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This article is extremely relevant to the epigenetic of anxiety and stress-related disorders. It is written neutrally and pulls great evidence and mechanisms in which epigenetic works.

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Phenotypic effects

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Early life experiences and environmental factors may lead to epigenetic modification at specific gene loci, leading to altered neuronal plasticity, function, and subsequent behavior. As mentioned, there are genetic markers in all living organisms. There can also be the presence of epigenetically marks and this are basically areas of modification on DNA that in with gene expression. Certain exposures within the environment can lead to the expression of genes in various ways which can contribute to behavioral plasticity patterns that can potentially also change the ways in which organism functions when under normal conditions [1]. 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. Variations in maternal care, such as maternal licking and grooming, indicates reduced HPA axis reactivity in subsequent generations. Such HPA axis modifications lead to decreased anxiety-like behavior in adulthood and increased glucocorticoid receptor levels leading to negative feedback on HPA reactivity and further behavioral modifications. Rodent models of maternal separation also reveal increased depressive-like behavior in offspring, decreased stress coping abilities, and changes in DNA methylation.

Transgenerational epigenetic influences

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Genome-wide association studies have shown that psychiatric disorders are partly heritable; however, heritability cannot be fully explained by classical Mendelian genetics, but rather epigenetics. There are many components in understanding the heritability of psychiatric disorders. [2]Understanding epigenetic modifications and its ability to impact epigenomes over generations is vital in analyzing potential behavioral disorders.[2] But we must acknowledge the concept of transgenerational epigenetics (epigenetic inheritance) which is the occurrence in which parents are able to transfer traits not present in their DNA sequencing to their offspring; it is the passing of environmentally manipulated traits for two or more generations without direct DNA alteration[3] For example, one study found transmission of DNA methylation patterns from fathers to offspring during spermatogenesis. Similarly, several studies have shown that traits of psychiatric illnesses (such as traits of PTSD and other anxiety disorders) can be transmitted epigenetically [4][5]Parental exposure to various stimuli, both positive and negative, can cause transgenerational . epigenetic and behavioral effects. [6]

Alcohol use disorder

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What is alcohol use disorder? Alcohol use disorder is a type of brain disorder that requires one to have dependency on alcohol. Alcohol use disorder can vary in severity. Alcohol dependence can impact stress and other disorders in many ways [7]. For example, stress-related disorders such as anxiety and PTSD are known to increase risk of alcohol use disorder (AUD), and they are often co-morbid. Mental disorders that pair with AUD can impacts the brain in many ways. For example, AUD can have the ability to aid those diagnosed with depression by alleviating depression symptoms such as insomnia, restlessness, and/ or the ability to re-engage in normal activities, and re-engage in hobbies. Bipolar disorder can cause manic episodes ranging fro different sudden mood changes. AUD can also be used to stall the same symptoms expressed in depression as well as with bipolar disorder. In some cases AUD can cause other brain disorders to worsen itself, or the symptoms of the disorder. A example of this can be seen in some with Obessive-Compulsive Disorder (can typically include anxiety “triggers” that often cause an individual to have very specific compulsions or obsessions. 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 [8][9]This may in part be due to the fact that alcohol can alleviate some symptoms of these disorders, thus promoting dependence on alcohol. Conversely, early exposure to alcohol can increase vulnerability to stress and stress-related disorders. AUD is a type of epigenetic influencing disorder, it is able to be passed down generation to generation epigenetically following a process mentioned before as trangenerational epigeneitics. [6] [10] Moreover, alcohol dependence and stress are known to follow similar neuronal pathways, and these pathways are often dysregulated by similar epigenetic modifications.

