Reducing fear memories in mice

Mike walsh
Date: Wednesday, July 19, 2017

New findings may have implications for treating PTSD.

Scientists at the University of Iowa and the University of Toledo have shown that briefly breathing carbon dioxide makes fear memories more susceptible to modification. Their studies in mice suggest an approach that might improve the effectiveness of exposure therapy in humans affected by post-traumatic stress disorder (PTSD).

Normal fear is an important evolutionary mechanism that can protect animals, including humans, from dangerous situations. But intense fear memories can be incapacitating when they are triggered by unrealistic threats or when the danger no longer exists.

PTSD is a relatively common disorder resulting from debilitating fear memories. According to the National Institute of Mental Health, almost 8 percent of Americans will experience PTSD at some point in their lives. Therapies that diminish excessive fear memories could potentially provide a much-needed way to treat PTSD.

“The discoveries provide basic insight into the modification of traumatic memories, a major goal for treating PTSD,” says Michael Welsh, MD, director of the Pappajohn Biomedical Institute at the UI, a professor of internal medicine in the UI Carver College of Medicine, and a Howard Hughes Medical Institute investigator.

One strategy for treating PTSD is exposure therapy. In exposure therapy, a patient is exposed to a triggering event in the absence of danger. However, this treatment, does not eliminate the original memory, but instead generates a new memory that overlies the original memory. As a result, the old memory may resurface, and patients can relapse.

It is known that recalling a memory makes the memory temporarily unstable and open to modification. Previous studies have also shown that applying exposure therapy when a fearful memory is unstable can weaken the original memory.

The UI team led by Welsh and Jianyang Du, PhD, investigated a method for increasing the instability of a recalled fear memory.

“Memories are encoded in neurons and the synapses (connections) between neurons,” explains Du, who was a postdoctoral researcher in Welsh’s lab at the UI and now is an assistant professor of biological sciences at the University of Toledo. “Our team’s hypothesis centered on the idea that increasing signaling activity at synapses during the memory retrieval process would increase the instability of the memory and render it more susceptible to modification.”

To increase signaling at synapses, the researchers used carbon dioxide inhalation to create a temporary burst of acidity in the brains of mice. The increased acidity activated acid-sensing ion channels (ASICs) at synapses in the amygdala, a brain region that’s important for creating and recalling fearful memories. Activation of these ASICs has been shown to be important for modulating signaling activity at synapses.

“We discovered that by briefly making the relevant synapses acidic, a fearful memory becomes more labile (unstable). From that labile state, the memory can be more effectively attenuated by exposure therapy,” Du says. The findings were recently published in the online journal eLife.

“We hope that this work lays the foundation for translation to the clinic,” says John Wemmie, MD, PhD, professor of psychiatry in the UI Carver College of Medicine. “Our findings may aid the development of new and effective complementary treatments for PTSD where there is currently a large unmet need.”

In addition to Du, Welsh, and Wemmie, the research team included Margaret Price, Rebecca Taugher, Daniel Grigsby, Jamison Ash, Austin Stark, Md Zubayer Hossain Saad, Kritika Singh, and Juthika Mandal.

The research was funded in part by grants from the National Institute of Mental Health, the American Heart Association, and the U.S. Department of Veterans Affairs.