Epigenetic Mechanisms Within the Cingulate Cortex Regulate Innate Anxiety-Like Behavior

Int J Neuropsychopharmacol. 2019 Apr 1;22(4):317-328. doi: 10.1093/ijnp/pyz004.


Background: Pathological anxiety originates from a complex interplay of genetic predisposition and environmental factors, acting via epigenetic mechanisms. Epigenetic processes that can counteract detrimental genetic risk towards innate high anxiety are not well characterized.

Methods: We used female mouse lines of selectively bred high (HAB)- vs low (LAB)-innate anxiety-related behavior and performed select environmental and pharmacological manipulations to alter anxiety levels as well as brain-specific manipulations and immunohistochemistry to investigate neuronal mechanisms associated with alterations in anxiety-related behavior.

Results: Inborn hyperanxiety of high anxiety-like phenotypes was effectively reduced by environmental enrichment exposure. c-Fos mapping revealed that hyperanxiety in high anxiety-like phenotypes was associated with blunted challenge-induced neuronal activation in the cingulate-cortex, which was normalized by environmental enrichment. Relating this finding with epigenetic modifications, we found that high anxiety-like phenotypes (compared with low-innate anxiety phenotypes) showed reduced acetylation in the hypoactivated cingulate-cortex neurons following a mild emotional challenge, which again was normalized by environmental enrichment. Paralleling the findings using environmental enrichment, systemic administration of histone-deacetylase-inhibitor MS-275 elicited an anxiolytic-like effect, which was correlated with increased acetylated-histone-3 levels within cingulate-cortex. Finally, as a proof-of-principle, local MS-275 injection into cingulate-cortex rescued enhanced innate anxiety and increased acetylated-histone-3 within the cingulate-cortex, suggesting this epigenetic mark as a biomarker for treatment success.

Conclusions: Taken together, the present findings provide the first causal evidence that the attenuation of high innate anxiety-like behavior via environmental/pharmacological manipulations is epigenetically mediated via acetylation changes within the cingulate-cortex. Finally, histone-3 specific histone-deacetylase-inhibitor could be of therapeutic importance in anxiety disorders.

Keywords: anxiolytic drug development; histone-3; immediate early gene; innate anxiety; prefrontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Anxiety* / drug therapy
  • Anxiety* / metabolism
  • Anxiety* / physiopathology
  • Anxiety* / rehabilitation
  • Behavior, Animal* / drug effects
  • Behavior, Animal* / physiology
  • Benzamides / pharmacology
  • Environment*
  • Epigenesis, Genetic*
  • Female
  • Gyrus Cinguli* / drug effects
  • Gyrus Cinguli* / metabolism
  • Gyrus Cinguli* / physiopathology
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histones / drug effects
  • Histones / metabolism
  • Instinct
  • Male
  • Mice
  • Mice, Inbred Strains
  • Proof of Concept Study
  • Pyridines / pharmacology


  • Anti-Anxiety Agents
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Histones
  • Pyridines
  • entinostat