The focus of this research proposal is to examine the role of histone deacetylase 3 (HDAC3) in vivo as a potential negative regulator of context-drug associated memory formation. Previous studies have shown that HDAC3 forms multi-protein complexes with HDACs 4 and 5 in vitro, via interactions with NCoR1 and 14-3-3 protein, respectively. We hypothesize that HDAC3 associates with HDACs 4 and/or 5 in vivo, in the hippocampus and nucleus accumbens (NAc), to translocate to the nucleus and deacetylates histones, repressing transcription necessary for long-term contextual memory formation associated with the acquisition of cocaine-induced conditioned place preference (CPP). Understanding the HDAC isoforms involved in context-drug associated memory formation will contribute to an understanding of the molecular mechanisms of long-term memory formation and drug-seeking behaviors and may eventually lead to selective pharmacotherapies which target chromatin modifying enzymes to treat drug addiction.
Specific Aim 1. To examine the effects of Hdac3 deletion on the expression of other HDACs and histone acetylation. Hypothesis: HDAC3 forms a complex with HDAC4 and 5 in vivo to facilitate nuclear localization and histone deacetylation.
Specific Aim 2. To examine the role of HDAC3 in acquisition of cocaine-induced CPP. Hypothesis: Loss of HDAC3 function will significantly facilitate the acquisition of cocaine-induced CPP.
Specific Aim 3. To examine whether HDAC3 serves as a critical negative regulator of cocaine- induced CPP acquisition. Hypothesis: Over-expression of HDAC3 and/or NCoR1 will prevent acquisition of cocaine-induced CPP. The research training program will be designed: 1) for the applicant to be trained in behavioral pharmacology techniques, allowing him to effectively study epigenetic mechanisms of context-drug associated memory formation;2) to train the applicant to be an independent investigator so he may be proficient in the future as a laboratory scientist, mentor and lead investigator in academia;and 3) to emphasize responsible conduct of research, including the humane treatment of animals used in laboratory experiments and ethical data analysis, mentoring of graduate and undergraduate students, building collaborations with other post- doctoral fellows and principal investigators and proficient design and execution of experiments. Those skills will allow the applicant to carry on independent investigations of his own during the next phase of his career as an academic research professor.
The philosophy of drug addiction has changed drastically from early misconceptions that addicts are simply unable to control themselves. It has become clear that the long-term intake of abusive substances fundamentally alters the neurochemistry of an addict such that he/she becomes dependent on the drug for either physical or mental well-being. Thus a complete understanding of the persistent neurological changes underlying drug dependency, such as epigenetic mechanisms of drug-induced alterations in gene expression, may reveal novel and specific pharmacotherapy targets for addiction treatments.
|Rogge, George A; Singh, Harsimran; Dang, Richard et al. (2013) HDAC3 is a negative regulator of cocaine-context-associated memory formation. J Neurosci 33:6623-32|
|Malvaez, Melissa; McQuown, Susan C; Rogge, George A et al. (2013) HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci U S A 110:2647-52|