P2X7受体介导小胶质细胞炎症反应抑制海马神经发生在卒中后抑郁中的作用及机制研究

Post-stroke depression (PSD) is an important factor affecting the prognosis of stroke patients, but the mechanism is not clear. It is reported that the inflammatory response and the inhibition of hippocampal neurogenesis after stroke is the key to the occurrence of PSD, but the regulation mechanism is not clear. Our previous studies have found that P2X7 receptor mediates activation of microglia to produce an inflammatory response in pathological conditions. But does the P2X7 receptor inhibit the hippocampus neurogenesis in PSD by activating microglia to produce inflammation? This project intends to use the mouse PSD model, both in vivo and in vitro experiments, comprehensive application of morphology, molecular biology and electrophysiology methods, to study the following three aspects. Firstly, to observe the regulation between expression of P2X7 receptor and activation of microglia in PSD mice，and to confirm the function of P2X7 receptor in PSD. Secondly, to investigate the regulating effect of P2X7 receptors on microglia and intracellular signal transduction pathways as the breakthrough point of release of TNF-α，IL-1β by miroglia. Thirdly, to clarify relationship between the inflammatory response mediated by P2X7 receptors on microglia and the changes of p75NTR in hippocampus, furthermore the inhibitory effect on neurogenesis in the hippocampus. In order to clarify the possible regulation mechanism of PSD, and to provides a new target for the prevention and treatment of PSD.

卒中后抑郁（PSD）是影响卒中患者预后不良的重要因素，但其机制还不明确。研究发现，卒中后的炎症反应、海马神经发生的抑制是PSD发生的关键，但其中的调节机制还不清楚。我们以往的研究发现，在病理条件下P2X7受体介导激活小胶质细胞产生炎性反应。但P2X7受体是否通过激活小胶质细胞产生炎症，抑制海马神经发生而引起PSD的发生？本项目拟采用小鼠PSD模型，结合在体及离体实验，综合应用形态学、分子生物学及电生理学等方法，研究①PSD小鼠小胶质细胞激活与P2X7受体表达变化的规律，证实小胶质细胞P2X7受体参与PSD的发生过程；②以小胶质细胞激活释放TNF-α，IL-1β为切入点，探讨P2X7受体对小胶质细胞激活的调节作用以及胞内信号传导通路；③阐明P2X7受体介导的小胶质细胞释放炎性因子与海马p75NTR变化的关系，以及对海马神经发生的抑制作用，阐明产生PSD的可能机制，为PSD的防治提供新的靶点。

卒中后抑郁（PSD）是影响卒中患者预后不良的重要因素，但其机制还不明确。研究发现，卒中后的炎症反应、海马神经发生的抑制是PSD发生的关键，但其中的调节机制还不清楚。我们以往的研究发现，在病理条件下P2X7受体介导激活小胶质细胞产生炎性反应。但P2X7受体是否通过激活小胶质细胞产生炎症，抑制海马神经发生而引起PSD的发生？本项目拟采用小鼠PSD模型，结合在体及离体实验，综合应用形态学、分子生物学及电生理学等方法，研究①PSD小鼠小胶质细胞激活与P2X7受体表达变化的规律，证实小胶质细胞P2X7受体参与PSD的发生过程；②以小胶质细胞激活释放TNF-α，IL-1β为切入点，探讨P2X7受体对小胶质细胞激活的调制作用以及胞内信号传导通路；③阐明P2X7受体介导的小胶质细胞释放炎性因子与海马p75NTR变化的关系，以及对海马神经发生的抑制作用，阐明产生PSD的可能机制，为PSD的防治提供新的靶点。