CELLULAR AND NEUROCHEMICAL MECHANISMS OF REM SLEEP

描述：(摘自申请者的摘要)这项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，目标是为现有的、但不完整的关于PPT胆碱能细胞活动调节与REM睡眠的产生和维持有关的知识做出贡献。更清楚地了解PPT细胞调节机制将使睡眠研究领域更接近于开发有效的治疗人类REM障碍的方法，如发作性睡病、猝倒、白天过度嗜睡，以及与精神和神经疾病相关的REM障碍，如抑郁症和阿尔茨海默病。这一建议的中心假设是，PPT胆碱能细胞通过特定的谷氨酸受体刺激，从而诱导REM睡眠。为了系统地验证这一假说，有四个具体的目的：1.确定在PPT中诱导最大REM睡眠的L-谷氨酸的最佳剂量。最佳剂量将通过将五种不同剂量的L谷氨酸或对照药物中的一种直接注射到PPT胆碱能区来确定，同时量化REM睡眠的影响。2.确定参与外源性L-谷氨酸-微量注射快速眼动睡眠的谷氨酸受体亚型(S)。这一目标将通过将特定的谷氨酸受体拮抗剂直接微量注射到PPT胆碱能细胞室来阻断最佳剂量的外源性L-谷氨酸的REM睡眠诱导效应。3.确定哪种谷氨酸受体类型(如果有的话)与内源性谷氨酸维持快速眼动睡眠有关。这一目标将通过将特定的拮抗剂或对照药物单独微量注射到PPT细胞隔间，同时量化REM睡眠的变化来实现。4.验证特定谷氨酸受体激活PPT细胞室的REM-ON和Wake-REM-on细胞是产生REM睡眠的原因的假设。这一目标将通过将REM睡眠抑制谷氨酸受体拮抗剂应用于已鉴定的REM-ON和Wake-REM-on PPT细胞来实现，同时记录自由活动大鼠的单个细胞单位活动。对参与PPT调节的REM睡眠调节的谷氨酸受体的药理学鉴定将是未来阐明REM睡眠产生的分子机制的重要一步。

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.