ROLE OF CYCLICAL DNA METHYLATION IN GENES CONTROLLED BY DRUGS OF ABUSE AND NATURAL REINFORCERS: IMPLICATIONS IN BEHAVIOR AND METABOLISM
Supervisors : Andries Kalsbeek & Patrick Anglard
To some extent, drugs of abuse like cocaine and natural reinforcers such as sucrose activate similarly the mesocorticolimbic reward system. The circadian system interacts with the latter to modulate reward in a time-of-day dependent manner. Moreover, cocaine can influence circadian periodicity, in part through the serotonergic neurotransmission. However, the neural circuits implicated for drugs of abuse and natural reinforcers do not completely overlap and subtle molecular differences produced in response to each reinforcer remain to be mostly characterized.
Since MeCP2 plays a crucial role in cocaine-induced behavior, we hypothesize that DNA methylation is a likely epigenetic modification involved in the mode of action of drugs of abuse resulting in cyclical changes in gene expression, but so far very few cocaine-induced methylated genes have been characterized. The aim of the project is to understand how cocaine compared to natural reinforcers differs in triggering long-lasting changes in gene expression and in DNA methylation.
Studies will be carried out in the brain and in peripheral tissues (liver, muscle or adipose tissue) involved in energy metabolism. Genes to be studied belong to either cocaine target genes identified from a genome-wide study characterizing differentially methylated DNA regions or to epigenetic factors (DNMTs, TET 1,TET 2,TET 3), to factors involved in circadian rhythmicity (CLOCK1, PER2,PER1,CRY1, CRY 2, Bmal1), or to the neuropeptide family (orexins, NPY) and other transcription factors (DBP1, Rev erbβ). Their kinetics of expression will be measured in response to various procedures of cocaine and food administration including time-of day intake. Finally, the role of some selected genes will be evaluated by pharmacological or gene silencing approaches using a self-administration paradigm considered as the most appropriate model of addiction behavior.
By identifying long-lasting molecular changes triggered by drugs of abuse and natural reinforcers, the project will lead to a better understanding of the mechanisms discriminating drug addiction and eating habits.