黑质多巴胺能神经元在睡眠-觉醒调节中的作用及分子机制

Sleep disorders are becoming increasingly serious medical and social problem. Most disorders especially neurologic disease are often concurrent with sleep disturbance. Sleep disorders are common in PD with incidence of about 64%. The prominent pathological change of PD is the degeneration and death of dopaminergic neurons in the midbrain Substantia nigra (SN). But how sleep-wake behaviors will change after specific loss of SN dopaminergic neurons? Whether direct activation or inhibition of SN dopaminergic neurons can initiate and/or maintain wakefulness or sleep? These are the core problems to be solved. To clarify the role of SN dopaminergic neurons in sleep wake regulation, the present research will adopt pharmacogenetics DREADD and optogenetics to directly and specifically activate or inhibit neurons in SN, in combination with methods and skills including in vitro electrophysiological recording, sleep behavior recording and analysis system, neurochemistry lesion, specific trace and immunohistochemistry staining. Our predicted results will reveal the neurobiological mechanisms of SN regulation in sleep-wake behavior and provide an insight in sleep disorders of SN dysfunctions, which will provide theoretical basis for discovering new targets of clinical intervention.

睡眠障碍正成为日益严重的医学和社会问题。很多疾病尤其是神经系统疾病常合并睡眠障碍。近年来研究发现有64%的帕金森病（Parkinson’s disease，PD）患者合并有睡眠障碍。PD的病理改变是中脑黑质（Substantia nigra, SN）多巴胺能神经元的变性死亡，但SN多巴胺能神经元特异性丢失对睡眠有何影响？直接激活/抑制SN多巴胺能神经元是否可以启动或/和维持觉醒/睡眠？其机制如何？这些是亟待解决的核心问题。本申请将借助遗传药理学DREADD法和光遗传学特异性地激活/抑制神经元，结合离体脑片电生理记录、基于脑电描记的睡眠行为解析系统、神经化学核团毁损、特异性示踪以及免疫组织化学等方法，阐明SN多巴胺能神经元在睡眠-觉醒调节中的作用，并探索其分子机制。预期结果将揭示SN调节睡眠-觉醒的神经生物学基础，以及SN功能异常性睡眠障碍的发病机制，为寻找临床干预新靶点提供理论依据。