Cellular and Molecular Neurobiology最新文献

Autism spectrum disorders (ASD) are neurodevelopmental conditions involving impaired neuronal processes such as connectivity, synaptogenesis, and migration. Prenatal exposure to valproic acid (VPA), an anticonvulsant and mood stabilizer, is linked to increased ASD risk, with timing as a key factor. However, the molecular mechanisms of VPA-induced neurodevelopmental disruptions remain unclear. Building on our previous study, which characterized VPA-induced prenatal and postnatal ASD models with impaired social behavior, repetitive patterns, and altered brain connectivity, this study examines molecular changes in neurogenic brain regions. We analyzed the prefrontal cortex, hippocampus, and subventricular zone at key developmental time points (postnatal days 14 and 21), assessing neurotrophins (BDNF, Nt-3, IGF-β, GDNF) and markers of cell migration (DCX), differentiation (NeuN, GFAP), and synaptogenesis (synaptophysin). Our findings show that both prenatal and postnatal VPA exposure disrupt neurogenesis, with prenatal effects being more severe and persistent. Prenatal VPA significantly reduced BDNF in the subventricular zone and DCX in the olfactory bulb, suggesting impaired migration, while morphological analysis revealed thickening of ventricular lateral wall and disrupted cellular organization. Postnatal exposure led to transient neurotrophin changes, including delayed IGF-β production and an abnormal rise of BDNF levels. Elevated GFAP and reduced NeuN or synaptophysin in the prefrontal cortex, alongside increased neuronal markers in the hippocampus, suggest region-specific neuroglial imbalances. These findings highlight the stage-dependent vulnerability of the developing brain to VPA exposure, revealing distinct mechanisms of disruption in prenatal and postnatal administration. They underscore the need to minimize exposure risks during late gestation and early postnatal periods, which are crucial for neurodevelopment.

The nervous system exhibits remarkable adaptability through neuroplasticity, which allows for structural and functional changes in response to intrinsic and extrinsic stimuli. This dynamic process underpins synaptic formation, elimination, learning, memory, and brain recovery after neurological insults. However, neuroplasticity can be compromised by neurotropic viral infections, which present significant challenges to the central nervous system (CNS). Viruses infiltrate the CNS through various mechanisms, including peripheral nerves, disruption of the blood-brain barrier (BBB), and evasion of the immune system, leading to acute or chronic neuronal pathologies. Moreover, these infections may trigger encephalitis, neuroinflammation, and synaptic dysfunction, thereby impairing neural circuits and compromising brain function. Persistent viral infection and chronic responses further exacerbate neuronal damage through oxidative stress, excitotoxicity, and disruption of neural progenitor cells. Collectively, these effects hinder neuroplasticity, resulting in cognitive deficits, behavioral changes, and long-lasting structural alterations. Understanding the mechanisms by which neurotropic viruses impair neuroplasticity is crucial for developing targeted therapeutic interventions. Strategies aimed at addressing viral persistence, mitigating inflammation, and promoting synaptic repair are critical to preserving brain health and functionality. This review provides a comprehensive overview of virus-induced neuronal pathologies and their effects on neuroplasticity, highlighting the importance of innovative treatments to enhance CNS resilience and recovery in affected individuals.

Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system, characterized by myelin damage caused by immune dysfunction and genetic factors. Nevertheless, the role of peripheral blood and immune cells in the development of MS remains poorly defined. We employed a two-sample Mendelian randomization (MR) approach, analyzing data from 91 blood cell perturbation phenotypes and 731 immune cell traits. Causal inference was conducted using multiple robust MR techniques, including inverse variance weighting, with mediation analysis and sensitivity tests (Cochran's Q, MR-Egger intercept, and leave-one-out analysis) performed to validate the results.The present study identified significant associations between 9 blood cell perturbation phenotypes and 34 immune cell traits with MS risk. The effect of neutrophil disturbances on MS was partially mediated by HLA-DR expression on B cells, with a mediation proportion of approximately 16.38%. Moreover, sensitivity analyses confirmed the robustness of these findings.This study suggests that specific blood cell perturbations may increase MS risk and reveals the mediating role of immune cells between blood and nervous system disturbances. In addition, we provide genetic evidence for understanding MS immune mechanisms, which could help guide the development of targeted immunotherapies.

