Post-traumatic stress disorder (PTSD) can develop after a traumatic event, with its impacts originating at the subcellular level (Girgenti, et al., 2017; Yehuda and Seckl, 2011). The pathophysiology of PTSD at this scale is characterized by a disruption of glucocorticoid (GC) hormone signaling which has implications on other cellular processes related to stress regulation.
Cortisol, the “stress hormone,” is the most notable GC in the pathophysiology of PTSD (Girgenti, et al., 2017). It is involved in consolidating and retrieving fearful memories and works to promote the body’s stress response (Binder, 2009). However, cortisol is also important in terminating this response via a negative feedback loop (Figure 1). PTSD has been observed to cause either hypercortisolism or (more commonly) hypocortisolism—a deficit of cortisol. This, however, is not due to dysfunction of the adrenal or pituitary glands, but involves this negative feedback loop (Yehuda and Seckl, 2011).
Hypocortisolism in those with PTSD is closely related to glucocorticoid receptors (GRs) (Girgenti, et al., 2017). GRs are transcription factors that move from the cytoplasm into the nucleus after GC binding and mediate the effect of cortisol (Binder, 2009). PTSD often causes supersensitivity to GRs which combines with the deficiency of cortisol to impair the negative feedback loop.
This negative feedback loop regulates the hypothalamic-pituitary-adrenal axis, which coordinates the body’s hormonal response to stress (Mendonça, Mangiavacchi and Rios, 2021). This stress response is fundamental for maintaining homeostasis (via the feedback loop), and similarly, the proper functioning of this negative feedback loop is vital for normal stress responses (Binder, 2009). As the subcellular effects of PTSD disrupt this feedback, it disrupts the body’s ability to carry out its natural stress response in a healthy manner.
The translocation and the action of glucocorticoid receptors on gene transcription is controlled by a molecular complex, the most significant part being the co-chaperone proteins which collaborate to transport molecules (Binder, 2009). The most notable of these is FK506-binding protein 5 (FKBP5), which binds to a GR and inhibits its translocation into the nucleus, and only detaches to allow this movement after cortisol binds to the GR (Girgenti, et al., 2017; Kang, et al., 2019). The transcription of FKBP5 (the gene that codes for FKBP5) is induced by the binding of the GR-GC complex to its promoter region (also known as a GRE) as part of the negative feedback loop (Figure 1) (Binder, 2009; Girgenti, et al., 2017).
Figure 1: A diagram showing the normal feedback loop (left) and the impacted feedback loop associated with PTSD (right). The normal feedback loop shows an adequate amount of cortisol, such that when less FKBP5 is present, and the GR-GC binding tendency increases, there is enough cortisol to allow for the binding and subsequent translocation to bind to a GRE and activate transcription of FKBP5. In the impaired feedback loop, there is not enough cortisol to allow for the translocation of GR and therefore the FKBP5 deficiency will not be countered, and the stress response will become disrupted (Girgenti, et al., 2017).
FKBP5 expression has been found to be reduced in patients with PTSD, which is consistent with the noted higher GR sensitivity, as increased expression of the gene has been found to decrease GR sensitivity (Binder, 2009). Less FKBP5 present increases the tendency of GRs to bind to GCs; however, cortisol production is suppressed, so there is not enough cortisol present for all available GRs, which interrupts the feedback loop (Mendonça, Mangiavacchi and Rios, 2021). In addition, there will be fewer GR-GC complexes translocating into the nucleus to prompt FKBP5 transcription, exacerbating the deficiency of FKBP5, further disrupting the feedback.
It is certainly disconcerting to think that such significant impacts to one’s life and psyche can be enforced by something so small and intangible as these molecules and processes. However, understanding the root of such disorders allows for the development of potential treatments and prevention mechanisms so that the impact is less devastating.
References
Binder, E.B., 2009. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology, [e-journal] 34, pp.S186–S195. https://doi.org/10.1016/j.psyneuen.2009.05.021.
Girgenti, M.J., Hare, B.D., Ghosal, S. and Duman, R.S., 2017. Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD. Current Psychiatry Reports, [e-journal] 19(11), p.85. https://doi.org/10.1007/s11920-017-0841-3.
