Activity-dependent processes are fundamental during development and adult learning and memory. These mechanisms are highly conserved and are evident in organisms across the animal kingdom. Activity- dependent plasticity at molecular and synaptic levels in Aplysia contributes to memory for a well-described form of sensitization (site-specific sensitization). The goal of this project is to elucidate the role of specific kinases in this activity-dependent memory in Aplysia and the ways these signaling cascades interact in the induction of activity-dependent memory at the behavioral, cellular, and molecular levels. Although I present these aims separately, I should emphasize that this organization is simply for conceptual clarity, the levels are highly interactive. A simple approach using standard inhibitors and activators will be employed during the completion of this training plan. I will study the activation of specific kinases and their requirement for plasticity at three levels: (1) activity-dependent intermediate-term memory for sensitization induced by tail-shock, (2) activity- dependent intermediate-term facilitation induced by coincident exposure to activity and serotonin, and (3) molecular plasticity induced by coincident exposure to global depolarization (high KCI) and serotonin. While the questions and approaches of my proposal are conceptually straightforward, they explore a novel terrain that can be informative and exciting. Aplysia is a powerful model system in which to study the mechanisms underlying forms of plasticity and memory. Because we can study molecules, synaptic plasticity, and behavior in the same system, we can make direct inferences that inform our experiments at each level of analysis. These experiments allow us to make more concrete connections between the plasticity we observe at different levels in order to form a clearer idea about how experience can affect the organization and function of the nervous system in ways that produce long-lasting behavioral changes. This project is of direct relevance to the goals of the NIH for two reasons. (1) It is important to understand the mechanisms that allow an organism to form memories and access them in order to be able to more effectively diagnose and treat individuals who suffer from abnormal or deficient memory. (2) A number of the molecules that underlie memory formation are also implicated in disorders, such as schizophrenia, and depression. This project will investigate the way that these important molecules interact. Understanding these interactions may help development of better therapeutic agents with fewer side effects that can help to improve the quality of life for individuals afflicted with disorders and disease. ? ?
