title: SIRT1-FOXO3a regulate cocaine actions in the nucleus accumbens.
abstract: Previous studies have shown that chronic cocaine 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 cocaine (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 cocaine 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) family to be a downstream mechanism 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.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004, and.
authors.forename: Deveroux
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Ningyi
authors.initials: N
authors.lastname: Shao
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Elizabeth
authors.identifier: http://orcid.org/0000-0002-2984-8705
authors.initials: E
authors.lastname: Heller
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Jian
authors.identifier: http://orcid.org/0000-0002-1177-9377
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Rachael
authors.initials: R
authors.lastname: Neve
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004, and.
authors.forename: Hee-Dae
authors.initials: HD
authors.lastname: Kim
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004, and.
authors.forename: Tanessa
authors.initials: T
authors.lastname: Call
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004, and.
authors.forename: Samantha
authors.initials: S
authors.lastname: Magazu
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Eric.Nestler@mssm.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D003042:Cocaine
keywords: ChIP-Seq; SIRT1; addiction; behavior; cocaine; genomics