Depression has emerged as a concerning factor in colon cancer progression and treatment, yet its underlying mechanisms and therapeutic targets remain poorly defined. This study aimed to elucidate how Show more
Depression has emerged as a concerning factor in colon cancer progression and treatment, yet its underlying mechanisms and therapeutic targets remain poorly defined. This study aimed to elucidate how depression affects colon cancer progression and chemotherapeutic response, and to explore potential molecular targets and therapeutic interventions involving the traditional Chinese medicine formula Sinisan (SNS) and its bioactive component Quercetin. A mouse model combining depression and colon cancer was established to evaluate behavioral alterations, tumor progression, and pathological features. RNA sequencing was performed to screen the differentially expressed genes. The effects of corticosterone (CORT) on proliferation, colony formation, migration, and GSTM2 expression were examined in HCT116 cells, followed by functional validation through GSTM2 overexpression and inhibition assays. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) were used to validate the binding of Quercetin to GSTM2. The therapeutic efficacy of SNS and Quercetin was assessed with respect to depressive symptoms, serum BDNF levels, NLRP3 inflammasome activity, and the potency of 5-fluorouracil (5-FU) chemotherapy. Mice with depression and colon cancer exhibited aggravated depressive behaviors and accelerated tumor progression. RNA-sequencing and network pharmacology analyses identified GSTM2 as a promising candidate target in colon cancer treatment, which was markedly down-regulated in the DP-CC group. CORT enhanced proliferation, colony formation, and migration of HCT116 cells while simultaneously suppressing GSTM2 expression. Conversely, GSTM2 levels negatively correlated with cell proliferation, colony formation, and chemoresistance in HCT116 cells. Treatment with SNS alleviated depressive symptoms, elevated serum BDNF, reduced NLRP3 inflammasome activity, and potentiated the efficacy of 5-FU chemotherapy. Quercetin, a bioactive component of SNS, bound to GSTM2 through hydrogen-bond and van-der-Waals interactions, up-regulated GSTM2 expression, and mitigated CORT-induced proliferation, colony formation, and chemoresistance. Our findings suggest that depression promotes colon-cancer progression by down-regulating GSTM2, whereas SNS restores GSTM2 expression and enhances chemotherapeutic response. 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 Show more
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
Depression is increasingly recognized as a disorder involving immune brain interactions beyond classical monoaminergic dysfunction. Among immune components, T cells have emerged as key regulators link Show more
Depression is increasingly recognized as a disorder involving immune brain interactions beyond classical monoaminergic dysfunction. Among immune components, T cells have emerged as key regulators linking peripheral immune dysregulation to central neuroinflammation and impaired neuroplasticity. Accumulating clinical and preclinical evidence indicates that alterations in T cell subsets, including regulatory T cells, Th1 cells, and Th17 cells, contribute to depressive pathophysiology through coordinated effects on blood-brain barrier permeability, glial activation, cytokine signaling, and neurotrophic support. This review synthesizes current evidence on the mechanisms by which T cells migrate into the central nervous system and modulate depressive behaviors. Particular emphasis is placed on the T cell regulation of brain derived neurotrophic factor signaling, and a role for T cell derived extracellular vesicles as modulators of immune neural communication and neuroplasticity. Finally, we discuss the therapeutic implications of targeting T cells in depression, including modulation of T cell subset balance, cytokine-based interventions, microbiota immune regulation, and inhibition of pathogenic T cell trafficking into the brain. Together, these findings position T cells as central orchestrators of immune neural crosstalk and promising targets for mechanism informed immunotherapies in depression. Show less
Diabetic neuropathic pain (DNP) is a common and debilitating complication of diabetes that profoundly reduces patient quality of life. Despite extensive research, current treatments remain largely sym Show more
Diabetic neuropathic pain (DNP) is a common and debilitating complication of diabetes that profoundly reduces patient quality of life. Despite extensive research, current treatments remain largely symptomatic, with limited efficacy and significant side effects. Microglia act as pivotal mediators of DNP through RAGE/TLR4/NLRP3-driven IL-1β and BDNF release that amplifies spinal pain signaling. Microglia respond directly to hyperglycemia-induced cues such as advanced glycation end-products, reactive oxygen species, ATP, and pro-inflammatory signals, becoming activated and releasing cytokines, chemokines, and neuromodulators including BDNF that amplify spinal pain signaling. This review synthesizes recent insights into the molecular triggers of microglial activation such as RAGE, TLRs, purinergic receptors, and inflammasomes and the downstream intracellular pathways including NF-κB, MAPK, PI3K/Akt, and BDNF-TrkB that drive neuroinflammation. We further examine neuroimmune crosstalk, including bidirectional microglia-neuron and microglia-astrocyte signaling, which sustains central sensitization. Translational studies linking these pathways to human DNP are evaluated, along with novel technologies that illuminate microglial phenotypes. Emerging therapeutic strategies focus on inhibition of these pathways, including RAGE antagonists and purinergic receptor blockers. However, a critical translational gap persists owing to insufficient human validation of microglial biomarkers and the limited fidelity of current animal models. By integrating basic and clinical findings, we underscore the promise of microglia-focused interventions to complement traditional analgesics and ultimately improve outcomes in DNP patients. Show less
