CELLULAR AND NEUROCHEMICAL MECHANISMS OF REM SLEEP

快速眼动睡眠的细胞和神经化学机制

• 批准号: 6392482
• 负责人: Subimal Datta
• 金额: $ 24.19万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392482
• 关键词: REM sleep; acetylcholine; brain electrical activity; dosage; electrodes; electrophysiology; glutamate receptor; glutamates; laboratory rat; microinjections; neurochemistry; neuropharmacology; neurotransmitter antagonist; neurotransmitter transport; single cell analysis; sleep regulatory center

DESCRIPTION: (adapted from applicant's abstract) The long term objective of this application is to elucidate the cellular and neurochemical mechanisms of REM sleep. More, specifically, the goal is to contribute to the existing, yet incomplete, body of knowledge on the regulation of the PPT cholinergic cell activity in relation to the generation and maintenance of REM sleep. A clearer understanding of PPT cell regulation mechanisms will move the field of sleep research closer to the development of effective treatments for human REM disorders, such as narcolepsy, cataplexy, excessive daytime sleepiness, and those REM disorders associated with psychiatric and neurological conditions such as depression and Alzheimer's disease. The central hypothesis of this proposal is that PPT cholinergic cells are stimulated via specific glutamate receptors to induce REM sleep. To test this hypothesis systematically, there are four specific aims: 1. Determine the optimal dosage of L-Glutamate in the PPT to induce the maximum amount of REM sleep. The optimal dosage will be determined by making discrete microinjections of one of five different doses of L-Glutamate or control vehicle directly into the PPT cholinergic compartment while quantifying the effects of REM sleep. 2. Identify the glutamate receptor subtype(s) that is involved in exogenous L-glutamate-microinjection-induced REM sleep. This goal will be achieved by microinjecting specific glutamate receptor antagonists directly into the PPT cholinergic cell compartment to block the REM sleep inducing effect of the optimal dose of exogenous L-glutamate. 3. Identify which glutamate receptor type, if any, is involved in the maintenance of REM sleep by endogenous glutamate. This goal will be achieved by making discrete microinjections of specific antagonists or control vehicle alone into the PPT cell compartment while quantifying changes in REM sleep. 4. Test the hypothesis that activation of REM-on and Wake- REM-on cells of the PPT cell compartment by specific glutamate receptors is causal for the generation of REM sleep. This aim will be achieved by applying the REM sleep suppressing glutamate receptor antagonist to identified REM-on and Wake-REM-on PPT cells while recording single cell unitary activity in freely moving rats. The pharmacological identification of glutamate receptors involved with PPT-modulated REM sleep regulation will be an important step toward future experiments to elucidate the molecular mechanisms of REM sleep generation.

描述：（改编自申请人的摘要）本申请的长期目标是阐明快速眼动睡眠的细胞和神经化学机制。更具体地说，我们的目标是为有关 PPT 胆碱能细胞活性调节（与 REM 睡眠的产生和维持相关）的现有但不完整的知识体系做出贡献。对 PPT 细胞调节机制的更清晰了解将使睡眠研究领域更接近开发人类 REM 疾病的有效治疗方法，例如发作性睡病、猝倒、白天过度嗜睡以及与精神和神经系统疾病（例如抑郁症）相关的 REM 疾病和阿尔茨海默病。该提议的中心假设是 PPT 胆碱能细胞通过特定的谷氨酸受体刺激来诱导快速眼动睡眠。为了系统地检验这一假设，有四个具体目标： 1. 确定 PPT 中 L-谷氨酸的最佳剂量，以诱导最大量的 REM 睡眠。最佳剂量将通过将五种不同剂量的 L-谷氨酸或对照载体中的一种直接微量注射到 PPT 胆碱能室中来确定，同时量化快速眼动睡眠的影响。 2. 确定参与外源性 L-谷氨酸微注射诱导的快速眼动睡眠的谷氨酸受体亚型。这一目标将通过将特定的谷氨酸受体拮抗剂直接显微注射到 PPT 胆碱能细胞区室中，以阻断最佳剂量的外源性 L-谷氨酸的快速眼动睡眠诱导作用来实现。 3. 确定哪种谷氨酸受体类型（如果有）参与内源性谷氨酸维持快速眼动睡眠。这一目标将通过将特定拮抗剂或单独的对照载体离散显微注射到 PPT 细胞室中，同时量化 REM 睡眠的变化来实现。 4. 检验以下假设：特定谷氨酸受体激活 PPT 细胞区室的 REM-on 和 Wake-REM-on 细胞是 REM 睡眠产生的原因。这一目标将通过应用 REM 睡眠抑制谷氨酸受体拮抗剂来识别 REM-on 和 Wake-REM-on PPT 细胞，同时记录自由活动大鼠的单细胞单一活动来实现。与 PPT 调节的 REM 睡眠调节相关的谷氨酸受体的药理学鉴定将是未来实验阐明 REM 睡眠产生的分子机制的重要一步。