoxin, which activates brain Na/K-ATPase, promotes dendritic spine formation and improves motor learning. On the other hand, brain-derived neurotrophic factor (BDNF) is also involved in axon elongation, branching, attraction, and the maturation of dendritic spines. Since trans-2-decenoic acid ethyl ester (DAEE), an ester of medium-chain fatty acid with ten carbons, activates the signaling pathway downstream of BDNF-TrkB, co-administration of digoxin and DAEE could further improve motor learning. This study compared the effects of digoxin, DAEE, or both on motor learning performance and locomotor activity in mice. Digoxin improved early performance in the rotarod test without changing locomotor activity, but did not affect final performance. DAEE increased activity in the open-field test but had no effect on the running wheel and did not influence motor learning in the rotarod test. On the other hand, the combination of digoxin and DAEE improved performance on the rotarod test later in the study. These data indicate that combining digoxin with DAEE delays the peak effects of motor learning compared to digoxin monotherapy, a temporal shift that may offer therapeutic advantages in rehabilitation outcomes. Show less

A vital question in neuroscience is whether and how efficiently cellular models may be differentiated into functional neuronal cells in culture. Despite the frequent use of the human neuroblastoma cell line SH-SY5Y, differentiation protocols vary extensively, with the most common being differentiation via the addition of retinoic acid and brain-derived neurotrophic factor. However, due to the lack of a reliable evaluation method, their adequacy as synaptic models remains unclear. Here, we investigate whether SH-SY5Y cells constitute a functional model for synaptic studies by phenotypically and ultrastructurally analyzing synaptogenesis in SH-SY5Y cells subjected to different differentiation protocols. Electron microscopy (EM) techniques, including conventional EM, cryo-EM, and cryo-electron tomography, were systematically applied to characterize synaptogenesis in SH-SY5Y cells. Further characterization was performed using immunostaining and functional assays, such as live exocytosis assays and whole-cell patch-clamp electrophysiology. Despite exhibiting some presynaptic-like features, differentiated SH-SY5Y cells do not form morphologically or functionally complete synapses under the conditions tested. Immunostaining results were consistent with previous findings, showing synaptic markers. However, functional investigations did not detect synaptic activity. High-throughput EM analyses revealed an absence of synaptic structures in these cells. Additionally, an alternative differentiation approach incorporating additional neurotrophic factors promoted the formation of presynaptic-like compartments containing synaptic vesicle-like vesicles (SVLVs). In contrast to typical synaptic vesicles, these SVLVs exhibited a pleomorphic size distribution and lacked connectors. These findings underscore the need for cautious interpretation of results derived from SH-SY5Y cells when investigating molecular synaptic architecture or function, as well as neurodegenerative diseases. Show less

Anshen Bunao Syrup (ABS), a traditional Chinese medicinal formula, is widely used to treat neurological disorders such as insomnia, dizziness, and neurasthenia. However, its antidepressant effect and underlying mechanisms remain insufficiently characterized. This study aims to comprehensively evaluate the antidepressant effect of ABS in a rat model, and to elucidate the underlying mechanism. Chronic unpredictable mild stress (CUMS) induced depressive rats were used to evaluate the antidepressant effect of ABS. Histopathological alterations in the hippocampus and colonic mucosa were examined using Nissl and H&E staining. Microglial activation was evaluated by Iba-1 immunohistochemical staining. Gut microbiota composition and metabolic profiles were analyzed using 16S rRNA sequencing and untargeted metabolomics. Differential gene expression and pathway regulation were investigated by transcriptomics and confirmed by Western Blot (WB). ABS significantly ameliorated depressive-like behaviors and elevated dopamine and 5-Hydroxytryptamine levels in cortical regions. Furthermore, ABS mitigated hippocampal neuronal damage, suppressed microglial overactivation and reduced oxidative stress in the cortex. 16S rRNA sequencing analysis showed that ABS exerted antidepressant effects via modulation of the "microbiota-gut-brain" axis, particularly by altering intestinal microbiota composition, enhancing gut function, and suppressing HPA axis hyperactivity. Metabolomics revealed that ABS corrected metabolic disturbances, and alleviated inflammation-related metabolic disturbances, while transcriptomics indicated regulation of the Npas4-BDNF-PI3K/AKT signaling pathway, which was further confirmed by WB. ABS significantly ameliorated depression in a CUMS rat model, primarily through coordinated regulation of gut microbiota, metabolic homeostasis, and the Npas4-BDNF-PI3K/AKT signaling pathway, providing integrative mechanistic insights into its antidepressant effects. Show less

