Drug addiction is a chronic, relapsing disorder in which drug-related associations are capable of exerting tremendouscontroloverbehaviorlongafterdrugconsumptionhasceased.Drugsofabusecauselong-lasting functionalandstructuralalterationsinthebrain?srewardcircuits,suchasthenucleusaccumbens.Recentwork hasproposedthatepigeneticmodifications,suchashistonemodificationorDNAmethylation,areresponsible forthiscocaine-inducedplasticity.Moreover,novelfindingsrevealthatdrugsofabuse,suchascocaine,induce epigeneticchangesinthenucleusaccumbensandthatthesechangescontrolcocaine-relatedneuroadaptations. 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 methylationontherewardcircuitbothinvitroandinvivo.
The specificaims ofthisproposedresearcharethat: 1)identifygeneexpressionandDNAmethylationchangesinNAcinresponsetodopaminegenome-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 methyltransferaseenzyme.Thiscontributionissignificantbecauseitisthefirststepinidentifyingthespecific epigeneticchangesthatarecriticalfortheneuralandbehavioralchangesfollowingexposuretodrugsofabuse. Theoverallhypothesisisthatsite-specificepigeneticmodificationsarecriticalcomponentsofbiochemicaland behavioralresponsestodrugsofabuse.Thepersistingalterationsthatoccurafterexposuretodrugsofabuse are believed to drive pathological drug seeking and relapse long after drug use has ceased. Therefore, understandingthesechangeswilladvancethefieldclosertotargetedtherapeuticsthatareabletoreversethe alterations.
Addiction is an important health issue that impacts many lives and is a large financial and social burden on the U.S. We are studying what molecular modifications are required for the potentially long-lasting changes seen in the reward circuit as a response to drugs of abuse with a new gene editing technology. A detailed understanding of the critical modifications of this pathway will lead to targeted therapeutics, which will lead to more effective therapeutics and an overall improved quality of life for those affected.
| Savell, Katherine E; Day, Jeremy J (2017) Applications of CRISPR/Cas9 in the Mammalian Central Nervous System. Yale J Biol Med 90:567-581 |
