Males and females have different susceptibility to trauma- and stress-related disorders like anxiety and post-traumatic stress disorder (PTSD), past studies have revealed. For instance, women develop PTSD at twice the rate of men. Researchers want to know why this is.

A growing body of evidence indicates that males and females processes fear memories differently. New research in mice from a team led by 2016 BBRF Young Investigator Elizabeth A. Heller, Ph.D., of the University of Pennsylvania, establishes some of the mechanisms involved. Understanding these mechanisms may aid in the future development of sex-specific treatments for anxiety disorders.

The team’s latest findings were reported online in Biological Psychiatry on December 5, 2018. They suggest that regulation of a gene called Cdk5 is an important source of the difference in the way males and females process fear memories. Differences were seen in the brain’s hippocampus, a center of memory formation, learning, and spatial orientation.

Evolution has generated a variety of mechanisms through which cells regulate the activity of their genes—the way they turn them on and off at specific moments. The regulatory mechanism relevant to Cdk5 and the processing of fear memories is called epigenetic regulation. This type of gene regulation is the result of molecular modifications, called epigenetic marks, being added to or removed from the DNA sequences that "spell out" genes. By adding or subtracting epigenetic marks, cells are able to activate or shut down specific genes.

Using mice as surrogates for humans—the mouse brain is very similar in many respects, including gene regulation processes—Dr. Heller and her colleagues discovered that the long-term retrieval of fear memories is stronger in males than in females. The reason: increased activation of Cdk5 in males, caused by epigenetic marks. The activation occurs in nerve cells in the hippocampus.

Using a novel technique called epigenetic editing, Dr. Heller and colleagues were able to discover a female-specific role of Cdk5 activation in weakening the retrieval of fear memories. This had female-specific consequences in the biological chain of actions following the gene’s activation.

These discoveries are part of our growing understanding of sex differences in the biology of how fearful events are remembered and suggest why sex is an important factor in brain and behavior disorders involving fear and stress, such as PTSD, depression, and anxiety.