Nearly one third of women of reproductive age in the United States are prescribed opioids annually; 14% of women fill an opioid prescription during pregnancy, and one in five report misuse. Opioid use during pregnancy has given rise to an increasing population of infants born with gestational opioid exposure. Although substantial clinical work has focused on treating these infants as they experience opioid withdrawal symptoms at the time of birth, notably few studies have examined the effects of gestational opioid exposure on brain development and long-term cognitive function. During typical brain development, endogenous opioids and their receptors are highly expressed by neural progenitor cells, neurons, and glia where they modulate cell proliferation, differentiation, and maturation. Thus, any disruption to the endogenous opioid system during the critical period of brain development may have lasting consequences on brain cell populations and the behaviors they influence. Indeed, opioid-exposed infants have smaller brains than age-matched peers and show significant neurodevelopmental impairment; they also have higher rates of learning disability at school age. To investigate how exposure to exogenous opioids during brain development affects neural maturation in the hippocampus, a brain region critical for learning and memory, our lab has developed a clinically relevant perigestational morphine exposure rat model. The current study reports that perigestational exposure to morphine delays postnatal hippocampal neuronal maturation, alters astrocyte and oligodendrocyte proliferation, and alters expression of brain-derived neurotrophic factor (BDNF), a protein crucial for healthy brain growth. Furthermore, we show that environmental enrichment rescues BDNF deficits, offering evidence for the effectiveness of non-invasive, non-pharmacological intervention for developmental consequences of perigestational opioid exposure. Show less

Anxiety is a common disorder characterized by excessive fear, tension, and physical symptoms, such as sweating and palpitations. There are approximately 16.6 % of patients worldwide affected by anxiety disorders, which have been classified as panic disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder, obsessivecompulsive disorder, and phobias. The amygdala plays a central role in regulating fear, anxiety, and aggression, particularly when influenced by trauma or heredity, which can contribute to the development of anxiety disorders. Another contributing factor is oxidative stress, characterized by reduced antioxidant levels and increased cellular damage. Neurotransmitters, such as serotonin, norepinephrine, and Gamma-Aminobutyric Acid, are critical in controlling anxiety. Anxiety also usually involves imbalances, in particular, low levels of serotonin and high norepinephrine. N-Methyl-D-aspartate and Cholecystokinin brain receptors are involved in long-term fear memory encoding, suggesting potential new targets for treating this condition. Although conventional pharmacological treatments such as benzodiazepines and selective serotonin reuptake inhibitors are effective, they are often associated with side effects, dependency, and limited long-term efficacy. In recent years, plant-based bioactive compounds have gained attention as potential alternatives or adjunct therapies for managing anxiety disorders, and they act in Gamma-Aminobutyric Acid modulation and monoamine regulation. Anxiety can be treated through herbal medicine using ethnopharmacology. Show less

Serotonergic psychedelics have attracted considerable interest as promising therapeutic agents. However, the molecular mechanisms linking their acute hallucinogenic-like effects to longer-lasting neuroplastic responses remain incompletely understood, partly because of the scarcity of native neural models suitable for mechanistic studies. Here, we developed a neural stem cell-derived in vitro model capable of differentiating into neuronal and glial lineages and, after characterization, used it to investigate the molecular pharmacology of serotonergic psychedelics. A panel comprising tryptamines, phenethylamines and ergolines, including psychedelic compounds and selected non-psychedelic analogues, was evaluated alongside ketamine and TrkB agonists. Endpoints included dendritogenesis, synaptogenesis, immediate-early gene induction, BDNF expression and lactate production. TrkB silencing abolished dendritogenic responses to serotonergic psychedelics, ketamine and TrkB agonists, whereas 5-HT Show less

Despite the growing interest in cell- and exosome-based therapies for neurological diseases including Alzheimer's disease (AD), there is still a gap in the investigation of more effective treatments in terms of efficacy, safety, and durability of effect. This study aimed to compare the therapeutic potential of astrocyte cells and their derived exosomes (AS-Exos) in restoring cognitive function in a mouse model of AD. AD model was induced by bilateral electrical lesioning of the nucleus basalis of Meynert (NBM). Astrocytes were isolated from neonatal rat brains, and AS-Exos were harvested from astrocyte-conditioned media using an AnaCell extraction kit. Seven days after lesion induction, astrocytes and AS-Exos were stereotaxically injected into the NBM. Four weeks later, behavioral assessments (passive avoidance and locomotor activity), electrophysiological recordings (EEG), and biochemical measurements of hippocampal brain-derived neurotrophic factor (BDNF) and acetylcholine (ACh) levels were performed. AS-Exos were confirmed as cup-shaped vesicles (30-150 nm) expressing the exosomal surface markers CD9, CD63, and CD81. NBM lesions significantly reduced step-through latency (STL), hippocampal BDNF and ACh levels, and disrupted EEG oscillatory patterns. Treatment with AS-Exos markedly improved STL and produced greater increases in hippocampal BDNF and ACh levels compared with AD and AD+saline groups. EEG analysis also revealed enhanced beta, alpha, and gamma power, with the most robust normalization observed in the AS-Exos group. AS-Exos demonstrated superior biochemical and electrophysiological benefits compared with astrocyte transplantation and provided equal or greater improvement in behavioral outcomes. These findings highlight AS-Exos as a promising cell-free therapeutic strategy for alleviating cognitive deficits associated with AD. Show less