Orthodontic tooth movement (OTM) is a biomechanically driven process governed by dynamic cellular and molecular signaling interactions between neural and skeletal systems. This review synthesizes curr Show more
Orthodontic tooth movement (OTM) is a biomechanically driven process governed by dynamic cellular and molecular signaling interactions between neural and skeletal systems. This review synthesizes current evidence on neuron-bone cell crosstalk and the coordinated involvement of immune and vascular components in regulating alveolar bone remodeling during OTM. Key neural contributors include sensory neurons (nociceptors), autonomic neurons, central nervous system (CNS) circuits, and Schwann cells, which communicate with osteoblasts, osteoclasts, and periodontal ligament cells to modulate their proliferation, differentiation, and functional activity. These interactions are mediated by defined signaling pathways, including neuropeptide signaling (CGRP-CLR, SP-NK1, NGF-TrkA, BDNF-TrkB), axon guidance signaling (Sema3A-PlexinA/Nrp1), adrenergic signaling (β2-AR-dependent pathways), and intracellular cascades such as Rac1-β-catenin, RhoA/ROCK2, and Notch3. Sensory nerves function as primary initiators by releasing neuropeptides that promote osteoclastogenesis in pressure zones and osteogenesis in tension zones, while simultaneously shaping local immune responses and vascular remodeling. The autonomic nervous system exerts context-dependent regulation, with sympathetic signaling favoring bone resorption and parasympathetic pathways emerging as modulators of osteogenesis and neurovascular homeostasis. CNS circuits integrate sensory and autonomic inputs to coordinate OTM kinetics and pain perception. Together, these neuro-osteogenic signaling networks define mechanistic targets for improving orthodontic outcomes and pain management via neuromodulation. Show less
Post-stroke depression (PSD) is a common neuropsychiatric complication affecting 30-50% of stroke survivors, impairing rehabilitation, quality of life, and prognosis. This narrative review synthesizes Show more
Post-stroke depression (PSD) is a common neuropsychiatric complication affecting 30-50% of stroke survivors, impairing rehabilitation, quality of life, and prognosis. This narrative review synthesizes recent evidence on PSD pathogenesis (neurotransmitter dysregulation, neuroinflammation, impaired neuroplasticity; psychosocial factors such as stress and social support deficits; gene-environment interactions including 5-HTT and BDNF polymorphisms), clinical interventions (pharmacotherapy with SSRIs/SNRIs, psychotherapy including CBT, neuromodulation via rTMS/tDCS/ECT, novel agents such as ketamine, and multidisciplinary models), and prevention (risk stratification, early screening with PHQ-9/HAMD, personalized biological/psychosocial strategies, and digital monitoring). Despite gaps in long-term data and validated biomarkers, multidisciplinary integrated care and precision medicine approaches offer promising avenues to optimize screening, early intervention, prevention, and long-term outcomes for stroke survivors. Show less
Gestational intermittent hypoxia (GIH), which serves as a model for obstructive sleep apnea (OSA), is associated with adverse maternal and neonatal outcomes, especially cognitive impairments in offspr Show more
Gestational intermittent hypoxia (GIH), which serves as a model for obstructive sleep apnea (OSA), is associated with adverse maternal and neonatal outcomes, especially cognitive impairments in offspring. Growing evidence supports that the anti-inflammatory actions of melatonin significantly influence the peripartum environment and contribute to the mitigation of neurodegeneration. However, the full impact of GIH on offspring cognition and the molecular mechanisms by which melatonin modulates these effects remain uncertain. Thus, in this study, we explored the neurobiological changes in GIH-exposed offspring and the mechanism underlying maternal melatonin supplementation in preventing these alterations using a murine model. C57BL/6J mice were exposed to GIH between gestational Days 15 and 21. Concurrently, dams received either vehicle or melatonin. The Morris water maze test was employed to evaluate offspring cognitive function, after which the offspring were euthanized at 2 months of age. The hippocampal levels of glial markers (ionized calcium-binding adapter molecule 1 [Iba-1], glial fibrillary acidic protein [GFAP]), NOD-like receptor thermal protein domain-associated protein 3 [NLRP3], nuclear factor-kappa B [NF-κB], tight-junction proteins (zonula occludens-1 [ZO-1], occludin), and synaptic plasticity-related proteins (brain-derived neurotrophic factor [BDNF], tropomyosin receptor kinase B [TrkB], postsynaptic density protein 95 [PSD-95], synaptophysin [SYN]) were quantified by enzyme-linked immunosorbent assay and western blot. Maternal melatonin supplementation significantly attenuated learning and memory impairments, reduced the protein levels of Iba-1 and GFAP by suppressing NLRP3/NF-κB signaling, and elevated those of ZO-1, occludin, BDNF, TrkB, PSD-95, and SYN. Additionally, melatonin mitigated inflammatory responses, glial cell activation, blood-brain barrier (BBB) leakage, and synaptic dysfunction induced by GIH in mice. Our results demonstrated that GIH-exposed mice exhibit cognitive deficits, alongside neuroinflammatory responses, leading to inflammasome activation, glial reactivity, BBB breakdown, and synaptic deficits. However, melatonin exerted significant protective effects against these deleterious effects. Show less
