Post-Traumatic Stress Disorder (PTSD) is a psychiatric disorder that may manifest after direct or indirect exposure to an extremely stressful or traumatizing event. PTSD is characterized by symptoms of recurrent intrusive memories related to the trauma, feelings of distress when exposed to trauma-related stimuli and avoidance of such stimuli, as well as changes in mood, cognition, alertness, and reactivity (2:1). Symptoms must persist for at least a month and cause significant distress and functional impairments, before a person can be diagnosed with PTSD. Despite the 11 million Americans suffering from PTSD during any given year, relatively little is known about the diseases underlying biological mechanisms and research has remained focused on methods of reducing symptoms rather than investigating the disease’s root cause (2). Given estimates that 75% of people experience at least one traumatic event during their life and the comparatively low incidence of PTSD, understanding the mechanisms underlying the disease may explain the differential susceptibility observed in the population (3).
Broadly, PTSD is believed to target the sympathetic nervous system which regulates the body’s fight or flight responses (1). However, significant changes in intracranial volume, grey matter distribution, and the transmission of neurotransmitters such as serotonin, dopamine, and norepinephrine are also thought to play a significant role (1; 2:265). More specifically, previous studies have suggested that PTSD is characterized by misfunction of the neurocircuitry implicated in stress response, fear learning, anxiety, and memory extinction (2; 2:3,34). Dysfunction of the Hippocampus, which is heavily involved in the creation of memories, is thought to be responsible for the disease’s recurring traumatic memories as well as its cognitive deficits, such as decreased verbal and working memory (2:39,40,41,42). Altered function of the prefrontal Cortex, involved in working memory, emotional regulation, and memory extinction, may also contribute to the persistence of traumatic memories (2:61,62). Although, the intense fear and anxiety accompanying traumatic memories is best explained by altered function of the Amygdala, the brain’s hub for emotional processing, which also plays significant roles in emotional regulation and memory extinction (2:61,65).
The physiological stress response associated with PTSD is often attributed to the Hypothalamic-Pituitary-Adrenal axis, whose dysregulation has been proposed as a biomarker of the disease. The HPA axis controls a hormonal cascade of corticotropin releasing factor, triggering adrenocorticotropic hormone and the release of the stress hormone, cortisol, into the blood stream (2, 2:137). Previous studies have shown that significant decreases in blood-cortisol levels in response to an environmental stressor is a quantitative metric by which to measure the altered HPA-axis reactivity strongly tied to PTSD (4). Additionally, it is thought that the HPA axis plays a key role in the developmental programming of offspring stress response. Studies demonstrating the HPA axis’ vulnerability to environmental agitators, further suggest that developmental modifications to this region’s neurocircuitry may influence and individual’s predisposition for PTSD (4;1).
Past research has found that the physiological repercussions of parental trauma may be passed down to future generation (1:1,2,3,4,5,6,7). Notable studies have suggested that parental smoking, alcoholism, obesity, exposure to environmental toxin, and food deprivation are capable of causing significant biological effects in offspring (1:183,184,185,186,187). Following the Holocaust, perhaps the most widespread and severe trauma in recent generations, a flurry of studies began studying behavioral, genetic, and physiological changes in the offspring of Holocaust survivors. While many of these studies failed to detect significant changes or were terminated due to severe methodological lapses, a few captured striking changes in the offspring (1:11,12,13). Some went as far as to say that the behavioral differences in the children made it seem as though the children themselves had experienced Holocaust-like conditions (1:8). Among these changes, researchers noted a higher incidence of mood and anxiety disorders such as PTSD, significant decreases in blood-cortisol levels, and altered reactivity of the HPA-axis compared to controls (1:60,61,62,63,66,26). (1:66) noted that the offspring of Holocaust survivors were more likely to develop PTSD within their lifetime, if their parents had also been diagnosed with PTSD. This finding was corroborated by others suggesting that genetic modifications in response to parental stressors corresponded to significant physiological changes in the offspring (1:8,11,12,13).
While environmental stressor such as toxins have been shown to lead to heritable genetic modifications in the offspring, these changes are relatively uncommon and are unlikely to be entirely responsible for the heritability of complex diseases such as PTSD (?). Epigenetic modifications are often induced by environmental stressors and involve altering the packing of chromatin to control gene expression without actually changing the DNA sequence itself (1;1:102,104,103). DNA methylation and histone acetylation are among the best described epigenetic modifications in the mammalian genome (1:105,106). In the chromosome, lengths of DNA are wrapped around a nucleosome, made of a collection of histone proteins. Each histone has a positively charged lysine tail that interacts with the DNA’s negatively charged phosphate backbone to tightly bind the conduit of genetic information. However, the charge of these lysine tails can be neutralized with the addition of an acetyl group. By neutralizing the positive charge of lysine tails, acetylated histones bind less closely to the DNA, leading to more loosely packed chromatin and increased gene expression. However, unacetylated histones bind more closely to DNA, leading to more tightly packaged chromatin and decreased gene expression. Histone Acetyl-transferases (HATs) and Histone Deacetylases (HDACs) are responsible for the addition or removal of acetyl groups, respectively. Other histone modification, such as histone methylation have also been shown to regulate gene expression, however the direct relationship between these molecular alterations and gene expression are less well understood (lecture notes).
