Wednesday, April 24, 2024
4/24/2024
Project Summary/Abstract Drug addiction is a chronic, relapsing disorder in which drug-related associations are capable of exerting tremendous control over behavior long after drug consumption has ceased. Drugs of abuse cause long-lasting functional and structural alterations in the brain’s reward circuits, such as the nucleus accumbens. Recent work has proposed that epigenetic modifications, such as histone modification or DNA methylation, are responsible for this cocaine-induced plasticity. Moreover, novel findings reveal that drugs of abuse, such as cocaine, induce epigenetic changes in the nucleus accumbens and that these changes control cocaine-related neuroadaptations. However, very little is known about how single, gene specific epigenetic modifications at genes implicated in addiction affect the reward circuit. This proposal will examine the effect of specific modifications of DNA methylation on the reward circuit both in vitro and in vivo. The specific aims of this proposed research are that: 1) identify gene expression and DNA methylation changes in NAc in response to dopamine genome-wide, 2) examine the role of gene-specific epigenetic modification on the NAc, and 3) characterize the role of gene- specific epigenetic modification on behavior. This will be achieved using a catalytically deactivated CRISPR- Cas9 fusion protein system, which will be used to alter gene-specific epigenetic states recruitment of a DNA methyltransferase enzyme. This contribution is significant because it is the first step in identifying the specific epigenetic changes that are critical for the neural and behavioral changes following exposure to drugs of abuse. The overall hypothesis is that site-specific epigenetic modifications are critical components of biochemical and behavioral responses to drugs of abuse. The persisting alterations that occur after exposure to drugs of abuse are believed to drive pathological drug seeking and relapse long after drug use has ceased. Therefore, understanding these changes will advance the field closer to targeted therapeutics that are able to reverse the alterations.
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