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 to the shape 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.”
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. Read more
Happiness can be elusive, both in personal life and as a scientific concept. That’s why this paper, recently published in Molecular Psychiatry, seemed so striking.
“A genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs.” Translation: a glimpse into the genetics of positive emotions.
Editorial note: Although the research team here is careful and confirms the findings in independent groups and in brain imaging and fear discrimination experiments, this is a preliminary result. More needs to be explored about how these genetic variants and others affect positive emotions.
“With relatively few studies on genetic underpinnings of positive emotions, we face the challenges of a nascent research area,” the authors write.
Perhaps ironically, the finding comes out of the Grady Trauma Project, a study of inner-city residents exposed to high rates of abuse and violence, aimed at understanding mechanisms of resilience and vulnerability in depression and PTSD.
“Resilience is a multidimensional phenomenon, and we were looking at just one aspect of it,” says first author Aliza Wingo. She worked with Kerry Ressler , now at Harvard, and Tanja Jovanovic and other members of the Grady Trauma Project team.
“Positive affect” is what the team was measuring, through responses on questionnaires. And the questions are asking for the extent that respondents feel a particular positive emotion in general, rather than that day or that week. Read more
Violence and trauma are certainly not gifts, but scientifically, the Grady Trauma Project keeps on giving, even after co-director Kerry Resslerâ€™s 2015 move to Massachusetts. Research at Emory on the neurobiology of post-traumatic stress disorder (PTSD) continues. This Nature Communications paper, published in December with VA-based psychiatrist Aliza Wingo as lead author, is an example.
Three interesting things about this paper:
- The focus on PTSD co-occurring with depression. As the authors note, several studies looking at traumatized individuals found PTSD and depression together more often than they were present separately. This was true of Atlanta inner city residents in the Grady Trauma Project, veterans and survivors of the 2001 World Trade Center attack.
- DICER: the gene whose activity is turned down in blood samples from people with PTSD plus depression. Its name evokes one of the three Fates in Greek mythology, Atropos, who cuts the thread of life. DICER is at the center of a cellular network of regulation, because it is part of the machinery that generates regulatory micro-RNAs.
- The findings recapitulate work in mouse models of stress and its effects on the brain, with a connection to the many-tentacled Wnt signaling/adhesion protein beta-catenin.
Some past posts on the Grady Trauma Projectâ€™s scientific fruits follow. Read more
In 2013, Brian Dias (at Yerkes) and Kerry Ressler (now at Harvard) describedÂ a surprising example of epigenetic inheritance.
They found that a mouse, exposed to a smell in combination with stress, could transmit the resulting sensitivity to that smell to its offspring. At the time, there wasn’t a lot of information about mechanism.
Now other scientistsÂ haveÂ substantiatedÂ a proposal that micro RNA in playing a role in sperm. See this story (“Sperm RNAs transmit stress”) from Kate Yandell in The ScientistÂ or this one from Rachel Zamzow at Spectrum, the Simons Foundation’s autism news site, for more. An added wrinkle is that thisÂ research showsÂ that descendantsÂ of stress-exposed mice show a muted response to stress.
Note for Emory readers: Dias is scheduled to give a Frontiers in Neuroscience talk on Friday.
This grant announcement from the American Heart Association caught Lab Land’s eye.Â All three of the scientists involved in this project, examining the connections between hypertension, inflammation and the sympathetic nervous system in PTSD, have Emory connections:
*Kerry Ressler, previously Emory Psychiatry/HHMI-supported/Yerkes-based lab/Grady Trauma Project, who moved this summer to Harvard’s McLean Hospital
Related findingÂ that emerged from the Grady Trauma Project: Blood pressure drugs linked with lower PTSD symptoms
*Paul Marvar, who worked with both David Harrison and Kerry Ressler at Emory, and is now at George Washington University
Related item on Marvar’s work: Immune cells required for stress-induced rise in blood pressure in animals
*Jeanie Park, kidney specialist who is here now! The grant is exploring the relationship between the sympathetic nervous system, regulation of blood pressure and PTSD.
2015Â TV interview with Park on her chronic kidney disease research
Two feature articles in Nature this week on work by Emory scientists.
One is from Virginia Hughes (Phenomena/SFARI/MATTER), delving into Kerry Ressler’s and Brian Dias’ surprising discovery in mice that sensitivity to a smell can be inherited, apparently epigenetically. Coincidentally, Ressler will be giving next week’s Dean’s Distinguished Faculty lecture (March 12, 5:30 pm at the School of Medicine).
Another is from Seattle global health writer Tom Paulson, on immunologist Bali Pulendran and using systems biology to unlock new insights into vaccine design.
This intriguing research has received plenty of attention, Â both when it was presented at the Society of Neuroscience meeting in the fall and then when the results were published in Nature Neuroscience.
The short summary is: researchers at Yerkes National Primate Research Center found that when a mouse learns to become afraid of a certain odor, his or her pups will be more Gafas Ray Ban Baratas sensitive to that odor, even though the pups have never encountered it.Â Both the parent mouse and pups have more space in the smell-processing part of their brains, called the olfactory bulb, devoted to the odor to which they are sensitive.
[Note: a feature on a similar phenomenon, transgenerational inheritance of the effects of chemical exposure, appeared in Science this week]
Somehow information about the parent’s experiences is being inherited. But how? Brian Dias and Kerry Ressler are now pursuing followup experiments to firmly establish what’s going on. They discuss their research in this video:
The connection between stress and blood pressure seems like common sense. Of course experiencing stress — like a narrow miss in morning traffic or dealing with a stubborn, whiny child — raises someoneâ€™s blood pressure.
Try reversing the cause-and-effect relationship: not from brain to body, but instead from body to brain. Could medication for controlling blood pressure moderate the effects of severe stress, and thus aid in controlling PTSD symptoms or in preventing the development of PTSD after trauma?
That was the intriguing implication arising from a 2012 paper from Grady Trauma Project investigators led by psychiatrist Kerry Ressler (lab at Yerkes, supported by HHMI).
They had found that traumatized civilians who take either of two classes of common blood pressure medications tend to have less severe post-traumatic stress symptoms. In particular, individuals taking ACE inhibitors (angiotensin converting enzyme)Â or ARBs (angiotensin receptor blockers)Â tended to have lower levels of hyperarousal and intrusive thoughts, and this effect was not observed with other blood pressure medications.
This was one of those observational findings that needs to be tested in an active way: â€œOK, people who are already taking more X experience less severe symptoms. But can we actually use X as an intervention?â€
In mice, it seems to work. Read more
Welcome to a feature of Lab Land we hope to have on a regular basis! Itâ€™s where we explain a word or phrase that is a hot topic of discussion in the science online world and particularly relevant to research going on at Emory.
Optogenetics allows researchers to stimulate specific brain cells with light. It involves introducing light-sensitive proteins from algae into the brain cells of mice, and then using a fiber optic cable to apply a laser signal to the relevant region of the brain.
Optogenetics is a leap beyond previous genetic engineering techniques that made it possible to turn on (or delete) a gene by feeding a mouse some extraneous chemical, such as the antibiotic tetracycline or the anti-hormone tamoxifen. Instead of wondering how long it takes that chemical to make its way into the brain, scientists can literally flick a switch and see near-instantaneous and localized effects. Read more