Public Release: 

Epigenetics contribute to male and female differences in fear memory

A study in Biological Psychiatry investigates sex-specific epigenetic regulation of fear memory


Philadelphia, January 17, 201

In a mouse model of traumatic memory, male mice recall fear-related memories better than female mice, according to a study in Biological Psychiatry. The difference between sexes was attributed to a gene important for creating fear memories and stress behavior, called cyclin dependent kinase 5 (Cdk5), which was naturally activated in male but not in female mice. The findings could help 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. Epigenetic activation of 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.

"There is growing evidence for sex differences in the neurobiology of fear. These differences may provide important new insights into novel sex-specific treatments for anxiety disorders," said John Krystal, MD, Editor of Biological Psychiatry.

Although 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. "We examined both sexes, and found male-specific epigenetic activation of Cdk5 expression after fear conditioning, a model of traumatic memory," said senior author Elizabeth A. Heller, PhD, University of Pennsylvania.

Dr. Heller and colleagues then 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.

"Taken together, epigenetic editing uncovered a female-specific role of Cdk5 activation in repressing fear-induced memory," said Dr. Heller. 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.


Notes for editors
The article is "Sex-specific regulation of fear memory by targeted epigenetic editing of Cdk5," by Ajinkya S. Sase, Sonia I. Lombroso, Brandon A. Santhumayor, Rozalyn R. Wood, Carissa J. Lim, Rachael L. Neve, and Elizabeth A. Heller ( It appears in Biological Psychiatry, published by Elsevier.

Copies of this paper are available to credentialed journalists upon request; please contact Rhiannon Bugno at or +1 214 648 0880. Journalists wishing to interview the authors may contact Elizabeth A. Heller at

The authors' affiliations and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry
Biological Psychiatry
is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 6th out of 142 Psychiatry titles and 9th out of 261 Neurosciences titles in the Journal Citations Reports® published by Clarivate Analytics. The 2017 Impact Factor score for Biological Psychiatry is 11.982.


About Elsevier Elsevier is a global information analytics business that helps institutions and professionals advance healthcare, open science and improve performance for the benefit of humanity. Elsevier provides digital solutions and tools in the areas of strategic research management, R&D performance, clinical decision support and professional education, including ScienceDirect, Scopus, SciVal, ClinicalKey and Sherpath. Elsevier publishes over 2,500 digitized journals, including The Lancet and Cell, more than 38,000 e-book titles and many iconic reference works, including Gray's Anatomy. Elsevier is part of RELX Group, a global provider of information and analytics for professionals and business customers across industries.

Media contact
Rhiannon Bugno, Editorial Office
Biological Psychiatry
+1 214 648 0880

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.