Epigenetic mechanisms within the cingulate cortex regulate innate anxiety-like behavior.

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 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 HABs was effectively reduced by environmental-enrichment (EE) exposure. c-Fos mapping revealed that hyperanxiety in HABs was associated with blunted challenge-induced neuronal activation in the cingulate-cortex (Cg1), which was normalized by EE. Relating this finding with epigenetic modifications, we found that HABs (compared to LABs) showed reduced acetylation in the hypoactivated Cg1 neurons following a mild emotional challenge, which again was normalized by EE. Paralleling the findings using EE, systemic administration of histone-deacetylase-inhibitor (HDACi) MS-275 elicited an anxiolytic-like effect, which was correlated with increased acetylated-histone-3 (acH3) levels within Cg1. Finally, as a proof-of-principle, local MS-275 injection into Cg1 rescued enhanced innate-anxiety and increased acH3 within Cg1 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 Cg1. Finally, histone-3 specific HDACi could be of therapeutic importance in anxiety disorders.