Is there sex-specific epigenetic regulation of fear memory?

A new study says yes, for mice anyway, and if it later is found to be similar in humans it could explain why fear and stress-related disorders affect men and women differently.

Fear and memory produce changes to genes that modulate gene expression, called epigenetic modifications, some contend. In a mouse model of traumatic memory, epigenetic activation of  gene important for creating fear memories and stress behavior, called cyclin dependent kinase 5 (Cdk5) increased naturally in males, but not in females, after the mice recalled a fear-related memory.

Artificial activation of Cdk5 had no effect in male mice in which Cdk5 was already naturally increased, but reduced the strength of fear memories in female mice, indicating sex differences in how fear is remembered.


Previous research had already shown that Cdk5 is activated by stress and regulates the strength of fear-related memories, it had only been studied in male mice. So senior author Elizabeth A. Heller, PhD, University of Pennsylvania, and colleagues used epigenetic editing to artificially increase Cdk5 activation in the hippocampus, the brain’s memory hub. “Remarkably, this manipulation reduced fear memory retrieval and increased Tau phosphorylation in female, but not male mice,” said Dr. Heller.

Phosphorylation of the protein tau by Cdk5 regulates learning and memory. Cdk5 activation and tau phosphorylation have been shown to cause negative effects on learning and memory in female mice, but not male mice. The authors suggest that Cdk5 expression is naturally blocked in females to protect them from these negative effects.

The epigenetic differences in male and female mice indicate sex differences in the biology of how fearful events are remembered, which highlights that sex should be an important consideration in the research and treatment of neuropsychiatric diseases that involve fear and stress, such as posttraumatic stress disorder, depression, and anxiety.

Citation: Ajinkya S. Sase, Sonia I. Lombroso, Brandon A. Santhumayor, Rozalyn R. Wood, Carissa J. Lim, Rachael L. Neve, Elizabeth A. Heller, 'Sex-specific regulation of fear memory by targeted epigenetic editing of Cdk5', Biological Psychiatry,