Psychostimulant Regulated Epigenetic Plasticity in Interneurons of the Nucleus Accumbens

Abstract

Exposure to psychostimulant drugs of abuse exerts lasting influences on brain function via the regulation of immediate and persistent gene transcription. These changes in gene transcription drive the development of addictive-like behavior by inducing cellular and synaptic plasticities in neurons within brain reward circuits including the nucleus accumbens (NAc). The long-lasting nature of addictive-like behaviors suggests they may be mediated by equally persistent mechanisms of transcriptional regulation such as epigenetic modifications of chromatin. However, an important limitation to testing this model using traditional methods for studying chromatin is the fact that brain regions like the NAc are comprised of a variety of interacting cell types that differentially shape the region’s impact on the circuit, that are not resolved by biochemical methods. In this dissertation I will overcome this barrier by using varied targeted methods to study cell-type specific changes in chromatin induced in the NAc by chronic amphetamine. We have data showing that silencing of PV+ interneurons significantly diminishes the locomotor sensitization to chronic psychostimulant exposure, revealing for the first time a function for these interneurons in addictive-like behaviors. PV+ interneurons of the NAc show amphetamine-induced transcription of genes like Fos and with repeated drug exposure display transcriptional desensitization of Fos, a process that is thought to be epigenetically mediated. This and other cellular adaptations occurring in PV+ interneurons persist through extensive withdrawal periods, suggesting a specific and lasting means by which these regulatory shifts underlying the behavioral response are imprinted on this cell type. Taking these data together, I hypothesize that changes to chromatin structure and gene expression in PV+ interneurons of the NAc contribute to the addictive-like behavioral changes and cellular adaptations seen following psychostimulant use. To test this, I will make use of a novel isolation method to specifically purify the nuclei of PV+ interneurons from the NAc and assay the chromatin and gene expression changes that persist following psychostimulant exposure and correlate with addictive-like behaviors. In this proposal I will identify the program of persistent amphetamine-regulated gene expression and chromatin remodeling genome-wide in PV+ interneurons of the NAc. I will subsequently use a variety of targeted bioinformatic analyses to survey the relationships between changes to the chromatin landscape genome-wide and lasting alterations in transcriptional regulation and cellular function. These studies will greatly propel our understanding of how epigenetic regulation of gene transcription can contribute to lasting changes in circuit function and behavioral output.