How Estrogen Modulates Fear Learning

Summary: Women with lower estrogen levels may be more susceptible to developing PTSD, a new study reports.

Source: Emory.

Low estrogen levels may make women more susceptible to the development of post-traumatic stress disorder (PTSD) at some points in their menstrual cycles or lifetimes, while high estrogen levels may be protective.

New research from Emory University School of Medicine and Harvard Medical School provides insight into how estrogen changes gene activity in the brain to achieve its protective effects.

The findings, published in Molecular Psychiatry, could inform the design of preventive treatments aimed at reducing the risk of PTSD after someone is traumatized.

The scientists examined blood samples from 278 women from the Grady Trauma Project, a study of low-income Atlanta residents with high levels of exposure to violence and abuse. They analyzed maps of DNA methylation, a modification of DNA that is usually a sign of genes that are turned off.

The group included adult women of child-bearing age, in which estrogen rises and falls with the menstrual cycle, and women that had gone through menopause and had much lower estrogen levels.

“We knew that estrogen affects the activity of many genes throughout the genome,” says Alicia Smith, PhD, associate professor and vice chair of research in the Department of Gynecology and Obstetrics at Emory University School of Medicine. “But if you look at the estrogen-modulated sites that are also associated with PTSD, just one pops out.”

Image shows a brain made of snakes.
This evocative illustration comes originally from a 2014 Emory Medicine article titled “The Anatomy of Fear”, which describes Grady Trauma Project research. image is credited to Emory.

That site is located in a gene called HDAC4, known to be critical for learning and memory in mice. Genetic variation in HDAC4 among the women was linked to a lower level of HDAC4 gene activity and differences in their ability to respond to and recover from fear, and also differences in “resting state” brain imaging. Women with the same variation also showed stronger connections in activation between the amygdala and the cingulate cortex, two regions of the brain involved in fear learning.

On top of that, experiments with female mice showed that the HDAC4 gene was activated in the amygdala while the mice were undergoing fear learning, but only when estrogen levels in the mice were low.

Smith says these results could lead to estrogen being used as a preventive treatment to lower the risk of PTSD after trauma. More information about how estrogen exerts its effects is coming to light; the authors note that in addition to modulating fear learning, estrogen has also been proposed to alter pain perception.

In this paper, estrogen’s effects in males were not studied; other scientists have found that in males, testosterone is converted into estrogen in the brain, where it plays a key role in development.

About this PTSD research article

The paper was a collaboration with Kerry Ressler, MD, PhD, previously at Emory and Yerkes National Primate Research Center and now at Harvard’s McLean Hospital, and Tanja Jovanovic, PhD and her team from Emory’s Department of Psychiatry and Behavioral Sciences. The first author of the paper is Stephanie Maddox, PhD, a post-doctoral researcher working with Ressler.

Funding: The research was supported by the National Institute of Mental Health (MH071537, MH096764, MH085806), the Brain & Behavior Research Foundation, the Howard Hughes Medical Institute, the Behrens-Weise Foundation and the NIH’s Office of Research Infrastructure Programs (Primate centers: P51OD011132).

Source: Quinn Eastman – Emory
Image Source: image is credited to Emory.
Original Research: Full open access research for “Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD” by S A Maddox, V Kilaru, J Shin, T Jovanovic, L M Almli, B G Dias, S D Norrholm, N Fani, V Michopoulos, Z Ding, K N Conneely, E B Binder, K J Ressler and A K Smith in Molecular Psychiatry. Published online January 17 2017 doi:10.1038/mp.2016.250

Cite This Article

[cbtabs][cbtab title=”MLA”]Emory “How Estrogen Modulates Fear Learning.” NeuroscienceNews. NeuroscienceNews, 18 January 2017.
<>.[/cbtab][cbtab title=”APA”]Emory (2017, January 18). How Estrogen Modulates Fear Learning. NeuroscienceNew. Retrieved January 18, 2017 from[/cbtab][cbtab title=”Chicago”]Emory “How Estrogen Modulates Fear Learning.” (accessed January 18, 2017).[/cbtab][/cbtabs]


Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD

Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome. For genes expressed in blood, we examined the association between each CpG site and PTSD diagnosis using linear models that adjusted for cell proportions and age. After multiple test correction, PTSD associated with methylation of CpG sites in the HDAC4 gene, which encodes histone deacetylase 4, and is involved in long-term memory formation and behavior. DNA methylation of HDAC4 CpG sites were tagged by a nearby single-nucleotide polymorphism (rs7570903), which also associated with HDAC4 expression, fear-potentiated startle and resting-state functional connectivity of the amygdala in traumatized humans. Using auditory Pavlovian fear conditioning in a rodent model, we examined the regulation of Hdac4 in the amygdala of ovariectomized (OVX) female mice. Hdac4 messenger RNA levels were higher in the amygdala 2 h after tone-shock presentations, compared with OVX-homecage control females. In naturally cycling females, tone-shock presentations increased Hdac4 expression relative to homecage controls for metestrous (low estrogen) but not the proestrous (high estrogen) group. Together, these results support an estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women.

“Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD” by S A Maddox, V Kilaru, J Shin, T Jovanovic, L M Almli, B G Dias, S D Norrholm, N Fani, V Michopoulos, Z Ding, K N Conneely, E B Binder, K J Ressler and A K Smith in Molecular Psychiatry. Published online January 17 2017 doi:10.1038/mp.2016.250

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