长期暴露杀虫剂鱼藤酮增加帕金森病(PD)发病风险。认知障碍是PD最常见的非运动症状，严重降低患者生活质量。但是，鱼藤酮能否损伤认知及相关分子机制目前尚不清楚。我们前期发现鱼藤酮诱导小鼠认知功能下降、海马和皮质神经元丢失、突触减少，伴随小胶质细胞激活和补体受体3(CR3)表达增高；敲除CR3明显减轻鱼藤酮诱导的神经毒性和认知障碍，推测鱼藤酮可能通过CR3调控小胶质细胞活化损伤认知功能。本项目拟应用CR3敲除小鼠、原代细胞结合siRNA敲低和CRISPR过表达CR3技术，研究鱼藤酮促进CR3表达与活化的分子机制；明确CR3在鱼藤酮诱导认知障碍和海马、皮质神经元损伤中的作用；阐明CR3通过NADPH氧化酶调控小胶质细胞M1极化和外泌体释放，损伤认知功能的分子机制；探讨靶向阻断CR3活化对鱼藤酮损伤认知功能的逆转作用，为阐明CR3调控鱼藤酮神经毒性及认知障碍的分子机理，筛选防治新靶点提供参考依据。

Chronic exposure to insecticide rotenone increases the risk of Parkinson’s disease (PD). Cognitive dysfunction is the most common non-motor symptom of PD, which greatly reduces the life quality of PD patients. However, whether rotenone exposure could damage cognition and related mechanisms remain unclear. Our pilot study showed that rotenone exposure induced cognitive decline, loss of hippocampal and cortical neurons as well as neuronal synapse, which were associated with microglial activation and elevated expression of complement receptor 3 (CR3) in the brain of mice. Genetic ablation of CR3 markedly reduced rotenone-induced neurotoxicity and cognitive deficits in mice, suggesting that CR3 may regulate rotenone-induced cognitive impairments through microglial activation. By using CR3-deficient mice and primary cultures combined with knock-down or over-expression of CR3 by siRNA or CRISPR, respectively, we aimed to investigate the molecular mechanisms of rotenone-induced expression and activation of microglial CR3. The role and underlying mechanisms of CR3-regulated microglial M1 polarization and exosome release via NADPH oxidase in rotenone-induced cognitive impairments and hippocampal and cortical neurodegeneration were investigated. Furthermore, the reversing effects of blocking CR3 against rotenone-induced cognitive deficits were also determined. This study will provide reference for elucidating the molecular mechanisms of CR3 in rotenone-induced neurotoxicity and cognitive impairments as well as screening novel prevention and treatment targets.