The basolateral amygdala (BLA) serves in the evaluation of reward. However, the causal molecular substrates in the BLA necessary for reward seeking behaviour are largely unknown. Reward conditioning induces long-lasting changes in epienzymes in limbic areas, including the amygdala. The current study probed the role of histone arginine methylation as a novel epigenetic mechanism in neuropeptide Y (NPY) gene regulation in the BLA during reward and reinforcement. For reward conditioning, adult Wistar rats were trained to self-administer sucrose pellets in a nose-poke operant chamber. Reward conditioning increased protein arginine methyltransferase 4 (PRMT4) and NPY in the BLA. Moreover, after operant conditioning, histone arginine methylation (H3R17me2a) and PRMT4 occupancy at the NPY promoter were heightened. PRMT4 was predominantly colocalised in the nucleus of the NPY-expressing cells in the BLA. Intra-BLA administration of specific siRNA or inhibitor of PRMT4 after conditioning waned the nose-poke activity, which was further reinstated during the subsequent 5 days. These effects of PRMT4 repression were correlated with the NPY expression and H3R17me2a levels at the NPY promoter. Furthermore, NPY peptide administration after PRMT4 siRNA or inhibitor infusion in BLA restored the nose-poke activity. PRMT4 is known to interact with CREB-binding protein (CBP). Therefore, co-occupancy of PRMT4 and CBP resulted in heightened histone acetylation (H3K14ac) in the conditioned rats. The current study suggests a pivotal role of PRMT4-mediated histone arginine methylation in NPY gene expression in the amygdala necessary for the reward-seeking behaviour.

This study evaluated the protective effects of celecoxib on epilepsy and explore its potential involvement in regulating pyroptosis and the high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4) signaling pathway. Adult male Sprague-Dawley rats were injected with ferrous chloride (FeCl₂) with or without celecoxib for 7 consecutive days. After sacrifice, tissues were collected for neurological function assessments, magnetic resonance imaging, and multiple tissue analyses. Intracerebral injection of FeCl₂ in rats induced severe seizures, microglial recruitment and polarization, ferroptosis, pyroptosis, and inflammation in the frontal cortex. In the hippocampus, FeCl₂ injection led to neuronal loss, reduced synaptic complexity, and aberrant HMGB1 expression. Celecoxib treatment delayed seizure onset and significantly reduced the severity and duration of seizures, the extent of injury, and neurological impairments caused by FeCl₂ exposure. These effects were mediated through the suppression of HMGB1/TLR4 signaling and inhibition of key pro-inflammatory cytokines. Celecoxib treatment mitigated neuronal loss, improved synaptic complexity, stabilized microglial activity, inhibited astrocyte proliferation, and modulated HMGB1 expression. In conclusion, celecoxib effectively attenuated FeCl₂-induced inflammation and neural injury partially by inhibiting the HMGB1/TLR4 pathway, thereby suppressing pyroptosis and reactive gliosis. These effects improved seizure, highlighting the therapeutic potential of celecoxib for managing epilepsy following hemorrhagic brain injury.

Neurodegeneration involves the progressive deterioration of neuronal structure and function, leading to deficits in cognition, motor skills, and other neurological processes. Parkinson's disease (PD) is notably prevalent among neurodegenerative disorders, characterized by dopaminergic neurodegeneration, protein misfolding, and an inflammatory brain environment. Despite advancements in understanding its pathophysiology, PD and other neurodegenerative conditions still lack effective disease-modifying therapies. This shortfall highlights the need for novel, multifactorial approaches to treatment. Recent research has spotlighted the gut-brain axis as a significant player in neurological health, particularly through the activity of gut-derived short-chain fatty acids (SCFAs). These microbial metabolites, primarily acetate, propionate, and butyrate, are produced via the fermentation of dietary fibers and are vital for maintaining intestinal and neural homeostasis. SCFAs exert anti-inflammatory effects, preserve blood-brain barrier integrity, and modulate neurotransmitter systems. Among them, butyrate shows notable neuroprotective capabilities, including histone deacetylase inhibition and mitochondrial enhancement. Disruption in SCFA production has been associated with PD progression, further underscoring their relevance. This review explores the mechanistic roles of SCFAs in modulating neurodegeneration, with an emphasis on PD. SCFA-based strategies offer a promising adjunctive route to restoring microbial balance, mitigating neuroinflammation, and safeguarding neurological function in neurodegenerative disorders.

