Cell-Type-Specific Epigenetic Priming of Gene Expression in Nucleus Accumbens by Cocaine

Abstract

A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe a novel epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled to increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relates to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we demonstrate that D1 MSN-selective Anp32e knockdown prevents cocaine-induced H2A.Z depletion and blocks cocaine's rewarding actions. By contrast, very different effects of cocaine exposure, withdrawal, and relapse were found for D2-MSNs. These findings establish histone variant exchange as an important mechanism and clinical target engaged by drugs of abuse to corrupt brain function and behavior.

Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

“…Last, it is important to emphasize that our human cohort includes a significant number of Black individuals, who have not been well represented in prior transcriptional studies of CUD, despite the recent evidence that such individuals are especially vulnerable to cocainerelated overdose deaths (4). Together, these findings represent a considerable advance in our understanding of the molecular (55). In this dataset, animals received a cocaine (20 mg/kg injection i.p.)…”

“…To gain insight into the potential involvement of D1 and D2 MSNs in the CUD-specific gene modules that were conserved in cocaine self-administering mice (see Fig. 5), we used a recently published dataset that examined the effects of cocaine on NAc transcription in a cell type-specific manner (55). D1 and D2 MSN transcriptomes were generated from NAc in two transgenic mouse lines (Drd1a::Egfp-L10a or Drd2a::Egfp-L10a) that enabled fluorescentactivated nuclei sorting for either cell type combined with population-specific RNA-seq.…”

“…Fisher's exact tests were conducted using the super exact test package in R as described previously to determine the enrichment of DETs in the NAc and CN (71). For select CUDrelated gene modules that were preserved in mouse self-administration, we performed D1 and D2 MSN-specific transcriptome analysis on conserved ensemble genes using subtype-specific RNA-seq datasets from mice that experienced chronic cocaine experience and prolonged withdrawal, with or without cocaine challenge (55).…”

“…Expression patterns of conserved human CUD gene networks in mouse D1 and D2 MSNs. To examine the contribution of D1 versus D2 MSNs in cocainerelated transcriptional regulation of conserved human (A to C) crimson, (D to F) lightyellow, and (G to H) skyblue networks, we used a recently published dataset that characterized cocaine-related changes in subtype-specific gene expression in the NAc(55). In this dataset, animals received a cocaine (20 mg/kg injection i.p.)…”

Remembering through the genome: the role of chromatin states in brain functions and diseases

“…One of the detrimental features associated with addiction is relapse, that can occur even after prolonged abstinence and is caused by "drug" memory. In mice, chronic exposure to cocaine followed by 30-day withdrawal increases chromatin accessibility at thousands of genomic regions including potential enhancer elements, in medium spiny neurons of NAc expressing the D1 dopamine receptor (cocaine target) [11]. Some of these regions are located close to genes stimulated by the drug.…”