Prenatal stress may lead to cognitive and behavioral dysfunction in the offspring. Large evidence has shown the deleterious effects of maternal stress on cognitive and behavioral functions of the offspring; however, the effect of paternal stress has not been well documented. In the present study, we aimed to investigate the effect of paternal stress (chronic electrical footshocks, post-traumatic stress disorder or PTSD-like model) on cognitive and behavioral functions, and brain-derived neurotrophic factor (BDNF) hippocampal level in both male and female offspring during adolescence. The father rat (stress-exposed) was exposed to three consecutive shocks in a fear conditioning apparatus for ten times during four weeks, in an uncertain and unpredictable schedule. Saline (0.5 mL) or lithium chloride (50 mg/kg) was intraperitoneally injected to male and female offspring during 21-41 postnatal day (PND). The results showed that paternal stress decreased locomotor activity in female offspring, and increased anxiety-like behavior in both male and female offspring, with more effect on females. Paternal stress also decreased pain subthreshold only in female offspring and impaired passive avoidance and spatial memory in both male and female offspring. Paternal stress also decreased BDNF expression level only in female offspring. However, lithium reversed most of the behavioral dysfunctions in rats' offspring with a history of paternal stress. We concluded that paternal stress significantly impairs cognitive and behavioral function in the offspring during adolescence, with more effect on females. Also, chronic lithium treatment may reverse the deleterious effects of paternal stress. Show less

There is a significant association between depressive episodes of bipolar disorder and non-suicidal self-injury (NSSI). Mindfulness-based cognitive therapy (MBCT) represents an evolution of cognitive behavioural therapy and serves as a comprehensive psychological intervention. Preliminary research suggests that MBCT may enhance cognitive flexibility and attentional adjustment in patients with depressive episodes of bipolar disorder by modulating brain activity. The aim of this study was to explore the effects of MBCT on behaviour, cognitive function, and serum precursor of brain-derived neurotrophic factor (proBDNF) levels in adolescents with depressive episodes of bipolar disorder. A total of 149 adolescent patients with bipolar disorder and depression with NSSI were randomly assigned. The Chinese version of the Adolescent Non-suicidal Self-Injury Assessment Questionnaire (ANSAQ) was used to measure NSSI symptoms. One group received MBCT in addition to treatment as usual (TAU) (n = 75), while the other group received TAU alone (n = 74). At baseline and at weeks 4 and 8 after treatment initiation, participants were assessed using the Barratt Impulsiveness Scale (BIS), the Hamilton Anxiety Scale (HAMA), the Repeatable Battery for the Assessment of Neuropsychological Status, and the Hamilton Depression Scale (HAMD). In addition, serum precursor Brain-Derived Neurotrophic Factor (proBDNF) levels were determined using an enzyme-linked immunosorbent assay. After 4 and 8 weeks of treatment, the MBCT group showed significantly greater improvement than the control group across the three BIS dimensions (motor impulsiveness, cognitive impulsiveness, and non-planning impulsiveness) (P < 0.001). HAMD scores in the MBCT group were significantly lower than those in the TAU group (4 weeks: MBCT:16.89 ± 1.45 vs TAU:17.27 ± 1.47, P < 0.05; 8 weeks: MBCT:9.24 ± 1.43 vs TAU:11.01 ± 1.84, P < 0.001). Similarly, HAMA scores were lower in the MBCT group (4 weeks: MBCT:13.14 ± 1.30 vs TAU:14.13 ± 1.65, P < 0.05; 8 weeks: MBCT:7.16 ± 1.68 vs TAU:8.17 ± 1.40, P < 0.001). Regarding cognitive function, the MBCT group demonstrated significantly higher scores in immediate memory (4 weeks: MBCT:72.31 ± 11.08 vs TAU:68.31 ± 9.36 P < 0.05; 8 weeks:MBCT:74.80 ± 13.06 vs TAU:71.87 ± 13.64, P < 0.05), delayed memory (4 weeks: MBCT:74.46 ± 11.50 vs TAU:70.20 ± 11.76, P < 0.05; 8 weeks: MBCT:76.54 ± 13.07 vs TAU:71.90 ± 12.60, P < 0.001), attention (4 weeks: MBCT:77.53 ± 11.41 vs TAU: 73.01 ± 13.21, P<0.05; 8 weeks: MBCT:84.56 ± 12.77 vs TAU:76.87 ± 11.38, P < 0.001), language ability (4weeks: MBCT:76.47 ± 12.17 vs TAU:72.13 ± 13.25 P < 0.05;8 weeks: MBCT:79.89 ± 15.02 vs TAU:74.83 ± 12.97, P < 0.05) and visuospatial ability (4 weeks:MBCT:89.04 ± 10.92 vs TAU:84.01 ± 12.67 P < 0.05;8 weeks:MBCT:90.23 ± 13.62 vs TAU:87.67 ± 12.74 P < 0.05) . In addition, serum proBDNF levels in the MBCT group were significantly lower than those in the TAU group at both 4 weeks (MBCT:1.34 ± 0.09 ng/mL vs TAU:1.40 ± 0.06 ng/mL, P < 0.05) and 8 weeks (MBCT:1.27 ± 0.07 ng/mL vs TAU:1.31 ± 0.04 ng/mL, P < 0.05). MBCT can effectively reduce impulsive behaviour, alleviate depressive and anxiety symptoms related to self-injurious behaviour in adolescents with bipolar depression, and decrease serum proBDNF levels. Additionally, immediate memory, delayed memory, attention, language, and visuospatial ability were significantly improved following treatment. Show less

