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

Abstract

Prolonged distress and dysregulated memory processes are the core features of post-traumatic stress disorder (PTSD) and represent the debilitating, persistent nature of the illness. However, the neurobiological mechanisms underlying the expression of these symptoms are challenging to study in human patients. Stress-enhanced fear learning (SEFL) paradigms, which encompass both stress and memory components in rodents, are emerging as valuable preclinical models of PTSD. Rodent models designed to study the long-term mechanisms of either stress or fear memory alone have identified a critical role for numerous epigenetic modifications to DNA and histone proteins. However, the epigenetic modifications underlying SEFL remain largely unknown. This review will provide a brief overview of the epigenetic modifications implicated in stress and fear memory independently, followed by a description of existing SEFL models and the few epigenetic mechanisms found to date to underlie SEFL. The results of the animal studies discussed here highlight neuroepigenetics as an essential area for future research in the context of PTSD through SEFL studies, because of its potential to identify novel candidates for neurotherapeutics targeting stress-induced pathogenic memories.Post-traumatic stress disorder (PTSD) is triggered by experiencing or witnessing a traumatic event and is characterized by pathogenic memory (e.g., recurrent, involuntary memories that trigger intense stress), avoidance of reminders, hyperarousal and reactivity, negative mood, cognitive alterations, and a persistence of symptoms for at least 1 mo. Although only a fraction of people exposed to trauma develop PTSD, a history of stress exposure prior to witnessing a traumatic event increases the risk (Breslau et al. 2014). Therefore, some animal models of PTSD use multidimensional stress and fear memory paradigms to model the disorder. In stress-enhanced fear learning (SEFL), a rodent is exposed to a stressor or combination of stressors prior to undergoing classical fear conditioning. Models that utilize SEFL closely reproduce many core symptoms of PTSD, including enhanced fear learning, generalized anxiety, heightened startle, and impaired extinction.

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

“…social hierarchy, stress adaptability). DNA methylation and histone modifications have been studied in the stress (68) and memory fields (13), and epigenetic interactions are likely after successive stressful events to confer resilience or susceptibility (27). Epigenetics may also impart gender-specific extinction impairments, as expression of DNA methyltransferase 3a confers resilience to “depression” in a variable stress paradigm (69).…”

“…These manipulations induce their own neuromolecular changes, precluding studies of the mechanisms underlying the genesis and perpetuation of the PTSD-like phenotype. Furthermore, outbred lines are used in all cases of differential susceptibility, limiting the ability to isolate epigenetic contributors, which are expected to be highly relevant to individual variability in susceptibility (27–30). Here we present a protocol that addresses these challenges, while retaining the behavioral phenotypes and neurochemical dysregulation demonstrated by existing PTSD-like models.…”

Neuroepigenetics of Post-Traumatic Stress Disorder

“…Animals exposed to these stressors exhibit characteristics that reflect those generally observed in PTSD, such as increased anxiety-like behaviors, exaggerated startle, and abnormal GC response (i.e., reduced basal GC levels and enhanced GC negative feedback), indicating that they may be appropriate for investigating psychological, trauma-induced cognitive/behavioral and neuroendocrine alterations 17,77,78 . In particular, animal models of PTSD that expose animals to trauma/stressor(s) before fear conditioning show greater face, construct, and predictive validity for PTSD than fear conditioning alone 62,75 , and can be used to determine the epigenetic effect of stress on subsequent fear learning 63 . In conjunction with our understanding from studies that investigated neuroepigenetics of stress and fear memory independently, epigenetic investigations using paradigms such as stress-enhanced fear learning (SEFL) should elucidate distinct mechanisms underlying the interaction between these two major facets of PTSD and have special promise for identifying mechanisms underlying resistance to extinction learning and the role of the BDNF pathway, which is widely implicated in both stress and fear memory 63 .…”

Epigenetic programming of the neuroendocrine stress response by adult life stress

“…Moreover, histone acetylation, especially in hippocampal H3 (Levenson et al 2004) and H4 (Peleg et al 2010), as well as amygdalar histone trimethylation of H3K4 (Gupta et al 2010), have been found to also promote fear encoding. Extensive reviews describing the involvement of epigenetic mechanisms in fear memory formation have been performed by Roth et al (2010), Zovkic et al (2013), Kwapis and Wood (2014), Rudenko and Tsai (2014), and Blouin et al (2016).…”