Kang, J.I., Kim, T.Y., Choi, J.H., So, H.S. and Kim, S.J., 2019. Allele-specific DNA methylation level of FKBP5 is associated with post-traumatic stress disorder. Psychoneuroendocrinology, [e-journal] 103, pp.1–7. https://doi.org/10.1016/j.psyneuen.2018.12.226.
Mendonça, M.S., Mangiavacchi, P.M. and Rios, Álvaro.F.L., 2021. Regulatory functions of FKBP5 intronic regions associated with psychiatric disorders. Journal of Psychiatric Research, [e-journal] 143, pp.1–8. https://doi.org/10.1016/j.jpsychires.2021.08.014.
Yehuda, R. and Seckl, J., 2011. Minireview: Stress-Related Psychiatric Disorders with Low Cortisol Levels: A Metabolic Hypothesis. Endocrinology, [e-journal] 152(12), pp.4496–4503. https://doi.org/10.1210/en.2011-1218.
Comments
21 Responses to “Homeostatic Impacts of PTSD at the Cellular Level”
Hey iSci!
My topic was inspired by learning about cellular processes in LifeSci iConS, applications of certain molecules in Chemistry iConS, and my own particular interest in neuroscience. This all led me to look at the pathophysiology and neuroendocrinology of PTSD and as I did my research I was able to focus in on this particular negative feedback loop.
I hope you enjoy reading my post as much as I enjoyed writing it!
Best,
Riley
Hi Riley,
Great blog post! The piece is well-researched and provides a comprehensive overview of the subcellular mechanisms underlying PTSD. You were able to explain complex physiological processes in an understandable manner. However, there are some areas where the writing can be improved:
– Consider rewording your first sentence to,”Post-traumatic stress disorder (PTSD) develops after traumatic events, with its impacts originating at the subcellular level.” In this way you are being more concise and directly get to the point.
-It would be great if you could add a sentence explaining what exactly hypocortisolism means, even if it seems obvious, it could still benefit readers. For example you could say, “Hypocortisolism refers to a condition where there is a lower-than-normal level of cortisol in the blood.”
– The concluding paragraph is insightful but might benefit from a more hopeful or forward-looking tone. Emphasizing the positive potential for understanding and treatment could offer a more uplifting end.
Looking forward to reading your final edits,
Alyssia
Hi Alyssia!
Thanks for the suggestions, I’ve incorporated them into my post!
Best,
Riley
Hello Riley!
This was a great post to read, and kept me engaged throughout!
I just have a few suggestions you may wish to consider:
– The second sentence in your second paragraph reads a bit awkwardly. I would suggest simply removing the “of” in the middle of the sentence to help with the flow.
– This is just a suggestion if you need to lower your word count, but, you say “negative feedback loop” quite frequently. It may be worth introducing an acronym here, and changing it to NFL, after introducing it the first time.
– I would be careful with your opening sentence in your conclusion. I understand that the biological process of PTSD is mediated by these processes, but, I perhaps wouldn’t say that PTSD is caused by these molecules and processes, as it is triggered by enduring a traumatic event. So the statement isn’t necessarily false, but it might be worth rewording.
– I would suggest making the “References” a header to differentiate it from the above text.
Overall, I really enjoyed reading this post and look forward to the final piece!
Cheers,
Jodi
Hi Jodi,
Thanks for the feedback!
I’ve adjusted my post according to your suggestions, however, I’ve chosen not to abbreviate “negative feedback loop” because I’m able to fit it into the word count and I find that too many acronyms can make posts difficult to process.
Best,
Riley
Hello Riley,
Excellent blog post! You did a great job at explaining the cellular mechanisms of PTSD in both a clear and concise way. While I do have feedback for you, most of what I have to say are minor nitpicks. Though I hope they can make your blog post even better.
1. The last sentence of your introduction feels a bit wordy at the end. I would replace “that have to do with” with something like “related to,” so that it flows smoother.
2. In your second paragraph you mention that PTSD does not occur due to a disfunction of the adrenal or pituitary glands. However, you never explain the relation these glands have to cortisol prior to their mention. While it’s implied that these glands release GCs, this may be confusing to those who don’t know that.
