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The high global prevalence of anxiety disorders, coupled with the limitations of existing treatments, constitutes a severe public health challenge. Chronic stress, as a core environmental trigger, has garnered increasing attention for its mechanism of mediating brain-derived neurotrophic factor (BDNF) imbalance through neuroinflammation. BDNF dysregulation may contribute to anxiety disorders, particularly in subtypes with heightened neuroinflammation. The objective of this review is to comprehensively and methodically explores the potential role of the "M1-like microglia-A1-like astrocyte axis (M1-A1 axis)" in linking chronic stress to BDNF dysregulation in anxiety disorders, and to provide a theoretical basis for intervention strategies targeting this axis. By synthesizing recent relevant clinical and preclinical evidence, this review integrates evidence from molecular to systems levels, focusing on the activation mechanisms of neuroinflammation under chronic stress, the crosstalk between glial cells, and their regulatory network on BDNF. Chronic stress is associated with peripheral and central cascades through hypothalamic-pituitary-adrenal (HPA) axis activation and gut microbiota disruption. Within the central nervous system (CNS), stress induces microglial polarization toward the pro-inflammatory microglial subpopulations (hereinafter referred to as M1-like microglia). The signals released by M1-like microglia, such as Interleukin-1 alpha (IL-1α), Tumor Necrosis Factor-alpha (TNF-α), and Complement Component 1q (C1q) (ITC), drive astrocytes to transform into the neurotoxic astrocyte states (hereinafter referred to as A1-like astrocyte), forming the "M1-A1 axis". This axis contributes to BDNF dysregulation through the following mechanisms: (1) Release of pro-inflammatory cytokines inhibits BDNF transcription and translation; (2) Induction of astrocytic lactate metabolism disruption, which impairs neuronal energy supply and acidifies the microenvironment, further amplifying inflammation and affecting BDNF expression; (3) Compromise of the blood-brain barrier(BBB)enables peripheral immune cells to penetrate into the CNS, and these cells work in synergy with central glial cells to amplify inflammation. The reduction in BDNF and the imbalance in the ratio of its precursor to mature form ultimately lead to impaired synaptic plasticity in brain regions like the hippocampus (HIP) and amygdala, precipitating anxiety-like behaviors. Existing pharmacological interventions are inadequate to reverse this pathological process. The M1-A1 axis may serve as a key node linking chronic stress to BDNF dysregulation and anxiety disorders. Targeting the phenotypic transformation of glial cells, repairing the BBB, or modulating glial cell metabolism (e.g., lactate shuttle) may represent potential strategies requiring further validation. Future research should focus on the spatiotemporal dynamics of this axis and its clinical translation. Show less

In the core of a stroke, cell death occurs within minutes. In the penumbra, activity quickly drops, but cells typically remain viable for several hours. Improving neuronal survival in the penumbra is crucial for enhancing recovery in patients with stroke. Earlier work showed that mild activation may improve recovery, but the mechanisms are unclear. Brain-derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions via activation of tyrosine receptor kinase B (TrkB) receptors, and its release is activity-dependent. This study explored the role of BDNF/TrkB signaling in neuronal survival under hypoxic conditions, using cultures of dissociated cortical rat neurons. When exposed to hypoxia, activity quickly drops and cells become apoptotic after ∼12 h, similar to observations in the ischemic penumbra. Inhibition of the TrkB receptor in healthy, normoxic cultures led to a fivefold increase in apoptosis, confirming the importance of BDNF/TrkB signaling for cell viability in these preparations. The addition of BDNF to hypoxic cultures significantly improved neuronal survival, comparable with the effects of mild activation. These findings suggest that the beneficial effect of mild stimulation to prevent apoptosis in hypoxic cultures is mediated by BDNF/TrkB signaling, offering insights for potential therapeutic strategies aimed at promoting neuronal recovery after a stroke. Show less

