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

Abstract

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.

Neuroinflammatory alterations in trait anxiety: modulatory effects of minocycline

“…Anxiety-like behavior of HAB and NAB mice was correlated with microglia alterations in the DG Behavioral testing in the LD test confirmed an enhanced anxiety-related behavior in HABs, compared to NAB controls ( Fig. 2a), as HAB mice spent less time in the brightly lit compartment of the testing arena (p < 0.01, t (15) = 3.146), and also entered the light arena less often (p < 0.01, t (8) = 3.484), as demonstrated previously 47,53 . To gain evidence linking behavior and neuroinflammatory parameters, we asked whether alterations in hippocampal microglia are associated with symptom severity of trait anxiety in HAB and NAB groups.…”

Enriched Environment Attenuates Enhanced Trait Anxiety in Association with Normalization of Aberrant Neuro-Inflammatory Events

“…Bedding was changed twice a week. After 28d of the EE, mice were subjected to open field (OF) and light–dark (LD) test, and perfused and sacrificed 2 h post-LD test [ 24 ].…”

“…The current study, therefore, used a mouse model which exhibits high-trait anxiety (HAB) compared to normal-anxiety (NAB) controls. This phenotype is the result of a selective breeding approach of CD-1 mice, according to anxiety scores assessed in the elevated plus maze test [ 24 ]. We tested whether and how beneficial (EE) environmental manipulations are capable of attenuating hyperanxiety.…”

Mitochondrial brain proteome acetylation levels and behavioural responsiveness to amphetamine are altered in mice lacking Sirt3

“…Alterations in normal PTM states of neuronal proteins-such as histones and tubulin-have been identified in several neurological conditions as well as pre-clinical model systems (Magiera et al, 2018;Fallah et al, 2021). Within the brain, increased acetyl-histone levels in the medial prefrontal cortex, amygdala, and cingulate cortex of mice (Whittle et al, 2016;Sah et al, 2019), as well as the basal nucleus of stria terminalis of rats (Ranjan et al, 2017), have been linked to increased locomotor and/or reduced anxiety and fear-like behaviours. Similarly, global loss of tubulin de-tyrosination in the mouse brain is associated with hyper-locomotion, impaired social interaction, and decreased anxiety-like behaviours Frontiers in Physiology frontiersin.org (Pagnamenta et al, 2019).…”