The long-term objective of this application is to identify the cellular and molecular mechanisms underlying the cognitive functions of sleep. Specifically, the goal of this renewal application is to investigate how the phasic pontine-wave (P-wave) generator and the hippocampus interact in sleep-dependent learning and memory processing in the rat. Clarifying the mechanisms of sleep-dependent learning and memory processing will advance the field of cognitive research toward the development of effective treatments for cognitive deficiencies associated with sleep disorders in humans. The central hypothesis of this proposal is that activation of phasic P-wave generating cells in the brainstem during REM sleep stimulates the post-synaptic cAMP/protein kinase A/cAMP response element binding protein (cAMP/PKA/CREB) pathway in the dorsal hippocampus as part of REM sleep-dependent memory processing.
3 specific aims have been designed to test this hypothesis systematically: 1. Determine whether the elimination of cells in the dorsal hippocampus attenuates 2-way active avoidance (TWAA) learning memory in post-sleep test trials. Cells will be lesioned by discrete microinjection of ibotenic acid into the CA1, CA3, and DG subfields of the dorsal hippocampus of different animals prior to TWAA training. After a sleep period, rats will be tested on the TWAA task and degrees of learning improvement will be compared between the specific subfield lesioned rats and sham lesioned rats. 2. Test the hypothesis that cAMP-dependent PKA activation in the dorsal hippocampus is involved in P-wave-generator-activation-dependent memory processing of TWAA learning. Effects of microinjecting a cAMP-dependent PKA inhibitor directly into the dorsal hippocampus to block P-wave generator activation will be measured with post-sleep TWAA testing to achieve this goal. 3. Test the hypothesis that P-wave generator activation increases phosphorylation of CREB (pCREB) and synthesis of activity-regulated cytoskeleton associated (Arc) protein in the dorsal hippocampus. Western blotting and immunocytochemical techniques will measure the levels of pCREB and Arc protein in the dorsal hippocampus. This proposal addresses, at the mechanistic level, the general question, what is the function of sleep? In addition, this research will propel sleep-dependent cognitive research toward treatments for cognitive impairments associated with jet lag, shift work, sleep deprivation and brainstem degenerative disorders.
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