Traumatic brain injury (TBI) is a well-recognized risk factor for late-life cognitive decline. However, few studies have examined individual differences in sex and genetics, which may modify risk. We examined sex differences in gene-TBI interactions for dementia risk genes apolipoprotein E (APOE) and selected brain-derived neurotrophic factor (BDNF) single-nucleotide polymorphisms (SNPs) in predicting late-life cognitive decline. We studied 4293 individuals without dementia at baseline (mean age: 74.93, SD: 6.87 years, 57% female). Approximately 25% reported a history of TBI. Linear mixed effects models examined associations between sex, TBI characteristics, APOE genotype, BDNF SNPs and their interactions, with cognitive decline. Compared to males, females experienced fewer TBIs across the lifespan, the majority occurring in late-life. Number of TBI interacted with sex and APOE genotype such that female APOE ε4 allele carriers with multiple TBIs exhibited worse outcomes on global cognition (P < .001; eg, ε4+/TBI2+ estimated marginal means [EMMs] from baseline to year 10 = -17.22 points compared with ε4-/TBI2+ = -7.21), whereas males did not exhibit differential decline by APOE ε4 alleles and TBI number. BDNF Val66Met genotype showed trend-level moderation of TBI history and cognitive decline, with slower decline experienced by heterozygous individuals with multiple TBIs compared with homozygous major allele carriers. There were few significant associations between timing and severity of TBI with cognitive outcomes. These results underscore the importance of considering individual differences of sex and APOE and BDNF-related gene variants on the long-term cognitive effects of TBI. Show less

Brain-derived neurotrophic factor (BDNF) has been suggested to support dopaminergic neuron's endurance and dopamine release. Its Val66Met polymorphism might modify Parkinson's disease (PD) evolution, although evidence in Asian populations remains limited. This study aimed to explore how the BDNF rs6265 genotypes are associated with the clinical characteristics and longitudinal progression patterns of PD patients in a Korean population. A total of 247 patients were enrolled and followed for a mean duration of 50.9 ± 23.9 months. Baseline and/or periodic assessments captured motor severity, non-motor burden, cognition, orthostatic stress, cardiac denervation, and presynaptic dopamine transporter availability. The repeated measures were manipulated to infer any genotypic differences in the trajectories of each clinical domain. Genotype frequencies were 31.2% (77/247) for Val/Val and 68.8% (170/247) for Met-allele carriers. Baseline clinical characteristics and presynaptic dopamine transporter availability were comparable between genotypes; however, Val homozygotes showed more preserved myocardial innervation and poorer non-frontal cognitive performance. Longitudinal analyses demonstrated genotype-specific increases in motor and cognitive severity. Compared to Met-allele carriers, the homozygous Val group exhibited accelerated motor progression and more rapid decline in frontal domain after three years of follow-up. The differences in myocardial denervation at diagnosis, cognitive profiles, and motor progression might suggest a potential modulatory role of BDNF polymorphism in PD progression in the Korean population. Show less

Studies have shown that sarcopenia and its related parameters are associated with cognition. Preclinical evidence suggests that myokines, such as irisin, Brain-Derived Neurotrophic Factor(BDNF), myostatin and Insulin-like Growth Factor-1(IGF-1) might explain this relationship. This study aimed to explore the associations between sarcopenia-related parameters and cognition, and whether myokines influence this association. Exploratory, cross-sectional analysis of data from the Exercise and Nutrition for Healthy AgeiNg (ENHANce,NCT03649698) study. Participants were older adults(≥65 years) with EWGSOP2-defined sarcopenia. Cognitive functioning was assessed by Mini-Mental State Examination(MMSE), Repeatable Battery for the Assessment of Neuropsychological Status(RBANS), Trail Making Test A&B(TMT), Stroop and Maze Test. Sarcopenia-related parameters were measured: Handgrip Strength, Chair Stand Test, appendicular Lean Mass(aLM), Gait Speed (GS) and Short Physical Performance Battery(SPPB). Serum myokines(IGF-1, irisin, myostatin, BDNF) were determined through ELISA. Associations between cognition and sarcopenia-related parameters were analyzed using multivariable regression, adjusting for potential confounders including myokines. Fifty-eight participants were included in this analysis (76.2 ± 6.7 years, ♀:65.5%). After adjustment for age, sex, body mass index, aLM was associated with MMSE(β = 0.193,p = 0.012), RBANS Total(β = 0.196,p = 0.007) and RBANS Attention(β = 0.215,p = 0.002), CST was associated with RBANS Language(β = -0.314,p = 0.030), SPPB was associated with Maze time(β = -0.364,p = 0.004) and TMT-B (β = -0.333,p = 0.013) and GS was associated with TMT-A(β = -0.324,p = 0.045). After adjustments for BDNF& IGF-1, the association between GS and TMT-A became non-significant. Irisin and myostatin did not influence the sarcopenia-cognition associations. Sarcopenia-related parameters are associated with global and specific cognitive domains. BDNF may, partially, explain the association between muscle mass and MMSE. Additional research with larger sample size is needed to confirm these findings. Show less

