Drug addiction, long-term memory and other lasting behavioral changes derive from plasticity of underlying neural circuits, driven by activity-regulated gene expression. Recent behavioral analyses demonstrate critical roles for two transcription factors, CREB and AP1 (usually a dimer of Fos and Jun) in regulating cocaine addiction. Induction of FosB, a dominant-negative Fos isoform, in rodent nucleus accumbens causes long-term behavioral sensitization and craving for cocaine; in contrast, induction of CREB reduces drug-reward by inducing adaptation to higher levels of cocaine. Despite the obvious importance of AP1 and CREB for behavioral plasticity, little is known about the mechanism of their action. Our recent observations are consistent with the unexpected, important hypothesis that AP1 acts upstream of CREB at the top of the hierarchy of known plasticity-associated transcription factors. While testing this hypotheses, this proposal aims to: a) more completely elaborate cellular functions of AP1; and b) identify molecular mechanisms that operate upstream and downstream of AP1. In the short term, the work will provide a description of cellular biological consequences of AP1 manipulations, and outline the hierarchies and relationships among regulatory proteins, like AP1, CREB and MAP kinases that initiate plasticity processes. In the longer term, effector molecules that mediate the processes of synaptic change will be identified and their functions analyzed. Drosophila melanogaster is an excellent model organism for these analyses. The commonality of underlying mechanisms involved in plasticity regulation in mammals and insects is indicated by the functional conservation of almost all known regulators of plasticity in both phyla. However, the rate of progress of the proposed analyses in Drosophila is much faster, facilitated not only by its short generation time and facility for genetics, but also by novel resources from Drosophila genome projects, microarray technologies and newly developed procedures for gene disruption, perturbation and replacement in vivo. The proposed experiments address an area of fundamental importance in synaptic remodeling events that underlie behavioral change. The work is particularly significant because it addresses the function of Fos and Jun, two critical regulators of drug addiction. In addition, by identifying activity-regulated neuronal proteins the program may contribute new, molecular markers of plasticity processes that underlie addiction. Finally, results from these experiments may identify and validate new molecules to target for pharmacological therapy.
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