Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli.
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.
Renthal
William
W
Department of Psychiatry and Basic Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
Maze
Ian
I
Krishnan
Vaishnav
V
Covington
Herbert E
HE
Xiao
Guanghua
G
Kumar
Arvind
A
Russo
Scott J
SJ
Graham
Ami
A
Tsankova
Nadia
N
Kippin
Tod E
TE
Kerstetter
Kerry A
KA
Neve
Rachael L
RL
Haggarty
Stephen J
SJ
McKinsey
Timothy A
TA
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
Nestler
Eric J
EJ
D000107:Acetylation / Q000187:drug effects; D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002843:Chromatin / Q000187:drug effects / Q000235:genetics; D002908:Chronic Disease; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004644:Emotions / Q000187:drug effects / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D012201:Reward; D013315:Stress, Psychological / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology
D002843:Chromatin; D018765:Dopamine Uptake Inhibitors; D006657:Histones; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D003042:Cocaine