For years, neuroscientist Li-Huei Tsai has been unraveling the brain circuits that underlie memory, searching for approaches that might be helpful in treating Alzheimer’s disease. In 2007, the Massachusetts Institute of Technology scientist identified an experimental drug that could restore lost memories in mice. Lately, she has been wondering whether that kind of drug might be useful to help people forget traumatic events that cause fear and anxiety.
In a study published Thursday in the journal Cell, Tsai and colleagues used a single dose of the drug, called an HDAC inhibitor, to help mice extinguish a fearful memory of a traumatic event that took place in the distant past.
The idea is simple: one therapy for post-traumatic stress disorder is to re-expose people to the trigger in a safe setting. The hope is that patients will rewrite the memory and learn not to fear the experience. But such therapies don’t always work and the effects may not last, so Tsai wondered if perhaps a dose of a drug that made the brain more malleable and plastic could help people learn the new association and permanently replace the fearful memory.
In studies with mice, Tsai and colleagues first repeatedly exposed the animals to a sound followed by a foot shock, until the mice began to freeze with fear in response to the tone alone. Then, researchers began to try and erase the memory by exposing the mice to the tone without the shock.
With one group of mice, researchers tried to extinguish the memories a day after the fearful memory was made, while in another they waited a month—with very different results. In mice that had only recently learned the association, the re-exposure regime successfully extinguished the memory. But in mice for whom the initial memory was in the distant past, it didn’t work very well.
When they paired the re-exposure therapy with an injection of the HDAC inhibitor drug that they showed helped prime their brains to learn the safe association, they found that the mice were better able to extinguish the fearful memory.
“If we combine this behavioral therapy with one single dose of HDAC inhibitor treatment, then we see this unbelievable, amazing effect on extinguishing the old fear memories’’ in mice, Tsai said. “This is really fascinating because we do not just see at the behavioral level—the animal showed this greatly improved behavior, but also at the functional and structural level in the brain.’’
Tsai does basic research, but hopes that the findings will be carried forward in the laboratories of scientists who study post-traumatic stress disorder, anxiety problems, and even addiction.
One of the obstacles to developing the HDAC inhibitors for use in treating people with memory problems, Tsai said, is that they would likely have to be given chronically and there is worry about the side effects they could cause after long-term use. Those risks would likely diminish greatly, she noted, if only one dose needed to be given, in the context of extinguishing a fear memory. It also might spur further development and work on such drugs, meaning safer versions could be developed in the future.