Microglia respond to stressors by secreting cytokines or growth factors, playing a crucial role in maintaining brain homeostasis. While the antidepressant-like effects of Polygonatum sibiricum polysaccharides (PSPs) have been observed in mice, their potential effectiveness involving microglial regulation remains unknown. This study investigates the antidepressant-like mechanism of PSP by regulating microglial phenotype and signaling pathways in the prefrontal cortex of chronic restraint stress (CRS)-induced mice. PSP was extracted, purified, characterized, and orally administered to CRS mice. High-performance gel permeation chromatography (HPGPC) revealed that PSP has a molecular weight of 5.6 kDa. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) showed that PSP exhibited a layered structure with densely packed, irregular surfaces. PSP treatment significantly increased sucrose preference (low: 71%, p < 0.01; medium: 69%, p < 0.05; high: 75%, p < 0.001 vs. CRS: 58%) and reduced immobility time (low: 74 s, p < 0.01; medium: 68 s, p < 0.01; high: 79 s, p < 0.05 vs. CRS: 129 s), indicating the alleviation of depressive-like behaviors. PSP inhibited microglial activation (PSP, 131/mm² vs. CRS, 173/mm², p = 0.057), reversing CRS-induced microglial hypertrophy and hyper-ramification. Furthermore, PSP inactivated microglial activation by inhibiting NLRP3/ASC/caspase-1/IL-1β signaling pathways, increasing BDNF synthesis and activating brain-derived neurotrophic factor (BDNF)-mediated neurogenesis (PSP, 80/per DG vs. CRS, 49/per DG, p < 0.01). In conclusion, PSP exerts antidepressant-like effects through the regulation of microglial activity and neuroinflammatory pathways, indicating it as a potential natural compound for depression treatment.

Chlorantraniliprole, a widely used anthranilic diamide insecticide, has been linked to adverse effects on mammalian health, yet the precise toxicological mechanisms affecting intestine and brain remain unclear. In this study, mice were exposed to chlorantraniliprole at doses of 80, 160, and 320 mg/kg over a 28-day period. Significant damage to the intestinal barrier was observed, evidenced by decreased expression of tight junction protein ZO-1 and increased levels of inflammatory markers. Cognitive impairments, including decreased locomotor activity, impaired reward response, and increased anhedonia, were observed in behavioral tests. Oxidative stress was overactivated in both colonic and hippocampal tissues. Chlorantraniliprole exposure caused gut dysbiosis, characterized by an increase in Lactobacillus and Allobaculum and a reduction in Parabacteroides. In addition, short-chain fatty acid (SCFA) production decreased following chlorantraniliprole exposure. Metabolomic profiling revealed an increase in lipid-related metabolites and peptides, but a decrease in organic acids and nucleic acids, indicating metabolic dysregulation. Furthermore, iron accumulation and mitochondrial damage were observed in colonic tissue. These findings suggest that chronic chlorantraniliprole exposure disrupts intestinal and neural homeostasis through interconnected pathways involving inflammation, oxidative stress, gut microbiota alterations, and metabolic dysfunction.