Premature ejaculation (PE) accompanied by anxiety or depression is a complex clinical condition at the intersection of male reproductive dysfunction and emotional disorders. Increasing evidence sugges Show more
Premature ejaculation (PE) accompanied by anxiety or depression is a complex clinical condition at the intersection of male reproductive dysfunction and emotional disorders. Increasing evidence suggests that serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) play central and interrelated roles in its pathogenesis. In this review we examine the bidirectional functions of 5-HT and BDNF in both the reproductive and nervous systems, highlighting their importance in regulating ejaculation, emotional stability, and synaptic plasticity. A comprehensive literature search (2010-2025) was conducted across multiple databases using relevant Medical Subject Headings (MeSH) terms, including pertinent original research and review articles, to synthesize the roles and regulatory pathways of 5-HT and BDNF in PE with comorbid anxiety or depression. We summarize the shared and distinct roles of 5-HT and BDNF in maintaining physiological balance across these systems and focus on their involvement in the major pathological processes underlying PE with anxiety or depression, including neurotransmitter imbalance, neuroendocrine dysregulation, inflammation, and oxidative stress. Furthermore, we outline the related signaling pathways through which 5-HT and BDNF exert their effects and interact. We also evaluate current pharmacological and non-pharmacological interventions targeting these molecules, demonstrating their potential to improve both ejaculatory control and emotional symptoms, and critically appraise selective serotonin reuptake inhibitor (SSRI)-related risks and highlighted the need for individualized dosing and monitoring. Emerging evidence suggests that Traditional Chinese Medicine formulations can extend intravaginal ejaculatory latency and mitigate mood symptoms and may serve as stand-alone or adjunctive options to reduce reliance on selective serotonin reuptake inhibitors (SSRIs). Overall, 5-HT and BDNF are not only deeply involved in the biological mechanisms of PE with comorbid psychological disorders, but also represent promising biomarkers and therapeutic targets, and their integrative neuro-reproductive regulatory functions provide new insights into the diagnosis and treatment of this multifaceted condition. Show less
Researchers have postulated a link between higher levels of brain-derived neurotrophic factor (BDNF) and more favorable outcomes in patients with normal pressure hydrocephalus (NPH). However, there is Show more
Researchers have postulated a link between higher levels of brain-derived neurotrophic factor (BDNF) and more favorable outcomes in patients with normal pressure hydrocephalus (NPH). However, there is no clear evidence regarding the causal association between neurotrophins and NPH. To delve deeper into this potential connection, scientists employed a rigorous method known as bidirectional Mendelian randomization (MR). This technique was utilized to explore the causal impact of various neurotrophins-such as BDNF, nerve growth factor (NGF), neurotrophin-3 (NT-3), NT-4, ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF)-on the development or progression of NPH. To investigate the causal relationship between five neurotrophin subtypes and NPH, we designed a two-sample Mendelian randomization (MR) study using comprehensive genome-wide association study (GWAS) data. Our primary approach involved the inverse-variance weighted (IVW) method. We also conducted reverse causality analysis to ensure robustness. Furthermore, we implemented complementary methods like the weighted median (WM), weighted mode, and MR-Egger to strengthen our findings. Sensitivity analyses, including MR-Egger, MR-PRESSO, leave-one-out, and Cochran's Q tests, were employed to validate results, explore heterogeneity and pleiotropy, and pinpoint potential biases. MR analysis of genetic prediction showed no statistical association of neurotrophins on NPH. However, a reverse analysis indicated a causal association between NPH and two neurotrophins: CNTF and GDNF. Specifically, individuals with NPH had a lower risk of CNTF (odds ratio: 0.7963, with a 95% confidence interval of 0.6537 to 0.9701, p = 0.0237) and a slightly reduced risk of GDNF (odds ratio: 0.9576, with a 95% confidence interval of 0.9226 to 0.9940, p = 0.0230). MR-Egger regression showed that pleiotropy did not affect the analysis. In addition, MR-PRESSO detected no outliers, and a leave-one-out analysis verified the robustness of the results. NPH was negatively and causally associated with CNTF and GDNF. Additional research is crucial to uncover the underlying mechanisms and devise strategies, including nutritional guidelines, to prevent NPH. Show less
