Regulated Genetic Studies of Memory Formation

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant):Memory is perhaps the most crucial component our cognitive life and is disrupted or altered in numerous psychiatric and neurodegenerative disorders. Yet we know surprisingly little at the cellular and molecular level about how neurons in the mammalian brain are modified to store memories. Much of this difficulty arises from the technical difficulty in modifying molecular signaling in discrete populations of neurons within the brain. This project uses a series of genetically modified mice that allow the regulated expression of transgenes to be targeted to discrete and overlapping subpopulations of neurons within the limbic system. We will use expression of an activated form of CaMKII that is able to disrupt previously established fear conditioned memories when expressed specifically in striatal neurons. We will test the hypothesis that CaMKII activation erases components of the memory trace by indiscriminate activation of cellular mechanisms that are normally used to encode information. The effect of CaMKII activation within various components of the limbic system including hippocampus and entorhinal cortex and amygdala on previously established memories will be examined. The effect of kinase activation on neuronal excitability, baseline synaptic transmission and synaptic plasticity will be examined. Finally, the molecular mechanisms of CaMKII function will be investigated by examining effects glutamate receptor trafficking. Taken together the results of these experiments will help provide an understanding of the role of CaMKII signaling in several brain structures and the role of these structures in encoding different components of memory.