Identification and Characterization of Molecular Inhibitors of Cognitive Performance

Addressing the issue of cognitive performance in the battlefield necessitates addressing the issue of sleep. Mounting evidence suggests that sleep deprivation impairs cognitive function by disrupting gene expression within the hippocampus. Our approach to cognitive enhancement of brain function under sleep deprivation will take advantage of the Clock mutant model that retains cognitive performance on spatial learning and memory tests despite reduced need for sleep. We propose that this Clock mutant exhibits resistance to the damaging effects of inadequate sleep on cognitive function. The question we will address is: how does the Clock gene, specifically, and sleep loss, in general, influence the anatomic substrates of learning and memory at the molecular/genetic level? Our technical objectives are to: 1) identify hippocampal gene expression changes during sleep in wild-type and Clock mutant with the latter having preserved memory function despite reduced sleep time, and 2) identify hippocampal gene expression changes during sleep deprivation in wild-type and circadian mutant Clock. We will identify pathways critical to cognitive performance through genome-wide comparisons of hippocampal gene expression. The comparison of transcriptional profiles from animals with resistance to sleep loss will enable us to identify unique molecular pathways critical to the preservation of cognitive function.