Experience-dependent neural plasticity underlies all aspects of an animal's response to drugs of addiction. Whether the animal is undergoing initial responses to the drug, sensitization or habituation of that response, long-term addiction, or withdrawal, the neuronal and molecular mechanisms that are recruited are likely to be similar, if not identical, to those used during normal plasticity. Therefore, a complete understanding of molecules and physiological processes that influence learning and memory formation is likely to help elucidate the roles that these play in responses to drugs of abuse. This proposal focuses on the circadian system, and one particular """"""""circadian"""""""" molecule, Per. Our Preliminary Results show that there are time of day effects on learning and memory formation, indicating that circadian factors affect these processes. In addition, genetic analysis shows that mutations in the per gene can either enhance or disrupt memory formation. Therefore, one of the main goals of this proposal is to determine if the central clock is important in the normal processes of learning and memory formation. To answer this question, novel, improved technology will be used to spatially and temporally regulate gene induction and cell ablation. Genetically inducible mosaic animals would be extremely useful for the analysis of any adult, neuronal function, including the anatomical dissection of drug responsiveness, learning and memory formation. In addition, a specific hypothesis, and its test, is proposed for the role of Per in various neuronal physiologies, including memory formation. This hypothesis, if true, may provide novel genetic tools and methodologies into fundamental problems of systems neuroscience, and opens up a new way to think about the cellular basis for plasticity and memory formation. Drosophila melanogaster is an excellent model organism for these studies. The universality of conserved molecules, cassettes of genes, and molecular mechanisms now extends from development to neuronal plasticity, learning, memory formation, circadian rhythms, sleep, neurodegenerative diseases and aging. The proposed work capitalizes on recent advances in genomic information, technological innovations and advances in the analyses of complex behavioral phenotypes in this system, and cannot be else whereat a reasonable pace or cost. Most critically, the work that is proposed would not have been conceptualized outside of the """"""""critical mass"""""""" of information that exists for flies.
