The heritability of sleep patterns has been documented in both human and animal studies, although the location or mechanism of action of genes which influence sleep has not yet been determined. Narcolepsy is a disorder characterized by abnormalities of rapid eye movement (REM) sleep and is highly associated with the human leucocyte antigen (HLA) DR1/DQw1. The immune system, which is under control of the major histocompatibility complex (MHC), has also been implicated in sleep regulation. These findings suggest three key questions regarding the relationship between the MHC and sleep: 1. Is MHC expression linked to control of REM sleep and, by implication, to the symptoms of narcolepsy? 2. If such an association exists, is it causally mediated by the effects of the peripheral immune system on sleep? 3. Does MHC expression confer differential central nervous system susceptibility to the sleep regulating effects of cytokines? We propose to investigate the possible linkage between the MHC and sleep in two inbred strains of rats, Lewis (L) and Brown Norway (BN), known to have significantly different patterns of REM sleep, immune function and CNS response to the cytokine interleukin-1 (IL-1). The linkage of sleep behavior to the MHC will be studied by determining physiologic sleep patterns and susceptibility to REM sleep triggering in (LxBN) F1, (F1 x parent) F2 and recombinant inbred animals vs. parental strains. The effects of the peripheral immune system on sleep regulation will be assessed in F1 rats reconstituted with parental bone marrow, while the strain-specific effects of IL-1 will be studied in parental F1, F2 and congenic rats to determine whether IL-1 effects on sleep are modulated by MHC expression.
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