The overall goal of this proposal is to characterize the changes in transcript levels which occur in the rodent brain during acquisition and consolidation of spatial and contextual memory. Spatial memory is associative in nature and relatives to the orientation and movement of an individual in space in relationship to the location of objects in the surrounding environment. Contextual memory establishes cognitive associations between surrounding environmental cues and specific events. A basic understanding of how spatial and contextual memories are formed will enable the design of appropriate treatment and prevention strategies for the various neurologic and neuropsychiatric conditions that display alterations in memory processing, such as Alzheimer's disease, stroke and post-traumatic-stress disorder. An expanding body of evidence reveals a role for the regulation of gene transcription in acquisition and consolidation of memory. Targeted mutation of the gene encoding the cAMP Responsive Element Binding protein (CREB) and in situ hybridization studies of several genes provide strong evidence in support of a role of gene transcription in long-term memory acquisition and consolidation. Our overall hypothesis is that CREB function is necessary to mediate changes in gene transcription throughout acquisition and consolidation of memory. We propose that learning and memory processes are accompanied by accumulation and down regulation of specific gene transcripts within different regions of the brain. Moreover, we hypothesize that a subset of the genes regulated during acquisition and consolidation of spatial memory in the Morris Water maze and the hole board food search task using both CREB knockout mice and inducible CREB mutants. DNA microarrays containing thousands of mouse cDNAs will be used in hybridization experiments using 33P labeled cDNA probes prepared from mouse brain mRNA extracted from animals at different stages of acquisition and consolidation of spatial memory.
Specific Aim 2 will monitor the expression of thousands of mouse genes in CREB knockout and inducible mutant mice to identify transcripts under CREB regulation in long-term memory associated with fear. Finally, Specific Aim 3 will study the changes in gene expression which occur in CREB mutant mice following induction of long-term potential in hippocampal slices. The proposed set of experiments will provide new and fundamental knowledge which concerns the molecular mechanisms subserving information storage in the brain.
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