Functional Neuroanatomy Underlying Excessive Sleepiness

项目摘要 睡眠障碍影响数以百万计的人，并可能与神经退行性疾病共病，如 帕金森氏病(PD)。除了帕金森病标志性的运动障碍外，睡眠障碍还包括 过度嗜睡，困扰着许多帕金森氏症患者，并显著降低他们的生活质量。然而， 帕金森病患者过度嗜睡的神经生物学机制尚不清楚。虽然 黑质致密部(SN)多巴胺(DA)神经元变性被认为是主要的 帕金森病的神经病理导致疾病的运动障碍，这些神经元不调节睡眠- 唤醒周期。腹侧中脑导水管周围灰质(VPAG)中未被研究的DA神经元群促进 觉醒，虽然这些DA神经元在帕金森病中不会退化，但这些神经元可能会发生功能障碍 帕金森病是由于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)的灾难性丧失 神经元出现在帕金森病中，实际上早于黑质神经元的死亡，LC促进觉醒及其活动 跟踪睡眠-唤醒周期，LC投射到vPAG。因此，我假设一个人的功能障碍 LC-VPAG唤醒回路是帕金森病患者过度嗜睡的基础。为了验证这一假设，该项目将在 体外电生理学，唤醒的行为分析，由Designer独有激活的Designer受体 药物(DREADD)和基因工程小鼠的特定部位行为药理学。目标1将 确定抑制vPAG中的LC传输是否会降低唤醒，目标2将测试 VPAG DA神经元的直接激活增加觉醒，Aim 3将决定神经生理学和 药理学在LC-VPAG觉醒回路中的作用。这些实验将考察这部小说的作用 唤醒中的LC-VPAG回路，以及该回路的功能障碍如何可能是过度嗜睡的原因 发生在帕金森病和其他睡眠障碍中。

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.