The central hypothesis of this proposal is that interleukin-1-beta is a key regulatory component of sleep. Much data support this hypothesis; administration of exogenous IL-1-beta enhances non-rapid eye movement sleep (NREMS); inhibition of IL-1-beta inhibits spontaneous NREMS and NREMS - induced by sleep deprivation; IL-1-beta mRNA has a diurnal rhythm in brain and increases after sleep deprivation.
In Specific Aim #1, the investigators will test the specific hypothesis that the IL-1 type I receptor (IL-1RI) is necessary for IL-1-mediated changes in sleep regulation. They will use a knockout mouse lacking this receptor; preliminary data suggest that these mice sleep less than strain controls. Further, they do not respond to IL-1-beta.
In Specific Aim #2 the investigators will test the hypothesis that the IL-1-beta and tumor necrosis factor-alpha (TNF) systems act in concert to regulate NREMS and are part of a larger functional gene group involved in sleep regulation. For these experiments, the investigators will use the IL--1RI knockout mouse and double knockout mouse which lacks both the IL-1RI and the TNF55-kD receptor.
Specific Aim #3 tests the hypothesis that somnogenic stimuli will induce changes in specific areas of brain in the levels of one or more of the members of the IL-1 receptor antagonist will be measured using reverse transcriptase polymerase chain reaction, Northern blot analyses and RNASE protection assays. The effects of various somnogens (sleep deprivation, muramyl dipeptide and acute mild increases in ambient temperature) on the levels and distribution of these mRNAs in brain will be determined. Anticipated results will help our understanding of how the brain is organized to produce sleep. They will also help our understanding of the cellular and molecular mechanisms of sleep regulation. Knowledge of such mechanisms is likely to be a necessary step toward our understanding of sleep function.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Psychobiology, Behavior, and Neuroscience Review Committee (PBN)
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Mitler, Merrill
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Washington State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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