CELLULAR AND NEUROCHEMICAL MECHANISMS OF REM SLEEP

产品说明：本申请的长期目标是阐明REM睡眠的细胞和神经化学机制。更具体地说，我们的目标是促进现有的，但不完整的，身体的知识调节PPT胆碱能细胞活性的产生和维持REM睡眠。对PPT细胞调节机制的更清楚的理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，例如嗜睡症，cataepsy，白天过度嗜睡，以及与精神和神经疾病相关的REM疾病，如抑郁症和阿尔茨海默病。这个建议的中心假设是PPT胆碱能细胞通过特定的谷氨酸受体刺激以诱导REM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-谷氨酸盐或对照载体之一直接离散微量注射到PPT胆碱能隔室中，同时定量REM睡眠的影响来确定。2.鉴定参与外源性L-谷氨酸微量注射诱导REM睡眠的谷氨酸受体亚型。这一目标将通过将特异性谷氨酸受体拮抗剂直接微量注射到PPT胆碱能细胞隔室中以阻断最佳剂量的外源性L-谷氨酸的REM睡眠诱导作用来实现。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REM睡眠。这一目标将通过将特异性拮抗剂或对照载体单独离散微量注射到PPT细胞区室中，同时定量REM睡眠的变化来实现。4.验证以下假设：PPT细胞区室的REM-on和Wake-REM-on细胞被特定谷氨酸受体激活是REM睡眠产生的原因。这一目的将通过将REM睡眠抑制谷氨酸受体拮抗剂应用于鉴定的REM-on和Wake-REM-on PPT细胞，同时记录自由活动大鼠的单细胞单位活性来实现。谷氨酸受体参与PPT调制REM睡眠调节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。

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.