基于TAAR1介导DAT稳定性研究针药结合干预CUMS大鼠前额叶神经元突触可塑性机制

抑郁症是一种常见的心境障碍，针药结合治疗抑郁症有效，但其作用机制仍不明确。本课题组前期研究发现，电针和帕罗西汀结合可改善慢性不可预见性温和刺激（CUMS）抑郁模型动物的抑郁样行为，伴随着前额叶影像学改变、突触结构以及多巴胺（DA）合成与释放相关蛋白含量的变化，提示针药结合抗抑郁可能通过影响前额叶突触可塑性及DA系统功能起效。多巴胺转运体（DAT）是维持突触间隙DA含量动态平衡的重要蛋白，近年来痕量胺相关受体1（TAAR1）被证实能改变DAT的功能，影响其在膜上的稳定性，参与调节中枢神经系统DA神经元放电及DA释放。因此，本研究拟运用电针和药物干预CUMS抑郁模型大鼠，观测前额叶突触可塑性的改变、TAAR1激活和DAT磷酸化等情况，最后再对TAAR1敲除动物进行干预，通过比较TAAR1对DAT膜上稳定性和前额叶突触可塑性的影响，为电针和药物结合治疗抑郁症提供实验依据。

Depression is a common mood disorder. The combination of eletroacupuncture and antidepressant is an effective treatment for depression, but the mechanism still remains unclear. Our previous studies have found that eletroacupuncture (at GV20 and GV29) with Paroxetine (a commonly used SSRI) can improve the depression-like behaviors of chronic unpredictable mild stress (CUMS) depression model rats, associated with changes of synaptic structure, as well as the synthesis and release of dopamine (DA) related protein in prefrontal cortex. These evidence indicated that eletroacupuncture combined with Paroxetine may take effect by influencing synaptic plasticity and DA system functions in the prefrontal cortex. Dopamine transporter (DAT) is an important protein to maintain the balance of DA content in the synaptic cleft. Recently, trace amine-associated receptor 1 (TAAR1) has been proved to play a role in changing the function and stability of DAT on the membrane, which leads to the regulation of DA neuron discharge and DA release in the central nervous system. Therefore, our group hypothesize that eletroacupuncture and Paroxetine influence the stability of DAT on the membrane through TAAR1, thereby changing the concentration of DA in the synaptic cleft and synaptic plasticity. Based on the hypothesis, electroacupuncture and Paroxetine will be applied on CUMS depression model rats. Firstly, evaluate the intervention effect, changes of synaptic plasticity in the prefrontal cortex, activation of TAAR1 and phosphorylation of DAT, etc. Secondly, TAAR1 knockout mice will be used to verify the hypothesis. The program aims to provide new theoretical and experimental data for the treatment of depression by electroacupuncture and antidepressant.