Epigenetics of anxiety and stress–related disorders
[2] Stress-induced epigenetic changes, particularly to genes that effect the hypothalamic–pituitary–adrenal (HPA) axis, persist into future generations, negatively impacting the capacity of offspring to adapt to stress.
Early life experiences, even when generations removed, can cause permanent epigenetic modifications of DNA resulting in changes in gene expression, endocrine function and metabolism.
Chronic variable stress induces offspring hypothalamic gene expression modifications, including elevated methylation levels of the BDNF promoter in the hippocampus.
[5] Epigenetic modifications as a result of absent maternal care lead to decreased estrogen receptor alpha expression, due to increased methylation at the gene's promoter.
Accordingly, transcriptional repression of DNMT1 in response to long-term stress-mimicking exposure causes decreased DNA methylation, which is a marker of gene activation.
[20] Biological vulnerability and HPA axis alterations may be observed after maternal epigenetic programing during pregnancy, leading to similar modifications in future generations.
Human studies investigating posttraumatic stress disorder (PTSD) and its effects on offspring have illustrated similar molecular and HPA axis modification and function.
[22] Strong relationships between maternal care and subsequent epigenetic modification in offspring, similar to that found in animal models, has been observed in humans.
[4] Therefore, environmental and experience-dependent synaptic reorganization and structure modifications may lead to increased stress vulnerability and brain dysfunction in future generations.
[4] Human models illustrating transgenerational stress effects are limited due to relatively novel exploration of the topic of epigenetics as well as lengthy follow-up intervals required for multi-generational studies.
Mouse models of traumatic early life stress exposure result in microRNA modifications and subsequent differences in gene expression and metabolic function.
[25] Chromatin remodeling in rodent offspring and altered gene expression within the limbic brain regions that may contribute to depression, stress, and anxiety-related disorders in future generations.
[5][1] Rodent models of maternal separation also reveal increased depressive-like behavior in offspring, decreased stress coping abilities, and changes in DNA methylation.
[1] An epidemiological study investigating behavioral, physiological, and molecular changes in the children of Holocaust survivors found epigenetic modifications of a glucocorticoid receptor gene, Nr3c1.
[20][31] Studies have found that early life stress induced through poor maternal care alters sperm epigenome in male mice.
For example, male mice that participated in voluntary physical exercise resulted in offspring that had reduced fear memory and anxiety-like behavior in response to stress.
Childhood trauma can severely affect the development of the brain, resulting in the alteration of neural circuits which are involved in emotional regulation and threat detection.
The NR3C1 gene encodes glucocorticoid receptor (GR) which is essential for glucose regulation and managing stress response through both genetic and epigenetic pathways.
[43][10] Histone modifications, like acetylation and deacetylation, play an important role in the development of PTSD, which is related to fear memory from traumatic events.
[43][10] The table below identifies differentially methylated regions (DMRs) across the genome which undergo PTSD-induced epigenetic changes which alter gene expression.
[58] The hypothalamus-pituitary-adrenal (HPA) axis is a neuroendocrine system largely involved in ascertaining the levels of cortisol circulating the body at any given point in time.
Traumatic experiences can induce epigenetic changes at the gene loci that are immune-related which can lead to immune dysregulation and an increased risk of PTSD.
With this type of disorder, although it can help in ways by relieving symptomatic stress, it can also aid in promoting addiction to alcohol which can be a negative impact if uncontrolled.
[74][76] Dysregulation of HDACs is significant because it can cause upregulation or downregulation of genes that have important downstream effects both in alcohol dependence and anxiety-like behaviors, and the interaction between the two.
[85][86][87][88][89] The trial performed on healthy subjects found that Valproate reduces anxiety and also acts as a nerve conduction inhibitor, which could be an explanation for some of its anxiety-reducing effects.
[93] Anxiety-like and depression-like behaviors caused by immobilization stress or nicotine addiction were also reduced in mice treated with the HDACi sodium butyrate and valproic acid.
[95] Preliminary research has been done about therapy involving small non-coding RNAs, demonstrating that they can regulate epigenetic mechanisms of gene expression and could present as biomarkers for disease.
[98] Moreover, research has also indicated that an appropriate release of glucocorticoids following acute stress may restore homeostatic equilibrium of the HPA axis, thereby preventing gradual sensitization, which is responsible for persistent cortisol reduction and increased PTSD susceptibility.
Thus, the appropriately-dosed administration of hydrocortisone promptly following the traumatic incident would normalize the HPA axis and potentially prevent PTSD onset.
Further comprehensive studies are required amidst more diverse populations under different traumatic conditions in order to ascertain factors of optimal usage of the drug and clarify the PTSD subgroups hydrocortisone is beneficial to.
