AMPK信号通路调控多巴胺能神经元的活化介导抑郁症的发生

临床和基础研究发现抑郁症患者及模型鼠的脑内存在明显的能量代谢异常，但具体机制并不明确。AMPK是细胞内重要的能量感受器，我们的前期研究发现：通过激活AMPK上调海马BDNF的表达，可明显改善社会失败模型鼠（SDS）的抑郁样行为。研究表明多巴胺能神经元簇状放电引起多巴胺神经递质的失调，继而引发的奖赏系统调控障碍是影响抑郁症快感缺失的核心机制。本项目拟通过SDS模型，DAT-Cre小鼠及Kir6.2-/-小鼠，借助行为学、病毒介导的AMPK表达的靶向调控、脑片电生理及分子生物学的手段，探讨AMPK是否通过表观遗传调控BDNF表达、影响K-ATP通道等钾离子通道活化，从而改变中脑边缘奖赏系统多巴胺能神经元的活性，参与抑郁症的发生和发展，将为抑郁症的治疗提供新的干预靶点。

Evidence from the clinic and the laboratory both revealed a energy metabolism dysfunction in depression patients and mice model, however the detail mechanism is unkown. Our previous study found that, activation of AMPK, an an essential intracellular energy sensor, significantly upregulates BDNF in the hippocampus and improve the depressive-like behavior in the chronic social defeat stress (SDS) mice model. Studies have shown that the bursting activity of dopaminergic neuron causes the abnormal release of dopamine and then triggered reward system dysregulation, results in anhedonia, which is the key pathogenesis of depression. Thereby, we proposed that AMPK change the activity of dopaminergic neurons in reward system via epigenetic regulation of the expression of BDNF and the activation of K + channels such as K-ATP channel, thus contributes to the pathogenesis of depression. We will employ several mice model (DAT-Cre mice, and Kir6.2 - / - mice) and multiple approach such as behavior test, optogenetic, brain electrophysiology, molecular biology to address our hypothesis. This project will connecting the dots between energy metabolism dysfunction and depression and provides a new target clinical intervention.