Fujian Tablets (FJT), a traditional Chinese medicinal (TCM) preparation, has been clinically used in the rehabilitation of neurological disorders related to ischemic brain injury in the context of TCM theory. However, its molecular mechanism underlying the promotion of post-ischemic stroke motor function recovery, especially via regulating corticospinal tract (CST) remodeling-a key structure for motor control-remains unelucidated. This study aimed to investigate the effect of FJT on CST remodeling in the denervated hemisphere and motor function recovery in middle cerebral artery occlusion (MCAO) rats, and to explore its potential mechanism by focusing on the balance between precursor brain-derived neurotrophic factor (proBDNF) and mature BDNF (mBDNF), which is tightly regulated by BDNF-cleaving enzymes (Pcsk1 and Furin). The MCAO rat model was established using the intraluminal filament method. Model rats were randomly divided into four groups: MCAO model group, FJT low-dose group, FJT medium-dose group, and FJT high-dose group. Motor function was evaluated by Catwalk gait analysis (assessing average speed, step length, and standing time). CST remodeling and conduction efficiency were determined via biotinylated dextran amine (BDA) neural tracing and motor evoked potential (MEP) detection, respectively. The mRNA and protein expressions of BDNF, cleaving enzymes (Pcsk1, Furin), and related receptors (TrkB, p75NTR, Sortilin) in brain tissues were measured using quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot. BDNF silencing experiment was performed to verify the role of BDNF in FJT-induced effects. Additionally, in vitro neuronal culture was used to observe the effects of FJT, exogenous mBDNF, and Pcsk1/Furin inhibitors on neuronal growth. Compared with the MCAO model group, medium-dose FJT exhibited the most significant therapeutic effects. Specifically, FJT notably improved gait parameters increasing average speed from 20.77 mm/s (MCAO) to 25.71 mm/s (FJT) and step length by approximately 21.14 %. Furthermore, FJT enhanced MEP conduction efficiency and promoted CST remodeling, characterized by a 5.26 % increase in BDA-positive nerve fibers and elevated growth-associated protein 43 (GAP43) expression in the denervated hemisphere. At the molecular level, FJT upregulated the mRNA and protein expressions of Pcsk1 and Furin, increased the levels of BDNF and its functional receptor TrkB, and downregulated the expressions of proBDNF-preferring receptors p75NTR and Sortilin, ultimately shifting the proBDNF/mBDNF ratio toward mBDNF dominance. BDNF silencing significantly attenuated these improvements, reversing FJT-induced motor recovery and CST remodeling. In vitro, FJT-promoted neuronal growth was mimicked by exogenous mBDNF but reversed by Pcsk1/Furin inhibitors. Compared with the MCAO model group, medium-dose FJT exhibited the most significant therapeutic effects. Specifically, FJT notably improved gait parameters, increasing the average speed from 20.77 mm/s (MCAO) to 25.71 mm/s (FJT) and step length by approximately 21.14 %. Furthermore, FJT enhanced MEP conduction efficiency and promoted CST remodeling, characterized by a 5.26% increase in BDA-positive nerve fibers and elevated Growth-Associated Protein 43 (GAP43) expression in the denervated hemisphere. At the molecular level, FJT upregulated the mRNA and protein expressions of Pcsk1 and Furin, increased the levels of BDNF and its functional receptor TrkB, and downregulated the expressions of proBDNF-preferring receptors p75NTR and Sortilin, ultimately shifting the proBDNF/mBDNF ratio toward mBDNF dominance. BDNF silencing significantly attenuated these improvements, reversing FJT-induced motor recovery and CST remodeling. In vitro, FJT-promoted neuronal growth was mimicked by exogenous mBDNF but reversed by Pcsk1/Furin inhibitors. Show less

Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2X7 receptor (P2X7R) plays a crucial role in neuroinflammation and pyroptosis, while Jujuboside A (JuA), a major saponin extracted from Ziziphus jujuba seeds, has been reported to exert significant antidepressant and analgesic effects. In this study, we systematically evaluated the regulatory effects of JuA on the P2X7R-brain-derived neurotrophic factor (BDNF) pathway and on pyroptosis and apoptosis using a rat model of colorectal distension (CRD) and primary neuron/astrocyte cultures. JuA markedly alleviated visceral hypersensitivity and depressive-like behaviors in CRD rats and reduced P2X7R expression in both the spinal cord (SC) and hippocampus (HPC). Further investigations in vitro revealed that JuA inhibited excessive P2X7R activation in SC astrocytes, thereby decreasing the expression of NLRP3, Caspase-1, GSDMD, IL-1β and TNF-α, indicating suppression of pyroptosis. Similarly, JuA exerted an anti-pyroptotic effect in HPC astrocytes and inhibited neuronal apoptosis by reducing Caspase-3 and Bax levels while increasing Bcl2 expression, leading to upregulation of HPC BDNF. Collectively, JuA targets P2X7R and suppresses downstream pyroptotic and apoptotic signaling in vitro, which may contribute to its neuroprotective effects. These findings provide experimental evidence supporting the potential of JuA as a therapeutic agent for comorbid visceral pain and depression. Show less

