description) The long term goal of our studies is to identify genetic factors that underlie molecular events involved in the regulation of sleep. A wealth of information on the neuroanatomy, neurochemistry and neurophysiology of sleep provides a firm foundation for the classical genetic approach to the studies of sleep proposed in this application. Due to the paucity of candidate genes for key regulators of sleep-wakefulness, we propose using forward genetics to screen for single gene mutations that affect sleep patterns in the mouse. This approach involves mutagenesis of the whole genome with a potent chemical mutagen, N-ethyl-N-nitrosourea (ENU), and the generation of a large number of progeny which will then be monitored for aberrant behavioral phenotypes (indicated by differences in levels of locomotor activity, the ratio between the length of the activity and rest phase, recovery rest following short term sleep loss, startle amplitude and pre-pulse inhibition of the startle response) that may point to sleep abnormalities. The relevance of the observed behavioral anomalies for identifying abnormal sleep will be verified with a standard electro-physiological assessment of sleep (by electroencephalogram and electromyogram) performed on the progeny of potential mutants. Further behavioral testing and neuropathological examination will be used to rule out possible pleiotropic mutations and/or identify neural correlates that may underlie the observed deviations in sleep parameters. The next step will involve genetic characterization and mapping of sleep mutants, which will facilitate the interpretation of behavioral findings, as well as provide the basis for the positional cloning of genes responsible for sleep anomalies. Human orthologs of loci defined by these single gene mutations may represent additive or interactive contributions to the polygenic component of inherited sleep disorders. Random mutagenesis and screening for aberrant behavioral traits in mice have not been extensively utilized and have great potential for discovering genes underlying the regulation of sleep and wakefulness in mammals. (end of description)
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