Orexins in Rapid Eye Movement Sleep Control.

描述（由申请方提供）：食欲素/下丘脑分泌素是对正常睡眠-觉醒至关重要的下丘脑神经肽。有大量证据表明食欲素与可被视为REM睡眠障碍的紧张症/发作性睡病有关。虽然食欲素神经元的细胞体仅位于外侧下丘脑中，但食欲素神经元发送广泛的投射并靶向在睡眠-觉醒控制中重要的脑区域。该研究计划的主要目标是了解食欲素控制REM睡眠的细胞和分子机制，从而为理解和治疗人类睡眠障碍（包括嗜睡症）提供坚实的基础。我们将使用多学科方法的新组合，包括在体内使用小干扰RNA（siRNA）敲低脑干的脑桥口侧/腹侧蓝斑下区（PNO）区域中的食欲素II型受体，以及敲低的定量真实的时间PCR验证和睡眠-觉醒的电图记录。我们的假设是，食欲素防止REM睡眠和REM相关的肌肉张力的发生，其作用于PNO中局部GABA能神经元上的食欲素II型受体。我们将在行为自由的大鼠PNO中施用针对食欲素II型受体的siRNA，预测REM睡眠沿着偶尔的痉挛/睡眠发作REM样发作所花费的时间量增加。我们进一步预测，对PNO外源性施用食欲素将增加对照（盐水和乱序siRNA处理的）大鼠的觉醒，但在siRNA处理的大鼠中将具有钝化的反应。相比之下，卡巴胆碱给药至PNO将在siRNA和对照（盐水和乱序siRNA处理的）大鼠中诱导具有短潜伏期的REM睡眠。公共卫生相关性本研究计划的广泛目标是了解食欲素控制睡眠-觉醒的细胞和分子机制，从而为理解和治疗人类睡眠障碍（包括嗜睡症）提供坚实的基础。

DESCRIPTION (provided by applicant): Orexins/Hypocretins are hypothalamic neuropeptides that are critical for normal sleep-wakefulness. There is considerable evidence linking orexins to cataplexy/narcolepsy, which may be regarded as REM sleep disorders. While the cell bodies of orexin neurons are exclusively localized in the lateral hypothalamus, orexin neurons send widespread projections and target brain regions that are important in sleep- wakefulness control. The broad objective of this program of research is to understand the cellular and molecular mechanisms by which orexin control REM sleep and thereby to provide a sound basis for the understanding and treatment of human sleep disorders, including narcolepsy. We will use novel combinations of multi- disciplinary methods including the in vivo use of small interfering RNA (siRNA) for knockdowns of orexin type II receptor in the pontis oralis/ventral subcoeruleus region (PNO) region of the brainstem with quantitative real time PCR verification of knockdowns and electrographic recording of sleep-wakefulness. Our hypothesis is that orexin prevents the occurrence of REM sleep and REM related muscle atonia by its action on orexin type II receptors on local GABAergic neurons in the PNO. We will administer siRNA against orexin type II receptor in the PNO in freely behaving rats, predicting an increase in the amount of time spent in REM sleep along with occasional cataplexy/sleep-onset REM-like episodes. We further predict that exogenous administration of orexins to the PNO will increase wakefulness in control (saline and scrambled siRNA treated) rats but will have a blunted response in the siRNA treated rats. In contrast, carbachol administration to the PNO will induce REM sleep with short latency in both siRNA and control (saline and scrambled siRNA treated) rats. PUBLIC HEALTH RELEVANCE The broad objective of this research program is to understand the cellular and molecular mechanisms by which orexins control sleep-wakefulness and thereby to provide a sound basis for the understanding and treatment of human sleep disorders, including narcolepsy.