Finding a way to erase harmful memories

MIT lab experiments could lead to post-traumatic treatments

MIT neuroscientist Li-Huei Tsai.Essdras M Suarez/ Boston Globe/File 2010/Globe Staff

In mind-control experiments over the past few years at the Massachusetts Institute of Technology, scientists have planted a false memory, activated a real memory, and, now, a team announced Thursday, erased a memory altogether.

Science fiction is real — at least for mice.

In the latest research finding, scientists reported that a single dose of an experimental drug combined with behavioral therapy could help mice forget a traumatic event that took place in the distant past.

The work is basic research that is far from being applied to people, but it is the latest in a series of astonishing demonstrations that are providing scientists new insight into the fundamental question of how memories are formed and persist. Ultimately, they hope these experiments will lead to new and more precise ways to treat conditions in which it would be better to forget, such as post-traumatic stress disorder, and ones in which memories are lost.

The quest to erase a memory began, curiously enough, with an effort to retrieve lost ones. Li-Huei Tsai, director of the Picower Institute for Learning and Memory at MIT, has long been searching for approaches that might be helpful in treating Alzheimer’s. In 2007, she identified an experimental drug that could restore lost memories in mice, apparently by activating processes in the brain involved in memory formation and learning. That work has continued, but she also began wondering whether that same type of drug could be used to help extinguish memories of traumatic events that cause fear and anxiety.

The idea was simple: One therapy for post-traumatic stress disorder is to re-expose people to the trigger of their fear, but in a safe setting. The hope is that patients will overwrite the bad memory with the new experience and learn not to fear the trigger. But such therapies don’t always work, so Tsai wondered whether a dose of the drug could help the brain replace the fearful memory.

In the study published in the journal Cell, Tsai and colleagues tried an experimental drug from a class of compounds called HDAC inhibitors, which activate genes involved in learning and 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 [a response] at the behavioral level . . . but also at the functional and structural level in the brain.”

Tsai and colleagues first exposed the animals to a stimulus — either a sound or putting them in a box — followed by a foot shock, until the mice began to freeze with fear in response to the tone or the box alone. Then, researchers began to try to erase the memory by exposing the mice to the tone or box 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; mice no longer froze in place. But in mice for which the initial memory was in the distant past, it didn’t work very well. The researchers found that the difference was accounted for by differences in gene activity. When recalling recent memories, the hippocampus, a part of the brain involved in memory, became more malleable. But recalling remote memories did not trigger the same changes.

When the scientists paired the re-exposure therapy with an injection of the HDAC inhibitor drug, they found that the mice were markedly better at forgetting that the tone or box signaled pain. The drug, they found, induced changes in the metabolism and connectivity of brain cells.

Dr. Jelena Radulovic, a professor of psychiatry at Northwestern University’s Feinberg School of Medicine, who was not involved in the research, said the work was outstanding.

“I particularly like it because of the new questions which will be asked after this paper, and because the mechanisms that were discovered will provide us with new tools to study memory and maybe tackle fear responses in patients,” she said.

The insight also comes at a time when neuroscientists are learning more and more about the specific brain circuits involved in memory. Last year, a team led by Nobel laureate Susumu Tonegawa of MIT showed that optogenetics, a transformative genetic technique that allows researchers to trigger specific brain cells with a laser, could be used to give a mouse a false memory of having its foot shocked. In 2012, Tonegawa showed that it was possible to activate a memory using the same technique.

Those demonstrations in mice are not practical for use in people because the technique requires genetic manipulation of brain cells and laser light to be funneled into the brain.

Tsai hopes that the work on using HDAC inhibitors to erase memories, however, will spur pharmaceutical companies to try developing drugs that use the same approach. One obstacle to using HDAC inhibitors to treat memory loss has been the potential for side effects, because of the need to take the drugs for a long time. Those risks would probably be diminished if only one dose was needed to extinguish a fear memory.