帕金森病（PD）和抑郁症存在共病现象，40%的PD患者伴有抑郁症状，而抑郁症确诊后患PD的几率比正常人群高3倍。PD后抑郁已被广泛研究，但抑郁诱发PD易感的机制尚无实验报道。本课题拟在抑郁叠加PD的小鼠模型中研究抑郁诱发PD的环路和分子机制，为预防和临床治疗PD提供新靶点：①整体水平：行为学和组织学证实抑郁小鼠对诱发PD的环境或遗传因素易感；②细胞水平：光/化学遗传学验证腹侧被盖区（VTA）的多巴胺能神经元（DA）激活参与上述过程；③环路水平：神经示踪验证抑郁导致VTA向黑质网状区（SNr）GABA能神经元的DA投射增加；电生理和钙成像检测抑郁小鼠SNr的抑制性放电上调；化学遗传学验证特异性抑制VTA/SNr环路可逆转抑郁诱发的PD易感；④分子水平：证明抑郁小鼠VTA向SNr投射的DA中CDK5激活并磷酸化其突触底物ANK2，上调VTA/SNr投射的突触功能，介导SNpc对MPTP易感。

Parkinson disease (PD) and depression have comorbidity. Nearly 40% PD patients are accompanied by depressive symptoms. In the meantime, the risk of PD is 3 times higher than that of the normal population after the diagnosis of depression. Depression after PD has been widely studied, but the structural basis of neural circuits and molecular mechanism of depression-induced susceptibility to PD has not been reported. In the current study, new technologies and methods, including animal behavior tests, chemogenetics (DREADD), optigenetics, anterograde and retrograde virus tracing techniques, electrophysiology using MED64, in vivo calcium imaging and molecular biology, were designed to study the structural basis of neural circuits, functional characteristics and molecular mechanism in depression-induced PD. 1) to find the behavioral and histological evidences to prove that depression leads to the susceptibility to PD by environmental or genetic factors. 2) prove that the dopaminergic neurons in VTA are involved in depression-induced PD using the methods of animal behavior, DREADD and optigenetics t; 3) to explore the structural basis of VTA/SNr neural circuits using whole brain mapping and anterograde/retrograde virus tracing techniques; 4) to study the role of CDK5 and its phospholated target ANK2 in the regulation of VTA/SNr neural circuit in depression-induced PD. The aim of the study is to provide a new perspective and target for understanding the pathogenesis and clinical treatment of depression and PD.