Degeneration of myelinating oligodendrocytes and the resulting breakdown of the myelin sheath are key drivers of neurodegeneration and disability across numerous central nervous system pathologies. Thus, a compelling strategy to preserve neuronal function is to promote endogenous myelin repair by oligodendrocyte precursor cells (OPCs). Extracellular vesicles (EVs) secreted by pro-regenerative microglia have been shown to enhance OPC maturation and remyelination across different experimental models. Yet, the mechanisms by which microglia-derived EVs exert their beneficial effects on OPCs are not fully understood. In this study, we performed transcriptomic profiling of primary murine OPCs treated during differentiation with EVs obtained from donor microglia following stimulation with pro-inflammatory cytokines (i-EVs), interleukin-4 (IL4-EVs), or mesenchymal stem cells in the presence of the inflammatory cocktail (MSC-EVs; GEO accession number: GSE304130). Compared to controls, IL4-EVs and MSC-EVs induced robust changes in gene expression, whereas i-EVs elicited far fewer alterations. Using bioinformatic analyses, we identified the molecular pathways significantly modulated by microglial EVs, revealing a large overlap between IL4-EV and MSC-EV targets. Notably, many of these shared pathways centered on mitochondrial function and bioenergetic metabolism. Upstream regulatory network inference further pinpointed candidate transcription factors and kinases that may drive EV-induced transcriptional reprogramming in OPCs. Hence, our findings indicate that rewiring mitochondria-associated pathways is a core mechanism underlying the pro-differentiation effects of microglial EVs on OPCs. Elucidating these intracellular circuits will open new avenues for developing EV-based or mitochondria-targeted remyelinating therapies.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by neuronal loss, attributed largely to oxidative stress and mitochondrial dysfunction. This study explores the synergistic neuroprotective effects of resveratrol and lithium chloride co-treatment, focusing on their impact on oxidative stress and autophagy via the p62/Keap1/Nrf2 signaling pathway. We focused on the multilevel evaluation of the monotherapy and co-treatment effects on neurons in terms of cellular and molecular features in vitro, such as metabolic activity, level of reactive oxygen/nitrogen species, total antioxidant capacity, DNA damage, level of ATP, neurite outgrowth, cell cycle and proteins level involved in intracellular signaling pathways, with particular emphasis on autophagy correlated with p62 protein. Additionally, we screened 92 genes involved in steps of protein aggregation, excitotoxicity, inflammation and oxidation. Studies have shown that co-treatment has stronger properties than monotherapy. Statistical analysis was conducted using one-way ANOVA followed by Dunnett's post hoc test. The treatment indicated strong antioxidant properties, activation of autophagy, and the correlated apoptosis pathway via p62/Keap/Nrf2/ARE. Moreover, the therapy induced neurite outgrowth and eliminated DNA damage without disturbing the cell cycle. Finally, in the HT-22 cell line, therapy activated key genes involved in cell signaling and inflammation. In contrast, in SH-SY5Y cells, therapy engaged genes related to proteolysis, cell cycle regulation, protein kinase signaling, and lipid metabolism. These findings underscore resveratrol and lithium chloride co-treatment as a promising therapeutic strategy for mitigating oxidative damage and enhancing neuroprotection in PD. Relying on natural compounds, this combination could serve as a preventive strategy for the elderly.

The O6-methylguanine-DNA methyltransferase (MGMT) plays a significant role in the pathogenesis and progression of glioma. Numerous enhancer variants, including those within the MGMT gene region and adjacent gene regions, have been found to be associated with cancer development and progression. We investigated the significance of enhancer variants located in the intergenic spacer far from the MGMT gene in relation to glioma susceptibility and progression. We recruited 402 glioma patients and 654 controls for this investigation using Sequenom MassARRAY genotyping. We identified a significantly elevated risk of glioma among carriers with the rs11016629 TG genotype compared to those with the GG genotype (OR = 1.41, 95% CI 1.03-1.93; P = 0.034). Subgroup analyses revealed that rs11016629 was significantly associated with glioma risk in subjects with WHO grade IV tumor (OR = 1.59, 95% CI 1.07-2.38; P = 0.023) and high-grade glioma (OR = 1.57, 95% CI 1.11-2.21; P = 0.011). Patients who underwent gross total resection with TG/TT genotypes exhibited a 2.66-fold higher risk of disease progression than GG carriers (HR = 2.66, 95% CI 1.23-5.79; P = 0.014). The study demonstrates that a MGMT enhancer variant rs11016629 contributes to both glioma susceptibility and progression.