多巴胺能神经变性诱发帕金森病抑郁的分子机制研究

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.

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。

帕金森病患者并发抑郁症，但是相关病理机制仍然不清楚。“帕金森病抑郁”作为神经系统-精神系统的共病，涉及多靶点的多巴胺能神经系统损害机制。多巴胺能神经元主要分布在中脑黑质致密区和腹侧被盖区，以及下丘脑和边缘系统。腹侧被盖区的多巴胺能神经纤维投射到杏仁核、海马和终纹床核参与情感行为的调控。我们发现神经毒素MPTP选择性损害小鼠的多巴胺能神经元诱发抑郁-焦虑行为，本课题进一步研究“多巴胺能神经变性诱发抑郁的分子机制”。实验结果显示：①腹侧被盖区（VTA）多巴胺能神经元缺失引起多巴胺1受体（D1R）介导的腹侧海马神经再生障碍。②前内侧终纹床核（amBNST）接收腹侧海马的谷氨酸神经传入，促进海马-amBNST突触传递，增加amBNST的GABA神经元活性。损害神经再生通过减弱GABA神经对下丘脑CRH神经细胞的抑制，导致下丘脑-垂体-肾上腺皮质内分泌轴（HPA）轴的活性亢进，从而诱发抑郁样行为；③VTA的多巴胺能神经变性通过破坏杏仁核兴奋-抑制回路平衡，抑制LTD诱导，阻止恐惧记忆的消除，诱导焦虑样行为；④PVN的多巴胺能神经元通过调节CRH神经细胞D2R介导的PKA-CREB通路，抑制CRH的表达；⑤下丘脑PVN的CRH神经元表达σ1受体，σ1受体活化通过抑制糖皮质激素受体磷酸化对HPA轴活性的负反馈调控作用；⑥VTA多巴胺能神经元缺失通过降低外侧终纹床核D1R介导GABA神经元活化，减弱GABAA受体对CRH神经的抑制，导致HPA轴增强。本研究的结果将提出帕金森病抑郁早期诊断和选择性治疗的新策略。