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A memory-weakening drug has shown promise in mice. Could Eternal Sunshine of the Spotless Mind someday be a reality? (Photo courtesy Focus Features)

A New Drug Could Help You Forget Long-Term Traumatic Memories

The drug has allowed mice to replace old anxiety-filled memories with new, harmless ones

In the 2004 sci-fi film Eternal Sunshine of the Spotless Mind, a pair of characters end their stormy romance with a bizarre solution: They pay a company called Lacuna, Inc. to erase all memory of the relationship from their brains as they sleep.

When the movie came out, the premise was pure fantasy. But a group of neuroscientists from MIT and elsewhere have recently identified a drug that could someday help us dislodge traumatic memories in the real world. 

The drug, a histone deacetylase inhibitor (HDACi), interferes with one of the ways that brain cells record memories, by precisely placing proteins called histones on certain segments of DNA, affecting which genes are expressed. The hope is that, using this principle, doctors could someday prescribe drugs that aid in the treatment of post-traumatic stress disorder (PTSD).

Right now, those seeking relief from PTSD typically use exposure therapy, in which a patient mentally revisits a traumatic memory in hopes of overcoming the anxiety associated with it. But "the options for treatment of PTSD are very limited. There's really no good medication, and exposure-based psychotherapy is often ineffective for older memories," says Li-Huei Tsai, the lead author of a new study documenting the research, published in the journal Cell. "This study suggests that mainuplating histone-based mechanisms involved in memory deserves a serious investigation, and could someday be applied to patients."

Exposure therapy usually involves intentionally re-experiencing stimuli associated with a traumatic memory in hopes of replacing the original memory with a new, harmless one. A war veteran experiencing PTSD, for instance, might put on a pair of virtual-reality goggles that portray a traumatic war experience, while consciously aware that he or she is safe in a therapist's office.

For relatively recent memories, this has been found to be relatively effective, in part because of the brain's natural neuroplasticity that allows it to replace associations. After a multi-year period of time, however, it seems that old memories harden, and can't be dislodged by new ones.

Interestingly, the same pattern has been observed in mice—and the use of an HDACi appears to be a way of lengthing the key period of neuroplasticity, which if it's able to be applied to humans could dramatically lengthen the time period for which exposure therapy is effective.

Researchers demonstrated this effect on neuroplasticity through trials in which mice were exposed to a brief electric shock just after hearing a loud tone, which forces them to associate the sound with a traumatic event. Normally, if the mice hear the same sound a day later without being shocked, they're able to replace the old memory with the new one, and will stop freezing up in fear when they hear the sound again. However, if a month passes before they listen to the sound again, the association between sound and pain is mentally cemented and permanent.

When the researchers examined activity going on at the molecular level, they noticed that the activity of histone proteins on DNA played a key role in the neuroplasticity that allowed the exposure to sound without a shock to dislodge very recent traumatic memories and replace them with new ones. This gave the researchers an idea: to use a drug like HDACi (currently used in research on cancer treatments) to artificially increase neuroplasticity for older memories by altering how histone proteins attach to DNA.

To do so, they exposed mice to the same tone-and-shock regimen, waited about a month without playing the tone, then injected them with an HDACi and tried to dislodge the memory with the same exposure treatment as before. This time, it worked. The mice didn't freezing up in terror when they heard the sound. On a cellular level, the researchers observed the same patterns that had normally only occured when day-old memories were replaced.

Obviously, humans are not mice, but previous research has suggested that the same principles related to neuroplasticity seem to apply to exposure therapy in both species. That's why the researchers suggest that combining an HDACi with conventional rexposure therapy could someday be a way to weaken the hold of older traumatic memories in people suffering from PTSD, replacing them with new memories devoid of anxiety.

"Persistent fearful memories are a problem very relavent to our society. A lot of people suffer from an inability to subside very traumatic events in their lives," Tsai says. "Combining this sort of treatment with exposure-based psychotherapy might eventually provide an option for them."

There are still a whole lot of hurdles to be cleared before this is a possibility. The MIT researchers—neuroscientists working in a rapidly emerging field called epigenetics, involving the regulation of gene expression—are attempting to answer basic questions about how the brain encodes memories. They're not researchers that develop drugs, so it'd likely be another team that carries the research forward, and it would first be necessary to prove that this sort of novel approach is safe for humans.

But it's worth noting that the researchers extended the mice's natural forgetting process, allowing the mice to replace a traumatic memory a month—rather than just a day—after it was formed. It's not as radical as Lacuna, Inc. magically erasing memories à la Eternal Sunshine, but it's also a lot more similar to the processes that already go on inside the brain, and therefore a much more realistic future treatment.

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