Laura Schinzel and Rosa Garcia-Hernandez ’18


Every 98 seconds, an American is sexually assaulted. 90% of the adult rape victims are female. Nearly all of them experience symptoms of post-traumatic stress disorder (PTSD) and severe distress in the weeks after the rape1. For many this suffering is connected to suicidal or depressive thoughts and can last for months or years, this is shown by 33% of women who are raped that think about commiting suicide. While we need social and political prevention of sexual assault, scientific research also has to consider that there is a high number of women suffering from PTSD after sexual assault. This is especially important since, so far, PTSD has mostly been associated with military and war trauma; hence, mainly with men. Yet, women are twice as likely as men to meet the criteria for PTSD. One of the reasons for that is that sexual assault is one of the traumatic experiences with the highest risk of developing into PTSD. Another one could be that our bodies work slightly different depending on our biological sex, whether we are male or female. Although there are some disorders that are more prevalent in females than in males, such as PTSD and Alzheimer’s Diseases, there is more research done on males2. This imbalance of studies may lead to a male-oriented approach in treatment. Therefore, it is important to look at the differences in males’ and females’ reaction to stress and any differences in how they process memories in order to be able provide effective treatment for both males and females.

PTSD is a neurological disorder that can develop after a shocking, scary, or dangerous event which alters how we react in stressful situations and how we make memories. The fear and stress that a person feels during the event triggers fast changes in the body, called “fight-or-flight“ response, as a defense mechanism against harm. People who have PTSD remain on the verge of this fight or flight state and feel stressed or frightened in safe situations3.

A stressful event like this can affect our DNA, the storage space for our genetic material that makes us unique and functioning. You can imagine the DNA like a weird newspaper containing many different scrambled letters that sometimes form words. These words would be our genes. If a gene is read it is “transformed“ into a protein which is involved in maintaining different body functions. Research in neuroepigenetics looks at how the environment can change the way our genes are read in the brain.

Stress is one of these environmental factors which can cause gene alterations in the brain, and thereby modify the way our memories are stored or the way we react to dangerous situations. If you think back of the newspaper metaphor, this means that stress can change the way we read the words in the newspaper. Like an exclamation mark added to the end of a word, changing the way we read it.

One important mechanism through which stress influences our genetics is DNA methylation. This type of modification causes DNA to tightly wrap around proteins and thereby blocks gene expression. In other words some genes of the DNA are “turned off” which prevents them from being read and carry out their normal function. To picture this process you can think of this modification as the crumbling of our newspaper in a way that makes it harder to read. Some of the words are not visible, because the newspaper is crumpled and sticks together, in the same way that DNA is hard to read while methylated because it is wrapped around proteins.

The experience of a traumatic event, can change DNA methylation patterns in different regions of the brain, specifically regions that affect memory formation. However, stress induces methylation patterns that differ between the two sexes, as in males and females crumple their newspapers differently so that different words are unreadable. Therefore, we will look into the effects of traumatic experiences on stress and memory, and how they differ between the sexes.

STRESS RESPONSES

In PTSD a person’s stress response is altered and these changes differ between the sexes4. When PTSD is developed from a traumatic experience one of the primary symptoms is hyperarousal, or jumpiness. In this state, triggers which prompt the person to think about their trauma, can kick the body into high alert. So the body is suddenly in a state of high arousal and increased stress, independent of real danger being present or not. As a person with PTSD is continuously confronted with triggers and the body’s high stress reaction, they often face lasting stress after a traumatic event.

In order to better understand this mechanism, think about how stressed you might feel when you have a difficult exam coming up. You might experience some sort of panic, have trouble sleeping, become anxious, and small daily life problems suddenly challenge you more than usually. Thoughts about the exam become prominent in your life, but luckily, you know that this stress will end as soon as that exam has passed.

In order to react to dangerous situations and guarantee survival our body activates the so called HPA axis. This axis describes how the different body parts in the brain or body communicate with each other in order to react to the environment and keep the body stable and functioning.

This communication functions through hormones, little chemical messengers, which bind to receptors in different locations. You can think of the hormone as a mail package that has to be delivered to a specific address, because that is what is written. But that also, due to its shape it only fits into a specific type of mailbox, which would be the receptor.

When we are stressed, neurons – cells of the brain, are told to secrete stress hormones, which are called CRF. These messengers reach other body parts and make them release other types of stress hormones, such as cortisol, which is one of the most important stress signalers. Cortisol docks on to cells and binds to glucocorticoid receptors which start a stress response, leading to a faster heart beat or more sweating. At the same time, cortisol communicates back to the brain and other body parts and “tells” them to stop releasing more stress hormone, which in turn ends the stress response.

