CREB IN DECLARATIVE AND NON-DECLARATIVE MEMORY IN MOUSE

Columbia University Health Sciences, New York NY

Investigators

Abstract

Different forms of memory employ different logical, serve different behavioral roles, and are associated with different neuroanatomical structures, but appear to use similar mechanisms of information storage. Specifically, memories are believed to e stored in plastic change in the connections between neurons. Abnormalities of synaptic plasticity have been suggested in the etiology of retardation, drug addiction, depression, and other pathological states. Synaptic plasticity, as well as many forms of learning, has an early and late phase; the late phase requires gene activation. The transcription CREB has been implicated as a major player in the induction of the genes required for long-lasting, late-phase plasticity. I have generated transgenic mice which expressing a dominant- negative allele of CREB, which interferes with its function in the induction of downstream genes. In one transgenic line, expression of the transgene is largely restricted to the CA1 region of the dorsal hippocampus; plasticity in this region has been strongly implicated in the learning of behavioral tasks. I have shown that mice of the line are deficient in the acquisition of spatial memory but not in a control task. A second line of mice expresses the transgene exclusively in the dorsal striatum, a structure that is required for the learning of certain habit-based tasks. These mice are deficient in two such tasks but not in hippocampus- dependent learning. Future studies under this fellowship will further explore the behavioral phenotype of these two lines of mice further characterize the molecular consequences of interfering with CREB function, and (in collaboration with others) investigate the electrophysiological correlates of these observed behavioral deficits. These studies will lead to an increased understanding of the mechanisms of different forms of learning in normal and pathological conditions.