The methylation of Cysteine-Guanine sites (CpG sites) constitutes a second mechanism modulating gene expression. DNA methylation is a covalent modification to the Cysteine residue which inhibits gene expression by directly interfering with the binding of transcription factors and recruiting HATs to hypermethylated regions or HDACs to unmethylated regions (5;5:Levenson and Sweatt 2005, Fuks et al 2003, Fujita et al 2003). DNA methyltransferases (DNMTs) are responsible for transferring methyl groups from a methyl donor, usually SAM, to the DNA. Previous investigations have identified an array of DNMTs responsible for maintaining methylation patterns at various stages of development. It has been suggested that DNMT1 is responsible for maintaining methylation states during cellular replication, while DNMT3a and DNMT3b are responsible for the establishment of new methylation patterns (de novo methylation) during embryogenesis and gametogenesis (7;7:2)
What is miRNA, a form of epigenetic modification
Differences
While the same epigenetic mechanisms are at play in both males and females, sex-specific differences have been identified throughout the epigenome and have been shown to contribute to sex-specific epigenetic inheritance patterns (9). In a rat model of trauma, maternal trauma was linked to lower circadian rhythm cortisol levels, decreased glucocorticoid sensitivity, and stable urinary cortisol levels in the offspring. Although, none of these results were consistent in the offspring from an identical paternal model of trauma, which suggests that there may be sex-specific epigenetic responses associated with stress disorders such as PTSD (1). Notably, there appears to be a critical window, outside of which the epigenetic effects of maternal trauma will not be transmitted to successive generations. This critical window appears to extend from birth until puberty when oocyte methylation patterns are established and maternal germ cell’s vulnerability to environmental stressors subsides (1:165; 1). Furthermore, previous studies investigating sex-specific methods of epigenetic have run into methodological road blocks. There is an abundance of research investigating the impact that an altered neonatal environment has on the offspring (4), however it is nearly impossible to eliminate the effects of the intrauterine environment, maternal care, or lactation have on maternal epigenetic inheritance (4:champagne 2008). For this reason, researchers cannot exclude extraneous maternal-fetal interactions or confidently tie epigenetic modifications in maternal germ cells to physiological changes in the offspring.
Methods of paternal epigenetic inheritance appear to be simpler, but are much less understood (4). Besides the absence of confounding intrauterine effects, past research in rats suggests that, for males, environmental stress at any post-natal period may induce epigenetic modification in paternal germ cells (3:9,11,13,45,51). This is likely because, unlike oogenesis in females, spermatogenesis remains active throughout a male’s life (1:174). Specifically, (4) clearly demonstrates that there is no male critical window by showing that environmental trauma to pre- and post-pubescent male mice led to the same changes in the stress response of subsequent offspring. Male rodents represent an ideal model in which to investigate intergenerational epigenetic transmission because males do not participate in offspring-rearing, eliminating the potential for confounding variables related to individual variations in paternal care (4:Rando et al 2012). Additionally, studying rodents eliminates the cumbersome task of identifying a homogeneous population of traumatized parents and allows for the avoidance of more complicated human aspects such as family dynamics, social psychology, and various theories implicated with the learning process (1).
Past findings describing both genetic and environmental contributions to the development of PTSD suggests the disease is a valid model in which to study the intergenerational transmission of epigenetic consequences related to parental adversity (3:5,6). Previous work on the subject suggests that, following paternal trauma, epigenetic modifications to paternal germ cells are capable of transmitting physiological stress-response adaptations to both male and female offspring (3:8,9,10,11,12,13;4). It is thought that adaptations, such as decreased baseline cortisol levels, confer evolutionary fitness to offspring by re-programming them in preparation for an especially brutal environment, as communicated by the epigenetic changes in the paternal germline (4). Given the sensitivity of the HPA axis to environmental stressors and its potential to reprogram stress response functions, it is suspected that epigenetic changes induced by parental trauma may influence the developing HPA axis or early hypothalamus (3;1) This is supported by other studies finding that parental exposure to alcohol, lead, chronic stress, or social defeat also invokes significant changes to HPA’s neurocircuitry (4: coe et al 2003, weaver et al 2004, virgolini et al 2006, hellemans et al 2008, Kapoor and Matthews 2008, mueller and bale 2008, dietz et al 2011, harris and speckl 2011, morgan and bale 2011). It has been hypothesized that such modifications to the developing HPA axis could confer a predisposition to stress-related disorders such as PTSD. This is because altered HPA axis function would likely reprogram offspring stress reactivity and altering an individual’s reactivity may inhibit their ability to appropriately respond to environmental stressors (3;4).
It is increasingly evident that epigenetic modifications play key roles in developmental processes, such as the establishment of baseline stress reactivity in the HPA axis. However, few epigenetic mechanisms related to development have bee identified (lecture notes; 5). This is likely because, while research has demonstrated epigenetic changes are synonymous with development, it is difficult to robustly connect this phenomenon with direct molecular changes (5). Two of the best described epigenetic mechanisms in development are X-inactivation and genomic imprinting. In mammals, females inherit two X chromosomes and one of these will be genetically deactivated to form a barr body. Previous studies suggest that the addition of methylation markers to histones, such as H3K4 play a key role in the deactivation process (5:Navarro 2006, sun et al 2006). However, there are likely a multitude of epigenetic mechanisms responsible for the genetic suppression of barr bodies throughout an organism’s lifetime (5). Similar mechanisms have also been associated with genomic imprinting, a phenomenon where the epigenetic silencing of a particular parent’s allele confers monoallelic inheritance, as seen in Prader Willis or Angelman syndromes (5,6). Over a hundred imprinted loci have been identified and it is widely thought that DNA methylation is responsible for this unique inheritance pattern (5).
Although it is still largely not understood, cellular differentiation is thought to be predominantly under epigenetic control (5)