Post-traumatic stress disorder (PTSD) causes debilitating nightmares, flashbacks and anxiety stemming from a catastrophic, often life-threatening traumatic event. Originally described in soldiers expo Show more
Post-traumatic stress disorder (PTSD) causes debilitating nightmares, flashbacks and anxiety stemming from a catastrophic, often life-threatening traumatic event. Originally described in soldiers exposed to the horrors of battle, PTSD is now recognized in civilian victims of assault, natural disasters and mass casualty events. Most people experiencing trauma do not develop PTSD, so understanding neurobiological mechanisms is crucial to predicting risk and developing targeted treatments. There have been many studies seeking to find biomarkers for PTSD, and their results have converged on several brain regions, molecular pathways and neuropsychological functions. In this review, we focus on selected findings about the glucocorticoid receptor (GR), the chaperone protein FKBP51 (FK506 binding protein 51), BDNF (brain-derived neurotrophic factor), fear memory reconsolidation and epigenetic regulation of gene expression in the hypothalamic-pituitary-adrenal (HPA) axis, amygdala and hippocampus. Together, these disparate aspects of brain function provide an emerging model for understanding the etiology and pathophysiology of PTSD. Avoidance of lethal threats is fundamental for survival, and this stringent evolutionary requirement has conserved many components of fear memory storage and behavioural response to danger. PTSD research can therefore rely on non-human animal model systems with better face and construct validity than most other psychiatric disorders. With this advantage, advances in PTSD biomarker identification are likely closer to clinical translation than in other mental illnesses. We attempt to highlight the most promising biomarkers that could be targeted by novel treatments and propose a map for future research work. Show less
Exercise as a non-pharmacological measure is important to increase the brain plasticity hence improving cognitive performance as well as mental health. This narrative review describes in depth the hie Show more
Exercise as a non-pharmacological measure is important to increase the brain plasticity hence improving cognitive performance as well as mental health. This narrative review describes in depth the hierarchical multiscale processes of neuroplasticity to exercise, including the presence of neurotrophic factor regulation, cellular metabolic adaptations and neurotransmitter remodeling, up to the structure and functional reorganization of brain networks as seen through neuroimaging, and concluding with adaptive cognitive and behavioral outcomes. We further investigate the role of personal variations in genetic time and social environments in moderating the neuroplasticity of exercise. Furthermore, the review identifies the importance of combining multimodal visualization methods with computational models in generating accurate workout prescriptions and their potential of translation into clinical and educational practice. Lastly, the research problems and "grand challenges" are addressed, with a focus on the importance of exercise as a pleiotropic behavior-intervention and its general implications to the area of promoting brain health. 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 Show more
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 dors Show more
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
Persistent functional impairment and psychological distress are common after stroke, highlighting the need for effective post-discharge nursing strategies. We performed a retrospective cohort study ev Show more
Persistent functional impairment and psychological distress are common after stroke, highlighting the need for effective post-discharge nursing strategies. We performed a retrospective cohort study evaluating the associations of a family-centered, new-media continuous nursing intervention on stroke recovery outcomes. The study included 107 patients with first-ever ischemic stroke who received either routine post-discharge care or a family-centered new-media continuous nursing intervention. Functional status, depressive symptoms, and quality of life were assessed at baseline and 6 months. Rehabilitation adherence, platform engagement indicators, and selected serum biomarkers related to neuroplasticity and inflammation were analyzed. Multivariable models were used to adjust for baseline clinical factors. At 6 months, the intervention group showed significantly greater improvements in Barthel Index scores, larger reductions in Patient Health Questionnaire-9 scores, and greater gains in quality of life compared with routine care. Rehabilitation compliance and medication adherence were higher in the intervention group. Within this group, greater platform engagement was associated with larger improvements in depressive symptoms and quality of life. In addition, patients receiving the intervention exhibited greater increases in serum brain-derived neurotrophic factor and endothelial progenitor cell counts, along with more pronounced reductions in IL-6 and TNF-α. Participation in the intervention remained independently associated with functional and psychological improvement after adjustment. Family-centered new-media continuous nursing is associated with improved functional independence, psychological recovery, adherence behaviors, and favorable biological changes in patients with ischemic stroke. Show less
