Exploring epigenetic regulation of fear memory and biomarkers associated with post-traumatic stress disorder

Abstract

This review examines recent work on epigenetic mechanisms underlying animal models of fear learning as well as its translational implications in disorders of fear regulation, such as Post-traumatic Stress Disorder (PTSD). Specifically, we will examine work outlining roles of differential histone acetylation and DNA-methylation associated with consolidation, reconsolidation, and extinction in Pavlovian fear paradigms. We then focus on the numerous studies examining the epigenetic modifications of the Brain-derived neurotrophin factor (BDNF) pathway and the extension of these findings from animal models to recent work in human clinical populations. We will also review recently published data on FKBP5 regulation of glucocorticoid receptor function, and how this is modulated in animal models of PTSD and in human clinical populations via epigenetic mechanisms. As glucocorticoid regulation of memory consolidation is well established in fear models, we examine how these recent data contribute to our broader understanding of fear memory formation. The combined recent progress in epigenetic modulation of memory with the advances in fear neurobiology suggest that this area may be critical to progress in our understanding of fear-related disorders with implications for new approaches to treatment and prevention.

Keywords: PTSD; amygdala; biomarkers; consolidation; extinction; fear memory; reconsolidation.

Figure 1

Schematic diagram of histone and DNA-methylation processes of epigenetic regulation of gene expression. The schematic diagram demonstrates the primary known functions of the different enzymes referred to within the review. (A) Histone acetyltransferases (HAT) add acetyl groups to histones, generally associated with relaxing wound DNA. (B) Histone deacetylases (HDAC) remove those acetyl groups. (C) Histone methyltransferases (HMT) add methyl groups to histones, generally associated with tightening wound DNA. (D) Histone demethylases (HDM) remove those methyl groups. (E) DNA methyltransferases (DNMT) add methyl groups to DNA, sometimes associated with DNA silencing.

Figure 2

Schematic diagram of different phases of fear learning, and predicted effects of inhibiting histone acetyltransferase, histone deacetylase, or DNA methyltransferase. The schematic diagram illustrates the predicted outcome of pharmacological inhibition of histone and DNA modifying enzymes on the primary aspects of fear memory. (Top) When treated with inhibitors during the consolidation phase of fear conditioning, short-term memory (STM) tests are not generally effected, but long-term memory (LTM) expression is impaired with HAT and DNMT inhibition or increased with HDAC inhibition. (Middle) When inhibitors are given after a brief memory reactivation, they may affect memory reconsolidation processes. In this case, there are no predicted effects on short-term memory post-reactivation (PR-STM); however, PR-LTM is impaired with HAT and DNMT inhibition or increased with HDAC inhibition. (Bottom) When inhibitors are given following extinction training, HAT inhibition is predicted to impair extinction retention while HDAC inhibition is predicted to enhance extinction retention.

Figure 3

Example of BDNF-mediated transcriptional activation, through epigenetic regulation of the homer1a synaptic plasticity gene in hippocampus and amygdala (Mahan et al., 2012). Fear conditioning rapidly increases BDNF-signaling in both the hippocampus and amygdala and results in activation of the TRKB pathway that activates MEK and ERK. ERK further phosphorylates CREB which is then translocated to the nucleus where it binds to CRE sites in the promoter region of homer1a. CREB subsequently recruits CBP which induces specific histone changes (A) increased acetylation in the hippocampus and (B) decreased methylation in the amygdala, both of which result in increased homer1a transcription (Figure courtesy of Amy Mahan, PhD).

Figure 4

FKBP5 regulation of GR function, and DNA methylation regulatory sites within the FKBP5 Gene (A) Schematic diagram of FKBP5 regulation of Glucocorticoid Receptor (GR) function. FKBP5 protein acts as an inhibitory chaperone, preventing GR translocation to the nucleus. With increasing cortisol binding, FKBP5 is displaced by FKBP4, allowing for translocation and gene activation, with more FKBP5 mRNA produced as one of the GR-sensitive genes, completing the intracellular negative feedback loop. (Figure courtesy of Elisabeth Binder). (B) DNA methylation of the FKBP locus, in which significant DNA methylation was observed in the promoter region, Intron 2 and intron 7 of the FKBP5 gene (Figure adapted from Klengel et al., 2013).