Impairments in memory function can range from the moderately inconvenient benign forgetfulness with normal aging to the devastating losses associated with Alzheimers disease. In addition, alterations in the mechanisms that underlie normal memory are thought to underlie psychiatric disorders such as depression and post-tramatic stress disorder and may contribute to relapse in addiction. This grant uses animal models to identify the cellular and molecular mechanisms of memory formation. We use a genetic technique that allows us to introduce genes into specific parts of the brain and to turn them on or off at different times either during learning or during memory retrieval. For example, in one study we looked at a mouse model of a human genetic disorder (Rubenstein Taybi Syndrome) associated with both developmental abnormalities and severe cognitive impairment. One question that we addressed was whether the cognitive defects found in adults were due a defect in brain development or due to abnormal gene function in the adult brain. By inducing the genetic lesion only in the adult we could show that it produced learning and memory defects acutely and that these defects could be reversed by turning off the defective gene. We also showed that the behavioral defects could be reversed in this mouse model with a drug that targeted the biochemical defect. We apply this approach to a number of different cellular signaling pathways in neurons that are thought to underlie memory. We try to identify not only the molecules involved but also the regions of the brain that are critically altered. In addition, we use a novel genetic approach to assess how neurons are activated during training and reactivated during retrieval of memories to try to understand the underlying cellular anatomy of memory. [unreadable] [unreadable]