Description:

"Control-Alter-Delete: Gene Regulatory Mechanisms in Brain Reward Circuitry"

Jeremy Day, PhD
Associate Professor of Neurobiology 
Director, Comprehensive Neuroscience Center 
Michael J. Friedlander Heersink Endowed Professor 
University of Alabama at Birmingham 

Drugs of abuse elevate dopamine levels in the nucleus accumbens (NAc) and alter transcriptional programs believed to promote long-lasting synaptic and behavioral adaptations. In this presentation, I will discuss our recent efforts leveraging single-nucleus RNA-sequencing (snRNA-seq) and Assay for Transposase Accessible Chromatin (snATAC-seq) to generate a comprehensive molecular atlas of cell subtypes in the NAc, defining both sex-specific and cell type-specific responses to acute and repeated drug experience in a rat model system. Our work demonstrates that psychostimulant drugs such as cocaine recruit activity-dependent transcriptional programs in the NAc to initiate dynamic chromatin reorganization at enhancer elements near genes implicated in synaptic function, including opioid neuropeptides. Using CRISPR-dCas9 transcriptional modulation, we show that this chromatin reorganization is required for stimulus-dependent responses to neuronal activation. Taken together, these results define the genome-wide transcriptional response to drugs of abuse with cellular precision, and highlight the mechanisms by which dopamine initiates experience-dependent chromatin remodeling and epigenetic reprogramming.