Cellular and Neurochemical Mechanisms of REM Sleep

描述（由申请人提供）：本申请的长期目标是进一步了解REM睡眠的细胞和神经化学机制。更具体地说，我们的目标是确定参与受体激活介导的调节REM睡眠在自由活动的大鼠脑桥被盖脚（PPT）的细胞内信号转导通路。最近的证据表明，设计用于修饰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，鉴定参与REM睡眠正常调节的细胞内分子可能导致设计未来一代治疗人类REM睡眠障碍的药物（例如内源性抑郁症、精神分裂症、惊恐发作、双相性精神障碍、发作性睡病、白天过度嗜睡）。该建议的中心假设是PPT胆碱能细胞区室中REM睡眠产生细胞的活性受特异性谷氨酸和GABA受体的激活调节。这些特殊的受体通过cAMP依赖性蛋白激酶A（PKA）传递它们的信息，以调节正常和谷氨酸诱导的REM睡眠。为了系统地检验这一假设，有四个具体目标：1。验证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量注射诱导的REM睡眠的假设。将cAMP和PKA抑制剂直接注射到PPT中以阻断自发性和谷氨酸诱导的REM睡眠将实现这一目标。2.验证PPT胆碱能细胞区室中特定GABA受体的激活抑制REM睡眠的假设。这一目标将通过向PPT中微量注射选择性GABA受体激动剂来阻断REM睡眠来实现。3.检验GABA受体介导的REM睡眠抑制的诱导是由于cAMP-PKA信号转导通路的抑制的假设。在PPT内微量注射选择性cAMP-PKA激活剂阻断GABA受体激动剂的REM睡眠抑制作用将达到这一目的。4.验证特定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。这一目的将通过将REM睡眠抑制GABA受体激动剂应用于鉴定的REM-on和Wake-REM-on PPT细胞，同时记录自由移动大鼠中的单细胞活性来实现。这些研究不仅与睡眠的基本神经生物学有关，而且与睡眠障碍和精神疾病有关。

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.