Faith Nguyen

Background: Post-traumatic stress disorder (PTSD) is a pathogenic response to a traumatic event that affects approximately 6% of the world¹ with reports higher in the younger population, females, and first responders⁴. PTSD has varied manifestations and treatment; however, there is currently no pharmacological therapy used to solely treat PTSD. Development of PTSD is associated with Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation, resulting in loss of its negative feedback loop^1-4. Several candidate genes have been identified such as FKBP5, CRHR1, and NR3C1 as possible culprits to HPA axis hypoactivity. NR3C1 encodes for a glucocorticoid receptor, and epigenetic modifications such as methylation are associated with HPA axis feedback loss, resulting in PTSD development. These findings could provide a new solution to PTSD treatment.

Objective: In this narrative review, we explored the epigenetic mechanisms of NR3C1 and its relationship in development and severity of PTSD.

Search Methods: An online search of PubMed database from 2017-2023 using the following keywords: “PTSD”, “NR3C1”, “methylation”, and “hypothalamic-pituitary adrenal axis.”

Results: Studies determined that downregulation of NR3C1 translation resulted in PTSD like behaviors in both animal and human models⁵. Traumatic events, such as social defeat stress and predator odor exposure, were associated with modifications in NR3C1 expression⁶. Studies varied regarding introduction of stress variable with some experiments studying a single life cycle with exposure in early life and others with prenatal exposure^5-9. Two studies also identified possible sex-specific responses to trauma, resulting in varied NR3C1 methylation^7,9. In the mice model, they found that female rats had increased NR3C1 expression in comparison to their male counterparts⁷. Over time, this difference in expression became less significant, indicating that traumatic events may modify NR3C1 in a time-dependent manner. One human study introduced hydrocortisone as a possible treatment for PTSD prevention⁹ which found that the group who consumed hydrocortisone had an accelerated decline in traumatic inclusions in comparison to the control group. They also identified specific drug- sex hormone interactions in relation to intrusions. Hydrocortisone treated males had fewer intrusions with increased estradiol levels whereas hydrocortisone treated females demonstrated the opposite pattern. The interactions with progesterone for males was reversed with greater intrusions as progesterone levels increased. Their female counterparts did not demonstrate as stark of a relationship.

Conclusion: Studies found that epigenetic modifications to NR3C1 contribute to HPA axis dysregulation, leading to predisposition of PTSD. Additionally, there is a possible sex-specific mechanism of NR3C1 methylation in relation to trauma. Due to the complex gene and hormone interactions of the HPA axis as well as different types of traumatic event exposures, further research is needed, however, possible NR3C1 targeting may provide a new avenue for PTSD prevention and treatment.

Works Cited:

1. Carvalho CM, Coimbra BM, Ota VK, Mello MF, Belangero SI. Single-nucleotide polymorphisms in genes related to the hypothalamic-pituitary-adrenal axis as risk factors for posttraumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet. 2017;174(7):671-682. doi:10.1002/ajmg.b.32564
2. Fischer S, Schumacher T, Knaevelsrud C, Ehlert U, Schumacher S. Genes and hormones of the hypothalamic-pituitary-adrenal axis in post-traumatic stress disorder. What is their role in symptom expression and treatment response?. J Neural Transm (Vienna). 2021;128(9):1279-1286. doi:10.1007/s00702-021-02330-2
3. Watkeys OJ, Kremerskothen K, Quidé Y, Fullerton JM, Green MJ. Glucocorticoid receptor gene (NR3C1) DNA methylation in association with trauma, psychopathology, transcript expression, or genotypic variation: A systematic review. Neurosci Biobehav Rev. 2018;95:85-122. doi:10.1016/j.neubiorev.2018.08.017
4. Shalev A, Liberzon I,  Marmar C. Post-Traumatic Stress Disorder. N Engl J Med. 2017;376(25):2459-2469. doi:10.1056/NEJMra1612499
5. Lu, WH., Chao, HW., Lin, PY. et al. CPEB3-dowregulated Nr3c1 mRNA translation confers resilience to developing posttraumatic stress disorder-like behavior in fear-conditioned mice. Neuropsychopharmacol. 46, 1669–1679 (2021). https://doi.org/10.1038/s41386-021-01017-2
6. Oh Y-E, Nguyen TB, Rami FZ, Karamikheirabad M, Chung Y-C. Impact of social defeat stress on DNA methylation in DRD2, Nr3c1, and STMN1 in wild-type and STMN1 knock-out mice. Clinical Psychopharmacology and Neuroscience. 2022;20(1):51-60. doi:10.9758/cpn.2022.20.1.51
7. St-Cyr S, Abuaish S, Sivanathan S, McGowan PO. Maternal programming of sex-specific responses to predator odor stress in adult rats. Hormones and Behavior. 2017;94:1-12. doi:10.1016/j.yhbeh.2017.06.005
8. Xin N, Wang D-T, Zhang L, Zhou Y, Cheng Y. Early developmental stage glucocorticoid exposure causes DNA methylation and behavioral defects in adult zebrafish. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 2022;256:109301. doi:10.1016/j.cbpc.2022.109301
9. Hennessy VE, Troebinger L, Iskandar G, Das RK, Kamboj SK. Accelerated forgetting of a trauma-like event in healthy men and women after a single dose of hydrocortisone. Transl Psychiatry. 2022;12(1):354. Published 2022 Aug 31. doi:10.1038/s41398-022-02126-2