脑卒中后星状胶质细胞mGluR5受体介导突触再生参与神经环路重塑及功能康复的机制研究

神经环路重塑是缺血性脑卒中后功能康复的基础。发育期星状胶质细胞可通过多种分子调控突触形成及神经环路构建，但脑卒中后星状胶质细胞是否通过类似方式参与神经环路重塑和功能康复尚不清楚。我们研究发现，星状胶质细胞在发育期高表达的代谢型谷氨酸受体5（mGluR5）在脑缺血后被重新诱导，激活mGluR5受体可促进脑缺血后的功能康复。据此假设：脑卒中后星状胶质细胞mGluR5受体的重表达，可能通过介导突触再生参与神经环路重塑及功能康复。所以，本项目将利用基因编辑、化学遗传学、功能磁共振、双光子成像等手段，探究脑缺血后干预星状胶质细胞mGluR5受体表达对运动感觉功能、神经环路重塑和突触再生的影响，并从细胞及动物层面研究mGluR5受体介导的信号通路，最终阐明脑卒中后星状胶质细胞mGluR5受体介导突触再生参与环路重塑和功能康复的机制。为将来以mGluR5受体为靶点的药物开发和康复治疗提供新的思路。

Neural circuit remodeling is the basis of motor and sensory recovery after ischemic stroke. It is known that astrocytes control the synaptogenesis and neural circuit formation through secreting synaptogenic cues during early brain development. But whether astrocyte participate neural circuit remodeling and functional recovery after stroke according to the same manner as in the developmental stage, it remains elusive. It is reported that astrocyte express highly mGluR5 in developmental stage, but the expression of mGluR5 decrease after astrocyte maturation. Our previous research showed that reemergence of astrocytic mGluR5 signaling could induce functional recovery after ischemic stroke. Therefore, our hypothesis is that astrocyte mGluR5 mediate synaptogenesis involving neural circuit remodeling and functional recovery after stroke. To verify our hypothesis, we will employ various kind of techniques such as gene editing, chemogenetic technique, functional Magnetic Resonance Imaging(fMRI) and two-photon microscopy to explore the effect of astrocyte mGluR5 on the sensory and motor function, neural circuit reorganization and synaptogenesis after stroke, and mGluR5 mediate signaling pathway in vivo and in vitro . We will clarify finally the underlying molecular mechanism of astrocyte mGluR5 impact synaptogenesis involving neural circuit remodeling and functional recovery after ischemia stroke, which could provide novel guidance for the drug development targeting astrocyte mGluR5 and new strategy for improving the functional recovery of stroke patients.