Early-life stress (ELS) is a key risk factor for adolescent depression. Si-Ni-San (SNS), a classic traditional Chinese medicine formula, has shown antidepressant potential, yet its effects on the dorsal raphe nucleus (DRN)-nucleus accumbens (NAc) serotonergic circuit remain unclear. This study aimed to investigate whether SNS alleviates adolescent depression by restoring DRN-NAc serotonergic circuit function and to identify the serotonin receptor mediating its synaptic effects in the NAc. Firstly, the antidepressant efficacy of SNS was evaluated in a mouse model of ELS. Subsequently, its underlying mechanism was explored through integrated neurophysiological, molecular, and pharmacological analyses. Depressive- and anxiety-like behaviors were assessed using behavioral tests (sucrose preference, tail suspension, forced swim, open field, and elevated plus maze). In vivo electrophysiolog was employed to monitor DRN neuronal activity. Chemogenetic manipulation was employed to regulate the DRN-NAc serotonergic circuit, while 5-HT4R function was assessed through pharmacological intervention and viral knockdown. Synaptic and molecular mechanisms were examined using Western blotting, qPCR, ELISA, and immunofluorescence. SNS alleviated depressive-like behaviors, enhanced neural activity and low-frequency oscillations in the DRN, and restored 5-hydroxytryptamine (5-HT) levels in the NAc. Mechanistically, SNS upregulated tryptophan hydroxylase 2 (TPH2) while downregulating indoleamine 2,3-dioxygenase 1 (IDO1), thus promoting 5-HT synthesis. Critically, the antidepressant effects of SNS were blocked by either chemogenetic inhibition of the DRN-NAc serotonergic circuit or pharmacological blockade of 5-HT4R in the NAc. Meanwhile, the knockdown of 5-HT4R abolished the ameliorative effects of SNS on depressive-like behaviors and associated synaptic remodeling, including the upregulation of brain-derived neurotrophic factor, postsynaptic density protein 95, and mushroom spine density. These results demonstrate that SNS alleviates depressive-like behaviors in adolescent male mice by restoring DRN-NAc serotonergic circuit function, enhancing 5-HT bioavailability, and promoting 5-HT4R-dependent synaptic plasticity in the NAc, revealing a circuit- and receptor-specific therapeutic mechanism. Show less

To retrospectively analyze the effects of Butylphthalide and Sodium Chloride Injection (BP-SC) combined with Argatroban (AG) on neurological deficits and hemorheology in progressive ischemic stroke (PIS) patients. A total of 123 PIS patients admitted to our hospital between April 2023 and April 2025 were retrospectively analyzed and divided into two groups according to the different treatment schemes: the control group (n=58; treated with AG) and the research group (n=65; treated with BP-SC and AG). Clinical efficacy, neurological deficits (assessed by the National Institutes of Health Stroke Scale [NIHSS]), neurological function (astrocyte-derived protein S100β, brain-derived neurotrophic factor [BDNF], and neuron-specific enolase [NSE]), hemorheology (fibrinogen [FIB], plasma viscosity [PV], whole blood low-shear viscosity [WBLSV]), vascular endothelial function (endothelin-1 [ET-1] and nitric oxide [NO]), inflammatory factors (high-sensitivity C-reactive protein [hs-CRP], interleukin-6 [IL-6], and tumor necrosis factor-α [TNF-α]), adverse events (gingival bleeding, subcutaneous ecchymosis, nausea, abdominal distension, and vomiting), the 90-day post-operative modified Rankin Scale (mRS) score were compared between the two groups. Compared with the control group, the research group demonstrated significantly higher overall effective rate and favorable prognosis rate. The research group also showed greater post-treatment reductions in the NIHSS score and levels of S100-β and NSE, along with a more pronounced elevation in BDNF level, indicating improved neuronal function. Additionally, the combined treatment significantly improved multiple hemorheological indices and endothelial function as evidenced by reduced ET-1 level and elevated NO level. Moreover, levels of hs-CRP, IL-6, and TNF-α were significantly decreased. However, the total incidence of adverse events was comparable between the two groups. Combined treatment with BP-SC and AG exerts more significant improvements in neurological deficits and hemorheological parameters in PIS patients. Show less

Substance Use Disorders (SUD) have escalated into a global public health crisis, with their core pathology encompassing not only physiological dependence and a heightened risk of relapse, but also profound social cognitive impairments caused by chronic substance abuse. These impairments constitute a major barrier to rehabilitation yet remain largely overlooked in current treatment frameworks. This review develops and substantiates an innovative theoretical framework centered on the "Exercise-Irisin-Social Brain" axis. We propose a core pathway hypothesis: regular exercise can induce the release of the myokine irisin from skeletal muscle, which then enters the bloodstream and crosses the blood-brain barrier to act on the prefrontal cortex, which is the central hub of social cognition and executive function. Through potential mechanisms including the upregulation of brain-derived neurotrophic factor and the suppression of neuroinflammation, irisin may contribute to the repair of the executive function network that underlies higher-order social cognition, thereby improving social cognitive abilities and ultimately providing a supportive foundation for the reconstruction of social functioning in individuals with SUD. This new paradigm not only provides a testable biological pathway for understanding how exercise may repair the addicted brain, but also transcends the limitations of traditional models that focus primarily on withdrawal and relapse, by elevating rehabilitation goals to emphasize the restoration of social functioning. Show less