Hyposalivation affects cognitive function. However, its impact on hippocampus-dependent memory remains unclear. Saliva contains brain-derived neurotrophic factor (BDNF), which is also synthesized in the hippocampus and can pass through the blood-brain barrier (BBB) to influence hippocampal plasticity. Therefore, we hypothesized that hyposalivation reduces peripheral BDNF availability, leading to decreased hippocampal BDNF levels and cognitive impairment. In this study, this relationship was investigated using an in vivo model of sialadenectomy-induced hyposalivation. A total of 24 8-week-old male ddY mice were divided into control and extraction (EXT) groups. The EXT group underwent submandibular and sublingual salivary gland extractions, whereas the control group underwent a sham operation. Saliva was collected at baseline (0 weeks) and at 2- and 3-weeks postoperatively. Cognitive function was assessed using the Y-maze, fear conditioning (FC), novel object recognition (NOR), and object location tests (OLT). Anxiety-like behavior was evaluated using the open field test (OFT) and elevated plus-maze (EPM) tests. Hippocampi were collected at 3 weeks post-operation for BDNF quantification using enzyme-linked immunosorbent assay, and its concentration in subregions of the hippocampus was determined by semi-quantitative analysis. Hyposalivation significantly impaired spatial working memory in the Y-maze test and contextual fear memory in the FC, both of which are hippocampus-dependent. NOR showed only a transient deficit at 24 h during the 2-week period (no significant difference in 3-week post-operation), whereas long-term spatial memory measured by the OLT exhibited a persistent 24-h impairment at both 2 and 3 weeks, indicating reduced long-term spatial memory rather than accelerated decay. No significant differences were observed in anxiety-like behavior. Although sialoadenectomy significantly reduced salivary secretion and total salivary BDNF output, the concentration of BDNF in saliva in both groups remained unchanged at 2- and 3-weeks post-operation. However, hippocampal BDNF levels were significantly lower in the EXT group than in the control group. These findings suggest that hyposalivation may selectively impair hippocampus-related spatial memory without affecting recognition memory or anxiety-related behaviors. Show less

The roots of Platycodon grandiflorus (Jacq.) A. DC. (Campanulaceae), known as Platycodi Radix (PR), have long been used as a traditional medicine for respiratory ailments and for relieving chest oppression, a symptom associated with qi stagnation and emotional imbalance resembling depressive states. However, the molecular mechanisms underlying this ethnopharmacological effect and neuroplastic signaling remain to be elucidated. This study aimed to investigate the antidepressant-like activities of PR and its triterpenoid saponins, platycodin D (PD) and platycodin D2 (PD2), and their underlying molecular mechanisms. In a chronic restraint stress (CRS) mouse model, antidepressant efficacy was evaluated using behavioral assessments, including open field tests and forced swimming tests. Hippocampal microarray and pathway enrichment analyses, as well as the compound combination-oriented natural product database unified terminology (COCONT) database, were used to explore signaling pathways and active components, respectively. The molecular mechanisms underlying brain-derived neurotrophic factor (BDNF) expression and secretion were investigated in N2a cells and hippocampal tissues. The activation of BDNF-related signaling pathways was examined using neurite outgrowth assays, quantitative PCR, immunoblotting, and immunofluorescence analysis. PR extract (PRE), PD, and PD2 significantly improved depressive-like behavioral deficits induced by CRS and restored the expression of hippocampal neuroplasticity markers, including BDNF, neurofilament light, and PSD95. These effects were accompanied by enhanced activities in ERK/cAMP-response element binding protein (CREB) and Akt/mechanistic target of rapamycin (mTOR) signaling pathways. These compounds promoted neurite outgrowth and triggered α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)-dependent Ca PR and its triterpenoid saponins, PD and PD2, could alleviate stress-induced depressive symptoms and modulate BDNF-centered neuroplasticity signaling, supporting their potential relevance as phytotherapeutic candidates for depressive disorders. Show less

