P2Y6R介导小胶质细胞吞噬ECS在双侧密集训练改善卒中后认知障碍中的作用及机制研究

卒中后认知障碍（PSCI）的防治是认知障碍研究领域的重大前沿问题。既往研究表明，PSCI的病理过程存在小胶质细胞激活，但其激活如何导致PSCI的具体机制未明。记忆印记细胞突触（ECS）近年来被证实是记忆形成的物理载体，c-fos基因标记常用于记忆印记细胞的可视化。课题组前期开发的双侧密集训练（BIT）显著改善MCAO小鼠的认知功能，伴有小胶质细胞P2Y6R这种吞噬介导受体的下调。由此，我们提出如下假说：脑卒中后小胶质细胞可能通过吞噬ECS促进PSCI的发生，而BIT可以抑制P2Y6R表达，减少小胶质细胞吞噬ECS从而改善PSCI。本研究拟采用c-fos-CreERT2:Ai14 C57BL/6转基因小鼠构建MCAO后PSCI小鼠模型，对小鼠进行BIT训练，通过行为学、电生理、FosTRAP等实验手段，探索BIT抑制小胶质细胞吞噬ECS改善PSCI的机制，为PSCI寻找新的治疗靶点提供依据。

The prevention and treatment of post-stroke cognitive impairment (PSCI) is a major frontier issue in the field of cognitive impairment. Previous studies have shown that there is microglia activation in the pathological process of PSCI, but the specific mechanism of how its activation leads to PSCI is unclear. Engram cell synapses (ECS) have been proven to be the physical carrier of memory formation in recent years, and c-fos gene markers are often used to visualize engram cells. The Bilateral intensive training (BIT) developed by our research team in the early stage can significantly improve the cognitive function of MCAO mice, accompanied by the down-regulation of the phagocytic-mediated receptor of microglia P2Y6R. Therefore, we put forward the following hypothesis: After stroke, microglia may promote the occurrence of PSCI through phagocytosis of ECS, and BIT can reduce the phagocytosis of ECS by inhibiting P2Y6R to improve PSCI. This study intends to use c-fos-CreERT2: Ai14 C57BL/6 transgenic mice to construct a PSCI model after MCAO, train the mice with BIT, and explore the mechanisms of BIT by experimental methods such as behavioral, electrophysiology, and FosTRAP, to explore the pathogenesis of PSCI and the mechanism of BIT to improve PSCI, in order to find new therapeutic targets for PSCI and establish effective PSCI prevention and treatment methods.