If you think about the mail metaphor, the whole system can be compared to junk mail or advertisements. At first the advertisements the company sends you are useful. Eventually, there are too many advertisements which clutter your mailbox. So, you have to tell the company to stop sending you mail advertisements. It is important to have a stress response that not only reacts effectively to dangerous situations but that also stops as soon as the danger is over.

It has been shown that chronic stress changes DNA methylation patterns in rodents. So, stress crumples and un-crumples parts of our newspaper. That is to say for some genes, DNA methylation is increased and for others decreased. A study showed that these changes are sex-specific and vary in different parts of the brain based on sex5. One of these changes, causes there to be less DNA methylation for the gene of the initial stress hormone, CRF. This means that it is easier to read, which makes it easier to make, so that it is there in a larger amount. In other words, increased CRF is similar with more advertising companies that keeps releasing cortisol or that keep sending you advertisements. The body has a harder time regulating stress response because there is too much cortisol, which would be similar to you getting too many advertisements.

Furthermore, it seems like stress increases DNA methylation of the gene for glucocorticoid receptors, which are stress hormone receptors (or mailboxes) that interact with cortisol (or advertisements). This means that the gene is harder to read; hence, the receptor is harder to make and so there is smaller amount of it. Leading to too much of the stress hormone cortisol freely floating in the body, because it cannot bind to its receptors6. There are not enough mailboxes for the advertisements that have been sent, which leads to an overflow of advertisements not in mailboxes. That’s interesting, stress causes epigenetic changes that lead to more stress hormone and less stress hormone receptors, or more advertisements AND less mailboxes for them.

DNA methylation happens with the help of a protein called DNMTs. DNMT is the one who crumples DNA and makes it hard to read. A study shows that the number of DNMTs in the body can increase in response to a traumatic event, which means that there would be increased DNA methylation or more things to crumple the newspaper7. This study also showed that female rats have significantly more DNMTs in parts of their brains important for arousal and stress. This means that female rodents might be more likely to turn off genes through DNA methylation which are important for stress resilience. An example for this are the glucocorticoid (stress hormone) receptors which we’ve encountered before. These changes lead to female rats having genes important for stress resilience turned off through methylation after a traumatic event.

The sex-specific effects on these stress hormones and receptors show how a dangerous, stressful event can change how our bodies react to stress. Also, it shows that female and male bodies’ epigenetics are differently affected. We have a lot of information about how stress specifically affects males, but not necessarily that much knowledge of how it affects females.

STORING MEMORIES

Knowing how these traumatic memories are created and stored in the brain could help us further understand how PTSD is developed and how its symptoms can be reduced in patients. One symptom that is very commonly experienced by those with PTSD is having intrusive memories of an event8: think fireworks reminding veterans of a battlefield. This is something that may be due to generalization, which happens when two different things sound or look similar enough to be interpreted as the same thing.

Generalization, in the context of PTSD, could explain why people with this disorder have a hard time using their current surroundings to manage their fear response. With the example of fireworks causing distress in veterans, generalization would manifest in the way that they are unable to distinguish the fireworks to the sound of gunshots, which they experienced in the battlefield. It is interesting to note that females and males have different responses to generalization. In a study that used context fear conditioning, in which rodents make an associative memory between a context (or a place) and a bad experience, which in this is getting a mild foot shock. Females, were shown to actually generalize more, so they showed a fear response to a place that looked similar to the one that they got shocked in, while males did not show a fear response9.

This difference between the two sexes was further explored in this study in how these memories were formed in the brain. They found that 2hile males used their hippocampus, which is a region of the brain associated with memories about a place, females used their amygdala, which is more heavily associated with memories about fear9. These differences are significant and are important to understand and take into account when talking about PTSD in females and males.

Another difference in the way that males and females form memories, is by their ability to go through fear extinction. Fear extinction is a way of dissociating (but not forgetting) that a certain cue (such as location, sound, or smell) corresponds to an experience. Let’s go back to the fireworks, so, veterans experiencing PTSD might have a hard time controlling their emotional response to fireworks as they remind them to gunshots or other various war time noises. Normally, people would stop reacting to the fireworks after multiple times of nothing bad happening. In veterans, this should technically mean that after hearing fireworks so many times, and not experiencing the same traumatic event that they experienced during war when hearing the gunshots, that they should no longer react or be scared of the fireworks.

In rodents, fear extinction means that after multiple times of being safe in a place where they were once shocked they should no longer be afraid of that place. However, a study showed that females are resistant to fear extinction, so they are still afraid of that place even after been shown multiple times that it is now safe10. After 10 days of being exposed to this location without the shock, females still show a fear response,while males do not. This difference was also further explored in the differences of the ways that males and females naturally encode fear extinction.