Recent evidence suggests that reduced peripheral levels of brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of bipolar disorder (BD), although its relevance in young populations remains uncertain. This systematic review synthesized studies that evaluated serum BDNF levels in children and adolescents with BD, examining its potential as a risk marker. Following PRISMA 2020 guidelines and a protocol registered in PROSPERO, searches were conducted in the Cochrane, MEDLINE, SciELO, and Scopus databases. Studies including participants aged 0-19 years diagnosed with BD according to DSM criteria were included. Studies with mixed samples (adults, children and adolescents) without separate age-group analyses were excluded. After screening and eligibility assessment, seven studies were included. Five of them included a control group, from which a meta-analysis was performed. Moderate methodological heterogeneity was observed and corrected after sensitivity analysis, reinforcing the robustness of the findings, although no statistically significant difference in serum BDNF levels was found between patients with bipolar disorder and controls. Current evidence does not support BDNF as a diagnostic biomarker for pediatric BD. Future studies with greater sample power and methodological standardization are needed to clarify its role in the risk and course of early-onset bipolar disorder. Show less

The gut microbiome and the central nervous system are intricately connected through a bidirectional communication system that plays a vital role in maintaining gut homeostasis and overall health. Disruptions in this interaction are linked to gastrointestinal and neuropsychiatric disorders, including anxiety. This review aims to provide a comprehensive analysis of the gut microbiota's role in anxiety and evaluate the therapeutic potential of prebiotics. This review synthesizes recent literature from databases including PubMed, Scopus, Web of Science, and Google Scholar, focusing on the gut microbiota's role in anxiety and the therapeutic potential of prebiotics. The microbiota-gut-brain axis communicates through multiple pathways, including the vagus nerve, immune signaling, microbial metabolites, and the hypothalamic-pituitary-adrenal (HPA) axis. Prebiotics modulate these pathways by enhancing beneficial microbial populations and influencing the production of neuroactive compounds. Key molecular targets implicated in this communication include brain-derived neurotrophic factor (BDNF), glucocorticoid receptors, and shortchain fatty acids, which modulate neurotransmitters such as GABA and serotonin, and influence neuroinflammatory pathways implicated in anxiety pathophysiology. The findings highlight the immunological, neurochemical, and endocrine mechanisms through which the gut microbiota interacts with neurophysiological systems. These mechanisms underscore the pharmacological potential of prebiotics in the management of psychiatric illnesses. The interplay between the gastrointestinal microbiota and neurophysiological systems provides key pharmacological insights into the potential of prebiotics as a therapeutic approach for managing psychiatric illnesses, detailing their mechanistic pathways and translational applications in clinical practice. Show less

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disorder characterized by extracellular Aβ accumulation and intracellular tau hyperphosphorylation. Currently, there are no effective therapeutic drugs available for AD. Regular exercise training has emerged as a promising physical intervention strategy for mitigating both the risk and progression of AD, but different types of exercise interventions show varied and conflicting results in AD treatment, with their differential effects and mechanisms still unelucidated. Using an Aβ oligomer-induced AD mouse model, we investigated therapeutic effects of voluntary wheel running, forced treadmill running, and combined exercise (voluntary combined with forced running) on AD pathologies. For depressive-like behavior, we conducted forced swimming test and tail suspension test; for cognition, Novel object recognition test (object recognition ability) and Morris water maze test (spatial learning and memory) was used respectively. We applied BrdU-DCX/NeuN/GFAP immunofluorescence co-staining to measure neurogenesis, Western blot to examine proteins associated with synapses, neurons, astrocytes, apoptosis, and BDNF signaling key components, serum metabolomics to identify exercise-induced metabolites. Furthermore, a clinical trial involving healthy subjects and patients with AD implemented an acute exercise intervention and utilized portable functional near-infrared spectroscopy to assess cortical activation and functional connectivity under conditions of both voluntary and forced exercise. Voluntary, forced, and combined exercise alleviated depressive-like phenotypes and short-term cognitive deficits in AD mice, while only forced exercise conferred sustained long-term memory benefit. All exercises boosted hippocampal neurogenesis by enhancing newborn cell (BrdU Our findings reveal distinct neuroprotective profiles of long-term voluntary, forced, and combined exercise interventions against Aβ oligomer neurotoxicity in an AD mouse model, and different acute exercise modalities also demonstrate distinct effects on cortical activation and functional connectivity in patients with AD. Our study provides novel insights into exercise modalities' therapeutic effects in ameliorating AD neuropathology. Show less

