Cellular and Neurochemical Mechanisms of REM Sleep

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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.