Holocaust

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Irene Shashar, a Holocaust survivor of the Warsaw ghetto, addressed MEPs on International Holocaust Remembrance Day

An epidemiological study investigating behavioral, physiological, andmolecular changes in the children of Holocaust survivors found epigenetic modifications of a glucocorticoid receptor gene, Nr3c1. This is significant because glucocorticoid is a regulator of the hypothalamus-pituitary-adrenal axis (HPA) and is known to affect stress response. These stress-related epigenetic changes were accompanied by other characteristics that indicated higher stress and anxiety in these offspring, including increased symptoms of PTSD, greater risk of anxiety, and higher levels of the stress hormone cortisol. The offspring demonstrate greater risk of developing PTSD in response to their own trauma[3]. Offspring with maternal exposure to the Holocaust during the mother's childhood has demonstrated significantly lower site 6 methylation[11]. The site 6 methylation impacts the stress response. In addition to PTSD risks in response to individual trauma in offspring, there has also been an increase in nightmares of offspring related to persecution and torment. [12]

Exercise

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Just as parental stress can alter epigenetics of offspring, parental exposure to positive environmental factors cause epigenetic modifications as well. 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. This behavioral change likely occurred due to expressions of small non-coding RNAs that were altered in sperm cells of the fathers.[13][14] Participation in aerobic exercise led to decreased cortisol levels in males. [15]

Hydrocortisone

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The medication hydrocortisone is a synthetic form of cortisol. In recent years, the administration of hydrocortisone has been tested as a possible preventative measure for the onset of PTSD symptoms. Ideally, it should be administered immediately after a traumatic event. The efficacy of hydrocortisone as a preventative intervention for PTSD has been confirmed by a meta-analysis of eight separate studies, and researchers believe the best results are obtained when hydrocortisone is administered within the first six hours of exposure to the traumatic event. In studies, patients who took hydrocortisone for ten days had better health, and less symptoms than the patients given a placebo. At this time, however, no curative properties have been discovered. Hydrocortisone's potential operates on two bases: restoration of normal HPA axis functioning and interference with memory consolidation.Epigenetics of anxiety and stress–related disorders[16]

Stress effect reversal

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Additionally, exposing fathers to enriching environments can reverse the effect of early life stress on their offspring. When early life stress is followed by environmental enrichment, anxiety-like behavior in offspring is prevented. Similar studies have been conducted in humans and suggest that DNA methylation plays a role. Other studies have been conducted to find drugs such as T2D and PPArG can be used as an epigenetic regulation for tissues associated with diabetes.[17] These drugs used show evidence for the therapies that can be associated with the stress effect reversal.

DNA methylation

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Epigenetic DNA Methylation

Through a number of human studies, PTSD is known to affect DNA methylation of CpG islands in several genes involved in numerous activities, including stress responses and neurotransmitter activity. CpGs are used to describe cytosine-guanine adjacent nucleotides within the same strand of DNA. CpG islands are defined by computer algorithms as being made up of at least 60% CpGs and being anywhere between 200 and 3000 base pairs in size. The methylation of these CpG islands can cause histone modifications which can lead to the condensation of chromatin which can ultimately alter gene expression.

DNMT enzyme

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DNA methyltransferase, DNMT, is an enzyme responsible for increased methylation of DNA. It has been found that DNMT and its associated increased methylation can regulate risk for memory consolidation and fear conditioning.

TET enzyme

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The removal of methyl groups from cytosine is initiated by a TET enzyme. TET is an enzyme known to oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) within the genome. This reaction initiates active DNA demethylation to ultimately alter gene expression. It has been found that the TET enzyme exists as two isoforms which are differentially regulated and expressed across brain regions. The regulation of these isoforms can affect synaptic connections and ultimately memory formation. The manipulation of the TET enzymes' expression levels has become a potential source of interest for PTSD medication.

