Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder

Abstract

Epigenetic alterations of the brain-derived neurotrophic factor (Bdnf) gene have been linked with memory, stress, and neuropsychiatric disorders. Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and BdnfDNA methylation. Adult male Sprague-Dawley rats were given psychosocial stress composed of two acute cat exposures in conjunction with 31 days of daily social instability. These manipulations have been shown previously to produce physiological and behavioral sequelae in rats that are comparable to symptoms observed in traumatized people with PTSD. We then assessed BdnfDNA methylation patterns (at exon IV) and gene expression. We have found here that the psychosocial stress regimen significantly increased BdnfDNA methylation in the dorsal hippocampus, with the most robust hypermethylation detected in the dorsal CA1 subregion. Conversely, the psychosocial stress regimen significantly decreased methylation in the ventral hippocampus (CA3). No changes in BdnfDNA methylation were detected in the medial prefrontal cortex or basolateral amygdala. In addition, there were decreased levels of BdnfmRNA in both the dorsal and ventral CA1. These results provide evidence that traumatic stress occurring in adulthood can induce CNS gene methylation, and specifically, support the hypothesis that epigenetic marking of the Bdnfgene may underlie hippocampal dysfunction in response to traumatic stress. Furthermore, this work provides support for the speculative notion that altered hippocampal BdnfDNA methylation is a cellular mechanism underlying the persistent cognitive deficits which are prominent features of the pathophysiology of PTSD.

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

“…In the earlier studies, the Diamond group found these manipulations to produce physiological and behavioral sequelae in rats that are comparable with symptoms observed in traumatized people with PTSD (Zoladz et al, 2008). The cat exposure combined with the psychosocial stress regimen significantly increased methylation of the BDNF gene in the dorsal hippocampus, with the most robust hypermethylation detected in the dorsal CA1 subregion (Roth et al, 2011). Conversely, the psychosocial stress regimen significantly decreased methylation in the ventral hippocampus (CA3).…”

“…To date, the hypothesis of a role for epigenetic mechanisms in PTSD and amygdala-dependent fear responses has only begun to be tested (Monsey et al, 2011;Roth et al, 2011;Smith et al, 2011). Thus, it is important to begin to assess the role of epigenetics in the amygdala and in PTSD, and the potential therapeutic efficacy of epigenetic drugs in alleviating PTSD.…”

“…The studies presented thus far challenge the view that DNA methylation is laid down early in life and remains unchanged thereafter, and suggest that DNA methylation can be actively removed in the process of memory consolidation Lubin and Sweatt, 2007;Miller et al, 2008;Miller and Sweatt, 2007;Roth et al, 2009;Roth et al, 2011). The idea of the occurrence of active DNA demethylation has been contentious.…”

“…A report of altered expression of the BDNF gene in the amygdala in response to fear learning (Ou and Gean, 2007) indicates that similar genes may be modified in the amygdala in response to fear conditioning. Moreover, we already provided evidence for epigenetic regulation of the BDNF gene in the prefrontal cortex in response to maternal maltreatment (Roth et al, 2009) and in the hippocampus of adult rodents using a predator-stress model of PTSD (Roth et al, 2011), suggesting that BDNF may be especially relevant for understanding the development of pathological fear. It is also worthwhile to examine potential changes in DNA methylation of DNMT1, DNMT3A, and DNMT3B genes themselves.…”

Hippocampal Network Connectivity and Activation Differentiates Post-Traumatic Stress Disorder From Generalized Anxiety Disorder

“…Kaouane et al (2012) have recently shown that infusion of glucocorticoids-which are secreted naturally in response to stressors-directly into the dorsal hippocampus both impairs the processing of memory and results in generalized fear memory and hyperreactive amygdala activity that also typically characterizes PTSD. Further, stressors also result in methylation of the Bdnf gene and decreased BDNF gene expression in the dorsal hippocampus (Kozlovsky et al, 2007;Roth et al, 2011). Site-specific deletion of Bdnf gene in the dorsal hippocampus results both in poor spatial memory and, importantly, in reduced extinction of conditioned fear, while preserving fear learning and endogenous anxiety (Heldt et al, 2007).…”