The effects of different exercise intensities on cognitive outcomes and brain-derived neurotrophic factor (BDNF) concentrations in adolescents with overweight/obesity are not yet fully elucidated. This study aimed: (a) to compare the prevalence of responders to cognitive function and BDNF concentration in adolescents with overweight/obesity participating in a 12-week intervention with high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT), and (b) to analyze whether cardiorespiratory fitness (CRF) can explain differences in inter-individual variability between responders and non-responders. Adolescents with overweight/obesity were assigned to HIIT (n = 15), MICT (n = 14), or CG (n = 24). Anthropometrics, body composition, CRF, basal BDNF, and cognitive performance (Trial Making Test (TMT) and Stroop Test (ST)) were evaluated pre- and post-intervention. Training was performed on stationary bikes (3×/week for 12 weeks). The prevalence of responders in ST and TMT was higher in the HIIT group than in CG (93-62%, p = 0.029; 67-33%, p = 0.043), with no differences in MICT. No group differences were found for BDNF responders (HIIT:73%-MICT:71%-CG:46%, p = 0.263). ST and TMT responders had greater CRF improvements than non-responders. HIIT elicited a higher prevalence of cognitive responders than CG. CRF improvements may partially explain individual variability in responsiveness to cognitive outcomes. This is the first study to examine and compare inter-individual variability in cognitive function and BDNF levels following MICT and HIIT interventions in adolescents with overweight/obesity; Exercise intensity and improvements in cardiorespiratory fitness are key factors for optimizing the cognitive effects of interventions in youth with overweight; Twelve weeks of supervised HIIT and MICT training led to increased rates of cognitive responders among adolescents with overweight/obesity. Show less

Post-traumatic stress disorder (PTSD), in its partial or full forms, is frequently observed in military populations. It is therefore important to predict the risk of PTSD prior to deployment. Since elevated allostatic load markers have been described in PTSD, we investigated whether these alterations pre-exist before PTSD onset. Our objective was to explore the ability of four allostatic load markers (urinary and blood cortisol, BDNF and 8-iso-PGF2α) to predict partial/full PTSD onset after a 6-month deployment. We conducted a prospective study in a French military cohort deployed to Afghanistan. PTSD was assessed before (M After controlling for age, pre-deployment PCLS scores, and the number of missions, we found that elevated M Asymptomatic subjects at risk of partial/full PTSD exhibit a common pattern of hypothalamic-pituitary axis dysregulation, similar to that observed in established PTSD. Show less

Preserving brain health is essential to maintaining quality of life and cognitive function with age. Exercise plays an essential role. Aerobic exercise such as running and cycling can enhance brain plasticity through increasing gray matter volume in the cerebellum and temporal lobe, as well as the density of connections in the brain's frontal and motor areas via upregulating brain-derived neurotrophic factor (BDNF) and serotonin systems. Anaerobic exercise, such as weightlifting, primarily increases gray matter volume in the basal ganglia and increases the density of connections in the posterior lobe of the cerebellum. In midlife, aerobic exercise can increase white matter integrity and cortical thickness in primary motor and somatosensory areas, while in older age it improves specific markers of cognitive function, such as episodic memory. With regards to neurodegenerative diseases, aerobic exercise has been linked to improved memory performance and reduced hippocampal atrophy in Alzheimer's disease. In Parkinson disease, aerobic exercise has shown to reduce brain atrophy, improve motor function and cognitive control, while anaerobic exercise improves motor performance and information processing. Overall, both aerobic and anaerobic exercises are integral and complementary to preserving brain health through effects on cognitive function and brain structure. Show less

Although chemotherapy remains a life-saving intervention for numerous cancer patients, it is often accompanied by depressive symptoms and cognitive impairments, "chemobrain." Noteworthy, multiple studies emphasize the role of glycogen synthase kinase 3β (GSK-3β) in depression and chemobrain; nevertheless, no available data relate GSK-3β inhibitors to chemobrain. Herein, this study aims to investigate the effect of the GSK-3β inhibitor, lithium, on behavioral and neurobiological abnormalities in a doxorubicin (DOX)-induced rat model of chemobrain. The chemobrain model was established through weekly intraperitoneal injections of doxorubicin (2 mg/kg/wk) for a duration of 4 weeks, whereas lithium (100 mg/kg/d, i.p.) was administered concomitantly over the same period. Behavioral, neurochemical, and histopathological evaluations were performed after the experimental protocol. DOX-induced depressive-like behaviors and cognitive impairments, with reduction in prefrontal cortex tropomyosin receptor kinase B receptors, brain-derived neurotrophic factor protein kinase B (BDNF), and phosphorylated protein kinase B, elevating the levels of the active form of GSK-3β, which lessened phosphorylated mammalian target of rapamycin/nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 and BDNF/synapsin-1 pathways, while triggering overexpression of NF-κB, proinflammatory cytokines, oxidative stress, apoptosis, tau hyperphosphorylation, and neurodegeneration. Lithium ameliorated DOX-induced behavioral, neurochemical, and histological abnormalities. To the best of our knowledge, this study presents the first evidence that lithium treatment can modulate DOX-induced depression and cognitive deficits, potentially through revamping the BDNF/tropomyosin-related kinase receptor B/protein kinase B/GSK-3β/mammalian target of rapamycin/nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 signaling cascade, thereby attenuating oxidative stress, neuroinflammation, apoptosis, neurofibrillary tangles, and subsequent neurodegeneration. SIGNIFICANCE STATEMENT: To the best of our knowledge, this study is the first to detect antidepressant and procognitive effects of lithium in DOX-induced chemobrain via GSK-3β inhibition. Accordingly, lithium offers a promising therapeutic target for the management of chemotherapy-induced depression and chemobrain. Show less

