纹状体多巴胺D1受体调控睡眠-觉醒的神经生物学机制

项目名称： 纹状体多巴胺D1受体调控睡眠-觉醒的神经生物学机制

项目编号： No.31471064

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 曲卫敏

作者单位： 复旦大学

项目金额： 90万元

中文摘要： 帕金森病患者日间过度嗜睡，多巴胺D1受体（Receptor, R）激动剂改善帕金森模型动物的嗜睡症状，增加动物觉醒量；D1R拮抗剂可增加睡眠。提示：D1R可能与觉醒调控相关，但分子机制和神经环路不明。D1R主要表达在纹状体、嗅结节等脑区。我们假说：纹状体D1R可能通过直接通路调节睡眠-觉醒。为了克服药理学方法缺乏高度特异性以及基因敲除动物的代偿作用，本课题将使用D1R-Cre小鼠，利用光遗传及被特定药物活化的受体DREADD法，特异性控制D1R阳性神经元活性、RNA干扰、D1R-Cre动物注射AAV-Flox-EGFP质粒解析神经通路和D1R KO动物等方法，研究纹状体多巴胺D1R调控睡眠-觉醒的作用及分子机制。预期结果对丰富和发展睡眠-觉醒调节理论，认识帕金森病睡眠障碍发病机理和睡眠药物开发提供重要的理论依据。

中文关键词： 多巴胺；D1；受体；睡眠；觉醒；纹状体

英文摘要： It has been reported that excessive daytime sleepiness was commonly observed in Parkinson disease. Dopamine D1 receptor (R) agonists alleviated excessive daytime sleepiness and increased amount of wakefulness in experimental parkinsonism animal models, whereas D1R antagonist increased sleep. These results indicate that D1R may regulate wakefulness. However, the underlying neural circuits and molecular mechanisms of D1R in sleep-wake regulation remain to be elucidated. We hypothesize that D1R may promote wakefulness via the direct pathway in the striatum. In the proposed research, we will employ novel techniques of Cre-flox, DREADD, shRNA and D1R KO mice to dissect neural circuits and role of dopamine D1R in sleep-wake regulation. The expected results will provide several lines of evidence to understand physiological sleep-wake cycle, to explore the mechanisms of sleep disturbances in Parkinson disease and help to develop effective drugs for treating insomnia patients.

英文关键词： Dopamine;D1 receptor;Sleep;Wake;Striatum