Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes

Carpenter, Marco D.; Hu, Qiwen; Bond, Allison; Lombroso, Sonia I.; Czarnecki, Kyle S.; Lim, Carissa J.; Song, Hongjun; Wimmer, Mathieu E.; Pierce, R. Christopher; Heller, Elizabeth A.

doi:10.1038/s41467-020-14331-y

Cited by 80 publications

(108 citation statements)

References 70 publications

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“…Although a number of studies have previously shown that discrete ensembles of MSNs are activated as a consequence of cocaine exposure (7,20,37), the present findings expand on this body of work in several important ways. For example, while our data are congruent with previously reported IEG changes (e.g., Fosb, Egr1, and Nr4a1) in response to drug experience (7,20,38), our results extend this work by revealing hundreds of other cocaine-induced gene changes in transcriptionally defined populations, many of which have not been previously explored in the context of addiction. Cell type-specific transcriptional profiling with snRNA-seq revealed that cocaine activates a subset of Drd1-MSNs and Drd2-MSNs, but this effect was more robust in the Drd1-MSN population-both in terms of number a public web browser where the datasets produced by these experiments can be viewed (available via day-lab.org/resources).…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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“…From our datasets we also found several genes implicated in cocaine action based on previous literature. From HC Acute cocaine exposure, we found upregulation of the immediate-early genes (IEGs) Nr4a1 and Fos [ 14 , 22 – 26 ]. Repeated home cage cocaine exposure (HC Chronic) upregulated expression of several genes that are increased within the midbrain of human chronic cocaine users ( Cdnk1a, Nfkbia and Fosb) [ 27 ] or by chronic cocaine in preclinical mouse studies ( Fosb ) [ 24 , 28 ].…”

Section: Resultsmentioning

confidence: 99%

Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area

Campbell

Chen

Beardwood

et al. 2021

Neuropsychopharmacol.

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During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.

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“…This is consistent with other studies examining HDAC activity in the NAc which have shown to regulate aspects of cocaine and cue-primed reinstatement and incubation of craving in rats, but not cocaine reinforcement ( Taniguchi et al, 2017 ; Li et al, 2018 ). Moreover, our impaired cocaine seeking effects presents a possible upstream mechanism for work from the Heller lab, where CRISPR-mediated overexpression of an HDAC3 target, Nr4a1, similarly resulted in decreased cocaine-seeking following cocaine IVSA ( Carpenter et al, 2020 ). It is possible that the contrasting effects of CPP versus cocaine seeking from our D1R-HDAC3 manipulation, may reflect differences in HDAC3-dependent mechanisms when cocaine is self-administered, as physiological differences in experimenter-administered and cocaine-self administration are reported ( Larson et al, 2011 ; McCutcheon et al, 2011 ; Anderson et al, 2018 ).…”

Section: Discussionmentioning

confidence: 96%

“…These cocaine-induced changes in Nr4a1 expression may be mediated by changes in H4K8Ac. HDAC3's deacetylase activity thus may be critical in driving downstream functions of Nr4a1, as Nr4a1 is critical in regulating both memory formation and cocaine action ( Kwapis et al, 2019 ; Carpenter et al, 2020 ). Interestingly, although HDAC3 occupancy was reduced at the Fos promoter, no changes in H4K8Ac were detected.…”

Section: Discussionmentioning

confidence: 99%

HDAC3 Activity within the Nucleus Accumbens Regulates Cocaine-Induced Plasticity and Behavior in a Cell-Type-Specific Manner

et al. 2021

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Epigenetic mechanisms regulate processes of neuroplasticity critical to cocaine-induced behaviors. This includes the Class I histone deacetylase (HDAC) HDAC3, known to act as a negative regulator of cocaine-associated memory formation within the nucleus accumbens (NAc). Despite this, it remains unknown how cocaine alters HDAC3-dependent mechanisms. Here, we profiled HDAC3 expression and activity in total NAc mouse tissue following cocaine exposure. Although chronic cocaine did not affect expression of Hdac3 within the NAc, chronic cocaine did affect promoter-specific changes in HDAC3 and H4K8Ac occupancy. These changes in promoter occupancy correlated with cocaine-induced changes in expression of plasticity-related genes. To causally determine whether cocaine-induced plasticity is mediated by HDAC3's deacetylase activity, we overexpressed a deacetylase-dead HDAC3 point mutant (HDAC3-Y298H-v5) within the NAc of adult male mice. We found that disrupting HDAC3's enzymatic activity altered selective changes in gene expression and synaptic plasticity following cocaine exposure, despite having no effects on cocaine-induced behaviors. In further assessing HDAC3's role within the NAc, we observed that chronic cocaine increases Hdac3 expression in Drd1 but not Drd2 -cells of the NAc. Moreover, we discovered that HDAC3 acts selectively within D1R cell-types to regulate cocaine-associated memory formation and cocaine-seeking. Overall, these results suggest that cocaine induces cell-type-specific changes in epigenetic mechanisms to promote plasticity important for driving cocaine-related behaviors. SIGNIFICANCE STATEMENT Drugs of abuse alter molecular mechanisms throughout the reward circuitry that can lead to persistent drug-associated behaviors. Epigenetic regulators are critical drivers of drug-induced changes in gene expression. Here, we demonstrate that the activity of an epigenetic enzyme promotes neuroplasticity within the nucleus accumbens (NAc) critical to cocaine action. In addition, we demonstrate that these changes in epigenetic activity drive cocaine-seeking behaviors in a cell-type-specific manner. These findings are key in understanding and targeting cocaine's impact of neural circuitry and behavior.

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Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes

Cited by 80 publications

References 70 publications

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

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

Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area

HDAC3 Activity within the Nucleus Accumbens Regulates Cocaine-Induced Plasticity and Behavior in a Cell-Type-Specific Manner

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