Chromatin and Gene Analyses

One of the major objectives of this Program Project Grant is to define the transcriptome and epigenome of stimulant and opiate addiction within the brain's reward circuitry and to use this information as a foundation from which to define novel mechanisms of neural and synaptic plasticity that control the addicted state. We use ChIP-Seq (chromatin immunoprecipitation followed by high throughput sequencing) to define, genome-wide, the range of chromatin modifications that are induced by drugs of abuse in specific brain reward regions. We also use RNA-Seq to identify, genome-wide, all RNAs whose expression levels are altered in these same regions in response to chronic drug exposure. A major feature of this work is the advanced bioinformatic analyses that are required to optimally mine the vast amounts of such data generated by our research. Program Project Grant investigators have led the field in genome-wide gene and chromatin analyses within addiction models, including pioneering these approaches in brain, which offers several unique technical challenges.

The figure shows the range of genes induced in nucleus accumbens in response to a challenge dose of cocaine in three groups of animals: drug naïve (acute), those that received prior chronic treatment with the drug (chronic), and those that received prior chronic treatment followed by a week of withdrawal (chronic+WD). Note how some of the genes induced acutely are no longer induced in cocaine-experienced animals. These genes are desensitized. At the same time, note how close to 3-fold more genes are induced by cocaine in experienced animals. These genes are sensitized. Program Project Grant work has shown how chromatin modifications mediate such gene desensitization and priming.

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