Before going into that difference, let us explain a little about BDNF (aka brain derived neurotrophic factor). BDNF is a protein that is important for learning and memory, and that is also known to be regulated by stress or trauma. More specifically, it is an important protein for context fear conditioning, which is the association between a context or a place and a bad experience that we have been talking about. Mice that cannot make normal amounts of BDNF cannot make that association well (Liu, Lyons, Mamounas, & Thompson, 2004).

This is important because that study on fear extinction also found that there is less BDNF in females when compared to males because there is greater DNA methylation in one of the BDNF genes10. This means that the gene is harder to read and therefore harder to make, which decreases the total amount of this protein in females. Going back to the newspaper, this means that the newspaper is crumpled more in females than in males. Therefore, females have less BDNF and because of this are less likely to learn to dissociate the place from the bad experience of being shocked. These differences, along with the information about generalization, are important to take into account because they specifically affect females, which we said have a higher incidence of PTSD. They are also significant because of how they relate to symptoms of PTSD, such as the prevalence of intrusive memories.

IMPLICATIONS FOR TREATMENT AND FURTHER STUDY

The big questions is, why is this important? Why do these differences between males and females matter? Well, let’s look at it this way. There are a lot of differences between male and female physiology that are currently unknown, of those that we do know with stress and memory, we see significant difference that could affect the way that treatment might help patients combat PTSD. Stress, as we discussed throughout the paper, elicits a response that affects epigenetics and this response is different based on whether you are male or female. Not just that, without adding stress to the equation, males and females start off with different levels of proteins, such as BDNF, which may be important for how they form memories. The fact that these differences may be further affected by stress during a traumatic event, has serious implications about the way that treatment is provided effectively.

Since there are important differences, shouldn’t we be treating patients with PTSD based on what they may need? If we focused our research more broadly on finding these sex-specific differences in stress and memory, we might be able to better combat the prevalence

of PTSD in females. Specifically, looking at the se sex differences could help us look more closely at the development of PTSD caused by sexual abuse, which really affects females, and start to provide a pathway for more sex-specific treatments to effectively treat this disorder in females.

References

  1. RAINN (n.d.). Victims of Sexual Violence: Statistics. Retrieved from https://www.rainn.org/statistics/victims-sexual-violence.
  2. Beery A.K. & Zucker I. (2011). Sex bias in neuroscience and biomedical research. Neuroscience & Biobehavioral reviews, 35(3): 565-572.
  3. NIMH (2016). Post-Traumatic Stress Disorder. Retrieved from https://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorder-ptsd/index.shtml
  4. Kloet, C. D., Vermetten, E., Geuze, E., Kavelaars, A., Heijnen, C., & Westenberg, H. (2006). Assessment of HPA-axis function in posttraumatic stress disorder: Pharmacological and non-pharmacological challenge tests, a review. Journal of Psychiatric Research, 40(6), 550-567. doi:10.1016/j.jpsychires.2005.08.002
  5. Sterrenburg L., Gaszner B., Boerrigter J., Santbergen L., Bramini M., Elliott E., Chen A., Peeters B.W.M.M., Roubus E.W., & Kozicz T. (2011). Chronic Stress Induces Sex-Specific Alterations in Methylation and Expression of Corticotropin-Releasing Factor Gene in the Rat. PLos ONE, 6(11):1-14.
  6. Mcgowan P.O., Sasaki A., D’Alessio A.C, Dymov S., Labonté P., Szyf M., Turecki G., and Meaney M.J. (2009). Epigenetic Regulation of the Glucocorticoid Receptor in Human Brain Associates with Childhood Abuse. Nature Neuroscience, 12(3): 342-48.
  7. Hodes, G. E., Pfau, M. L., Purushothaman, I., Ahn, H. F., Golden, S. A., Christoffel, D. J., . . . Russo, S. J. (2015, 12). Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress. Journal of Neuroscience, 35(50), 16362-16376. doi:10.1523/jneurosci.1392-15.2015
  8. National Center for PTSD (2012). Symptoms of PTSD. U.S. Department of Veterans Affairs. Retrieved from https://www.ptsd.va.gov/public/PTSD-overview/basics/symptoms_of_ptsd.asp.
  9. Keiser A.A., Turnbull L.M., Darian M.A., Feldman D.E., Song I., & Tronson N.C. (2017). Sex Differences in Context Fear Generalization and Recruitment of Hippocampus and Amygdala during Retrieval. Neuropsychopharmacology, 24: 397-407.
  10. Baker-Andresen D., Flavell C.R., Li X., & Bredy T.W. (2013). Activation of BDNF signaling prevents the return of fear in female mice. Learning and Memory, 20: 237:240.
  11. Sillivan, S. E., Vaissière, T., & Miller, C. A. (2015, 01). Neuroepigenetic regulation of pathogenic memories. Neuroepigenetics, 1, 28-33. doi:10.1016/j.nepig.2014.10.003

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