黑质-底丘脑核多巴胺能系统在左旋多巴诱导的异动症中的作用机制研究

Levodopa-induced dyskinesia (LID) is a common complication of Parkinson's disease, but its mechanism is still unclear. The electrical activity of neurons in subthalamic nucleus (STN) may change abnormally in LID, and STN is also an important target of deep brain stimulation in the treatment of LID. Studies have shown that dopaminergic neurons in substantia nigra can directly project to STN and regulate the activity of STN neurons through dopamine receptors, but the role and mechanism of substantia nigra-STN dopaminergic system in LID are still unclear. In this study, magnetic resonance and PET studies of LID patients will be used to clarify the changes and mechanisms of substantia nigra-STN neural connection; viral tracing, electron microscopy, high performance liquid chromatography and other molecular biological studies of LID animal models will be used to confirm the changes and mechanisms of substantia nigra-STN neural connection; and finally optogenetics and local injection of drugs will be used to interfere with dopamine receptors in STN and the improvement of LID will be assessed. The aim of this study is to elucidate the mechanism of substantia nigra-STN dopaminergic system in LID at the level of nerve circuit, subcellular and molecular, and to seek potential therapeutic targets for LID.

左旋多巴诱导的异动症（levodopa induced dyskinesia，LID）是帕金森病的常见并发症，但其发生机制尚不明确。底丘脑核（subthalamic nucleus，STN）神经元电活动在LID中会发生异常改变，STN也是深部脑刺激治疗LID的重要靶点。研究表明，黑质多巴胺能神经元可以直接投射到STN，并通过多巴胺受体调节STN神经元的活动，但黑质-STN多巴胺能系统在LID发生发展中的作用及机制仍然不清楚。本研究拟通过临床LID患者磁共振及PET研究明确黑质-STN神经连接的改变及机制；另外通过基础LID动物模型病毒示踪、电镜、高效液相及其他分子生物学方法进一步验证黑质-STN神经连接的改变及机制；最后通过光遗传和局部注射药物干预STN区相关受体，观察LID改善情况。旨在从神经环路、亚细胞及分子水平阐释黑质-STN多巴胺能系统在LID中的作用机制，寻求潜在的治疗靶点。

左旋多巴诱导的异动症（levodopa induced dyskinesia，LID）是帕金森病的常见并发症，但其发生机制尚不明确。底丘脑核（subthalamic nucleus，STN）神经元电活动在LID中会发生异常改变，STN也是深部脑刺激治疗LID的重要靶点。研究表明，黑质多巴胺能神经元可以直接投射到STN，并通过多巴胺受体调节STN神经元的活动，但黑质-STN多巴胺能系统在LID发生发展中的作用及机制仍然不清楚。本研究通过成功创建LID动物模型，并通过病毒示踪、电镜、高效液相及其他分子生物学方法验证黑质-STN神经连接的改变及机制，然后通过局部注射药物干预STN区相关受体，观察对LID行为的改善情况。研究发现，在LID大鼠模型STN区域多巴胺受体2型（D2DR）表达含量下降，且D2DR下游相关分子水平表达也有所改变，与D2DR表达含量变化一致，最后在LID大鼠STN区注射D2DR激动剂可以改善LID行为。本研究从神经环路、亚细胞及分子水平阐释黑质-STN多巴胺能系统在LID中的作用机制很可能与STN区D2DR受体相关，为LID的治疗提供了潜在的治疗靶点。