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Substance use disorder is characterized by compulsive seeking behavior that is associated with aberrant synaptic plasticity in mature neurons. Environmental enrichment (EE) has been shown to increase adult hippocampal neurogenesis and exert beneficial effects on addictive behaviors. However, the mechanisms of EE's effects on methamphetamine (METH)-induced synaptic plasticity in mature and newborn neurons remain unclear. We reported that EE decreased METH-induced seeking behavior with a decrease in the activity of mature granule cells and an increase in the number of newborn granule cells. Furthermore, the aberrant glutamatergic transmission in hippocampal mature and newborn granule cells was differentially regulated by EE. Moreover, EE restored the normal synaptic plasticity, accompanied by enhancement of brain derived neurotrophic factor (BDNF) expression. Importantly, the intervention of BDNF reversed the effects of EE on METH-induced reinstatement behavior and glutamatergic transmission in both mature and newborn cells. Finally, specifically knocking out the newborn neurons reversed the changes of EE in abnormal plasticity of mature neurons, as well as in seeking and cognitive behaviors. Taken together, regulating synaptic plasticity of mature and newborn neurons is involved in METH-induced seeking behavior and cognitive impairments, which highlights a critical role of adult neurogenesis in the treatment of METH addiction. Show less

Impaired nuclear translocation of glucocorticoid receptor (GR) has been implicated in hippocampal vulnerability in Alzheimer's disease (AD), yet the molecular basis of this defect remains poorly understood. This study identified Huntingtin-associated protein 1 (Hap1) as a critical regulator of GR nuclear translocation in the hippocampus. Specifically, Hap1 expression progressively declined in the hippocampus of APP/PS1 mice with advancing age and pathological burden. Hippocampal Hap1 knockdown induced pronounced cognitive deficits and synaptic deterioration, as indicated by reduced dendritic arborization, decreased spine density, impaired long-term potentiation, and exacerbated amyloid-β deposition. Mechanistic analyses showed that Hap1 deficiency increased GR ubiquitination and proteasomal degradation and, more importantly, disrupted ligand-dependent GR translocation to the nucleus, thereby attenuating GR-dependent brain-derived neurotrophic factor transcription. In parallel, Hap1 knockdown elevated corticosterone concentration and induced depression-like behavior, consistent with hypothalamic-pituitary-adrenal axis dysregulation. Collectively, these findings establish defective GR nuclear trafficking driven by loss of Hap1 function as a key pathomechanism linking intracellular transport failure to synaptic dysfunction in AD and highlight Hap1 as a potential therapeutic target. Show less

Irritable bowel syndrome (IBS) associated with early-life stress (ELS) commonly manifests as anxiety and visceral hypersensitivity. However, the pathogenic mechanisms underlying these effects are not fully understood. This study aims to investigate the role of brain-derived neurotrophic factor (BDNF) as a key mediator of ELS-induced changes through the brain-gut axis. A Sprague-Dawley male maternal separation (MS) rat model was used to induce anxiety and visceral hypersensitivity associated with ELS. BDNF levels were measured in the limbic system (cingulate gyrus, amygdala, and hippocampus) and serum. The correlation between BDNF levels, anxiety, and visceral hypersensitivity was analyzed. Corticotropin-releasing factor (CRF) expression in the hippocampus and the extent of visceral hyper-sensitivity were assessed in control, MS, and MS+K252a (a BDNF receptor antagonist) groups. MS rats exhibited higher levels of anxiety and visceral hypersensitivity compared to controls. BDNF production in the hippocampus was elevated in MS rats and positively correlated with anxiety (r = -0.78, p < 0.05) and visceral hypersensitivity (r = 0.93, p < 0.01). CRF expression, a key mediator of stress and visceral hypersensitivity, was also increased in the hippocampus of MS rats. Inhibition of BDNF signaling using K252a reduced CRF expression and alleviated visceral hypersensitivity. This study demonstrates that BDNF may mediate ELS-induced anxiety and visceral hypersensitivity through hippocampal TrkB-CRF signaling, providing a mechanistic basis for targeting BDNF in stress-related IBS. Show less

Exercise enhances learning and memory, not only through improved cardiometabolic but also through body-brain interactions mediated by secreted factors. Given the prominent role of skeletal muscle during exercise, muscle-derived factors, myokines, are believed to mediate the exercise-induced cognitive enhancements. Here, we demonstrate that intramuscular Serpina1e is upregulated following exercise in male mice. Systemic delivery of recombinant Serpina1e or intramuscular overexpression of Serpina1e reproduces exercise-induced memory enhancements in sedentary male mice. Conversely, muscle-specific depletion of Serpina1e abolishes hippocampal memory enhancement, indicating a requirement of muscle-derived Serpina1e for these cognitive benefits. Mechanistically, elevated plasma Serpina1e stimulates neurogenesis, brain-derived neurotrophic factor (BDNF) expression, and neurite growth in the hippocampus by crossing the blood-cerebrospinal fluid (CSF) and blood-brain barrier. Our findings identify Serpina1e as a key mediator of skeletal muscle-brain interaction that enables the beneficial effects of exercise on cognitive function. Show less

