GENETIC VARIATION INFLUENCING SLEEP REGULATION

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This proposal seeks to identify genes implicated in the normal expression and regulation of sleep and the sleep EEG in mice. We have identified several sleep and EEG related phenotypes that strongly vary with genotype in inbred strains of mice. In this proposal, we intend to follow these candidate phenotypes in segregating progeny derived from the inbred strains for which these phenotypes differed the most. We propose to first study the segregation of "candidate" phenotypes in a set of 21 recombinant inbred (RI) strains of mice that were derived from two progenitor strains (i.e. AKR x DBA/2). Subsequent pheno- and genotyping of inter-and/or backcross progeny will yield more detailed information on genomic localizations that may be used to explain genotypic variance in the traits of interest (QTL-mapping and linkage analysis). Furthermore, we can make use of these spontaneous intra-species differences in sleep to answer basic sleep physiology issues. These issues concern the homeostatic regulation of SWS and REMS, their interaction with each other and with brain temperature, and the neurophysiological substrate of SWS intensity measured by EEG delta power. The large difference in the time constant of the wakefulness-dependent increase in SWS delta power between AKR and DBA/2 that we have found, is of special interest because it suggests that the accumulation of sleep need is under genetic control. Identifying genetic factors underlying the normal expression and regulation of sleep and the sleep EEG will further our understanding of the neurophysiological mechanisms that govern sleep and will potentially have large implications for sleep disorders in general and those with a genetic predisposition in particular.