A dopamine-induced gene expression signature regulates neuronal function and cocaine response

Academic Article


  • Drugs of abuse elevate dopamine levels in the nucleus accumbens (NAc) and alter transcriptional programs believed to promote long-lasting synaptic and behavioral adaptations. Here, we leveraged single-nucleus RNA-sequencing to generate a comprehensive molecular atlas of cell subtypes in the NAc, defining both sex-specific and cell type–specific responses to acute cocaine experience in a rat model system. Using this transcriptional map, we identified an immediate early gene expression program that is up-regulated following cocaine experience in vivo and dopamine receptor activation in vitro. Multiplexed induction of this gene program with a large-scale CRISPR-dCas9 activation strategy initiated a secondary synapse-centric transcriptional profile, altered striatal physiology in vitro, and enhanced cocaine sensitization in vivo. Together, these results define the transcriptional response to cocaine with cellular precision and demonstrate that drug-responsive gene programs can potentiate both physiological and behavioral adaptations to drugs of abuse.
  • Authors

    Published In

  • Science Advances  Journal
  • Digital Object Identifier (doi)

    Author List

  • Savell KE; Tuscher JJ; Zipperly ME; Duke CG; Phillips RA; Bauman AJ; Thukral S; Sultan FA; Goska NA; Ianov L
  • Volume

  • 6
  • Issue

  • 26