TITLE: Post traumatic stress syndrome (PTSD) and epigenetics


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Posttraumatic stress disorder (PTSD) is a severe disorder that is related to exposure to trauma. It remarkably impairs the quality of life and hampers normal functioning of the human system. Epigenetic modifications for example the DNA methylation can be actuated by external environmental factors or gene expressions in a propagative manner that can be transmissible. Due to this, epigenetics can explain the differential variations of responses to trauma exposure. Epigenetic mechanisms have been seen to alter the risk of PTSD as they show both genetic and environmental factors. In this study, evidences for epigenetic variations in the animal models for PSTD has been described. Regulation of stress hormones has been used to show how epigenetics varies in the animal models (rodents) for PTSD. Studies for epigenome related studies which depict associations with PTSD have also been summarized.


















Table of Contents




Animals Models. 2

Simulation of PTSD.. 2

Gene expression profiling. 3

Sequencing of methylated DNA.. 3

Extraction of DNA and purification. 3

Preparation of Library. 3


Behavior and body development tests. 4

HPA responses. 4

Profiling of gene expression. 4

Methylation sequencing. 4

Differentially methylated genes versus gene expression profiles. 4














DNA methylation; Epigenetics; PTSD; Trauma


















HPA Axis – Hypothalamic–pituitary–adrenal axis

BAM – Bacteriological Analytical Manual

SAM – Systolicanteriormotion

DMR – differentiallymethylatedregion

PTSD -Post traumatic stress syndrome

NR3CI – Nuclear Receptor Subfamily 3 Group C Member 1

DNA – Deoxyribonucleic acid.












Genetic disorders are caused when there are changes in the DNA of a person. This change could be due to mutation in one’s DNA. Mutations can be caused by either errors in replication of the DNA or by changes on the external environment for example lifestyle habits like smoking, radiation or variations in the DNA sequence (Roth, et al., 2011). Epigenetics involves the study of changes in the expression of genes that does not necessarily involve changes in the sequence of the DNA, that is, changes in the phenotypical characteristics that does not affect genotypic structure (Zannas, Provençal & Binder 2015). It through the epigenetic processes, that the cell function and structure are determined. Epigenetic variations can also be caused by changes in the environment factors such as exposure to toxicans (Marsit, 2015). Research has shown that there are at least three processes that may initiate and propagate epigenetic variations in the human system. These processes are: histone modification, non-coding RNA- associated gene silencing and DNA methylation (Pitman et al., 2012). However, more research studies are continually discovering the contribution of epigenetics in the pathogenesis of human disorders and diseases. Post-traumatic stress disorder (PTSD) is a psychiatrist disorder that is stress-related, and is presumed to be caused by interactions between traumatic experiences and a number of genetic factors (Skelton et al., 2012). This disorder is mainly characterized by signs of intrusion, avoidance, and cases of vigorous arousal following a traumatic incident. Recently, there has been an association between epigenetic mechanisms and risk of PTSD. Proofs from a number of human studies support the role that epigenetics play in the pathogenesis of PTSD. Studies involving fear conditioned models also support the role of epigenetics in the occurrence of PTSD. Many studies that have been done in humans and animals show that an epigenetic adjustment of distinctive genes contributes to the pathogenesis of PTSD. Using blood samples, Uddin et al. (2010) evaluated the methylation patterns of PTSD patients and compared it with that of the patients without PTSD. The study established that subjects with PTSD had altered DNA methylation level. Additionally, there is substantial evidence on controlled epigenetics in lab animals subjected to fear-instilling situations (Kwapis & Wood, 2014). According to the study, new learning can be achieved by exposing an individual to the frightening stimulus, but with no aversive outcome. Therefore, if the individual no longer relates the reminder with danger, then the individual’s fear for the given stimulus will lessen. In the study, histone acetylation, DNA methylation, and histone methylation was implicated for the development of extinction learning. However, the later research focused more on histone acetylation than the other two factors. The research in focus therefore, will aim to establish the role of histone methlyation in promoting extinction learning. This research is based on the hypothesis that histone methylation diminish response to fear stimuli. Therefore, if this hypothesis will be true, then it will be concluded that fear-controlled stimuli enhances healing of PTSD. The knowledge obtained from this study will significantly contribute to the management of PTSD cases.


