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

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.

Astrocyte-derived TNF and glutamate critically modulate microglia reactivity by methamphetamine

“…Next, we compared our cluster of 207 differentially expressed transcripts upon Meth exposure with clusters previously reported for microglial signature program 38, 39 , aging 40 , disease-associated (DAM) 41 , injury-related (IRM) 40 , drug exposure 42, 43 , or the microglial engulfment module 38 ( Suppl. Fig.…”

“…Temperatures were evaluated at 13 time points, each point represents the mean temperature (n=3 animals per group) for one timepoint. C: Venn’s diagrams representing cluster analysis comparing the 207 Meth-altered genes cluster found in our RNA.-seq analysis, with clusters previously reported for healthy 38, 39 , aging 40 , disease-associated (DAM) 41 , injured 40 , drug exposed microglia 42, 43 , or with clusters previously associated to specific microglia functions 38 . Comparisons were conducted by contingency analysis, using the Fisher’s exact test and the Baptista-Pike method to calculate the odds-ratio.…”

Dynamic dichotomy of accumbal population activity underlies cocaine sensitization

“…Some neurons code for reward and their predictors (Roitman, Wheeler, and Carelli 2005), consummatory behavior (Taha and Fields 2005), or action selection (Nicola 2007). Additionally, within the D1R-expressing subclass of SPNs, diversity might be determined by additional molecular markers (Savell et al 2020), or projection specificity. For example, the activity of D1R SPNs projecting to midbrain, ventral pallidum (Kupchik et al 2015) or lateral hypothalamus (O’Connor et al 2015) may segregate with movement, incentive saliency or cocaine response.…”

Egr2 induction in Drd1+ ensembles of the ventrolateral striatum supports the development of cocaine reward

“…IEG expression is well accepted to be the substrate for long term modulations supporting memory formation (Alberini, 2009; Alberini and Kandel, 2015). Although cocaine induced IEG expression has been extensively characterized in rodents (Caster and Kuhn, 2009; Gao et al, 2017b; Guez-Barber et al, 2011; Moratalla et al, 1996; Piechota et al, 2010; Robison and Nestler, 2011; Savell et al, 2020; Steiner, 2016; Valjent, 2006; Zahm et al, 2010), these studies were mostly limited in the number of genes analyzed, and restricted to isolated brain structures following specific drug regimes. Addressing the cocaine-induced transcriptome, we observed transcriptional recruitment of the LCtx, Amy, NAc and DS, of which, the DS was most prominent.…”