The epigenome refers to the molecular modifications that decorate DNA and its associated proteins. Such modifications are highly dynamic, enabling gene function to respond to environmental stimuli. The Heller Lab studies the mechanisms by which remodeling of the epigenome leads to aberrant neuronal gene function and behavior. To approach this problem, we directly manipulate histone and DNA modifications at specific genes in vivo, using viral delivery of novel epigenetic editing tools. We focus on uncovering the mechanisms by which chromatin modifications interact with the transcriptional machinery following exposure to psychostimulants, such as drugs of abuse and stress. We use high-throughput sequencing and state-of-the-art analytical platforms to identify genes at which drug- or stress-regulation of a known epigenomic signature correlates with changes in gene expression. We can then target individual modifications and examine their causal relevance to transcriptional regulation and subsequent behavioral adaptations. This ‘bottom-up’ approach allows direct elucidation of the causal relevance of epigenetic remodeling in the brain. Interestingly, the behavioral disease traits of addiction and depression persist long after cessation of the harmful experience. Stable epigenetic remodeling is an attractive mechanism for such long-lasting effects and presents an intriguing target for therapeutic intervention.