Major depressive disorder is associated with deficits in hippocampal synaptic plasticity that depend on brain-derived neurotrophic factor (BDNF) release from both axonal and dendritic compartments. Antidepressant efficacy requires enhanced BDNF signaling, thought to be mediated by drug-induced BDNF release from postsynaptic dendritic spines. Here, we show that fast-acting antidepressants rapidly trigger BDNF secretion from presynaptic terminals in hippocampal area CA3. At antidepressant-relevant concentrations, ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) induced BDNF release within minutes from mossy fiber terminals of dentate granule neurons in rat hippocampal cultures, with no detectable secretion from dendritic spines. This antidepressant-evoked BDNF release required presynaptic NMDA receptors (preNMDARs). Conditional genetic deletion of preNMDARs from granule neurons abolished ketamine- and HNK-induced BDNF exocytosis in acute mouse hippocampal slices, establishing a presynaptic receptor mechanism for antidepressant-induced neurotrophin release. In CA3 pyramidal neurons that receive mossy fiber input, both compounds induced rapid remodeling of dendritic spines, resulting in increased spine density. Together, these findings identify presynaptic terminals as a previously unrecognized source of antidepressant-evoked BDNF release and establish a new cellular mechanism for the rapid synaptic effects of fast-acting antidepressants. Show less

Research on the different aspects of bipolar disorder (BD) in special populations, such as youth with autism spectrum disorder (ASD) is limited. This case-controlled study aimed to investigate the serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) in youth with ASD with and without comorbid BD. Forty young subjects (13.47 ± 2.89 years) diagnosed with ASD with comorbid BD were included in the case group, and 40 age/gender-matched subjects with diagnosis of ASD without any mood disorders were included in the control group. The serum levels of BDNF, GDNF, and NGF were measured using enzyme-linked immunosorbent assays. The Childhood Autism Rating Scale (CARS) was used to assess ASD severity in the subjects. Serum BDNF levels were significantly lower in the case group than in the control group (p = 0.002). No significant differences were observed in GDNF and NGF levels between the two groups (p > 0.05). The severity of ASD was significantly higher in the case group (p = 0.001). Low serum BDNF levels may be associated with BD comorbidity in youth with ASD. Given the difficulty in diagnosing BD in this population, serum BDNF levels may be a biomarker associated with the development/diagnosis of BD in youth with ASD. Further studies with larger sample sizes are required to validate these findings. Show less

Gradual loss of cognitive abilities is common during ageing but might also result in mild cognitive impairment and dementia. Research suggests that neurotrophins, such as brain derived neurotrophic factor (BDNF), and neurosteroids, such as dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), play crucial role in cognitive functions and are often dysregulated in neurocognitive disorders. This study aimed to investigate variations in the genes for BDNF and sulfotransferase 2A1 (SULT2A1), the enzyme converting DHEA into DHEAS, as well as plasma BDNF and DHEAS levels, in individuals with normal cognition, and mild, moderate, and severe cognitive impairment. Cognitive functions of 453 participants were evaluated using Mini-Mental State Examination (MMSE) and Clock Drawing test (CDT). Genotyping of BDNF (rs6265) and SULT2A1 (rs2637125) polymorphisms was conducted, and plasma BDNF and DHEAS concentrations were determined by enzyme-linked immunosorbent assays (ELISA). Obtained results demonstrated that participants with moderate to severe cognitive impairment had significantly lower plasma BDNF and DHEAS levels, compared to individuals with normal cognition. In contrast to DHEAS, BDNF changes were more pronounced in men than in women. However, no significant associations of BDNF rs6265 and SULT2A1 rs2637125 polymorphisms with cognitive decline, or with plasma BDNF and DHEAS levels, respectively, were observed. Compared to CDT, MMSE was superior in distinguishing plasma BDNF and DHEAS variations, especially between individuals with mild and moderate to severe cognitive impairment. Further studies should investigate the potential of BDNF and DHEAS as peripheral biomarkers of cognitive decline and possible benefits of their replacement therapy in neurocognitive disorders. Show less

