运动的抗抑郁机制——线粒体介导的炎症反应与神经元胰岛素抵抗研究

细胞因子（CK）激活吲哚胺2,3-双加氧酶（IDO），IDO活化可使色氨酸循犬尿氨酸途径分解代谢，进而诱发ROS的产生，ROS可导致神经元线粒体DNA缺失、功能异常，从而介入抑郁症的发生。线粒体功能异常与抑郁症（CNS）及其2型糖尿病（外周组织）的发病密切相关，常用抗抑郁药物会增加糖尿病的发病风险。AMPK激活剂AICAR对大脑胰岛素信号和线粒体功能的促进作用揭示神经系统胰岛素抵抗的可能性，这将有助于深入理解抑郁症与糖尿病间的病理关系。运动可能通过线粒体重塑防治糖尿病和抑郁症。本项目拟探讨：1）海马与前额皮质的线粒体功能与促炎细胞因子在运动改善抑郁行为中的关联机制；2）线粒体功能激活剂AICAR与运动对抑郁行为的防治作用及其神经生化机制；3）神经元胰岛素抵抗诱导抑郁行为的可能性及改善机制。预期成果将进一步阐明抑郁症与炎症反应、线粒体功能相关的发病机制，为抗抑郁的药物研发和行为干预提供靶点。

The presence of a proinflammatory state activates the tryptophan- and serotonin-degrading enzyme indoleamin 2,3-dioxygenase (IDO), leading to increased consumption of tryptophan. Stimulation of IDO and kynurenine monooxygenase by pro-inflammatory states further results in the production of tryptophan, which is involved in major depression. This also cause lowered mitochondrial energy metabolism, the generation of ROS and lipid peroxidation, and an increase in neuroexcitatory and neurotoxic effects. Mitochondrial dysfucntion is implicated in the pathology of both depression and type 2 diabetes(T2DB), however, continuing use of antidepressant medication is associated with an increased relative risk of T2DB. Concurrent effects of AICAR (a pharmacological activator of AMPK) on brain insulin action and mitochondrial function suggest a potential of neural insulin resistance, which may further increase our understanding on the link between depression and T2DB. Fortunately, regular exercise is often regarded as an effective treatment of depression and diabetes for its role in mitochondrial remodeling. Therefore, the current study aims to explore: 1) whether and how cytokines and mitochondrial dysfunction are involved in the effects of exercise on depressive-like behaviors; 2) whether and how AICAR and exercise, as a drug or physical therapy, have an antidepressant effect on depression; 3) whether and how neural insulin resistance induces drpressive-like behaviors. The prospective findings are supposed to further understand the pathophysiology of depression, and suggest a new target or guide for pharmacological research and development against depression.