Animals Models

This research is going to use animal models (rodents) since it is very complex to use human models.

Twenty five male rats weighing between 222 and 278g and 11 female rats of Sprague-Dawley species weighing between 220 and 278 g will be used in this research. The rats are to be conditioned for a period of one week in a closed experimental room at a non-varying temperature of 21 degrees Celsius, for a 10-hour darkness period, availing water and food, throughout the duration. After the conditioning period, the males and the females will be allowed to copulate. Pregnancy will be ascertained through virginal plugs’ examination. After that, 20 pregnant candidates be isolated into two groups; control group and the PTSD group, with each group containing 12 rats (N=12). During parturition period, all the rats will be exposed to a stress of an equal level. On day 5 of observation, the difference between the two groups of candidates will be examined. Particularly, the body weight and gestation period will be evaluated. All the off springs will be taken care and given food together with their mothers until the 30th day after parturition. This experiment will be conducted as per the standards and guidelines of the relevant regulatory standards on the use of laboratory animals. Every measure will be put to control discomfort and pain, and minimize the number of rats that will be used in this study. Euthanasia will be applied through decollation.

Simulation of PTSD

Extended stress will be applied to pregnant rats to arouse PTSD. The extended stress method was invented by Israel Liberzon and its use revealed neuro-endocrinological discrepancies in PTSD patients (Yamamoto et al., 2009).

The lab animals in the PTSD step will be maintained for 2 hours, and later floated in water maintained at 225oC in a 45 by 65 cm tube. 5 rats will be made to swim at once, and this procedure will be conducted between day 7 and 13 following confirmed pregnancy of the rats. These pregnant rats will be observed to complete the whole study process successfully; without any participant rat dying or experiencing fatigue during the simulation process.

Gene expression profiling

Gene expression will be profiled through; RNA extraction and purification, followed by amplification and results. Eventually, the acquired results will be recorded.

Sequencing of methylated DNA

Methylated DNA sequencing will be done in a stringent condition using commercially manufactured ELISA-based kits described by Kurdyukov & Bullock (2016). The ELISA method will enable a quick assessment of DNA methylation status. The rapid ELISA method is preferred because it is quick and easy to conduct hence will be suitable for the identification of large alteration in global DNA methylation.

Extraction of DNA and purification

DNA extraction and purification will be done using Tissue Kit and DNeasy Blood as per the manufacturer’s manual, after which it will be measured by the use of a NanoDrop spectrophotometer. The entire samples will be validated for use in the subsequent procedure Chavez et al., 2010).

Preparation of Library

Genomic DNA Fragmentation will be done as per the instructions of the preparation guide. Augmentation of the DNA deposits will be attained by surfacing onto a Methylated DNA Precipitation kit.

Analysis of Data

The analysis of data will be conduction following the sequenced outlined below:

  1. Raw reads
  2. Reading preprocesses
  • Genome mapping
  1. BAM/SAM
  2. DMR detection
  3. Related gene hormones


Behavior and body development tests

The t-test results of the weights of the PTSD group offspring and the controlled group offspring will be recorded. It is expected that the weights of the PTSD group of offspring will be significantly lower than the weight of the control group offspring.

HPA responses

HPA reaction to stress by the offspring will be recorded. The level of reaction to stress by the offspring will be ascertained by the level of grooming attention received from their mothers. High levels of grooming or licking of the offspring by the mothers will imply high response to stress.

Profiling of gene expression

The PTSD group will be evaluated against the control group so as to ascertain the up regulated and down regulated genes. All the involved genes will be interpreted using the Gene Oncology database.

Methylation sequencing

The total genes will be screened, and then all the differentially expressed genes (mythlated loci distribution) will be done for all the chromosomes; sex chromosomes excluded.