The increase in cannabinoid use among adolescents has become a public health concern in North America, with more than one-third of 12th graders in the United States reporting consumption of some form of cannabis within the past year (2023). Male adolescent Sprague-Dawley rats received two intraperitoneal injections, either WIN (0.8 mg/kg) or saline solution (0.9% NaCl) every 48 h, from postnatal day (PND) 30 to 37. On the final day (PND 38), a single injection of either WIN or saline was administered. The rat's whole brain tissue was collected an hour after the last injection. Chronic WIN administration during adolescence caused a significant increase in pro-BDNF levels in the brain's CbVr and m-BDNF in the mPFC. Our findings suggest that chronic WIN administration can alter the baseline levels of pro and m-BDNF in the brains of male adolescent rats, which may have implications for synaptic plasticity and neurodevelopment. Show less

Rodent studies have shown that psychedelic drugs can enhance fear extinction. However, investigations to date have relied on normative aversive conditioning procedures, which limit their relevance to trauma-related memories, as these tend to be overgeneralized and resistant to extinction. Fear extinction depends on activity and plasticity within the infralimbic (IL) region of the medial prefrontal cortex and is regulated by brain-derived neurotrophic factor (BDNF). Ayahuasca (AYA), a brew containing the serotonergic psychedelic N,N-dimethyltryptamine (DMT), facilitates fear extinction in rodents and increases BDNF levels/signaling. Here, we investigated whether AYA attenuates extinction deficits and generalized fear induced by preconditioning restraint stress or high-intensity contextual fear conditioning, and whether these effects depend on BDNF-TrkB receptor signaling in the IL cortex. Adult male and female rats underwent the protocols above and received oral AYA one hour before each of the two extinction sessions conducted on consecutive days. Repeated administration of AYA containing 0.3 mg/kg of DMT enhanced extinction learning and its retention, effects that were abolished by bilateral intra-IL cortex infusion of an anti-BDNF antibody or the TrkB receptor antagonist ANA-12. AYA treatment also reduced fear generalization, an action that was BDNF-dependent in the IL cortex of females but not males. Overall, these findings indicate that AYA can modulate maladaptive fear memories through cortical mechanisms involving BDNF signaling, highlighting the potential of psychedelics as enhancers for extinguishing difficult-to-treat memories like those underlying post-traumatic stress disorder. Show less

Depression is a major global health burden, and current treatments are limited by delayed onset and incomplete efficacy, highlighting the need for novel, mechanism-based therapies. Chronic restraint stress (CRS) induces behavioral, hormonal, and synaptic changes relevant to depression, but the role of adiponectin signaling remains unclear. Here, we examined whether the adiponectin receptor agonist AdipoRon exerts antidepressant-like effects via brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in mice subjected to 14 days of CRS. CRS produced anxiety- and depression-like behaviors, elevated plasma corticosterone, reduced circulating adiponectin, and selectively decreased hippocampal adiponectin and adiponectin receptor 2 (AdipoR2), accompanied by reduced PSD-95 and GluA1 in CA3 and the dentate gyrus (DG). AdipoRon treatment (20 mg/kg, days 8-14) prevented behavioral deficits, normalized corticosterone and adiponectin levels, and restored hippocampal AdipoR2, PSD-95, and GluA1 expression in CA3 and DG. AdipoRon also reversed CRS-induced decreases in hippocampal phosphorylated AMPK (p-AMPK), PPARα, BDNF, and phosphorylated TrkB (p-TrkB), with p-AMPK/AMPK and PPARα levels positively correlating with BDNF. Immunofluorescence confirmed BDNF recovery in CA3 and DG. Importantly, pretreatment with the TrkB antagonist ANA-12 abolished the behavioral, hormonal, and molecular effects of AdipoRon, indicating that its actions require BDNF-TrkB activation. These findings suggest that AdipoRon mitigates CRS-induced deficits via hippocampal AdipoR2-AMPK-PPARα-BDNF-TrkB signaling and highlight AdipoR2 as a promising target for depression therapy under chronic stress. Show less