Validate the clinical utility of exosome cargo (miRNAs/proteins) and NLRP3/BDNF as key regulatory molecules for acupuncture-mediated spinal cord injury (SCI) recovery. From the establishment of the da Show more
Validate the clinical utility of exosome cargo (miRNAs/proteins) and NLRP3/BDNF as key regulatory molecules for acupuncture-mediated spinal cord injury (SCI) recovery. From the establishment of the database to May 2025, a literature search was conducted on PubMed, and Embase, using keywords ["exosome cargo" or "exosome"], ["acupuncture" or "acupuncture and moxibustion" or "electroacupuncture" or "EA"], ["spinal cord injury" or "SCI"], ["immune regulation"], ["inflammatory reaction"], ["neuroregeneration" or "nerve"]. Including peer-reviewed studies on human/animal models, articles that do not meet the requirements are excluded. Preclinically, MSC-exosomal miR-145-5p suppressed TLR4/NF-κB signaling, reducing spinal IL-1β by 47% in SD rats. Schwann cell-exosomal MFG-E8 activated SOCS3/STAT3, increasing M2 macrophage CD206 by 63% and raising rat BBB scores by 3.8 points; Treg-exosomal miR-2861 upregulated tight junction proteins (occludin/ZO-1) to repair the blood-spinal cord barrier. Acupuncture (EA at GV14/GV4) upregulated spinal BDNF by 72% and NGF by 58% via Wnt/β-catenin, while EA at GV6/GV9 downregulated NLRP3 by 42-58% and TNF-α by 35-47%. Clinically, EA at EX-B2 increased ASIA scores by 3.2±1.1 points (Guo et al). Besides, 5x/week EA improved ASIA vs 3x/week (+6.4 points). EA+exercise reduced MAS by 1.6-2.9 points, with outcomes correlated to peripheral NLRP3 reduction, BDNF elevation, and MBI/WISCIII increases. Exosome cargo (miR-145-5p/MFG-E8) and NLRP3/BDNF are key regulatory molecules underlying acupuncture-mediated SCI recovery. However, limitations (small RCT samples, heterogeneous acupuncture protocols, unstandardized exosome isolation) hinder translation. Future work should focus on standardized biomarker detection, exosome engineering, and large-scale clinical trials. Show less
Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA d Show more
Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA during chronic intermittent ethanol exposure: initial sensitization was followed by a phase of attenuated and dysregulated response upon the first high-concentration exposure, culminating in stable hyper-responsiveness. Chronic ethanol exposure impaired long-term potentiation of GABAergic synapses (LTP Show less
The objective of our investigation was to explore the features of gut microbiota dysbiosis and the concentrations of gut metabolites in relation to white matter injury (WMI). Furthermore, we sought to Show more
The objective of our investigation was to explore the features of gut microbiota dysbiosis and the concentrations of gut metabolites in relation to white matter injury (WMI). Furthermore, we sought to evaluate the influence of gut dysbiosis on neuroinflammation in WMI via intestinal metabolites, and its contribution to pathogenesis. A cerebral hypoxia-ischemia-induced WMI model was established in 3-day-old Sprague-Dawley rats. Liquid chromatography-mass spectrometry/gas chromatography-mass spectrometry analyses and 16S rRNA gene sequencing were undertaken to ascertain WMI biomarkers. Mechanistic experiments were used to analyse activation of the H3K9ac/BDNF/TrkB pathway and neuroinflammation. The analysis of 16S rRNA sequencing disclosed gut microbiota dysbiosis in WMI rats, quantified using linear discriminant analysis effect size. Overall, 341 differentially expressed metabolic markers between the WMI and Sham groups were discovered. The Kyoto Encyclopedia of Genes and Genomes network enhancement evaluation revealed significant downregulation of 20 metabolic processes in the WMI group, which is strongly related to changes in fecal microbial metabolites, and the synthesis process of unsaturated fatty acids was the most significant. Gut microbiota dysbiosis may influence WMI by downregulating metabolites such as eicosapentaenoic acid (EPA). Fecal microbiota transplantation increased EPA concentration in the brain tissue of WMI rats. Gut microbiota-derived EPA promoted H3K9ac and BDNF/TrkB expression and inhibited the transcription of pro-inflammatory TNF- WMI induces gut dysbiosis involving down-regulation of unsaturated fatty acid synthesis. Fecal microbiota transplantation leads to increased levels of EPA. Gut microbiota-derived EPA increases levels of acetylated histone H3K9ac, causes activation of the BDNF/TrkB pathway, reduces neuroinflammation, and improves WMI-associated myelination disorders. It provides a basis for targeted treatment of white matter injury in the future. Show less
Xiaohui Zhai, Dongshi Wang · 2026 · Neuroscience and biobehavioral reviews · Elsevier · added 2026-04-24
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 pro Show more
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
Serum extracellular vesicle (EV) microRNAs (miRNAs) are promising biomarkers for ischemic stroke (IS), but their role in transient ischemic attack (TIA) remains unclear. This study aimed to evaluate E Show more
