CBP in the Nucleus Accumbens Regulates Cocaine-Induced Histone Acetylation and Is Critical for Cocaine-Associated Behaviors

University of California, Irvine, Department of Neurobiology and Behavior and Center for the Neurobiology of Learning and Memory, Irvine, California 92697-3800, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 11/2011; 31(47):16941-8. DOI: 10.1523/JNEUROSCI.2747-11.2011
Source: PubMed

ABSTRACT Cocaine exposure triggers molecular events that lead to long-lasting changes in brain structure and function. These changes can lead to the development of persistent and robust behavioral adaptations that characterize addiction. Recent evidence suggests the regulation of transcription via chromatin modification, such as histone acetylation, has an important role in the development of addictive behavior. Histone acetylation is regulated by histone acetyltransferases (HATs), which acetylate histones and promote transcription, and histone deacetylases (HDACs), which remove acetyl groups and silence transcription. Studies have demonstrated that HDACs may negatively regulate cocaine-induced behaviors, but very little is known about the role of specific HATs in long-lasting drug-induced plasticity. The histone acetyltransferase CREB-binding protein (CBP) mediates transcriptional activation by recruiting basal transcription machinery and acetylating histones. CBP is a critically important chromatin-modifying enzyme involved in regulating gene expression required for long-term plasticity and memory. However, the role of CBP in cocaine-induced behaviors remains largely unknown. We examined the role of CBP in drug-induced plasticity using CBP-FLOX genetically modified mice in combination with adeno-associated virus expressing Cre-recombinase to generate focal homozygous deletions of Cbp in the nucleus accumbens (NAc). A complete loss of CBP in NAc neurons results in decreased histone acetylation and significantly altered c-fos expression in response to cocaine. Furthermore, the deletion of CBP in the NAc correlates with significant impairments in cocaine sensitivity and context-cocaine associated memory. This is the first study to demonstrate a definitive role for CBP in modulating gene expression that may subserve drug-seeking behaviors.

Download full-text


Available from: Emanuela Mhillaj, Jan 12, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glucocorticoid hormones exert crucial effects on the brain in relation to physiology, endocrine regulation, mood and cognition. Their two receptor types, glucocorticoid and mineralocorticoid receptors (MR and GR), are members of the nuclear receptor superfamily and act in large measure as transcription factors. The outcome of MR/GR action on the genome depends on interaction with members from different protein families, which are of crucial importance for cross-talk with other neuronal and hormonal signals that impinge on the glucocorticoid sensitive circuitry. Relevant interacting proteins include other transcription factors that may either tether the receptor to the DNA, or that bind in the vicinity of GR and MR to tune the transcriptional response. In addition, transcriptional coregulator proteins constitute the actual signal transduction pathway to the transcription machinery. We review the current evidence for involvement of individual coregulators in GR-dependent effects on stress responses, and learning and memory. We discuss the use of in vitro and in silico tools to predict those coregulators that are of importance for particular brain processes. Finally, we discuss the potential of selective receptor modulators that may only allow a subset of all interactions, thus allowing more selective targeting of glucocorticoid-dependent processes in the brain.
    Neuroscience 03/2013; DOI:10.1016/j.neuroscience.2013.03.038 · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Learning triggers alterations in gene transcription in brain regions such as the hippocampus and the entorhinal cortex (EC) that are necessary for long-term memory (LTM) formation. Here, we identify an essential role for the G9a/G9a-like protein (GLP) lysine dimethyltransferase complex and the histone H3 lysine 9 dimethylation (H3K9me2) marks it catalyzes, in the transcriptional regulation of genes in area CA1 of the rat hippocampus and the EC during memory consolidation. Contextual fear learning increased global levels of H3K9me2 in area CA1 and the EC, with observable changes at the Zif268, DNMT3a, BDNF exon IV, and cFOS gene promoters, which occurred in concert with mRNA expression. Inhibition of G9a/GLP in the EC, but not in the hippocampus, enhanced contextual fear conditioning relative to control animals. The inhibition of G9a/GLP in the EC induced several histone modifications that include not only methylation but also acetylation. Surprisingly, we found that downregulation of G9a/GLP activity in the EC enhanced H3K9me2 in area CA1, resulting in transcriptional silencing of the non-memory permissive gene COMT in the hippocampus. In addition, synaptic plasticity studies at two distinct EC-CA1 cellular pathways revealed that G9a/GLP activity is critical for hippocampus-dependent long-term potentiation initiated in the EC via the perforant pathway, but not the temporoammonic pathway. Together, these data demonstrate that G9a/GLP differentially regulates gene transcription in the hippocampus and the EC during memory consolidation. Furthermore, these findings support the possibility of a role for G9a/GLP in the regulation of cellular and molecular cross talk between these two brain regions during LTM formation.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(16):5440-53. DOI:10.1523/JNEUROSCI.0147-12.2012 · 6.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: How do drugs of abuse, such as cocaine, cause stable changes in neural plasticity that in turn drive long-term changes in behavior? What kind of mechanism can underlie such stable changes in neural plasticity? One prime candidate mechanism is epigenetic mechanisms of chromatin regulation. Chromatin regulation has been shown to generate short-term and long-term molecular memory within an individual cell. They have also been shown to underlie cell fate decisions (or cellular memory). Now, there is accumulating evidence that in the CNS, these same mechanisms may be pivotal for drug-induced changes in gene expression and ultimately long-term behavioral changes. As these mechanisms are also being found to be fundamental for learning and memory, an exciting new possibility is the extinction of drug-seeking behavior by manipulation of epigenetic mechanisms. In this review, we critically discuss the evidence demonstrating a key role for chromatin regulation via histone acetylation in cocaine action.Neuropsychopharmacology Reviews advance online publication, 22 August 2012; doi:10.1038/npp.2012.154.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2012; 38(1). DOI:10.1038/npp.2012.154 · 7.83 Impact Factor

Similar Publications