Experiencing a traumatic event sometimes produces long-lasting biological changes that can lead to an exaggerated fear response to future stressful events, such as what occurs in individuals with post-traumatic stress disorder (PTSD). To better understand the regulatory mechanisms in the brain that produce this biological memory and exaggerated fear response, a team of researchers from Penn State and the University of Wisconsin-Milwaukee has been awarded a five-year, $3.2 million grant from the U.S. National Institutes of Health's National Institute of Mental Health.
According to the researchers, about 7% of people in the United States experience PTSD at some point in their life; however, there is not currently a treatment that consistently improves PTSD in all patients. Additionally, women are about twice as likely to experience PTSD than men, but it is unclear why.
"Fear is an important aspect of survival, but an exaggerated response, such as with PTSD and other anxiety disorders, can cause harm if it interferes with normal functioning," said Janine Kwapis, Paul Berg Early Career Professor in the Biological Sciences in the Penn State Eberly College of Science and leader of the research team. "We want to know what's happening during a traumatic event that persistently changes how our brain functions and how that differs between men and women."
Kwapis and her team are using a mouse-model system to study a part of the brain called the amygdala, which she said is known as the site of fear. While their work is in mice, Kwapis explained that these structures are highly conserved across mammals and can lend important insight into how fear memories are formed in humans.
Specifically, they are exploring how proteins called histones, which help package long strings of DNA into a more compact form, can temporarily modify certain genes in the brain during stressful events. By changing how tightly they bind to DNA, histones can alter how accessible genes are to the cellular machinery that turns them on or off without changing the gene's underlying genetic sequence. This kind of temporary change is called an epigenetic modification.
"Our hypothesis is that when that trauma event occurs, there are epigenetic mechanisms that mark genes critical for fear memory, so that those genes are ready to be expressed really rapidly if something else bad happens," Kwapis said. "It forms a molecular memory - long-lasting biological changes - with effects that persist well after the fearful event ends. In the case of trauma, that response might be too intense or happen too frequently during subsequent events."
Kwapis and her research group previously identified that a histone modifier called HDAC3 is active in memory formation during stressful events. By blocking this protein's activity during a mildly stressful event, she said, it changes the event into one that is remembered very strongly, as if it were more traumatic.
"We want to better understand how this mechanism works and see if there are other epigenetic mechanisms that operate in similar ways." she said. "If we can characterize this molecular memory for trauma, theoretically we could find a way to manipulate it to lessen or even reverse the effects and, in the best-case scenario, erase PTSD."
In addition to thoroughly investigating HDAC3, the team will use RNA sequencing to identify genes in the amygdala that are expressed excessively during subsequent stress events. They will also use a technique called ChIP-seq to map areas of the genome that are affected by these histone changes during trauma. After cross-referencing these results, the team will use CRISPR/Cas9 gene-editing techniques to manipulate top candidate genes to try to prevent these exaggerated fear responses.
"It's likely that many different genes and epigenetic regulators are operating to impact memory formation during stressful events, and we hope to gain a better understanding of how the system works together," said Istvan Albert, research professor of bioinformatics in the Penn State Department of Biochemistry and Molecular Biology and co-investigator on the grant. "Once we know how the system works, it could become possible to target specific genes or histones to manipulate the system in ways that may contribute to future therapies for PTSD and other anxiety disorders."
The research team will also explore why females are more likely to form stronger fear responses. They previously found that female mice show an amplified response to a mild stressor that has no lingering effects in male mice.
"We want to know if it takes less stress for females to develop a stronger fear memory, or if something else is happening that enables this exaggerated response," said Karyn Frick, distinguished professor of psychology at the University of Wisconsin-Milwaukee, and co-investigator of the grant. "Females and males often have very different responses to the exact same stimulation, but the biological reasons for those differences are still not fully understood."
The researchers said that their work also has implications for other instances where the brain might overreact, such as anxiety disorders.
"We're ultimately studying how one experience can impact the brain in a way that has long-lasting changes," Kwapis said. "How does the brain establish a biological memory, and what are the conditions where that goes from being helpful for survival to being something that interferes with or negatively impacts your life? Starting to answer these questions could have important implications for human health."