Serum extracellular vesicle (EV) microRNAs (miRNAs) are promising biomarkers for ischemic stroke (IS), but their role in transient ischemic attack (TIA) remains unclear. This study aimed to evaluate EV miRNAs as non-invasive diagnostic tools for IS and TIA. Using single-molecule sequencing, miRNAs were profiled in pooled sera from 50 IS patients and 50 controls. Altered miRNAs were validated via individual qRT‑PCR in the same cohort and tested in expanded internal (100 IS, 40 TIA, 100 controls) and external validation cohorts (32 IS, 8 TIA, 32 controls). Diagnostic performance was assessed via ROC and logistic regression analyses. Bioinformatics and in vitro oxygen-glucose deprivation/reperfusion (OGD/R) models were employed to explore mechanisms. Initial screening identified 134 differentially expressed EV miRNAs (36 upregulated, 98 downregulated) in IS. Validation confirmed significantly decreased let-7f-5p in IS and TIA, and elevated miR-486-5p and let-7b-5p in IS, with let-7b-5p higher in IS than TIA. A combined EV miRNA panel may effectively distinguish IS and TIA from controls, and stratify IS severity and TIA subsequent stroke risk. Multivariable logistic regression showed increased EV let-7b-5p independently associated with IS, and reduced let-7f-5p with IS/TIA. Bioinformatic analysis predicted FOXO1 and BDNF as key targets; decreased FOXO1 and increased BDNF were observed in IS serum and serum EVs, and FOXO1 downregulation was replicated in an OGD/R cellular model. A serum EV miRNA signature (downregulated let-7f-5p, upregulated miR-486-5p and let-7b-5p) may serve as a non-invasive biomarker panel for assessing IS severity and TIA stroke risk. Dysregulation of these miRNAs and their targets may contribute to ischemic injury pathology. Show less
Post-cardiac surgery anxiety or depression (PCPAD) is a common neuropsychiatric complication following cardiovascular interventional procedures, which significantly increases the risk of adverse cardi Show more
Post-cardiac surgery anxiety or depression (PCPAD) is a common neuropsychiatric complication following cardiovascular interventional procedures, which significantly increases the risk of adverse cardiovascular events and long-term mortality. Existing treatment strategies have limitations, and clinical needs remain unmet. The gut-brain axis (GBA) serves as a core network regulating neuroimmune and endocrine responses, and its imbalance involves key links such as intestinal flora dysbiosis and neuroimmune crosstalk disorders. It is closely related to the pathogenesis of this complication, providing a novel perspective for targeted interventions. This review aims to systematically clarify the mechanism of GBA in PCPAD, comprehensively explore therapeutic strategies targeting this axis, and focus on the intervention value and application potential of natural products. The study was designed and conducted in strict accordance with the PRISMA 2020 guidelines. Relevant literatures were searched from PubMed, Web of Science Core Collection, ScienceDirect, Embase, Cochrane Library, and CNKI databases from their inception to December 2025. Literatures focusing on GBA-related mechanisms of PCPAD or investigating the mechanisms and clinical applications of natural products targeting GBA for PCPAD treatment were included. Conference abstracts, case reports, duplicate publications, and other ineligible literatures were excluded. Through quality control strategies including double independent screening and verification, priority inclusion of high-credibility evidence, and data cross-validation, 168 eligible literatures were finally included. The composition and functions of GBA, its imbalance mechanisms, and the basic and clinical evidence of natural product-based interventions were systematically analyzed. Studies have shown that GBA imbalance is the core pathogenesis of PCPAD, among which the inflammatory cascade initiated by intestinal flora dysbiosis, abnormal activation of the neuroendocrine axis, disorder of immune-nerve crosstalk, and abnormal gene and epigenetic regulation are key pathological links. In summary, GBA imbalance, especially gut microbiota dysbiosis and neuroimmune interactions, plays a critical role in the pathogenesis of PCPAD. Natural products (including traditional Chinese medicine (TCM) monomers, TCM compound prescriptions, patented TCM drugs, and natural products from other plant sources worldwide) can exert therapeutic effects by synergistically regulating GBA homeostasis through multiple targets. Specifically, they include increasing the abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus, promoting the production of anti-inflammatory metabolites such as short-chain fatty acids, repairing intestinal barrier function, inhibiting pro-inflammatory pathways such as NF-κB and NLRP3 inflammasome, and regulating the levels of neurotransmitters and neurotrophic factors such as 5-HT and BDNF. Basic and clinical studies have confirmed that these natural products have high biocompatibility and low toxic side effects, and are compatible with the safe medication needs of patients during the organ function recovery period after cardiac surgery. Several natural products have been proven to modulate GBA dysfunction, with potential for clinical therapeutic application. This review systematically elucidates a new paradigm of precise intervention for PCPAD via natural products that regulate GBA through multiple targets, addressing the limitation of traditional single-target therapies and providing a low-cost, easily promotable solution for clinical translation. Additionally, natural product-based interventions offer a novel approach for treating post-cardiac surgery complications. In the future, it is necessary to further conduct large-sample, multicenter clinical trials to clarify their mechanisms of action and standardized dosage regimens, strengthen toxicological research, facilitate the translation from basic research to clinical practice, and provide more precise therapeutic strategies for patients. Show less