Differentially methylated genes versus gene expression profiles

Out of the total genes profiled, the number of differentially expressed genes will be identified and recorded. Amongst the differently expressed genes, it is expected that hyper-methylation will be observed to have down regulated gene expression while hypo-methylation is likely to up regulate gene expression.


An association between the epigenetic expressions of the HPA with stress has been established by various studies (Videlock et al., 2009). Immune instability is an epigenetic field which has received increased attention in the modern days. PTSD has been associated with the destabilization of the peripheral immune functions owing to the long-term impacts of the HPA alignment (Uddin et al., 2013).

Recently, research has confirmed that the PTSD of a mother can confer negative traits to the offspring. Research findings have also established that epigenetic factors define the relations between maternal stress and the phonotypical characteristics of the postnatal phase. Maternal stress is the progenitor of a significant number of the offspring’s physical and hyper arousal indicators. Findings from the research in focus will show the potential that PTSD has on the physical and behavioral outcome of their offspring; and this will be evaluated by low body weight and low score in the OFT test. Mulligan et al. 2012) observed that maternal stress potentially alter the offspring’s epigenetic marks. The study also observed established a correlation between prenatal stress and the offspring’s body weight as the enhancers of methylation of the NR3C1 receptor.

Together with other stressors, maternal PTSD is capable of influencing the hormonal levels and behavioral outcome of the offspring (Uddin et al., 2010). Maternal PTSD promotes changes in the stress-response of the HPA alignment, influence neo-transmitters distribution, and contributes to the intrauterine growth retardation.

The study results will indicate the rodent’s expressedgenetic changes. Therefore, depending on the findings, severe stress could be caused by histone variations in the human system due to remarkable changes in histone modifications, more especially in the hippocampus. For example, elevated stress levels will be seen to lead to increased alterations in gene expressions. When adult rodents were exposed to chronic stress, epigenetic changes will be expected to be observed.

Inducing chronic stress in adult animals will be seen to lead to epigenetic modifications, involving key genes that are involved in the signaling of the HPA axis, such as Hsp 9097 and Chr.

The study indicates a strong correlation between stress and epigenetic variations. This study will not use human humans as models as this would be complex to carry out; considering the ethical and procedural measures required when dealing with humans. Studies that have been done are likely to agree with the findings of this study, evidencing that epigeneticchanges have a direct effect on the central nervous system. Relate studies have shown that repeated exposure to traumatic events has a strong correlation to the disease course of PTSD in adults.

The PTSD lifetime is estimated to be between 6% and 11% (Zannas, Provençal & Binder 2015). Stress and environmental factors increase the risk of developing PTSD, especially when a personexposed to experiences that is likely to trigger trauma. In the research in focus, epigenetic mechanisms is associated with risk of PTSD as the studies that have been conducted depict genetic and environmental influences as the main factors contributing to PTSD.


Results from this study are likely to show that the PTSD of a mother, during pregnancy; can the case of pregnancy can hamper or slow down physical characteristics and development of the CNS. The underline factor for this phenomenon can be linked to the gene expressions and alterations related to the neurotransmitters, which may occur due to the genome methylation deregulation. Additionally, circulatory system disorders in offspring could be owed to the PTSD of the mother affecting particular genes such as Epn3, F5, and Itgb6, andMyh2.

Based on the proposed study and the previous related studies, the differential responses to trauma exposure by different people may be explained as either the influence of acquired or inherited genetic alterations. Factors that can induce changes in the gene structure are also likely to trigger epigenetic changes, especially when induced by environmental factors such as trauma, or fear inducing experiences.

Differential responds to trauma experiences by different individuals can only be explained by the effect of epigenetic to PTSD. Epigenetic changes are also more likely to affect genes, either by altering them or permanently disorient them. However, more research would need to be conducted to establish how epigenetics is related to the pathogenesis of PTSD.  Researching in this field can also lead to discovery of the sub-types of PTSD.






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