This study aims to establish a standardized mouse model of Alzheimer's disease(AD) with spleen-kidney deficiency and stagnant phlegm syndrome(AD-SKDSP) based on TCM theory, so as to provide a disease-syndrome combined model that aligns with the TCM diagnosis and treatment paradigm of "disease-syndrome-formula-efficacy" for modern research on AD prevention and treatment. Four-month-old male double-transgenic APP/PS1 mice were used as AD model animals. A standardized animal model of AD-SKDSP was constructed by high-sugar and high-fat diet feeding combined with ice-water bath and tail-clamping stimulation. The mice were randomly divided into an AD model group, an AD-SKDSP group, an AD Zhinao Capsule group, and a normal control group consisting of same-litter and age-matched male C57BL/6J mice. Corresponding drug treatments were administered at designated time points. During the eight-week modeling period, the following parameters were measured: physical sign scores, grip strength, body weight, 24-hour food intake, 24-hour fecal water content, female mouse fertility, Morris water maze performance, nose-tongue-collateral-foot color, hippocampus detected by hematoxylin-eosin(HE) staining, Aβ₍₁₋₄₂₎ and brain-derived neurotrophic factor(BDNF) detected by immunohistochemistry, whole blood and plasma viscosity, 2-hour D-xylose, testosterone(T), estradiol(E₂₎, calcium(Ca), phosphorus(P), bone Gla protein(BGP), hippocampal synapsin(SYN) and postsynaptic density protein 95(PSD-95) mRNAs, and SYN, PSD-95, and BDNF proteins. The results showed that by the end of the 4th week, compared with the normal control group, the AD model group, AD-SKDSP group, and AD Zhinao Capsule group exhibited progressively increased physical sign scores and 24-hour fecal water content, and progressively decreased grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). Compared with the AD model group, the AD-SKDSP group and AD Zhinao Capsule group showed significantly increased physical sign scores and 24-hour fecal water content, along with significantly reduced grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). From the 5th week onward, compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant reductions in physical sign scores and 24-hour fecal water content, as well as significant increases in grip strength, body weight, and 24-hour food intake with prolonged intragastric administration of Zhinao Capsule(P<0.05, P<0.01). By the end of the 8th week, compared with the normal control group, the AD model group and AD-SKDSP group exhibited significantly decreased female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E₂, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression. Meanwhile, platform latency, hippocampal Aβ₍₁₋₄₂₎ expression, and whole blood and plasma viscosity(low, medium, and high shear rates) were significantly increased, while platform crossings and target quadrant swimming time were markedly reduced(P<0.05, P<0.01). Hippocampal CA1 neurons in these groups displayed partial loss of normal morphology, with pyknotic or swollen nuclei, deep blue staining, disorganized distribution, and a thickness of "3-5" layers. Compared with the AD model group, the AD-SKDSP group showed significant reductions in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E₂, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant increases in platform latency, hippocampal Aβ₍₁₋₄₂₎ expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant decreases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neurons exhibited irregular shapes, increased nuclear pyknosis, intensified deep blue staining, a thickness of "1-3" layers, and chaotic distribution. Compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant increases in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E₂, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant decreases in platform latency, hippocampal Aβ₍₁₋₄₂₎ expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant increases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neuronal pathology was markedly alleviated. In summary, guided by the holistic concept and syndrome differentiation theory of TCM and on the basis of characteristics of "spleen deficiency", "kidney deficiency", and "intermingled phlegm and blood stasis", this study successfully established a standardized AD-SKDSP animal model by combining a high-sugar and high-fat diet with ice-water bath and tail-clamping stimulation for eight weeks. This modeling method exhibits strong controllability, minimal physicochemical stimulation, reproducibility, and verifiability, providing a stable and standardized disease-syndrome combined animal model for future research on the "disease-syndrome-formula-efficacy" paradigm in AD-SKDSP. Show less

Attention deficit hyperactivity disorder(ADHD), a common neurodevelopmental disorder in children, is characterized by inattention, hyperactivity, and impulsivity. Epidemiological surveys show that the prevalence of ADHD in children is gradually increasing worldwide, and it is the most common childhood mental disorder in China. Because of the complex clinical symptoms, multiple co-morbidities, and unknown etiology, ADHD has far-reaching negative impacts on individuals, families, and the society. Behavioral interventions, as a pillar in the management of ADHD, play a targeted role in improving children's social functioning, with significant benefits supported by evidence. However, they are constrained by uneven resources, poor compliance, and insufficient continuity, Western medicine has multiple adverse effects and unclear long-term effects in the treatment of ADHD despite the definite efficacy. Accordingly, there is an urgent need to find safe and effective therapies suitable for children. With a holistic view and treatment based on syndrome differentiation, traditional Chinese medicine(TCM) has significant advantages in treating ADHD via multiple targets, which involves dopamine(DA), norepinephrine(NE), 5-hydroxytryptamine(5-HT), cyclic adenosine monophosphate(cAMP), brain-derived neurotrophic factor(BDNF) and other signaling pathways. Through these pathways, TCM can treat ADHD through the regulation of neurotransmitters, enhancement of prefrontal and striatal functions, enhancement of neuronal protection, attenuation of neuroinflammation, and reduction of neuronal apoptosis. However, a systematic study remains to be conducted. This paper summarizes the signaling pathways related to the treatment of ADHD by TCM in the past two decades, aiming to provide reference for delving into the mechanism and exploring effective TCM prescriptions for ADHD in children and to give full play to the advantages of the efficacy and characteristics of TCM. Show less

A single nucleotide polymorphism in the brain derived neurotrophic factor (BDNF)-encoding gene leads to diminished BDNF signaling resulting from Val66Met and has been linked to obesity. Previous imaging studies regarding the impact of BDNF Val66Met on the central serotonin system, which is involved in behavior, cognition and control of satiety, have not focused on body weight or food-intake related behavior. We revisited a cohort of thirty non-depressed individuals with obesity and 15 normal-weight controls. 29 obese and 13 controls underwent [ Show less

