Faculty Collaboration Database

A dopamine-induced gene expression signature regulates neuronal function and cocaine response. Sci Adv 2020 Jun;6(26):eaba4221

Date

07/09/2020

Pubmed ID

32637607

Pubmed Central ID

PMC7314536

DOI

10.1126/sciadv.aba4221

Scopus ID

2-s2.0-85087503928 (requires institutional sign-in at Scopus site)   74 Citations

Abstract

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.

Author List

Savell KE, Tuscher JJ, Zipperly ME, Duke CG, Phillips RA 3rd, Bauman AJ, Thukral S, Sultan FA, Goska NA, Ianov L, Day JJ

Author

Jennifer J. Tuscher PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cocaine
Dopamine
Female
Male
Mice
Mice, Inbred C57BL
Nucleus Accumbens
Rats
Transcriptome