Early vascular regeneration is important for the speedy recovery of neurological function following ischemic stroke. M2-like microglia polarization decreases and vascular regeneration weakens with agi Show more
Early vascular regeneration is important for the speedy recovery of neurological function following ischemic stroke. M2-like microglia polarization decreases and vascular regeneration weakens with aging. The function of mitochondrial respiratory chain is dependent on M2-like polarization in microglia. A murine model of middle cerebral artery occlusion (MCAO) was used to perform animal behavioral assessments, immunoblotting, tube formation and chick embryo chorioallantoic membrane assays. A D-galactose-induced cellular senescence model was established in BV2 cells. Aging significantly exacerbates acute brain injury 24 hours post-cerebral ischemia-reperfusion, with increased expression of M1-like microglial markers and a concomitant decrease in M2-like microglial markers. Additionally, aging can inhibit DARS2 protein expression, adversely affect angiogenesis and reduce brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGFA) expression. In vitro, oxygen-glucose deprivation/reoxygenation and re-glucose (OGD/R) demonstrated that This study suggests that aging impedes M2-like microglial polarization by downregulating DARS2 expression in microglia, thereby impairing emergency angiogenesis during acute ischemic stroke and exacerbating neuronal damage. Show less
Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has Show more
Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity. At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD. Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD. Show less
Traumatic spinal cord injury (SCI) induces neuronal apoptosis and neuroinflammation, which exacerbate secondary damage and hinder functional recovery. Efficient clearance of apoptotic cells and modula Show more
Traumatic spinal cord injury (SCI) induces neuronal apoptosis and neuroinflammation, which exacerbate secondary damage and hinder functional recovery. Efficient clearance of apoptotic cells and modulation of the inflammatory microenvironment of spinal cord are essential for promoting tissue repair. This study aimed to investigate whether Midkine (MDK), a heparin-binding growth factor, facilitates functional recovery after SCI and explores the underlying mechanisms. A rat model of moderate SCI was established using Allen's impact method. Lentiviral vectors were used to overexpress MDK in the spinal cord. Behavioral assessments, including BBB score and gait analysis, were performed to evaluate motor function recovery. Motor evoked potentials (MEPs) serve as a neurophysiological tool for evaluating the functional integrity of the corticospinal tract. In vivo and in vitro experiments were conducted to assess microglial efferocytosis and elucidate the underlying molecular mechanisms. Transcriptomic bioinformatic analysis suggests that SCI is characterized by pronounced accumulation of apoptotic cells and robust neuroinflammatory responses, whereas single-cell analysis implicates MDK as a key contributor to neurorepair after SCI. MDK expression is dynamically regulated following SCI, with an early upregulation followed by a gradual decline over time, its location predominantly observed around microglial cells. Functionally, MDK overexpression significantly enhances motor recovery after SCI, accompanied by reduced neuroinflammation, decreased neuronal apoptosis, and improved neuroprotection. Mechanistically, MDK promotes microglial efferocytosis both in vivo and in vitro, activates the AKT/mTOR signaling pathway, upregulates BDNF and LRP-1 expression, and facilitates microglial polarization toward an anti-inflammatory M2 phenotype. Notably, inhibition of LRP-1 with receptor-associated protein (RAP) abolished the efferocytic and neuroprotective effects of recombinant MDK, highlighting LRP-1 as a key mediator of MDK's actions in microglia. Our study unveils the MDK/LRP-1/efferocytosis axis as a previously unrecognized therapeutic target for SCI. By orchestrating apoptotic cell clearance, dampening neuroinflammation, and fostering neuroprotection, this axis critically shapes the post-injury microenvironment to facilitate recovery. These findings suggest that MDK-centered therapy may represent a strategy for spinal cord repair, with LRP-1 modulation offering precise control over microglial responses. Show less
Perineural invasion (PNI) represents a uniquely distinctive pathway for tumor metastasis, but its underlying molecular mechanisms and therapy remain unclear. Bioinformatics analysis and transcriptomic Show more
Perineural invasion (PNI) represents a uniquely distinctive pathway for tumor metastasis, but its underlying molecular mechanisms and therapy remain unclear. Bioinformatics analysis and transcriptomic sequencing were first employed to investigate the involvement of the BDNF/TrkB axis in the ESCC PNI, which was validated with ESCC cells co-cultured with a dorsal root ganglia system (ESCC/DRG model), a mouse PNI model, and ESCC tissues, mainly using microscopic imaging, IVIS Spectrum The BDNF/TrkB axis is closely associated with the PNI in ESCC. This pathway plays a pivotal role in driving PNI progression via Akt signaling. Deguelin was identified as an effective inhibitor of PNI in ESCC. Mechanistically, BDNF was revealed to be a key binding target of Deguelin, which disrupts PNI development by modulating the BDNF/TrkB/Akt axis. Notably, overexpression of BDNF can counteract Deguelin's inhibitory effects on ESCC growth and PNI progression. The BDNF/TrkB axis promotes the progression of ESCC PNI, and Deguelin inhibits ESCC PNI by targeting this axis, enhancing the understanding of PNI's molecular mechanisms and offering new therapeutic options. Show less
