Many neuropsychiatric diseases involve associative learning. The most obvious of these are the addictions (in which neutral cues in the environment come to evoke strong craving for drugs of abuse) and anxiety disorders (e.g., post-traumatic stress disorder, PTSD, in which neutral cues in the environment of the traumatic event come to evoke strong fear reactions). Epigenetics refers to the process by which cellular traits are established and inherited without a change in DNA sequence. These mechanisms of cellular memory also orchestrate the activity of genes in the adult brain, and recent findings suggest a role for epigenetic factors in the etiology of psychiatric disease. Thus, given the prevalence and co-morbidity of cocaine addiction and fear-related anxiety, and the increasing appreciation that environmental factors play a major role in determining mental health (""""""""DNA is not destiny""""""""), a deeper understanding of common epigenetic mechanisms associated with learning in coordinated models of addiction and fear is both timely and relevant.
Aim 1 will employ a genome-wide approach using state-of-the-art technology to investigate epigenetic mechanisms regulating gene expression during the acquisition and extinction of cocaine-seeking behavior in a self-administration model of cocaine addiction, and of fear-related learning in a parallel model of auditory conditioned fear.
Aim 2 will validate candidate genes by using ChIP and bisulphite mapping to examine histone modifications and DNA methylation around, and within, individual gene promoters, and correlate them with gene expression in brain regions supporting both forms of learning. These effects will be examined at different time points post-training in an effort to elucidate their role in spontaneous incubation and relapse.
Aim 3 will study whether manipulations that induce local histone hyperacetylation, histone demethylation or inhibition of DNA methylation, during cocaine-self administration and fear training will prejudice animals toward incubation, while the same manipulation during extinction will prevent relapse of cocaine-seeking and of conditioned fear. These studies aim to elucidate common epigenetic factors contributing to psychiatric disease, and to explore the epigenome as a therapeutic point of intervention for cocaine addiction, PTSD and phobia.
Using analagous procedures, we will study the importance of common epigenetic mechanisms in animal models of cocaine addiction and fear-related anxiety disorders. These studies may yield improved therapeutic intervention strategies based on facilitating extinction learning through the use of specialized pharmacological adjuncts during psychotherapy for co-morbid psychiatric disorders.
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