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PMID:17988634

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Citation

Renthal, W, Maze, I, Krishnan, V, Covington, HE 3rd, Xiao, G, Kumar, A, Russo, SJ, Graham, A, Tsankova, N, Kippin, TE, Kerstetter, KA, Neve, RL, Haggarty, SJ, McKinsey, TA, Bassel-Duby, R, Olson, EN and Nestler, EJ (2007) Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 56:517-29

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.

Links

PubMed Online version:10.1016/j.neuron.2007.09.032

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:HDAC5

acts_upstream_of_or_within

GO:0042220: response to cocaine

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3056065

P

Seeded From UniProt

complete

MOUSE:HDAC5

acts_upstream_of_or_within

GO:0042220: response to cocaine

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HDAC5

acts_upstream_of_or_within

GO:0033555: multicellular organismal response to stress

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3056065

P

Seeded From UniProt

complete


See also

References

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