Gene Regulation and Synaptic Plasticity in Sleep

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DESCRIPTION (provided by applicant): A large body of evidence suggests that sleep plays a significant role in the consolidation of memories of day-time events. For example, animals that are actively learning a particular paradigm display enhanced REM sleep, while animals which are REM deprived following learning display memory deficits on retest. Little is known, however, about the brain mechanisms that underlie the role of sleep in memory consolidation. We recently discovered that Zif-268, an immediate early gene (IEG) linked with neuronal plasticity, is activated in certain brain areas in animals exposed to an enriched environment, and then reactivated in the ensuing REM sleep-in comparison to animals kept in their home cages. Preliminary data from our lab indicate that such reactivation also occurs in REM sleep that follows presentation of a potent olfactory stimulus, or induction of hippocampal long-term potentiation (LTP), the latter being a model of synaptic plasticity. We hypothesize that gene reactivation during REM sleep may be involved in the role that REM plays in memory consolidation. The present proposal is aimed at testing this possibility. In Aim I we will ref1ne our preliminary observations by determining whether gene reactivation in sleep also occurs in animals exposed to specific learning paradigms (e.g., spatial memory; motor learning, olfactory stimulation) during wakefulness; the timecourse and brain distribution of a battery of representative IEGs, as well as the influence of different sleep phases, will be examined. These specific paradigms represent more restricted experiences than the enriched environment exposure; they should result in more restricted gene reactivation patterns that can be more easily correlated with the nature of the stimulation during wakefulness. Aim 2 is to characterize gene reactivation in sleep that follows induction of hippocampal LTP. This will allow us to very precisely control the site, intensity and timing of the stimulation. In Aim 3, we will assess the effect of blocking gene reactivation during sleep (with brain injections of RNA and protein synthesis blockers) on spatial memory retention and maintenance of LTP. In Aim 4, we will utilize a combination of molecular, pharmacological and electrophysiological techniques to investigate possible interactions between limbic and neocortical structures during sleep. These studies should yield significant insights into basic mechanisms related to the role of sleep in learning and memory.