帕金森病患者常并发抑郁症——帕金森病抑郁，但是有关其病理机制仍不清楚。基于神经毒素MPTP选择性损害小鼠中脑的多巴胺能神经元，导致海马和杏仁核的多巴胺能神经纤维明显减少，诱发运动障碍和抑郁-焦虑行为的前期研究结果，本课题将采用MPTP-小鼠、多巴胺受体基因敲除或药物阻断小鼠，研究多巴胺能神经变性①对背-腹侧海马齿状回干细胞增殖和分化，新生神经元存活和成熟，以及回路整合的影响及其分子机制；②对杏仁核BLA兴奋-抑制回路平衡的影响，以及变异突触可塑性的诱导；③对杏仁核CeA-CRF细胞和GABA神经活性的影响。④进一步探讨海马神经再生障碍、BLA兴奋-抑制失衡和CeA神经-内分泌失调之间的相互影响，造成HPA应激轴活性亢进的机制，揭示“多巴胺能神经变性诱发抑郁的分子机制”。⑤评价帕金森病患者的抑郁发生与背-腹侧海马齿状回体积和皮质醇水平的相关性，提出帕金森病抑郁早期诊断和选择性治疗的新策略。

Parkinson’s disease (PD) is characterized by motor symptoms with a high risk for affective disorder. However, the neurobiological mechanisms of anxiety and depression in PD patients still remain unclear. We observed that the exposure of mice to neurotoxicant MPTP caused a significant loss of dopaminergic neurons in substantia nigra (SN) and ventral tegmental area (VTA) with the reduction of dopaminergic fibers in hippocampus and amygdale. The MPTP-mice showed the anxiety and depression-like behaviors. In the present study, we will use the MPTP-mice, the dopamine receptor (D1R, D2R) knockout mice, D1R and D2R antagonists-treated mice to further explore the influence of dopaminergic neurons degeneration induced by MPTP on ① the process of adult neurogenesis, including the proliferation of stem cells, differentiation of progenitor cells, the neurite growth and survival of newborn neurons in dorsal and ventral hippocampal dentate gyrus and the underlying mechanisms; ② the balance of neuronal excitatory-inhibitory in the basolateral amygdala (BLA), and the induction of meta-plasticity; ③ the expression and release of corticotrophin releasing hormone (CRH)，activity of GABAergic neurons in the nucleus of central amygdale (CeA). ④ Further study will focus on exploring the regulation of hippocampal neurogenesis deficits, the imbalance of neuronal excitatory-inhibitory and synaptic meta-plasticity in BLA and the enhancement of CeA-CRF on hypothalamo-pituitary-adrenocortical (HPA) stress axis and their correlation, which can help for understanding the mechanisms underlying the depression of Parkinson's disease. ⑤ We will evaluate the relationship between depression and dorsal-ventral hippocampal volume or the levels of corticosterone and ACTH in PD patients, which can supply a new strategy for the early diagnosis and treatment of depression in Parkinson's disease.