Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli

William Renthal; Ian Maze; Vaishnav Krishnan; Herbert E Covington 3rd; 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

doi:10.1016/j.neuron.2007.09.032

Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli

Neuron. 2007 Nov 8;56(3):517-29. doi: 10.1016/j.neuron.2007.09.032.

Authors

William Renthal¹, Ian Maze, Vaishnav Krishnan, Herbert E Covington 3rd, 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

Affiliation

¹ Department of Psychiatry and Basic Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.

PMID: 17988634
DOI: 10.1016/j.neuron.2007.09.032

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation / drug effects
Adaptation, Physiological / drug effects
Adaptation, Physiological / genetics
Animals
Chromatin / drug effects
Chromatin / genetics
Chronic Disease
Cocaine / pharmacology
Cocaine-Related Disorders / enzymology*
Cocaine-Related Disorders / genetics*
Cocaine-Related Disorders / physiopathology
Disease Models, Animal
Dopamine Uptake Inhibitors / pharmacology
Emotions / drug effects
Emotions / physiology
Epigenesis, Genetic / genetics*
Gene Expression Regulation, Enzymologic / drug effects
Gene Expression Regulation, Enzymologic / genetics
Histone Deacetylases / genetics*
Histones / metabolism
Mice
Mice, Inbred C57BL
Nucleus Accumbens / drug effects
Nucleus Accumbens / enzymology
Nucleus Accumbens / physiopathology
Reward
Stress, Psychological / enzymology*
Stress, Psychological / genetics*
Stress, Psychological / physiopathology

Substances

Chromatin
Dopamine Uptake Inhibitors
Histones
Hdac5 protein, mouse
Histone Deacetylases
Cocaine

Associated data

GEO/GSE9134