3. In your third paragraph the last sentence is a bit long and parts of it feel repetitive. Consider breaking it down into two sentences.
Overall this was a fantastically written blog post! Keep up the good work.
Cheers,
Naira
Hi Naira,
Thanks for your comment!
I’ve included your suggestions.
I chose not to discuss the pituitary and adrenal glands as I do consider this common knowledge for the audience (it is part of Ontario’s SNC2D and SBI4U curricula!) and the endocrine system at a larger scale is not the focus of my post, this was just a way to introduce my next paragraph.
Best,
Riley
Hi Riley,
This was a very interesting blog post! I just have a few suggestions:
– Remember to include a comma before “et al” in your internal citations according to the ARU Harvard guide.
– In the first paragraph, second sentence, I would recommend reorganizing it to remove the possessive on PTSD, as it is an inanimate object/idea. Same thing with the first sentence in the fifth paragraph.
– In the fifth paragraph, do you need to introduce the idea of GREs if you don’t refer to them again? By removing that part, it may improve the flow of the sentence for the reader.
– I find the use of “perhaps” in your second and last paragraph a bit informal and would recommend removing them.
Overall, this was extremely well-written! Happy editing!
Vikram
Hi Vikram,
Thanks for the suggestions, I’ve made an effort to incorporate all of them!
I chose to mention GREs as they are indicated in my figure. To make it clearer, I’ve rephrased that point and noted them in my figure caption.
Best,
Riley
Hi Riley,
Great work on this blog post! It is well researched, informative, and interesting to read.
I have a few suggestions that I hope will be helpful in your editing process:
– In your first paragraph, consider finding a synonym for disorder in your explanation of PTSD (obviously keep in the definition), as you say it twice in quick succession.
– Consider giving a quick couple words on what cortisol is to help readers who may not know, (ie, Cortisol, a steroid hormone, …”)
– I might also rephrase the second sentence of paragraph 2: “It is involved in consolidating and retrieving of fearful memories, and in general, GCs promote the body’s stress response” as it has a bit of an odd flow. I suggest ” It is involved in consolidating and retrieving fearful memories, and, along with many other GC’s, plays an important role in promoting the body’s stress response.”
– I would move your figure to after your explanation of FKB5P, as you reference it in your figure caption but we do not know what it is yet.
– As someone else has said above, I would also suggest formatting your heading for references to make them distinguishable.
Overall, awesome job on this blog post and keep up the great work. Looking forward to reading your final draft!
– Zoe Iczkovitz
Hey Zoe,
Thanks for the feedback, I’ve adjusted my post accordingly!
Best,
Riley
Hi Riley,
Great blog post! I found the study of PTSD at the molecular level really interesting. Here some things I found helpful, and some suggestions:
– I recommend switching the order of information in the beginning of your second paragraph to improve flow. Here’s an alternative that might give you an idea: Out of the many GCs involved in the pathophysiology of PTSD, cortisol is well-known due to its involvement in consolidating and retrieving fearful memories (Girgenti et al., 2017). They also are vital in terminating these memories via a negative feedback loop.
– There was a brief mention about how the GCs promote the body’s stress response in your second paragraph. I would suggest either elaborating on this (if you have the space) or removing it if you can.
– The last sentence of your third paragraph can be split into two for better flow. The period could be added after “normal stress responses.”
– I found that your in-depth picture really helped in understanding both Figure 1, and the explanation behind the negative feedback loop.
Overall, the post was both informative and interesting. Looking forward to the final copy.
Happy editing,
Chichi
Hey Chichi!
Thanks for the suggestions! I’ve implemented all of them, however, I don’t have the word count to elaborate too much on GCs in general, but I discuss cortisol in depth and I think noting the idea of GCs is necessary to give context for my discussion of cortisol.
