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

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

doi:10.1038/s41467-020-14331-y

Abstract

Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced neuroadaptations. Such mechanisms may be exploited to develop novel therapies for cocaine addiction, but a molecular target has not yet been identified. Here we profiled mouse gene expression during early and late cocaine abstinence to identify putative regulators of neural homeostasis. Cocaine activated the transcription factor, Nr4a1, and its target gene, Cartpt, a key molecule involved in dopamine metabolism. Sustained activation of Cartpt at late abstinence was coupled with depletion of the repressive histone modification, H3K27me3, and enrichment of activating marks, H3K27ac and H3K4me3. Using both CRISPR-mediated and small molecule Nr4a1 activation, we demonstrated the direct causal role of Nr4a1 in sustained activation of Cartpt and in attenuation of cocaine-evoked behavior. Our findings provide evidence that targeting abstinence-induced homeostatic gene expression is a potential therapeutic target in cocaine addiction.

Highlights

Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced neuroadaptations
We found no significant differences in the activation of Nr4a1 in the ventral tegmental area (VTA) or prefrontal cortex (PFC) at either 1day or 28-days of abstinence, suggesting a nucleus accumbens (NAc)-specific mechanism of Nr4a1-dependent transcription across abstinence
The majority of studies at the cellular level have focused on cocaine-induced adaptations at either early or late abstinence, which limits understanding of how processes that occur during abstinence affect subsequent behavior

Summary

Introduction

Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced neuroadaptations. Endogenous homeostatic mechanisms may restore and even reverse normal function to reward-related brain areas[5,6] Both preclinical[7] and human[8] studies indicate that drug-induced synaptic plasticity and the associated drug memories are reversible. To identify a master regulator of homeostatic gene expression, we profiled global transcriptomic changes in the NAc, VTA, and PFC at early and late abstinence following cocaine self-administration in mice. Using this approach, we identified a key role for the transcription factor, nuclear receptor subfamily 4 group A member 1 (Nr4a1), in regulating homeostatic target gene expression and cocaine-evoked behavior. Our findings are consistent with prior studies that show cocaine-induced expression of Nr4a110,11,27

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Conclusion