This study aimed to investigate the effect of different preferences of food-derived odors (common food flavors/spices) on the appetite, immune system, and CNS of mice through 15 days of olfactory expo Show more
This study aimed to investigate the effect of different preferences of food-derived odors (common food flavors/spices) on the appetite, immune system, and CNS of mice through 15 days of olfactory exposure. According to the ranking of sniffing duration, beef essence was chosen as a pleasant odor, while garlic essence was chosen as an unpleasant odor. Results showed that food intake and body weight gradually increased in all groups, with the lowest values observed in the garlic odor group. Unpleasant garlic odor suppressed the mRNA transcription levels of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the hypothalamic arcuate nucleus, along with elevated leptin levels, thereby inhibiting food intake and causing body weight loss. In addition, the serum TNF-α, IL-2, and IL-6 levels in the garlic odor group were significantly higher than those in the beef and control groups, which indicated that the immune system may be impaired by the exposure to unpleasant garlic odor. Furthermore, pleasant beef odors could promote the differentiation of hippocampal neurons and the levels of brain-derived neurotrophic factors and glial cell line-derived neurotrophic factor, which may have great potential in improving neurological disorders. Conclusively, unpleasant odors may suppress immune function or modulate the CNS by establishing an odor-CNS-immune pathway, while pleasant food odors affect only the CNS. The present study preliminarily provides novel insights that different preferences for food odors could affect the body weight, immune system, and CNS. It may serve as a reference for further research and development of aromatherapy as an adjuvant medicine and therapeutic method. 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 n Show more
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
The primary treatment for schizophrenia currently relies on medication. Nevertheless, the efficacy of medication for Cognitive Impairment Associated with Schizophrenia (CIAS) is constrained, and it is Show more
The primary treatment for schizophrenia currently relies on medication. Nevertheless, the efficacy of medication for Cognitive Impairment Associated with Schizophrenia (CIAS) is constrained, and it is also accompanied by side effects. Consequently, the investigation of novel non-pharmacological strategies is essential. High-definition transcranial direct current stimulation (HD-tDCS) and aerobic exercise (AE) have emerged as promising approaches for cognitive enhancement in individuals with schizophrenia. This study aims to evaluate the efficacy of integrating HD-tDCS with AE for CIAS and to elucidate the underlying mechanisms of this synergistic intervention. A randomized, double-blind, controlled trial will be conducted. The CIAS will be randomly allocated to one of four groups: MRI-guided HD-tDCS + AE, MRI-guided HD-tDCS alone, AE alone, and a control group. Structural magnetic resonance imaging (MRI) data will be obtained to determine the optimal electrode placement. The central electrode will be positioned over the medial prefrontal cortex (mPFC). Both HD-tDCS and AE will be administered five times per week over a four-week period, resulting in a total of 20 sessions. The primary outcome measure will be the change in cognitive function, evaluated using the MATRICS Consensus Cognitive Battery. Secondary outcomes will include changes assessed by the Repeatable Battery for the Assessment of Neuropsychological Status and the Wisconsin Card Sorting Test which are designed to evaluate global and executive functions. The Facial Emotion Perception Test and the Voice Emotion Perception Test will be utilized to assess social cognition. The severity of clinical symptoms will be quantified through the Positive and Negative Syndrome Scale and the Brief Psychiatric Rating Scale. This study will incorporate functional near-infrared spectroscopy, MRI, electroencephalography, P300 event-related potential, eye movement examination and plasma brain-derived neurotrophic factor (BDNF) levels to investigate the underlying mechanisms. Assessments will be evaluated at baseline (T0), after 2 weeks (T1), after 4 weeks (T2), and after 6 months (T3). The integration of MRI-guided HD-tDCS targeting the mPFC and AE presents an efficacious and individualized treatment strategy for CIAS. This proof-of-concept study may provide a multi-dimensional view of biological mechanisms underlying HD-tDCS combined with AE in precision psychiatry. The study is registered with https://www.chictr.org.cn/ protocol registration number ChiCTR2500106980 (date of registration: 1. August. 2025). It was approved by the Research Ethics Committee of the Second Affiliated Hospital of Xinxiang Medical University (Approval Code: XYEFYLL-2025-16, Approval Date: 17 February 2025). Recruitment began in December 2025. Show less