CELLULAR AND NEUROCHEMICAL MECHANISMS OF REM SLEEP

描述：（改编自申请人摘要）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，我们的目标是促进现有的，但不完整的，关于PPT胆碱能细胞活性调节与快速眼动睡眠的产生和维持的知识体系。更清楚地了解PPT细胞的调节机制将使睡眠研究领域更接近于开发人类快速眼动障碍的有效治疗方法，如嗜睡症、猝厥、白天过度嗜睡，以及与精神和神经疾病相关的快速眼动障碍，如抑郁症和阿尔茨海默病。本研究的中心假设是，通过特定的谷氨酸受体刺激PPT胆碱能细胞诱导快速眼动睡眠。为了系统地验证这一假设，有四个具体目标：1。确定PPT中l -谷氨酸的最佳剂量，以诱导最大量的快速眼动睡眠。将5种不同剂量的l -谷氨酸或对照物中的一种直接显微注射到PPT胆碱能室，同时量化快速眼动睡眠的影响，从而确定最佳剂量。2. 确定外源性l -谷氨酸微注射诱导的快速眼动睡眠中涉及的谷氨酸受体亚型。通过将特异性谷氨酸受体拮抗剂直接微注射到PPT胆碱能细胞室，阻断最佳剂量外源性l -谷氨酸诱导快速眼动睡眠的作用，可以实现这一目标。3. 确定哪种谷氨酸受体类型（如果有的话）参与内源性谷氨酸维持快速眼动睡眠。这一目标将通过在定量快速眼动睡眠变化的同时将特异性拮抗剂或对照物单独注射到PPT细胞室来实现。4. 验证特定谷氨酸受体激活PPT细胞区快速眼动和清醒眼动细胞是快速眼动睡眠产生的原因。这一目标将通过应用快速眼动睡眠抑制谷氨酸受体拮抗剂来鉴定快速眼动和唤醒快速眼动的PPT细胞，同时记录自由运动大鼠的单细胞单一活动来实现。谷氨酸受体参与pt调控的快速眼动睡眠调节的药理学鉴定将是未来实验阐明快速眼动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.