Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes.
Marco D. Carpenter,Qiwen Hu,Allison M. Bond,Sonia I. Lombroso,Kyle S. Czarnecki,Carissa J. Lim,Hongjun Song,Mathieu E. Wimmer,R. Christopher Pierce,Elizabeth A. Heller +9 more
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TLDR
A molecular mechanism whereby Nr4a1 activation leads to persistent changes in gene expression, chromatin and behaviour, in the context of cocaine abstinence is defined, providing evidence that targeting abstinence-induced homeostatic gene expression is a potential therapeutic target in cocaine addiction.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.read more
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A dopamine-induced gene expression signature regulates neuronal function and cocaine response
Katherine E. Savell,Jennifer J. Tuscher,Morgan E. Zipperly,Corey G. Duke,Robert A. Phillips,Allison J. Bauman,Saakshi Thukral,Faraz A. Sultan,Nicholas A. Goska,Lara Ianov,Jeremy J. Day +10 more
TL;DR: A comprehensive molecular atlas of cell subtypes in the NAc is generated, defining both sex-specific and cell type–specific responses to acute cocaine experience in a rat model system and demonstrating that drug-responsive gene programs can potentiate both physiological and behavioral adaptations to drugs of abuse.
Journal ArticleDOI
In vivo locus-specific editing of the neuroepigenome
TL;DR: Recent efforts in using locus-specific neuroepigenome editing in vivo to define causal relationships between a single chromatin modification at a specific gene in a defined cell population and downstream measures at the molecular, cellular, circuit and behavioural levels are described.
Journal ArticleDOI
Transgenic mice for in vivo epigenome editing with CRISPR-based systems.
Matthew Gemberling,Keith Siklenka,Erica Rodriguez,Katherine R. Tonn-Eisinger,Alejandro Barrera,Fang Liu,Ariel Kantor,Liqing Li,Valentina Cigliola,Mariah F. Hazlett,Courtney A. Williams,Luke C. Bartelt,Victoria J. Madigan,Josephine C. Bodle,Heather Daniels,Douglas C. Rouse,Isaac B. Hilton,Isaac B. Hilton,Aravind Asokan,Maria Ciofani,Kenneth D. Poss,Timothy E. Reddy,Anne E. West,Charles A. Gersbach +23 more
TL;DR: In this article, two conditional transgenic mouse lines based on CRISPRa and CRISpri enable epigenome editing in vivo and demonstrate regulation of target genes and corresponding changes to epigenetic states and downstream phenotypes in the brain and liver in vivo.
Journal ArticleDOI
Epigenetic Mechanisms in Drug Relapse
TL;DR: A review of studies that have examined epigenetic mechanisms that contribute to relapse to cocaine, amphetamine, methamphetamine, morphine, heroin, nicotine, or alcohol seeking, as assessed in rodent models and the implications for translational research on the potential use of systemically administered epigenetic enzyme inhibitors for relapse prevention in human drug users.
Journal ArticleDOI
Key transcription factors mediating cocaine-induced plasticity in the nucleus accumbens.
Collin D. Teague,Eric J. Nestler +1 more
TL;DR: The authors synthesize the literature on transcription factors mediating cocaine action in the nucleus accumbens, discuss the advancements and remaining limitations of current experimental approaches, and emphasize recent work leveraging bioinformatic tools and neuroepigenomic editing to study transcription factors involved in cocaine addiction.
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