Functional Neuroanatomy Underlying Excessive Sleepiness

项目摘要 睡眠障碍影响数百万人，并可能与神经退行性疾病共病， 帕金森病（PD）。除了PD的标志性运动障碍外，睡眠障碍，包括 过度嗜睡困扰着许多PD患者，并显著降低了他们的生活质量。然而，在这方面， 帕金森病中过度嗜睡的神经生物学机制仍有待阐明。虽然 黑质腹侧部（SN）多巴胺（DA）神经元的变性被认为是原发性的 PD的神经病理学负责疾病的运动障碍，这些神经元不介导睡眠- 唤醒周期在中脑导水管周围灰质（vPAG）中，一个研究不足的DA神经元群体促进了 虽然这些DA神经元在PD中不退化，但这些神经元的功能障碍可能发生 去甲肾上腺素能输入减少所致。事实上，去甲肾上腺素能蓝斑（LC）的灾难性损失 神经元的死亡发生在PD中，并且实际上先于SN神经元的死亡，LC促进唤醒及其活性 跟踪睡眠-觉醒周期，LC投影到vPAG。因此，我假设， LC-vPAG唤醒回路是PD患者过度嗜睡的基础。为了验证这一假设，该项目将利用 体外电生理学，唤醒的行为测定，设计者受体仅由设计者激活 药物（DREADDs）和基因工程小鼠的位点特异性行为药理学。目标1将 确定vPAG中LC传输的抑制是否会降低唤醒，目标2将测试是否 vPAG DA神经元的直接激活增加唤醒，并且Aim 3将确定神经生理学和 药理学介导LC-vPAG唤醒回路。这些实验将研究这部小说的作用 LC-vPAG回路在觉醒中的作用，以及该回路的功能障碍如何导致过度嗜睡， 发生在PD和其他睡眠障碍中。

Project Summary Sleep disorders affect millions of people and can be co-morbid with neurodegenerative diseases such as Parkinson's disease (PD). In addition to the iconic motor impairments of PD, sleep disorders, including excessive sleepiness, plague many individuals with PD and significantly reduce their quality of life. However, the neurobiological mechanisms underlying excessive sleepiness in PD remain to be elucidated. Although degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SN) is considered the primary neuropathology of PD responsible for the disease's motor impairments, these neurons do not mediate sleep- wake cycles. An understudied population of DA neurons in the ventral periaqueductal gray (vPAG) promote wakefulness, and although these DA neurons do not degenerate in PD, dysfunction of these neurons may occur in PD due to reduced noradrenergic input. Indeed, catastrophic loss of noradrenergic locus coeruleus (LC) neurons occurs in PD and actually precedes the death of SN neurons, the LC promotes arousal and its activity tracks with sleep-wake cycles, and the LC projects to the vPAG. Therefore, I hypothesize that dysfunction of an LC-vPAG arousal circuit underlies excessive sleepiness in PD. To test this hypothesis, this project will utilize in vitro electrophysiology, behavioral assays of arousal, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), and site-specific behavioral pharmacology in genetically engineered mice. Aim 1 will determine whether suppression of LC transmission in the vPAG decreases arousal, Aim 2 will test whether direct activation of vPAG DA neurons increases arousal, and Aim 3 will determine the neurophysiology and pharmacology mediating the LC-vPAG arousal circuit. These experiments will investigate the role of this novel LC-vPAG circuit in arousal and how dysfunctions of this circuit may underlie the excessive sleepiness that occurs in PD and other sleep disorders.