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Chronic stress is increasingly acknowledged as a pivotal precipitating factor in the pathogenesis of neuropsychiatric and neurodegenerative disorders, notably including depression and Alzheimer's disease (AD). Astrocytes, which constitute the predominant population of glial cells involved in the maintenance of synaptic homeostasis, the recycling of neurotransmitters, and the provision of metabolic support, display a pronounced susceptibility to sustained exposure to stress. The deleterious effects of astrocytic dysfunction instigate a series of neuroinflammatory and synaptic modifications that undermine both cognitive and emotional resilience. This review articulates the mechanistic interactions between stress-induced astrocyte dysfunction, neuroinflammatory signaling, and compromised neuroplasticity, underscoring the converging pathways that are implicated in both depression and AD. A thorough synthesis of the literature from 2020 to 2025 was conducted utilizing databases such as PubMed, Scopus, and Web of Science, with an emphasis on molecular, in vitro, in vivo, and translational studies that examine the modulation of astrocytic function under conditions of chronic stress and its pertinence to depression and AD. The chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis precipitates morphological alterations, diminished expression of glutamate transporters (GLT-1/EAAT2), disrupted brain-derived neurotrophic factor (BDNF) signaling, and an augmented release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) from astrocytes. These biochemical alterations exacerbate excitotoxicity, disturb monoaminergic and glutamatergic neurotransmission, and hasten synaptic degeneration. In the context of depression, this phenomenon is manifested as impaired mood regulation and a decline in neurogenesis. In AD, it synergistically interacts with amyloid-beta and tau pathologies to facilitate progressive cognitive impairment. Both conditions exhibit a common feature of diminished neurosignaling plasticity, which limits the brain's capacity for adaptation and repair. Astrocyte dysfunction constitutes a central mechanistic nexus wherein chronic stress, neuroinflammation, and synaptic pathology intersect to promote the progression of depression and AD. The targeting of astrocytic health via the modulation of reactive astrocyte phenotypes, the restoration of glutamate homeostasis, and the enhancement of neurotrophic signaling emerges as a promising therapeutic avenue for alleviating stress-related neurodegeneration and mood disorders. Show less

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal development, synaptic plasticity, and cognitive function, and its dysregulation is implicated in various neurodegenerative and neuropsychiatric disorders. To noninvasively monitor dynamic changes in Bdnf expression in vivo, we developed a novel transgenic mouse line, Bdnf-AkaLuc transgenic (Tg) mice, in which the coding region of BDNF was replaced in a BAC transgene with a mutant luciferase, AkaLuc. This luciferase is optimized for the synthetic substrate AkaLumine, which emits near-infrared bioluminescence suitable for deep-tissue imaging. This engineered bioluminescence imaging (BLI) system, termed AkaBLI, enables robust and highly sensitive detection of bioluminescence in the brains of living mice, significantly outperforming our previous Bdnf-Luciferase Tg model. Using this system, we successfully visualized activity-dependent Bdnf mRNA induction in response to pilocarpine-induced status epilepticus. To overcome the limitations of repeated imaging, we identified optimal BLI intervals and established a hairless Bdnf-AkaLuc Tg line, facilitating long-term longitudinal monitoring. Furthermore, by crossing Bdnf-AkaLuc Tg mice with 5xFAD Alzheimer's disease model mice, we successfully visualized reductions in Bdnf expression in the brains of living 5xFAD mice. Our study introduces a powerful tool for noninvasive, continuous visualization of Bdnf regulation under both physiological and disease-related conditions. This imaging approach holds potential for advancing our understanding of BDNF-related brain function and for evaluating therapeutic strategies targeting BDNF in neurological disorders. Show less

Psychedelic compounds such as psilocybin, Lysergic Acid Diethylamide (LSD), N,Ndimethyltryptamine (DMT), and 3,4-methylenedioxymethamphetamine (MDMA) are emerging as novel therapeutics for neuropsychiatric disorders, including depression, Post-Traumatic Stress Disorder (PTSD), and addiction. Acting primarily through serotonin 5-HT2A receptor agonism, they activate intracellular cascades involving Brain-Derived Neurotrophic Factor (BDNF), Tropomyosin receptor kinase B (TrkB), and the mammalian target of rapamycin (mTOR) pathway, leading to enhanced neuroplasticity and synaptogenesis. Recent evidence demonstrates direct TrkB binding and sustained cortical remodeling, underlying their rapid and durable antidepressant effects. Advanced Drug Delivery Systems (DDS)-including liposomes, Solid Lipid Nanoparticles (SLNs), and Poly(lactic-co-glycolic acid) (PLGA) carriers-are being engineered to achieve controlled, braintargeted, and stimuli-responsive release while minimizing systemic toxicity. Integration with microfluidic fabrication, Artificial Intelligence (AI)-based dosing, and non-invasive routes such as intranasal and transdermal delivery improves precision and patient adherence. By merging neuropharmacology with materials science, these innovations are redefining psychedelic-assisted therapy through enhanced safety, personalized dosing, and translational potential for central nervous system disorders. Show less

