E2F3a transcription factor mediates behavioral, cellular, and DNA-protein regulation of cocaine reward in the nucleus accumbens

Addiction is driven by complex transcriptional changes in the brain's reward circuitry, particularly within the nucleus accumbens (NAc). While the transcription factor E2F3a has been implicated in cocaine-induced plasticity, its specific role across different neuronal cell types and sexes remained unclear. This study sought to determine whether E2F3a acts as a central mediator of cocaine reward and to map its genome-wide targets in the NAc.

The researchers employed a multi-faceted approach using both mice and rats. In mice, they used Cre-dependent viral vectors to selectively overexpress or knock down E2F3a in either D1-type or D2-type medium spiny neurons (MSNs) and assessed the effects on cocaine-induced conditioned place preference (CPP). In rats, they used behavioral economics and self-administration tasks to evaluate how E2F3a knockdown in the NAc influences motivation and drug-taking behavior. Finally, they used CUT&RUN-seq to identify the genome-wide DNA-binding sites of E2F3a following chronic cocaine exposure.

The study established that E2F3a in D1-MSNs is a critical substrate for cocaine reward. Overexpression of E2F3a in D1-MSNs increased cocaine CPP at subthreshold doses, while knockdown prevented it at higher doses; these effects were consistent across both male and female mice. In contrast, manipulating E2F3a in D2-MSNs had no effect on reward. Behavioral economics in rats further revealed that E2F3a knockdown reduces cocaine intake at low prices but increases the effort (motivation) to obtain the drug as the cost increases, suggesting that E2F3a modulates sensitivity to cocaine reinforcement. Genome-wide mapping showed that cocaine exposure significantly increases E2F3a binding at promoter regions of genes involved in neurotransmission and synaptic plasticity.

These findings identify E2F3a as a key upstream regulator of the transcriptional and behavioral adaptations that characterize cocaine use disorder. By demonstrating that E2F3a acts specifically through D1-MSNs to drive reward in both sexes, this research provides a clearer understanding of the molecular architecture of addiction and highlights a potential target for future therapeutic interventions.