基于钙调神经磷酸酶的电针治疗抑郁症的机制研究

The acupuncture-induced anti-depressive effect has been used widely to alleviate depression. Considering the clinical therapyof acupuncture, it is inevitable to clear the mechanism of acupuncture-induced anti-depressive effect. Calcineurin is a serine/threonine protein phosphatase that regulates neurotransmission, neuronal structure and plasticity, and neuronal excitability in mood disorders, including depression. Our previous study indicated that hippocampal CA3 calcineurin activity, not DG or CA1 area, decreased after development of depression. Calcineurin inhibition in the CA3 induced depressive-like behavior and reversed the antidepressant-like effect of venlafaxine. As the downstream molecular Activation of CA3 mGluR2/3 normalized the depressive-like behavior induced by the calcineurin inhibitor. Other previous study indicated that acupuncture could increase brain area CaN mRNA expression to protect brain function with prescription specificity. So CaN may be one molecular mechanism of acupuncture-induced anti-depressive effect. Based on the research platform of electro-acupuncture induced anti-depressive effect, this project plans to used multiple measures such as molecular biological detection, tool medition injection into specific brain area and animal behavioral tests, to investigate the adoptive changes of CA3 Calcineurin and downstream mGluR2/3, to reveal relationship between molecular manipulation and biological effect, and provide the experimental basis for improving acupuncture effect.

针灸治疗抑郁症具有较好的临床疗效，但作用机制尚未完全阐明，制约了其在临床进一步推广应用，阐释针灸抗抑郁的机制对于明确其科学理论以及增强临床疗效具有重要价值。我们的前期研究表明，海马CA3区钙调神经磷酸酶（Calcineurin, CaN）活性的下降是慢性应激致大鼠抑郁样行为形成的原因之一，传统抗抑郁药可以通过增强大鼠海马CA3区CaN的活性发挥药效，mGluR2/3作为下游分子介导了CaN抗抑郁的作用。其他研究者证明针刺可能通过上调脑部CaN起到脑保护的作用。因此本课题旨在探索CaN信号通路是否是针灸治疗抑郁症的分子机制之一，选用经典的电针抗抑郁效应平台，将分子生物学检测、特定脑区工具药干预、动物行为学检测等方法有机结合，探索海马CA3区CaN及其下游分子mGluR2/3的神经适应性变化及干预-效应关系，为阐明电针抗抑郁效应的关键作用分子提供确凿的因果证据。

针灸治疗抑郁症具有较好的临床疗效，但作用机制尚未完全阐明，制约了其在临床进一步推广应用，阐释针灸抗抑郁的机制对于明确其科学理论以及增强临床疗效具有重要价值。蛋白质磷酸化修饰是生物体内最重要的共价修饰方式之一。蛋白质的磷酸化和去磷酸化这一可逆过程调节着包括细胞增殖、发育、分化、信号转导、细胞凋亡、神经活动、肌肉收缩及肿瘤发生等过程在内的所有生命活动。有研究表明，海马CA3区钙调神经磷酸酶（Calcineurin, CaN）活性的下降是慢性应激致大鼠抑郁样行为形成的原因之一，传统抗抑郁药可以通过增强大鼠海马CA3区CaN的活性发挥药效，因此本课题选用电针抗抑郁效应平台，从单通量角度探索CaN信号通路是否是针灸治疗抑郁症的分子机制之一，用蛋白免疫印迹技术探索海马CA3区CaN适应性变化。从多通量角度探索海马磷酸化蛋白组学在电针抗抑郁中的作用。说明海马蛋白磷酸化在电针抗抑郁中发生变化，为阐明电针抗抑郁效应的关键作用分子提供确凿的因果证据。