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）该应用的长期目标是阐明REM睡眠的细胞和神经化学机制。更具体地说，目的是为与REM睡眠的产生和维持有关PPT胆碱能细胞活性调节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的了解将使睡眠研究领域更接近于开发人类REM疾病的有效治疗方法，例如发作性疾病，瘫痪，白天过度嗜睡，以及与精神病和神经疾病有关的REM疾病，例如抑郁症和阿尔茨海默氏病。该提议的中心假设是通过特定的谷氨酸受体刺激PPT胆碱能细胞以诱导REM睡眠。为了系统地检验该假设，有四个具体的目的：1。确定PPT中L-谷氨酸的最佳剂量以诱导最大的REM睡眠量。最佳剂量将通过对五种不同剂量的L-谷氨酸或对照车直接进行PPT胆碱能室中的五种不同剂量的L-谷氨酸或对照车进行离散微分注射来确定。 2。识别与外源L-谷氨酸 - 微注射诱导的REM睡眠有关的谷氨酸受体亚型。将通过将特定的特定谷氨酸受体拮抗剂直接进入PPT胆碱能细胞室，以阻止外源性L-谷氨酸最佳剂量的REM睡眠诱导作用来实现此目标。 3。确定哪种谷氨酸受体类型（如果有）与内源性谷氨酸保持REM睡眠有关。将通过将特定拮抗剂或对照车仅对PPT细胞室进行离散的显微注射，同时量化REM睡眠的变化，从而实现此目标。 4。检验以下假设：特定的谷氨酸受体的PPT细胞室的恢复和唤醒细胞的激活是REM睡眠产生的原因。通过将REM睡眠抑制谷氨酸受体拮抗剂施加到鉴定的REM-ON和WAKE-REM-ON PPT细胞时，可以实现此目标，同时记录自由移动大鼠的单细胞单位活性。与PPT调节的REM睡眠调节有关的谷氨酸受体的药理鉴定将是迈向未来实验的重要一步，以阐明REM睡眠产生的分子机制。