Best,
Riley
Hi Riley,
Very interesting post on the homeostatic impacts of PTSD at the cellular level. Here are some suggestions that will hopefully make your post even better:
1. In the fourth paragraph, second sentence, perhaps add “the” before nucleus, and I would suggest taking out ligand and just having GC if GC is specific as a ligand to GR
2. Second last paragraph second sentence, the comma before however should be replaced with a semicolon
3. In figure 1, FKBP5 is mentioned and also GR is also mentioned; these acronyms are not explained until later; perhaps expand on what they mean in the figure caption
4. For the last sentence of the figure caption, I would suggest rephrasing it to something along the lines of “In the impaired feedback loop, there is not enough cortisol to allow for the translocation of GR, which results in FKBP5 deficiency not being countered. This ultimately leads to the stress response becoming disrupted.”
Overall, this was a very well written blog post, and I look forward to reading your final draft!
Jonathan
Hi Jonathan,
Thank you for the suggestions, I’ve adjusted accordingly.
Best,
Riley
Hi Riley,
This was a super cool post that explained a lot of the science behind these kinds of disorders, and I found it super interesting to read.
Just a few suggestions:
– In your second paragraph, you mention that the stress response is terminated through a negative feedback loop twice (in your third sentence and last sentence). Consider turning these sentences into one statement so it’s not redundant.
– The last sentence of your third paragraph seems a bit wordy, so I would break it down into two sentences. For example: “The proper functioning of this negative feedback loop is vital for normal stress responses. As the subcellular effects of PTSD disrupt this feedback, it disrupts the body’s ability to carry out a natural response in a healthy manner”.
– Consider briefly explaining the definition of a “co-chaperone protein”.
– In your reference section, make sure you include the type of medium in your citations.
Overall, this was an extremely well-written post. I’m excited to see your final draft!
Jenny
Hi Jenny,
Thank you for the feedback!
I’ve implemented all of your suggestions, but I’ve chosen to leave my second paragraphs as they are. I don’t find that they are redundant as one elaborates on the other, and the sentence in between is necessary to give context for my explanation of the term that I had previously introduced.
Best,
Riley
Hi Riley!
This post is so creative, I love the topic so much! Only two suggestions from me!
– I think it may be worth it to define a couple more terms and the roles they have in the human body. For example glucocorticoid, and the role it plays in the human body. Another example is cortisol, and defining how it is a stress hormone.
– It would be clearer that your references have begun if the title was a little larger.
Other than that this was fantastically written, amazing job!
Hey Julie!
Thanks for the suggestions, I’ve incorporated both of them!
Best,
Riley
Hi Riley,
This was a very informative and engaging read! I learned a lot about the cellular and molecular mechanisms of PTSD despite not having much prior knowledge. You did a great job presenting complex information in a concise yet understandable way. I only have a couple of minor suggestions that could potentially improve the flow of the blog:
1. I think it is possible to merge the second and third paragraphs without losing details to make it more concise. While there is a clear transition in content, it reads a bit jumbled. You could potentially say,
“Cortisol, the “stress hormone,” is the most notable GC in the pathophysiology of PTSD (Girgenti, et al., 2017). Aside from producing stress responses, cortisol is also involved in consolidating and retrieving fearful memories and terminating them via a negative feedback loop (Figure 1) (Binder, 2009). It regulates the hypothalamic-pituitary-adrenal axis, which maintains homeostasis by coordinating the body’s hormonal response to stress (Mendonça, Mangiavacchi and Rios, 2021). The subcellular effects of PTSD disrupt this feedback commonly via hypocortisolism—a deficit of cortisol in cells. Subsequently, the body’s ability to carry out its natural stress response in a healthy manner is hampered (Yehuda and Seckl, 2011).”
2. If I am not wrong, GR is mentioned first before the figure but the full form is introduced after. To keep in line with convention, consider stating the full-time when GR is mentioned first.
3. If word count permits, consider editing the conclusion to state a small summary of the blog along with the provided future implications. It makes a stronger conclusion that will allow you to secure a higher score for the blog.
Overall, this is a very well-written blog that only requires minor optional changes for improvement. Looking forward to the final version!
Happy Editing,
Rai
Hi Raiyan,
Thanks for the suggestions.
I actually had some of my paragraphs out of order from my previous edits!
Unfortunately, I don’t have enough word count to expand my conclusion too much, however, I feel that in shorter writing such as this, summarizing in the conclusion sounds very repetitive and diminishes the quality.
Best,
Riley