Gut microbiota alterations are associated with the onset of depression; however, the underlying mechanisms remain unclear. Activation of hippocampal AMP-activated protein kinase (AMPK) in ulcerative colitis mice with disrupted gut microbiota balance produces antidepressant effects. However, the relationship between hippocampal AMPK and antibiotic treatment (ABX)-induced depression-like behavior remains unclear. Therefore, we aimed to investigate whether 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), an AMPK activator, is associated with the prevention of ABX-induced depression-like behaviors. ABX mice exhibited depression-like behaviors, as evidenced by prolonged immobility and reduced sucrose preference. In the hippocampus of the ABX mice, Iba1 and pro-inflammatory microglial markers were upregulated, whereas brain-derived neurotrophic factor (BDNF), CD206, arginase-1, and interleukin-10 were downregulated. Additionally, levels of AMPK phosphorylation, cAMP response element binding protein (CREB), and tropomyosin-related kinase B (TrkB) were decreased. AICAR administration attenuated these behavioral and molecular alterations. Phosphorylated AMPK was colocalized with the neuronal marker-NeuN-and microglial marker-Iba1. AICAR ameliorated the reduction in hippocampal neuron proliferation and survival and reduced microglial activation-associated morphological changes in the hippocampus. These findings suggest that AICAR administration is associated with antidepressant-like effects, potentially involving enhanced neurogenesis and attenuation of neuroinflammation in the hippocampus of ABX mice. Together, this study highlights the significance of hippocampal AMPK phosphorylation in depression associated with gut microbiota alterations, and suggests a potential target for therapeutic interventions. Show less

The accumulation of Aβ plaques and hyperphosphorylation of Tau neuropathologically characterize Alzheimer's disease (AD). Synaptic dysfunction and endoplasmic reticulum (ER) stress precede overt neuropathology. ER stress is characterized by the accumulation of unfolded/misfolded proteins, which leads to activation of the adaptive signaling pathway, the unfolded protein response (UPR). Chronic or unresolved ER stress, as in disease, is maladaptive and triggers the integrated stress response (ISR). We hypothesize that targeted attenuation of ISR activation would mitigate the early cognitive deficits and molecular pathology in the triple transgenic (3xTg) mouse model of AD. To test this hypothesis, we used an adeno-associated viral (AAV) vector to overexpress BiP, the key ER chaperone and UPR regulator, in the hippocampi of young 3xTg mice. BiP overexpression reduced phosphorylated PERK (pPERK), a marker of ISR activation, and increased synaptic proteins BDNF, PSD95, and choline acetyltransferase marker (ChAT). Hippocampal-dependent working memory, social memory, long-term spatial memory, and REM theta power were improved without changes in locomotion. BiP overexpression reduced neuroinflammation, as evidenced by a decrease in the astrocyte marker GFAP. Additionally, Aβ and Aβ42 levels were reduced in the hippocampus and cortex. Collectively, these findings indicate that modulation of ER stress via BiP overexpression ameliorates early cognitive and molecular alterations associated with AD. Show less

Press needle therapy, may alleviate depressive-like behaviors. Male rats were randomly allocated into four groups ( Press-needle ameliorated depressive-like behaviors in CUMS-exposed rats, restored body weight gain and improved behavioral performance. The treatment upregulated the hippocampal BDNF/TrkB/CREB signaling pathway, increasing BDNF, TrkB, CREB, AKT, and PI3K in the hippocampus. The therapy modulated serotonergic neurotransmission by increasing hippocampal 5-HTT expression, while downregulating 5-HT1A and 5-HT2C receptors and PKA. Notably, press-needle exerted anti-neuroinflammatory effects, reducing hippocampal and serum levels of TNF-α and IL-6. Histopathological analysis confirmed its neuroprotective efficacy, demonstrating attenuated neuronal damage in hippocampal tissues. Show less

