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.
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