There is now widespread agreement that different "types" of memory are processed by different areas of the brain. One of the primary brain areas involved in the processing and temporary storage of some forms of memory is the hippocampus; however, relatively little known about the specific types of memory dependent on the hippocampus and the biological mechanisms underlying this process and storage. Like most brain areas, the hippocampus can be divided into separate functional and anatomical subregions, which have recently been shown to contribute differentially to two forms of memory commonly referred to as contextual memory (i.e. memory for the spatial contexts in which certain events occur) and trace memory (i.e. short-term memory for specific information). This project will systematically examine the contributions of these hippocampal subregions to contextual and trace learning by using techniques designed to temporarily inactivate, or "turn off" these areas either before learning or before recall at a later time. Moreover, recently data suggest that the activity of a specific gene, ARC, is regulated within these brain areas by learning. In order to more fully understand the biochemical processes underlying memory formation, this project will further examine the activity of this learning-related gene within the hippocampus during and after learning. These inactivation and genetic studies will provide a significantly more precise characterization of the types of memory processed by each of these hippocampal subregions as well as the basic biological mechanisms by which this processing and storage occurs. These studies will also provide important training opportunities for both graduate and undergraduate students who are pursuing careers in science. Graduate students will receive intensive training in research techniques and scholarship, help mentor undergraduate students, and all will present their research projects at national and international meetings.
Through support from NSF, our laboratory has recently discovered that forming new memories and/or recalling old ones "turns on" one gene and its protein product, activity-regulated cytoskeletal protein (Arc), in a brain area called the hippocampus. (The hippocampus is known to be critically involved in many forms of learning, and cell death in the hippocampus is the primary cause of memory impairment during the early stages of Alzheimer’s disease). We have also found that temporarily turning off this gene in the hippocampus blocks new learning while having no effect on previously established memories. Moreover, we found that expression of the Arc gene is critically dependent on calcium influx through the NMDA receptor, a particular form of neurotransmitter receptor implicated in the initial formation of some forms of memory. In a related, collaborative project with researchers at MIT and reported in Science, we found that learning to relate an unpleasant event with the place where that event occurred activates another gene, Npas4, specifically within a small cluster of brain cells within the hippocampus, in an area called CA3. The results suggest that activation of Npas4 initiates a cascade of intracellular biochemical events that, in turn, strengthen the connections between individual brain cells within the hippocampus and ultimately results in the formation of lasting memories.
