Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Abstract

Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study

“…The finding of dexamethasone facilitation of extinction supports recent results from a translational rodent model of PTSD-like behavior in which dexamethasone administration enhanced fear extinction and extinction retention in a dose-dependent manner (Sawamura et al, 2016). Additional studies in rodents have shown the efficacy of dexamethasone in decreasing FPS and contextual fear during fear extinction paradigms (Yang et al, 2006).…”

Life stress, glucocorticoid signaling, and the aging epigenome: Implications for aging-related diseases

“…In line with this hypothesis, a decrease in global methylation follows exposure of cultured cells to GR agonists, and these changes are accompanied by senescence-related alterations in gene expression and increased sensitivity of cells to oxidative stress (Bose et al, 2010;Bose et al, 2015). As we discussed above, glucocorticoids decrease DNA methylation via two distinct but synergistic mechanisms: 1) counteracting of mechanisms that maintain DNA methylation, resulting for example from decreases in the levels or activity of DNMT1 (Gassen et al, 2015;Yang et al, 2012); and 2) upregulation of enzymes involved in active demethylation, such as the Tet family of 5-methylcytosine dioxygenases (Bose et al, 2015;Sawamura et al, 2015). Stressors and glucocorticoids are not the only factors that impact these processes.…”

“…This GR-induced demethylation is rapid and dynamic, suggesting that it is driven by active demethylating mechanisms. Indeed, exposure to glucocorticoids may upregulate enzymes involved in active demethylation, such as the Tet family of 5-methylcytosine dioxygenases in neuronal tissue (Bose et al, 2015;Sawamura et al, 2015). Nonetheless, glucocorticoids have also been shown to decrease in a dosedependent manner the expression of the gene encoding DNA methyltransferase 1 (DNMT1), the enzyme responsible for maintaining DNA methylation after cell division, in the mouse hippocampus .…”

The potential of epigenetics in stress-enhanced fear learning models of PTSD

“…A reduction in FKBP5 levels have been reported in PTSD patients (Yehuda et al 2009), and changes in methylation of the FKBP5 gene have been found in holocaust survivors and their offspring (Yehuda et al 2015a). Pretreatment with the synthetic corticosteroid dexamethasone prior to extinction not only rescued stress-induced fear extinction deficits but also regulated the expression of Fkbp5 mRNA and expression of the DNA methylation regulators Dnmt3a and 3b and Tet1, 2, and 3 (Sawamura et al 2016). The correlative data from this study demonstrate a pattern of Fkbp5 methylation linked to an accelerated extinction profile in an SEFL model, strengthening the notion that DNA methylation of key genes involved in both stress and memory may impact the degree of stress-enhanced fear learning, extinction, and retention.…”

“…For instance, SPS before fear conditioning results in a delayed extinction profile (Yamamoto et al 2009;Chauveau et al 2012;Sawamura et al 2016), an effect that can be rescued by treatment with an HDAC inhibitor (Matsumoto et al 2013). This is not surprising, given that HDAC inhibitors increase acetylation to support extinction learning and decrease anxiety in animal stress paradigms (Yamawaki et al 2012;Valvassori et al 2014).…”