“But what mechanism connected trauma exposure to low cortisol to future PTSD? We began a series of studies to answer this question. Significantly, we found that Vietnam veterans with PTSD had a greater number of glucocorticoid receptors. These are proteins to which cortisol binds to exert its diverse influences. That suggested a greater sensitivity to cortisol: a small increase in the hormone’s concentration would precipitate a disproportionate physiological reaction. But it wasn’t until we looked more closely at the molecular underpinnings of cortisol functioning—in part by examining epigenetics—that we understood how exposure to trauma might reset the cortisol feedback loop.

In the 1990s scientists were realizing that the output of our genes is sensitive to factors not written directly into our genetic code. Genes provide the templates for producing proteins. But much like cakes baked using the same ingredients may turn out differently depending on variations in the oven’s temperature, how much of those proteins gets produced, or “expressed,” depends on the environment. The discovery gave rise to epigenetics, the study of what influences gene expression and how. It proved crucial to understanding both the neurobiology of PTSD and the intergenerational effects of trauma.

Epigeneticists explore the switches that turn gene expression on and off. One such mechanism, called methylation, involves a methyl group—a methane molecule that is missing one of its four hydrogen atoms, leaving a chemical bond free to attach to another atom or molecule. Methylation is a process by which, in the presence of specific enzymes, methyl groups attach to key sites on a strand of DNA or within the complex of DNA and proteins known as chromatin. By occupying these sites like roadblocks on a highway, methyl groups can alter transcription, a basic step in gene expression where a piece of RNA is made from a DNA template. Increased methylation generally impedes RNA transcription, whereas less methylation enhances transcription. These changes are enduring in that they survive normal cell division and require specific enzymes for their removal.

In 2015 our group became one of the first to pinpoint epigenetic changes on stress-related genes of veterans with PTSD. These alterations partially explained why trauma’s effects were so persistent, lasting for decades. Specifically we observed reduced methylation in an important region of NR3C1, a gene that encodes the glucocorticoid receptor, likely increasing the sensitivity of these receptors.

This epigenetic modification suggests a potential explanation for how trauma might reset cortisol levels. The body regulates the stress response through a complicated feedback mechanism. A rise in cortisol levels will prompt the body to produce less of the hormone, which may drive up the numbers and responsiveness of glucocorticoid receptors. Given the epigenetic and other changes occurring with sustained responses to trauma, the feedback loop might become recalibrated. In people who have already endured trauma, their stress systems might be sensitized and their cortisol levels diminished—increasing their adrenaline response to further trauma and leading to PTSD.”


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