Chaihu Shugan San (CSS), a classical Traditional Chinese Medicine (TCM) formula, was first recorded in Jingyue Quanshu (1624 AD) for treating "liver qi stagnation" (Yu Syndrome), a TCM diagnostic pattern analogous to modern mood disorders. Although CSS has been prescribed for emotional distress, irritability, and depressive symptoms for centuries, the neurobiological mechanisms underlying its antidepressant efficacy, particularly in the context of gender-specific pathology, remain poorly revealed. The present study probed the antidepressant effects of CSS in female mice, while elucidating the underlying molecular mechanisms involving hippocampal neuroinflammation and neuroplasticity. We hypothesized that CSS reverses chronic stress-induced depressive phenotypes by suppressing interleukin-6 (IL-6), which in turn facilitates cAMP-CaMKII-BDNF signaling pathway in the hippocampus. Adult female C57BL/6J mice were subjected to a 5-week chronic unpredictable mild stress (CUMS) regimen to evoke depressive-like behaviors. During the final 2 weeks of the regimen, CSS was administered intragastrically at 0.5, 1.0, or 1.5 g/kg, with fluoxetine (10 mg/kg) as the positive control. Behavioral assessments included forced swimming test (FST), sucrose preference test (SPT), open field test (OFT), and tail suspension test (TST). Hippocampal IL-6, cAMP, CaMKII, and BDNF levels were quantified by ELISA. Mechanistic validation employed acute hippocampal microinjection of recombinant IL-6 (1 μg/site) and systemic administration of the CaMKII inhibitor KN-93 (6 mg/kg). Chemical constituents were identified by UHPLC-QTOF MS. CSS alleviated CUMS-induced depressive-like behaviors in a dose-dependent manner, cutting down immobility time in TST/FST and reinstating sucrose preference, similar to the action of fluoxetine. CSS significantly suppressed hippocampal IL-6 while upregulating cAMP, CaMKII activity, and BDNF expression. Acute IL-6 elevation completely abolished both the behavioral antidepressant effects and molecular actions of CSS. Pharmacological inhibition of CaMKII blocked CSS-induced behavioral improvement and its upregulation of cAMP-BDNF signaling, without affecting basal behaviors. CSS exhibited no anxiogenic or locomotor side effects. CSS exerts potent antidepressant effects in female mice through coordinated suppression of hippocampal IL-6 and activation of the cAMP-CaMKII-BDNF neuroplasticity-related pathway, with CaMKII playing a critical role in this process. These findings offer scientific evidence for the traditional use of CSS in addressing emotional disorders and highlight its therapeutic potential as a multi-targeted, anti-inflammatory botanical medicine for female-specific depression. Show less

Recent studies have indicated that stem cells could provide therapeutic benefits in several neurological conditions, including Alzheimer's disease (AD). Adipose-derived stem cells (ADSCs) offer many advantages in that they are readily available from individual hosts, are robust, and secrete many factors that promote neuronal growth and homeostasis. We transfected ADSCs with a viral construct for brain-derived neurotrophic factor (BDNF) and examined the effects of transplanting these cells into the hippocampus of 7-mo-old APPswe/PS1dE9 mice. After 6 mo, the hippocampus was examined for stem-cell survival, effects on BDNF and neprilysin-2 (NEP-2) levels, dendritic morphology using microtubule associated protein 2 (MAP2) immunohistochemistry, and amyloid plaque load. We found that transplanted BDNF-ADSCs had survived after 6 mo. BDNF and NEP-2 levels were higher than sham controls, and dendritic architecture was improved. In addition, amyloid plaque numbers were reduced. BDNF-ADSCs appear to confer benefits by simultaneously enhancing amyloid clearance and promoting neuronal structural repair. This multifaceted approach highlights the potential of engineering stem cells to target multiple pathophysiological hallmarks of AD, positioning BDNF-ADSCs as a powerful and synergistic cell-gene therapy strategy for this devastating disorder. Show less

Cholinergic dysfunction is a key contributor to cognitive impairment observed in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Although acetylcholinesterase (AChE) inhibitors have been the mainstay of symptomatic treatment for over two decades, their limited efficacy and adverse effects underscore the need for alternative therapeutic approaches. Recent evidence indicates that mechanical stimulation can modulate neuronal and glial signaling through mechanotransduction, suggesting a potential strategy to enhance cognitive function via non-pharmacological means. Here, we developed a head-mounted vibrotactile stimulation system (HVSS) that delivers controlled vibration to the cranium and evaluated its effects in a pharmacological model of acute cholinergic dysfunction induced by scopolamine. To this end, male C57BL/6 mice received scopolamine (1 mg/kg, i.p.; on days 7, 14, and 28) and were exposed to daily vibrotactile stimulation at 20, 40, or 80 Hz for 28 days. Behavioral performance was assessed using passive avoidance and Morris water maze tests, followed by biochemical and histological analyses. HVSS at 40 Hz and 80 Hz significantly improved cognitive performance, enhanced hippocampal cholinergic function, reduced oxidative damage, and upregulated memory-related signaling genes, including BDNF, PI3K, AKt, ERK1/2, CREB, and CAMK4. These findings suggest that high-frequency HVSS improves memory hippocampal cholinergic function via activation of memory-related signaling pathways, highlighting its potential as a safe, non-pharmacological neuromodulatory strategy for cholinergic dysfunction-related cognitive decline. 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

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