Acute stress can increase the presence of a key DNA modification called 5hmC throughout a portion of the brain called the hippocampus, vital in memory and learning, according to a study published in November 2015 in the journal Neurobiology of Disease. These modifications, observed in mice, may alter the activity of a variety of neurons and nerve signaling proteins in response to stress, and could be related to stress’ effects on the brain in anxiety and traumatic stress disorders.

By focusing on 5hmC’s link to stress, the research team, led by Reid Alisch, Ph.D., of the University of Wisconsin, has moved closer to explaining exactly how acute stress alters gene expression in the brain. The team also included Ligia A. Papale, Ph.D., a NARSAD 2014 Young Investigator, and 2010 Young Investigator Qi Zhang, Ph.D. at Wisconsin, and Emory University researcher Peng Jin, Ph.D., a NARSAD 2013 Independent Investigator. Previous studies have shown that the 5hmC DNA modification helps to regulate neuron activity, and that stress can increase levels of the modification in a few genes. Dr. Papale and colleagues decided to look at how widespread this increase might be, by performing a genome-wide search for 5hmC in the hippocampi of mice exposed to 30 minutes of stressful confinement followed by an hour’s rest. (Mammals have two hippocampal formations, one on each side of the brain.) The scientists then compared these data with changes in gene expression in the hippocampi following the stressful event.

The team found a significant overlap—about 20 percent--between genes with the 5hmC modification and genes that changed their expression in response to stress. Some of these genes have been identified previously with a stress response, while some of the other genes have no known role in stress but have been linked to other neuropsychiatric disorders such as schizophrenia.

The results offer a new glimpse at how gene modifications like 5hmC contribute to the neurological response to stress, and potentially the brain’s recovery from stress, the scientists say. In the future, they would like to compare this modification in female and male brains (all the mice in the study were male) and determine what role 5hmC may have in gene expression changes related to chronic, long-term stress.