Orexins in Rapid Eye Movement Sleep Control.

快速眼动睡眠控制中的食欲素。

基本信息

批准号：
7565894
负责人：
MAHESH M THAKKAR
金额：
$ 6.3万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2010-09-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：食欲素/下丘脑分泌素是下丘脑神经肽，对于正常的睡眠-觉醒至关重要。有大量证据表明食欲素与猝倒/发作性睡病有关，这可能被视为快速眼动睡眠障碍。虽然食欲素神经元的细胞体仅位于外侧下丘脑，但食欲素神经元会发送广泛的投射并瞄准对睡眠-觉醒控制很重要的大脑区域。该研究计划的广泛目标是了解食欲素控制快速眼动睡眠的细胞和分子机制，从而为理解和治疗人类睡眠障碍（包括发作性睡病）提供坚实的基础。我们将采用多学科方法的新颖组合，包括体内使用小干扰 RNA (siRNA) 敲低脑干口桥/腹侧蓝膜下区 (PNO) 区域的食欲素 II 型受体，并进行定量实时 PCR 验证击倒和睡眠-觉醒的电图记录。我们的假设是，食欲素通过对 PNO 局部 GABA 能神经元上的食欲素 II 型受体的作用，防止快速眼动睡眠和快速眼动相关的肌肉无力的发生。我们将在自由行为的大鼠中施用针对 PNO 中食欲素 II 型受体的 siRNA，预测快速眼动睡眠时间的增加以及偶尔的猝倒/睡眠发作类快速眼动发作。我们进一步预测，向 PNO 外源施用食欲素将增加对照（盐水和乱序 siRNA 处理）大鼠的清醒度，但 siRNA 处理的大鼠的反应会减弱。相反，在 siRNA 和对照（盐水和乱序 siRNA 处理）大鼠中，对 PNO 施用卡巴胆碱会诱导短潜伏期的 REM 睡眠。公共健康相关性该研究计划的主要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（包括发作性睡病）提供坚实的基础。