Sleep apnea is associated with excessive daytime sleepiness and hence an increased risk of vehicular crashes. The basic mechanism underlying this sleepiness is unknown. Currently it is proposed that increasing sleepiness results from accumulation of molecules that promote sleep. While several such molecules have been identified, perhaps the clearest evidence is for adenosine. We do not known, however, how adenosine levels in critical brain regions are regulated in relation to the sleep/wake cycle nor whether there is within the brain a regional specificity to this regulation. This proposal is based on the fundamental notion that regulation of enzymes involved in adenosine metabolism (and/or nucleoside transporters) in relationship to the circadian system and to sleep homeostasis play a major role in setting adenosine levels in relation to sleep need. This postulated mechanism provides a powerful, novel method to achieve interaction between the sleep and circadian systems. This hypothesis will be addressed in a complementary series of studies with investigators at two universities (University of Pennsylvania and University of Manitoba) who have complementary skills. In one series of studies, we will directly measure total adenosine levels in several different brain regions relevant to sleep, and how these levels changes across the day and following different durations of sleep deprivation. In other studies, we will determine the diurnal changes in the relevant enzymes (adenosine kinase, adenosine deaminase, and 5'-nucleotidase) in brain regions relevant to sleep. We will study the relative role of the circadian and sleep homeostatic system in mediating such changes. To address how the adenosine enzymes might themselves be regulated, we will address, in another series of studies, whether changes in enzyme activity are correlated with alterations in mRNA abundance for the relevant enzymes. mRNA analysis will also be used to assess whether similar temporal changes occur in nucleoside transporters. All of these studies will be done in rats. Our hypothesis would predict, however, that animals with different diurnal distributions of their sleep/wake cycles will have different diurnal variations in adenosine and its enzymes in brain regions relevant for sleep control. Such an animal is the Octodon degus and we will address in our final protocol whether there is predicted differences in the diurnal changes in adenosine and its enzymes of metabolism in this species as compared to rat. Taken together, these studies will provide a comprehensive picture about how brain adenosine is regulated in relation to sleep need.
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