Epigenetic Mechanisms of Memories Associated with Cocaine Reward

Miller, Courtney

Abstract

Drug addiction is marked by a conditioned physiological response and intense craving when abusers encounter stimuli associated with the drug's rewarding effects. Memory of these drug-paired cues is highly resistant to extinction and is a major contributor to relapse. Understanding on a molecular and cellular level how these factors promote relapse, despite negative consequences, has become a major focus of addiction research. Recently, we have reported the surprising finding that both histone modifications and direct covalent modification of DMA underly normal memory formation. The goal of the current project is to study the epigenetic basis of cocaine addiction, with a specific emphasis on understanding the epigenetic mechanisms active during drug-associated memory formation and relapse to drug seeking. During the mentored phase of this project, I will continue studying the role of epigenetic modifications in memory formation. In addition, I will investigate the role of epigenetics in memory retrieval, a process important to the study of drug addiction, and I will learn and develop new techniques that will provide important avenues for the study of epigenetic modifications that I will utilize during both the mentored and independent phases. During the independent phase, I will investigate the hypothesis that epigenetic modifications are important for the formation, retrieval and reconsolidation of cocaine-associated memories. This will be achieved by studying the specific enzymes responsible for catalyzing histone modifications and cytosine methylation through gene expression analysis, the use of transgenic mice and intra-CNS infusions of drugs that inhibit or augment these enzymes. In addition, I will investigate the specific genes that are methylated, as well as the associated chromatin modifications using a variety of techniques, including methylation microarray, sequencing and chromatin immunoprecipitation (ChIP). By understanding the role of the epigenome in the establishment arid maintenance of drug addiction, novel sites of therapeutic intervention may be discovered. Relevance: As drug addiction develops, addicts learn to associate the rewarding effects of the drug with stimuli that are present at the time of drug use. Using an animal model of addiction, this proposal explores the hypothesis that cocaine-induced modifications to an organism's epigenome are integral to the formation and expression of the aberrant memories that contribute to relapse in addicts.