Histone Deacetylase 5 Epigenetically Controls Behavioral Adaptations to Chronic Emotional Stimuli

William Renthal, Ian Maze, Vaishnav Krishnan, Herbert E. Covington, Guanghua Xiao, Arvind Kumar, Scott J. Russo, Ami Graham, Nadia Tsankova, Tod E. Kippin, Kerry A. Kerstetter, Rachael L. Neve, Stephen J. Haggarty, Timothy A. McKinsey, Rhonda Bassel-Duby, Eric N. Olson, Eric J. Nestler

Research output: Contribution to journalArticlepeer-review

517 Scopus citations


Previous work has identified alterations in histone acetylation in animal models of drug addiction and depression. However, the mechanisms which integrate drugs and stress with changes in chromatin structure remain unclear. Here, we identify the activity-dependent class II histone deacetylase, HDAC5, as a central integrator of these stimuli with changes in chromatin structure and gene expression. Chronic, but not acute, exposure to cocaine or stress decreases HDAC5 function in the nucleus accumbens (NAc), a major brain reward region, which allows for increased histone acetylation and transcription of HDAC5 target genes. This regulation is behaviorally important, as loss of HDAC5 causes hypersensitive responses to chronic, not acute, cocaine or stress. These findings suggest that proper balance of histone acetylation is a crucial factor in the saliency of a given stimulus and that disruption of this balance is involved in the transition from an acute adaptive response to a chronic psychiatric illness.

Original languageEnglish (US)
Pages (from-to)517-529
Number of pages13
Issue number3
StatePublished - Nov 8 2007


  • DNA

ASJC Scopus subject areas

  • Neuroscience(all)


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