Epigenetic modulation of chronic anxiety and pain by histone deacetylation

Mol Psychiatry. 2015 Oct;20(10):1219-31. doi: 10.1038/mp.2014.122. Epub 2014 Oct 7.


Prolonged exposure of the central amygdala (CeA) to elevated corticosteroids (CORT) facilitates long-term anxiety and pain through activation of glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF). However, the mechanisms maintaining these responses are unknown. Since chronic phenotypes can be sustained by epigenetic mechanisms, including histone modifications such as deacetylation, we tested the hypothesis that histone deacetylation contributes to the maintenance of chronic anxiety and pain induced by prolonged exposure of the CeA to CORT. We found that bilateral infusions of a histone deacetylase inhibitor into the CeA attenuated anxiety-like behavior as well as somatic and visceral hypersensitivity resulting from elevated CORT exposure. Moreover, we delineated a novel pathway through which histone deacetylation could contribute to CORT regulation of GR and subsequent CRF expression in the CeA. Specifically, deacetylation of histone 3 at lysine 9 (H3K9), through the coordinated action of the NAD+-dependent protein deacetylase sirtuin-6 (SIRT6) and nuclear factor kappa B (NFκB), sequesters GR expression leading to disinhibition of CRF. Our results indicate that epigenetic programming in the amygdala, specifically histone modifications, is important in the maintenance of chronic anxiety and pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / metabolism
  • Animals
  • Anxiety Disorders / genetics*
  • Anxiety Disorders / metabolism*
  • Behavior, Animal / physiology
  • Central Amygdaloid Nucleus / metabolism
  • Corticotropin-Releasing Hormone / metabolism*
  • Disease Models, Animal
  • Epigenomics
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Histones / metabolism*
  • Male
  • NF-kappa B p50 Subunit / metabolism
  • Pain / genetics*
  • Pain / metabolism*
  • Rats
  • Rats, Inbred F344
  • Receptors, Glucocorticoid / metabolism
  • Sirtuins / metabolism


  • Adrenal Cortex Hormones
  • Histones
  • NF-kappa B p50 Subunit
  • Receptors, Glucocorticoid
  • Corticotropin-Releasing Hormone
  • Sirtuins
  • sirtuin 6, rat
  • Histone Deacetylases