Buchanania lanzan Spreng. (Anacardiaceae) seeds (BLHA) are the cheaper alternative to almonds used in the confectionery industry. The flour powder of seeds is used as a thickening agent to prepare sauces and flavourings for a batter. The socioeconomic importance of this species lies in its medicinal properties for curing diabetes. The study explored the multifaceted neuroprotective role of BLHA (500 mg/kg) in hyperlipidic high-fat diet streptozotocin (HFD/STZ)-induced type2 diabetic neuropathy (T2DN) rats via glucose metabolism, insulin resistance, and inflammation to mitigate nerve damage. Molecular docking analysis was performed to identify specific molecular targets of bioactive compounds in T2DN pathogenesis. Serum diabetic parameters, such as serum glucose (SG), insulin (SI), total protein (TP), triglycerides (TG), blood urea nitrogen (BUN), creatinine (Cr), HDL-C, and LDL-C, were studied. A strong correlation between HbA1C and insulin resistance assessed by HOMA-IR. Oxidative stress triggers the production of free radicals, so the antioxidant indicators in serum, tissues, and proinflammatory cytokines in the liver, brain, and pancreas were measured in T2DN rats. Effects on neurochemicals, BACE1, Aβ BLHA at 500 mg/kg significantly improved hyperglycemic (SG, SI, HOMA-IR, HbA1C), hepatic (AST, ALT, ALP, TP, TB), dyslipidemic (TC, TG, HDL-C, LDL-C), and kidney function markers (creatinine, BUN) in T2DN rats. BLHA restored oxidative (CAT, GSH, SOD, MDA) and cytokine markers (TNF-α, IL6) in the liver, pancreas, and brain cortex. Oxidative stress-impaired neurotransmitters were alleviated by enhancing cholinesterase (AChE, BChE) and BACE1 activities, and by ameliorating Aβ The multifaceted actions of dietary polyphenols, antioxidants, and antidiabetic compounds (Catechol, 2-Hydroxy-5-methylbenzaldehyde, 8-Octadecenoic acid methyl ester, n-Hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl)ethyl ester, β-Sitosterol, Hexadecenoic acid methyl ester) in BLHA modulated glucose metabolism, restored HOMA-IR, and reduced inflammation by protecting against oxidative stress, as a result, it improved neurotransmission and reduced neuropeptide aggregation in T2DN rats. The dock score of β-sitosterol (AChE: -12.7; BChE: -14.8; IL6: -9.8; and Atp1a3: -13.3 kcal/mol) correlated with the experimental evidence. Show less

This study examines neuroanatomical and molecular changes that may be responsible for cognitive impairment in the BTBR mouse model of autism. Compared to control C57Bl/6 mice, BTBR mice exhibited cognitive inflexibility, impaired in an operant learning task. MRI revealed significant brain abnormalities, including reduced cortical volume, smaller ventricles, and asymmetry in the dorsal hippocampus, accompanied by neuronal loss. BTBR mice also showed impaired cerebrospinal fluid dynamics, with reduced production and outflow. Molecular analysis revealed brain region-specific reduction in the expression of Bdnf exons 1, 2, 3, and 4 in untrained BTBR mice. Furthermore, learning induced changes in transcription of Bdnf exons exclusively in BTBR. Elevated proBDNF levels and an increased proBDNF/mature BDNF ratio in the frontal cortex and striatum indicated aberrant BDNF processing. These findings suggest that ASD-related cognitive impairments are linked to a complex of neurodevelopmental abnormalities, potentially connected to disrupted transcription, processing, and signaling of BDNF. Show less

Anxiety and depression are growing global burdens with limited drug options. Traditional Chinese medicine (TCM) offers unique advantages, including Roudoukou-Suanzaoren (RS), an ancient TCM-derived beverage with the potential for treating these conditions. This study aims to explore whether this combination improves the outcomes. The results show that the main constituents of RS include flavonoids, terpenoids, alkaloids, and phenylpropanoids. Behavioral and histopathological analyses demonstrate that RS alleviates chronic restraint stress (CRS)-induced anxiety- and depression-like behaviors and attenuates neuropathological damage in relevant brain regions; the underlying mechanism is likely mediated by the CREB/BDNF/TrkB signaling pathway. Meanwhile, RS reduces proinflammatory cytokines in tissues, decreases hippocampal microglial numbers, and increases astrocytes. Additionally, RS attenuates colonic injury, restores intestinal permeability, upregulates tight-junction proteins, and improves gut microbiota dysbiosis. This study highlights that RS exerts antianxiety and antidepression effects by modulating the gut microbiota, controlling inflammatory responses, and increasing BDNF levels through the "gut-brain axis" pathway. Show less

