DESCRIPTION (provided by applicant): The long-term goals of our research are to understand the molecular and cellular mechanisms of learning and memory in the brain. This application will focus on memory retrieval, a fundamental yet mysterious component believed to involve a rapid reconstructive process involving a new recapitulation of the learned information. Over the past several years, conditional gene knockout techniques have been shown to be increasingly valuable for molecular analysis of learning and memory processes. However, because these available techniques either lack temporal controls or only offer limited temporal resolutions, the molecular manipulations and analyses of memory retrieval process have not been rigorously attempted. This proposal will take advantage of our newly developed fourth-generation genetic technology that permits high time-resolution manipulations and analyses of the memory retrieval process. A comprehensive set of biochemical, genetic, and behavioral experiments will be conducted to demonstrate that memory retrieval, like other stages of memory process, can be selectively interfered through rapid manipulation of activity of a gene product known to play a crucial role in the regulation of synaptic plasticity. Another set of integrated analyses will be carried out to determine the possible cellular and neural mechanisms underlying the observed retrieval deficits. Finally, detailed electrophysiological analyses and additional genetic manipulations will be performed to further test the proposed hypothesis. Development and application of new genetic technology should increase researchers' ability to observe, manipulate, and discover the molecular and cellular processes underlying learning and memory in the mammalian brain. It is conceivable that such progress might eventually lead to new strategy for potential therapeutic interventions for the prevention and treatment of memory-related disorders.