Date of this Version
Journal of Neuroscience
Previous studies have shown that chronic cocain administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocain (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocain causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) familty to be a downstream mechanis through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action.
Originally published in the Journal of Neuroscience © 2015 Society for Neuroscience. Now available Open Access under a Creative Commons Attribution International 4.0 License (CC BY 4.0).
addiction, behavior, ChIP-Seq, cocaine, genomics, SIRT1
Ferguson, Deveroux; Shao, Ningyi; Heller, Elizabeth A.; Feng, Jian; Neve, Rachael L.; Kim, Hee-Dae; Shen, Li; and Nestler, Eric J., "SIRT1-FOXO3a Regulate Cocain Actions in the Nucleus Accumbens" (2015). Departmental Papers (Department of Systems Pharmacology and Translational Therapeutics). 5.
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Date Posted:22 January 2018
This document has been peer reviewed.