How is progress going to be made in understanding memory, including emotional memory and its disorders? We propose that it is important to start looking at phases of memory beyond immediate and short-term memory, beyond the initial involvement of the hippocampus. We need to alter the focus from these initial events to longer-term processes such as structural reorganization. Our refocus needs to switch from the molecular processes controlling receptor modification to those controlling synaptic and dendritic structure. Furthermore, our attention should also change from hippocampus to neocortex, as a wealth of evidence implicates neocortex in remote memory. The overall goal of the proposed Conte Center for Forward Genetic Approaches to Cortical Plasticity is to identify novel mechanisms of neural plasticity that operate in the neocortex and are critical for both remote memory and cortical plasticity. To accomplish this goal we propose to use state-of-the-art transgenic, electrophysiological and imaging approaches, including a novel genetic screen designed to identify mouse KOs and transgenics that affect remote, but not recent memory. The following is an outline of the framework of the Center that takes advantage of the long-standing (>10 years) collaborative relationship among its members: 1) The Silva laboratory will identify KOs and transgenics that have 7-, but no 1-day memory deficits for contextual conditioning, one of the most studied rodent models of emotional memory. Importantly, a pilot screen of 55 mutants already identified two with normal 1-day, but deficient 7-day memory. 2) The selected 7-day memory mutants will be screened for somatosensory (Fox Laboratory) and visual (Stryker Laboratory) cortical plasticity deficits. Out of the two memory mutants selected so far in our screen, one has been studied by the Fox group and found to have abnormal somatosensory plasticity! Our previous collaborative work also identified another mutation with the same properties (aCaMKII null heterozygous mutation). 3) Mutants that affect all three forms of plasticity will be studied collaboratively by all three laboratories with electrophysiology, in vivo imaging and behavioral tools. 4) Key genes identified in the screen will be floxed and the resulting conditional mutants will be studied in detail by the Center. The key idea is to leverage the wealth of tools and information available for somatosensory and visual cortical plasticity to understand the plasticity mechanisms underlying the harder-to-study process of remote memory storage in neocortical networks.
The studies proposed here will not only shed light on poorly understood mechanisms of remote memory, they will also provide important insights for the development of treatments for memory disorders associated with psychiatric and neurologic conditions such as schizophrenia, depression and Alzheimer's disease.
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