This is a request for five years of support under the ADAMHA Research Scientist Development Award Program. The long-term objective of this research project is to analyze the cellular and molecular mechanisms of an example of associative learning and memory. The studies proposed in this grant will provide insights into general principles underlying memory for an associative experience following one-trial conditioning, and contribute to the elucidation of the events critical for the transformation of memory into a more enduring form, long-term memory. Toward these goals, a multidisciplinary approach to the study of associative learning and memory will be carried out in the marine mollusc Hermissenda, a preparation that has proven useful in biophysical and molecular studies of learning. The research will use a combination of cellular neurophysiological, biophysical, biochemical, and behavioral techniques to study short and long-term memory in intact and isolated nervous systems. One primary goal of the research is an investigation of the contribution of protein phosphorylation to the time-dependent processes underlying the induction, maintenance and expression of short- and long-term memory. The recent discovery that inhibiting protein kinase C with broad spectrum kinase inhibitors or depleting kinase levels by down-regulation, blocks the induction of short-term, but not long-term memory provides additional evidence that different molecular mechanisms may underlie these two phases of memory. Studies are proposed to further investigate the dissociation between short and long-term memory and the contribution that protein kinases and protein phosphorylation may make to the induction, maintenance, and expression of different memory stages. A second goal of this project is to analyze the specific membrane conductances that are modified by one-trial conditioning, and identify the contribution of enhanced excitability and modifications in synaptic strength to the expression of long-term memory. The third major goal is to identify the neural circuitry underlying locomotion and develop a semi-intact preparation for simultaneously recording from motor neurons and measuring conditioned modification of behavior. These studies should help to elucidate basic mechanisms of short and long-term memory and how such mechanisms may be related to clinical disorders of memory.
