On the role of epigenetic modifications of HPA axis in posttraumatic stress disorder and resilience

Abstract

Stress is a fundamental adaptive response that invokes amygdala and hypothalamus-pituitary-adrenal (HPA) axis along with other brain regions. Extreme or chronic stress, however, can result in a multitude of neuropsychiatric disorders, including anxiety, paranoia, bipolar disorder (BP), major depressive disorder (MDD), and posttraumatic stress disorder (PTSD). Despite widespread exposure to trauma (70.4%), the incidence of PTSD is relatively low (6.8%), suggesting that either individual susceptibility or adaptability driven by epigenetic and genetic mechanisms are likely at play. PTSD takes hold from exposure to traumatic events, such as death threats or severe abuse, with its severity being impacted by the magnitude of trauma, its frequency, and the nature. This comprehensive review examines how traumatic experiences and epigenetic modifications in hypothalamic-pituitary axis (HPA), such as DNA methylation, histone modifications, noncoding RNAs, and chromatin remodeling, are transmitted across generations, and impact genes such as FKBP prolyl isomerase 5 (FKBP5), nuclear receptor subfamily 3 group C member 1 (NR3C1), brain-derived neurotrophic factor (BDNF), and solute carrier family 6 member 4 (SLC6A4). It also provides a comprehensive overview on trauma reversal, resilience mechanisms, and pro-resilience factors such as histone acetyltransferases (HATs)/histone deacetylases (HDACs) ratio, dehydroepiandrosterone (DHEA)/cortisol ratio, testosterone levels, and neuropeptide Y, thus highlighting potential therapeutic approaches for trauma-related disorders. The studies highlighted here underscore the narrative, for the first time, that the examination and treatment of PTSD and other depressive disorders must invoke a multitude of approaches to seek out the most effective and personalized strategies. We also hope that the discussion emanating from this review will also inform government policies directed toward intergenerational trauma and PTSD.

Keywords: HPA axis; PTSD; epigenetics; resilience; stress.