Paternal stress inheritance

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Paternal stress is an important factor in the determination of inheritance of genes as well as maternal stress inheritance. Factors such as environment and experiences can alter the epigenetic of paternal genes as well as in sperm. Epigenetic changes to the DNA in sperm ("epigenetic tags") prior to conception can be passed to offspring. The paternal phenotype will be inherited into the offspring due to genetic information being stored in the sperm. In studies, it is shown as rodent offspring are fostered mono-parentally and have no direct exposure with their fathers, offspring born of stressed male rodents provide a good model for transgenerational stress inheritance. Direct injection of sperm RNAs to wild type oocytes results in reproducible stress-related modifications. Small non-coding RNAs may serve as a potential mechanism for stress-related genetic changes in offspring. Mouse models of traumatic early life stress exposure result in microRNA modifications and subsequent differences in gene expression and metabolic function. This effect was reproducible by sperm RNA injection, leading to similar gene modifications in future generations. The novelty of this research suggests direct mechanisms capable of altering epigenetics by stress-related factors.

Parental exposure to trauma and stress

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Trauma and stress experienced by a parent can cause epigenetic changes to its offspring. This has been observed both in population and experimental studies.

Transgenerational Stress Effects

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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. Several models, however, have investigated the role of epigenetic inheritance and transgenerational stress effects. Transgenerational stress in humans, as in animal models, induces effects influencing social behavior, reproductive success, cognitive ability, and stress response.Similar to animal models, human studies have investigated the role of epigenetics and transgenerational inheritance molecularly as it relates to the HPA system. Prenatal influences, such as emotional stress, nutrition depravation, toxin exposure, hypoxia, increased maternal HPA activity, and cortisol levels may activate or affect HPA axis activity of offspring, despite placental barrier.

DNA methylation

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DNA methylation is a type of epigenetic modification in which methyl groups are added to cytosines of DNA. It is located on the fifth position of cytosine which has importance in the development of mammals.[18] DNA methylation is an important regulator of gene expression and is usually associated with gene repression. DNA Methylation is a mechanism which can suppress gene expression. It can be inherited through cell divisions in development, and is involved with cell memory. Changes in methylation occur due to mutated or deregulated chromatin regulators. This process is also used in marking cancers for diagnosis.

Childhood exposure to trauma

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Early life development and childhood trauma

Mental health disorders that can be caused by epigenetic alterations.

Healthy development early in life is critical. Early life is characterized by rapid development and increased susceptibility to modifications. 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. Childhood trauma has been associated with a wide array of mental health disorders such as bipolar disorder, anxiety, post traumatic stress disorder (PTSD), and depression.[19]

PTSD Inheritability

Research involving PTSD in those who experienced childhood trauma had a 25% to 60% inheritability rate, which is a relatively low to moderate rate. This study suggests that other factors play a role in the contribution to this disorder such as gene interactions involving epigenetic modifications. These epigenetic modifications, specifically DNA methylation can lead to the phenotypic expression of mental disorders.[19]

Changes to the HPA Axis Due to Childhood Trauma

Hypothalamic-pituatary-adrenal (HPA) axis is essential component of the neuroendocrine system that regulates stress response. Persistent dysregulation of the stress response pathway resulting from childhood trauma causes alterations in the (HPA). These alterations lead to prolonged harmful physiological and physical changes.[20][19]

Postmortem Brain Tissue DNA Methylation

A DNA methylation study was done by Labonte on postmortem human brain tissue comparing humans with or without a history of childhood abuse who died by suicide. Childhood abuse and trauma was associated with increased cytosine methylation of the NR3C1 promoter resulting in the decrease of GR expression. The NR3C1 gene encodes glucocorticoid receptor (GR) which is essential for glucose regulation and managing stress response through both genetic and epigenetic pathways.[19]

References

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1. Smeeth, D., Beck, S., Karam, E. G., & Pluess, M. (2021, July). The role of epigenetics in psychological resilience. The lancet. Psychiatry. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561637/

  1. ^ Yehuda, Rachel; Lehrner, Amy (2018-10). "Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms". World Psychiatry. 17 (3): 243–257. doi:10.1002/wps.20568. ISSN 1723-8617. PMC 6127768. PMID 30192087. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
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