Growing evidence suggests that resveratrol possesses neuroprotective properties against arsenic toxicity. This study investigated whether resveratrol could ameliorate arsenic-induced depression-like behaviors in male Naval Medical Research Institute (NMRI) mice and explored potential molecular mechanisms. Mice were exposed to arsenic (50 mg/L in drinking water) for 4 weeks and treated with resveratrol (10 or 20 mg/kg). Behavioral assessments included the hole-board test (HBT) for exploratory behavior, and the sucrose splash test (SST), tail suspension test (TST), and forced swim test (FST) for depression-like behaviors. The mRNA levels of Bdnf, Creb1, and Dvl1 in the brain were analyzed by qRT-PCR. Arsenic exposure induced significant depression-like behaviors, characterized by decreased grooming in SST and increased immobility in TST and FST. Resveratrol treatment prevented these behavioral alterations and exhibited intrinsic antidepressant effects in naïve mice, with dose-dependent reductions in immobility time (FST) and increased grooming (SST). Notably, resveratrol (20 mg/kg) enhanced rearing frequency in naïve mice and decreased it in the arsenic-treated mice. At the molecular level, arsenic downregulated Bdnf expression, while resveratrol restored its levels. In contrast, no significant changes in Creb1 and Dvl1 expression were observed. These findings indicate that resveratrol mitigates arsenic-induced depression-like behaviors primarily through the modulation of Bdnf-dependent pathways, independent of Creb1 and Dvl1. These results position resveratrol as a potential antidepressant and underscore its therapeutic promise for mood disorders associated with environmental toxicant exposure. Show less

This study aimed to investigate the therapeutic effects of minocycline on neuropathic pain by examining its regulatory influence on hippocampal proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels, given the established involvement of neuroinflammation and BDNF dysregulation in the pathogenesis of neuropathic pain and associated neurological dysfunctions. This study used a rat model of neuropathic pain induced by L5 spinal nerve transection (L5-SNT). Forty-eight male Sprague-Dawley rats were divided into four groups: naive, sham-operated, model + saline, and model + minocycline. Minocycline was administered intraperitoneally at 40 mg/kg daily. Mechanical allodynia was assessed using the von Frey test, while real-time reverse transcription and ELISA were employed to quantify hippocampal expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and BDNF at various time points postsurgery. L5-SNT induced significant mechanical allodynia in the model + saline group, which was significantly attenuated by minocycline treatment in the model + minocycline group on days 3, 7, and 11 postsurgery (P < 0.05). Minocycline significantly reduced TNF-α, IL-6, and BDNF levels in the hippocampus, particularly on day 7 post-SNT (P < 0.05); however, minocycline did not significantly affect IL-1β levels. These findings suggest that minocycline's analgesic effects may be mediated through the downregulation of key proinflammatory cytokines and BDNF in the hippocampus. Minocycline administration significantly mitigates mechanical allodynia and modulates hippocampal neuroinflammatory markers in a rat model of neuropathic pain. These results highlight minocycline's potential as a therapeutic option for neuropathic pain, particularly in targeting neuroinflammation within the hippocampus. Show less

This research aimed to explore the serum levels of calcium/calmodulin-dependent protein kinase II (CaMKII) in hyperventilation syndrome (HVS) patients and its correlation with psychological disorders. This prospective observational study enrolled 168 HVS patients who came to our hospital from February 2021 to January 2023. The serum CaMKII, 5-hydroxytryptamine (5-HT), and brain-derived neurotrophic factor (BDNF) levels were measured by enzyme-linked immunosorbent assay method. Hamilton depression rating scale was used to assess the depression status of all study subjects. Hamilton anxiety rating scale, the self-rating anxiety scale, and the self-rating depression scale were used to further evaluate the psychological status of all patients. The self-rating depression scale, Hamilton anxiety rating scale, and self-rating anxiety scale scores in the depression group were significantly elevated compared to the non-depression group (P < .05). The serum CaMKII, 5-HT, and BDNF levels were significantly declined in the depression group compared to the non-depression group. Pearson analysis showed a positive correlation among CaMKII levels, 5-HT levels, and BDNF levels. Serum levels of CaMKII were associated with the psychological status of HVS patients (depression and anxiety). CaMKII could be used to predict depression in HVS patients. CaMKII was a risk factor for depression in HVS patients. This study showed that the serum CaMKII levels decreased in HVS patients with depression. The serum CaMKII level was correlated with 5-HT, BDNF and could be used to predict depression in HVS patients. Show less