Major depressive disorder (MDD) is a debilitating neuropsychiatric condition characterized by persistent low mood, affecting approximately 322 million individuals worldwide. With a staggering 15% mortality rate due to suicide among patients, MDD represents a critical global health challenge. Emerging evidence implicates microRNAs (miRNAs) in the pathogenesis of neuropsychiatric disorders; however, the role of miR-146a-3p in MDD-particularly its mechanistic involvement and potential as a diagnostic biomarker-remains unexplored. In this study, we integrated multi-database bioinformatics analyses with experimental validation to identify miR-146a-3p as a key regulator of MDD progression. Our computational screening revealed miR-146a-3p as a putative risk-associated non-coding RNA, alongside brain-derived neurotrophic factor (BDNF), a well-established MDD susceptibility gene. In vivo studies demonstrated a significant upregulation of miR-146a-3p and concurrent downregulation of BDNF in MDD model mice. Further bioinformatic predictions and dual-luciferase reporter assays confirmed a direct interaction between miR-146a-3p and BDNF mRNA, leading to post-transcriptional suppression of BDNF expression. Mechanistically, miR-146a-3p overexpression impaired synaptic plasticity, as evidenced by reduced levels of key synaptic proteins such as postsynaptic density protein 95 (PSD95) and synapsin (SYN-1), while in vitro transfection experiments validated its negative regulation of BDNF. Critically, intranasal delivery of a miR-146a-3p antagomir or exogenous BDNF protein rescued depressive-like behaviors in murine models, as assessed by open-field, forced swim, and tail suspension tests. These interventions restored synaptic protein expression and ameliorated behavioral deficits, suggesting a therapeutic avenue for MDD. Our findings establish miR-146a-3p as a pivotal epigenetic modulator of MDD pathogenesis, acting through direct suppression of BDNF-dependent synaptic plasticity. The reversibility of this pathway via antagomir inhibition highlights miR-146a-3p's dual potential as both a diagnostic biomarker and a therapeutic target. This study provides foundational insights for developing miRNA-based interventions in mood disorders. Show less

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

Sleep deprivation (SD) is a critical risk factor for cognitive decline and is closely linked to psychiatric disorders. The hippocampal CA2 region is critically involved in encoding social memory and regulating emotional behavior, and it has been implicated in various neuropsychiatric conditions. However, how SD affects CA2-dependent synaptic plasticity and related behaviors remains poorly understood. Here, we subjected mice to 5 h of SD via gentle handling and examined synaptic plasticity, molecular signaling, and social recognition memory. Electrophysiological recordings revealed that SD markedly impaired long-term potentiation (LTP) in CA2 and disrupted social recognition memory, as evidenced by failure to distinguish novel from familiar conspecifics. These deficits were accompanied by upregulation of adenosine A1 receptors and PDE4A5, along with reduced expression of plasticity-related proteins including PKMζ, ERK, and BDNF. Moreover, caffeine-induced synaptic potentiation was diminished in SD mice, whereas caffeine supplementation reversed both synaptic and behavioral impairments. Together, these findings demonstrate that SD compromises CA2-dependent plasticity and social cognition through adenosine receptor signaling and identify CA2 as a vulnerable, therapeutically relevant region. Targeting adenosine pathways may represent a novel strategy to mitigate sleep loss-related cognitive dysfunction in neuropsychiatric disorders. Show less

The chronic unpredictable mild stress (CUMS) paradigm is a well-known preclinical model used to investigate the pathophysiology of stress-induced neuropsychiatric disorders. This review integrates recent findings to elucidate how chronic stress initiates a multifaceted cascade involving neuroendocrine dysregulation, metabolic dysfunction, immune activation and synaptic impairment. Persistent stimulation of hypothalamic-pituitary adrenal (HPA) axis results in hypercortisolaemia, insulin resistance and compromised neuroplasticity through dysregulated BDNF-TrkB signalling, oxidative stress and activation of inflammatory pathways. Compelling evidence highlights both the Gut brain axis (GBA) and epigenetic alterations as central to stress-induced neuropathology. Stress-mediated microbial dysbiosis and intestinal barrier disruption amplify central inflammation through altered tryptophan metabolism and immune neurotransmitter signalling. Simultaneously, epigenetic modification including DNA methylation, histone remodelling and microRNAs encodes transcriptional changes that results in behavioural and cognitive deficits. While, CUMS model offers strong face and predictive validity but its translational relevance is constrained by protocol validity and limited modelling of psychological stressors. Nonetheless, it remains instrumental for evaluating pharmacological and non-pharmacological interventions targeting inflammatory, neurotrophic and metabolic pathways. Future refinement should incorporate biomarker discovery and gene-environment interaction paradigms. In synthesizing these diverse mechanistic insights, this review underscores the value of the CUMS model in identifying system-level therapeutic targets and advancing translational research in stress-related brain disorder. Show less