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: 7037402
• 负责人: Subimal Datta
• 金额: $ 27.6万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037402
• 关键词: GABA receptor; REM sleep; acetylcholine; biological signal transduction; brain electrical activity; electrodes; electrophysiology; glutamate receptor; glutamates; laboratory rat; microinjections; neurobiology; neurochemistry; neuropharmacology; neurotransmitter antagonist; neurotransmitter transport; protein kinase A; single cell analysis; sleep regulatory center; tegmentum

DESCRIPTION (provided by applicant): The long-term objective of this application is to further our understanding of cellular and neurochemical mechanisms of REM sleep. More specifically, the goal is to identify Pedunculo Pontine Tegmentum (PPT) intracellular signal transduction pathways involved in the receptor activation-mediated regulation of REM sleep in the freely moving rat. Recent evidence indicates that novel compounds designed to modify intracellular transduction pathways have therapeutic potential for endogenous depression, cancer, hypothermia, and pathological aggregation of platelets, thus the identification of the intracellular molecules involved in normal regulation of REM sleep may lead to the design of the future generation of drugs to treat REM sleep disorders in humans (e.g. endogenous depression, schizophrenia, panic attacks, bipolar disorders, narcolepsy, excessive daytime sleepiness).The central hypothesis of this proposal is that the activity of REM sleep generating cells in the PPT cholinergic cell compartment is regulated by the activation of specific glutamate and GABA receptors. These particular receptors convey their message via cAMP-dependent protein kinase A (PKA) to regulate normal and glutamate-induced REM sleep. To test this hypothesis systematically, there are four specific aims: 1. Test the hypothesis that cAMP-PKA intracellular signaling molecules in the PPT cholinergic cell compartment are involved in natural and glutamate-microinjection-induced REM sleep. Microinjecting cAMP and PKA inhibitors directly into the PPT to block spontaneous and glutamate-induced REM sleep will achieve this goal. 2. Test the hypothesis that the activation of specific GABA-receptors in the PPT cholinergic cell compartment suppresses REM sleep. This goal will be achieved by microinjecting selective GABA receptor agonists into the PPT to block REM sleep. 3. Test the hypothesis that the induction of GABA-receptor-mediated suppression of REM sleep is due to the inhibition of the cAMP-PKA signal transduction pathway. Microinjecting selective cAMP-PKA activator into the PPT to block the REM sleep suppressing effect of GABA receptor agonist will achieve this goal. 4. Test the hypothesis that the activation of specific GABA receptors suppresses REM sleep by suppressing the activity of REM-on and Wake-REM-on cells in the PPI. This aim will be achieved by applying the REM sleep suppressing GABA receptor agonist to identified REM-on and Wake-REM-on PPT cells while recording single cell activity in freely moving rats. These studies are relevant not only to questions about the basic neurobiology of sleep but also to questions of sleep disorders and mental illness.

描述（由申请人提供）：本申请的长期目标是进一步了解快速眼动睡眠的细胞和神经化学机制。更具体地说，我们的目标是确定自由活动大鼠中参与受体激活介导的快速眼动睡眠调节的 Pedunculo 桥脑被盖 (PPT) 细胞内信号转导途径。最近的证据表明，旨在改变细胞内转导途径的新型化合物具有治疗内源性抑郁症、癌症、体温过低和血小板病理性聚集的潜力，因此，识别参与快速眼动睡眠正常调节的细胞内分子可能会导致设计下一代治疗人类快速眼动睡眠障碍（例如内源性抑郁症、精神分裂症、惊恐发作、双向情感障碍、发作性睡病、白天过度嗜睡）的药物。该提议认为，PPT 胆碱能细胞室中快速眼动睡眠生成细胞的活性是通过特定谷氨酸和 GABA 受体的激活来调节的。这些特殊受体通过 cAMP 依赖性蛋白激酶 A (PKA) 传递信息，调节正常和谷氨酸诱导的快速眼动睡眠。为了系统地检验这一假设，有四个具体目标： 1. 检验 PPT 胆碱能细胞区室中的 cAMP-PKA 细胞内信号分子参与自然和谷氨酸微注射诱导的 REM 睡眠的假设。将 cAMP 和 PKA 抑制剂直接显微注射到 PPT 中以阻止自发性和谷氨酸诱导的 REM 睡眠将实现这一目标。 2. 检验 PPT 胆碱能细胞区室中特定 GABA 受体的激活会抑制 REM 睡眠的假设。这一目标将通过将选择性 GABA 受体激动剂显微注射到 PPT 中以阻止 REM 睡眠来实现。 3. 检验以下假设：GABA 受体介导的快速眼动睡眠抑制是由于 cAMP-PKA 信号转导途径的抑制所致。将选择性cAMP-PKA激活剂显微注射到PPT中以阻断GABA受体激动剂的REM睡眠抑制作用将实现这一目标。 4. 检验特定 GABA 受体的激活通过抑制 PPI 中 REM-on 和 Wake-REM-on 细胞的活动来抑制 REM 睡眠的假设。这一目标将通过应用抑制 REM 睡眠的 GABA 受体激动剂来识别 REM-on 和 Wake-REM-on PPT 细胞，同时记录自由活动大鼠的单细胞活动来实现。这些研究不仅与睡眠的基本神经生物学问题相关，而且与睡眠障碍和精神疾病问题相关。