Epigenomic Mechanisms of Early Adversity and HPA Dysfunction: Considerations for PTSD Research

Abstract

Childhood adversity can have life-long consequences for the response to stressful events later in life. Abuse or severe neglect are well-known risk factors for post-traumatic stress disorder (PTSD), at least in part via changes in neural systems mediating the endocrine response to stress. Determining the biological signatures of risk for stress-related mental disorders such as PTSD is important for identifying homogenous subgroups and improving treatment options. This review will focus on epigenetic regulation in early life by adversity and parental care – prime mediators of offspring neurodevelopment – in order to address several questions: (1) what have studies of humans and analogous animal models taught us about molecular mechanisms underlying changes in stress-sensitive physiological systems in response to early life trauma? (2) What are the considerations for studies relating early adversity and PTSD risk, going forward? I will summarize studies in animals and humans that address the epigenetic response to early adversity in the brain and in peripheral tissues. In so doing, I will describe work on the glucocorticoid receptor and other well-characterized genes within the stress response pathway and then turn to genomic studies to illustrate the use of increasingly powerful high-throughput approaches to the study of epigenomic mechanisms.

Knockdown of steroid receptors in the central nucleus of the amygdala induces heightened pain behaviors in the rat

“…Epigenetic processes have been implicated in long-term changes in GR and CRF expression following early life adversity (Anacker et al, 2014; Reul et al, 2015). There is also evidence for epigenetic modifications of GR expression in other stress paradigms, including models of post-traumatic stress disorder (McGowan, 2013; Stankiewicz et al, 2013; Reul, 2014). In the CORT-implant model, we have recently demonstrated changes in histone acetylation are responsible for the prolonged decrease in GR expression and prolonged increase in CRF expression in the CeA (Tran et al, 2014b).…”

Epigenetic mechanisms underlying learning and the inheritance of learned behaviors

“…Additionally, as much work has noted that the glucocorticoid receptor (GR) is integral in the stress response system due to its activation by the HPA axis (42), recent studies have turned to examine how stress exposure may epigenetically alter GR-signaling (reviewed by McGowan et al, 2013) (43). In particular, recent studies from both animal models and human clinical population have examined the epigenetic regulation of fkbp5 , a gene which regulates GR receptor translocation and functions as part of a negative feedback loop to govern GR dynamics (Figure 3A ) .…”

Environmental Alterations of Epigenetics Prior to the Birth

“…For example, studies show that maternal post-traumatic stress disorder (PTSD) can be transmitted across generations (Yehuda & Bierer, 2008; Yehuda, Schmeidler, Wainberg, Binder-Brynes, & Duvdevani, 1998) and is associated with dysregulation of neurobiological systems, such as the hypothalamus-pituitary- adrenal (HPA) axis (Boscarino, 1996; Mason, Giller, Kosten, Ostroff, & Podd, 1986; McGowan, 2013). Stress is implicated in the development of mental disorders and other adverse outcomes such as low birth weight (Reed, 2012), poor maternal-infant bonding (Muzik, Marcus, & Flynn, 2009), and infant sleep and behavioral problems at 18 months (Hairston et al, 2011).…”

“…Maternal PTSD (McGowan, 2013), maternal separation (Lewis, Staudinger, Scheck, & Olive, 2013), depression (Dalton, Kolshus, & McLoughlin, 2014; Heim & Binder, 2012), maternal care (Champagne & Curley, 2009), childhood adversity or early life stress (Franklin et al, 2010; Murgatroyd et al, 2009; Roth, Lubin, Funk, & Sweatt, 2009), and paternal stress (Rodgers, Morgan, Bronson, Revello, & Bale, 2013), are environmental inputs that have been shown to affect the epigenetic profile of the offspring. The most prominent mechanism for trans-generational epigenetic regulation in response to prenatal stress is via the hypothalamic-pituitary-adrenal (HPA) axis.…”