脑卒中是全球第二大死因，我国脑卒中发病率占全球首位。近三十年来神经保护药物的研发均告失败，原因之一在于脑卒中患者多为老年人，而基础研究并未采用老年动物。申请者前期研究发现老年小鼠在缺血性脑卒中后小胶质细胞与神经元的接触较年轻小鼠明显减少。进一步发现，小胶质细胞表面受体P2Y12R是调控小胶质细胞与神经元接触的关键蛋白。我们提出假说：在老年小鼠在缺血性脑卒中后，通过调控小胶质细胞FoxO1转录因子增加P2Y12R蛋白的表达，可以促进小胶质细胞与神经元胞体形成接触，从而减少缺血性脑卒中后神经元损伤。本课题拟采用ATACseq、慢病毒转染、透射电镜等技术，结合模式动物与人体标本，探究老年小鼠在缺血性脑卒中后促进小胶质细胞与神经元接触的调控因子及其具体分子机制。以期为研发缺血性脑卒中后神经保护药物提供新思路。

Stroke is the second leading cause of death in the world, and the incidence of stroke in China ranks first in the world. In the past three decades, all the clinical trials of neuroprotection in stroke failed despite previous success in preclinical models. One reason is that stroke is most prevalent in elderly men and women, whereas preclinical models mostly test young animals. We previously found that the decrease of interactions between microglia and neurons in aged mice. Furthermore, P2Y12R is a key protein in regulating the communications between microglia and neurons. Our hypothesis is that up-regulation of transcription factor, FoxO1, can increase the expression of P2Y12R in microglia, promoting the interactions between microglia and neurons leading to the improvements of neurological function in aged mice after ischemic stroke. This study aims to explore the pathological characteristics and regulatory mechanism of the interactions between microglia and neurons in aged mice after ischemic stroke, with ATACseq, lentivirus, transmission electron microscope, etc. This study may provide a new strategy to explore neuroprotectants for ischemic stroke.