This study aimed to investigate the effects of L-borneol on the molecular, biochemical, and histological damage caused by acrylamide (ACR) in the hippocampus of adult male Wistar rats. It also examined the impact of L-borneol on spatial memory and anxiety-like behaviors in these animals. Animals were divided into four groups: control, L-borneol, ACR, and ACR + L-borneol. ACR (25 mg/kg) and L-borneol (50 mg/kg) were administered orally for 21 consecutive days. L-borneol reduced levels of malondialdehyde and nitric oxide, increased glutathione content, and enhanced superoxide dismutase activity in the hippocampus of rats treated with ACR. In addition, L-borneol lowered the expression of pro-inflammatory markers, nuclear factor-κB, and inducible nitric oxide synthase in the hippocampus. It effectively prevented changes in the expression of apoptosis-related genes, which are associated with decreased neuronal death in the cornus ammonis 1 and dentate gyrus regions. Moreover, L-borneol increased the expression of sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), brain-derived neurotrophic factor, and alpha 7-nicotinic acetylcholine receptors, while reducing the expression and activity of acetylcholinesterase. Finally, L-borneol improved spatial memory and reduced anxiety-like behaviors. In conclusion, L-borneol enhances behavioral performance in ACR-exposed animals by decreasing oxidative and nitrosative stress, as well as inhibiting inflammation and apoptosis. It appears that the upregulation of the SIRT1/Nrf2/HO-1 signaling pathway and the stimulation of acetylcholine signaling are crucial for mitigating ACR-induced neurotoxicity. Show less

Memantine (Mem), an uncompetitive antagonist of the N-methyl-D-aspartate receptor (NMDAr), has demonstrated neuroprotective effects in preclinical stroke models by reducing excitotoxic damage. However, the efficacy of low acute doses administered during the immediate post-ischemic phase remains insufficiently characterized. Male rats underwent permanent middle cerebral artery occlusion (pMCAO) and received a single intraperitoneal dose of Mem (5 mg/kg) two hours post-occlusion. Neurological deficits were assessed using the modified Neurological Severity Score (mNSS). Infarct area and neuronal preservation were quantified using MAP2 immunohistochemistry. BDNF and PSD95 protein levels were measured by ELISA, and their gene expression was evaluated via RT-PCR. Mem treatment significantly reduced infarct area (p = 0.000029) and attenuated neurological deficits (p < 0.0001). MAP2 immunoreactivity was higher in the Mem-treated group (p = 0.000003), indicating preservation of neuronal structure. BDNF protein levels did not differ between the pMCAO and pMCAO+Mem groups; PSD95 protein and its corresponding DLG4 mRNA were increased in the pMCAO group compared with Sham. In the other groups, levels remained unchanged. Early administration of low-dose memantine confers acute neuroprotection after stroke by reducing tissue damage and preserving neuronal integrity, without affecting ischemia-induced BDNF and PSD95 protein and gene expression. These findings suggest a selective early neuroprotective mechanism and highlight the need for long-term and sex-inclusive studies to further evaluate memantine's therapeutic potential. Show less

Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain, offering novel therapeutic strategies for neuropsychiatric disorders. Recent findings reveal that beyond their transient psychotropic effects, these compounds activate serotonin 5-HT Show less

This study aimed to explore the effect and mechanism of polyphyllin Ⅱ in improving di(2-ethylhexyl)phthalate(DEHP)-induced learning and memory impairment. In the experiment, male C57BL/6 mice were randomly divided into five groups: a control group, a model group(exposed to 5 mg·kg~(-1) DEHP), and polyphyllin Ⅱ groups(5 mg·kg~(-1) DEHP + 0.5 mg·kg~(-1) polyphyllin Ⅱ, DEHP + 1 mg·kg~(-1) polyphyllin Ⅱ, and DEHP + 2 mg·kg~(-1) polyphyllin Ⅱ). The learning and memory function of mice was tested using the Morris water maze. The hippocampal neuron structure was detected by Nissl staining. The expression of casein kinase Ⅱ subunit beta(CK2b), protein kinase B(Akt)-cAMP response element binding protein(CREB) pathway-related proteins, as well as postsynaptic density protein 95(PSD95) and synapsin 1 was determined by immunofluorescence and Western blot. The brain-derived neurotrophic factor(BDNF) expression was measured by enzyme-linked immunosorbent assay(ELISA). The results showed that compared with the control group, DEHP induced learning and memory impairment, as well as hippocampal neuronal apoptosis in mice. Additionally, DEHP downregulated CK2b, inhibited the Akt-CREB pathway, and downregulated the PSD95, synapsin1, and BDNF expression. After polyphyllin Ⅱ administration, DEHP-induced learning and memory impairment was significantly improved, with inhibited hippocampal neuronal apoptosis, restored CK2b expression, reactivated Akt-CREB pathway, as well as restored expression of PSD95, synapsin1, and BDNF. Furthermore, the surface plasmon resonance(SPR) experiment of N2a cells demonstrated that polyphyllin Ⅱ targeted CK2b and stabilized its expression. After using siRNA to inhibit CK2b, the neuroprotective effect of polyphyllin Ⅱ was also significantly inhibited, and neuronal apoptosis was reinduced. In conclusion, polyphyllin Ⅱ can ameliorate DEHP-induced learning and memory impairment, with its potential mechanism involving the Akt-CREB pathway activation via CK2b upregulation, which leads to restored PSD95 and synapsin1 expression, and synaptic plasticity, as well as inhibited neuronal apoptosis, ultimately exerting a neuroprotective effect. This study suggests that polyphyllin Ⅱ possesses a neuroprotective effect and has potential application value in improving cognitive impairment. Show less