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Drugs Found with Potential to Replace Traumatic Memories

Li-Huei Tsai

Li-Huei Tsai (Massachusetts Institute of Technology)

Neuroscientists at Massachusetts Institute of Technology found a class of drug compounds, some of which are now in use, can erase fear-causing memories in lab mice, and thus could treat post-traumatic stress disorder. The team from the lab of Li-Huei Tsai in MIT’s Picower Institute for Learning and Memory published its findings today in the journal Cell (paid subscription required).

Post-traumatic stress disorder (PTSD) is believed to result from the carry-over of fear from situations where an individual is physically harmed or threatened with harm. The condition can also arise when people witness physical harm inflicted on loved ones. Dealing with these fears often involves seeking out support from friends or family, or other behavioral coping strategies. National Institute of Mental Health estimates some 7.7 million American adults suffer from PTSD.

These behavioral interventions can be limited by the entrenched nature of traumatic memories, particularly memories going back a long period of time. Tsai’s team, that includes participants from Washington University in St. Louis and Massachusetts General Hospital in Boston, studied the ability of a type of drug known as histone deacetylase or HDAC inhibitors to make the brain more plastic or malleable, thus more capable of overriding the painful earlier memories with newer memories.

In this study, the team created fear-producing conditions for lab mice by delivering electric shocks when entering a separate chamber. As expected, the experience caused the mice to fear entering the chamber, as evidenced by freezing when approaching the chamber’s entrance.

The researchers then stopped shocking the mice to extinguish the fears. Where the mice were shocked only a day earlier, the mice were able to resume their previous non-traumatized behavior. Where the fear-producing training had occurred 30 days earlier, however, the mice could not stop freezing at the chamber’s entrance.

Earlier work by Tsai and others show the formation of memories causes changes in the complex of DNA and proteins in the chromosomes of nerve cells. In the new study, the researchers found the DNA and proteins in genes of nerve cells associated with memories experienced chemical changes in other proteins known as histones, when the shocks were administered to mice in the fear-producing chamber.

When the shocks were removed from the chamber, the fear-producing changes in the histone chemistry were overriden by new memories, which the team attributed to inactivation of a protein known as HDAC2. When HDAC2 is inhibited, new memories can form, helping create an histone chemistry in the nerve cells less associated with fear.

However, Tsai and colleagues found this regeneration process to occur only in the nerve cells of mice who experienced the shocks one day earlier. Among the mice who experienced the shocks 30 days earlier, there were no such changes in histone chemistry. In these cases the HDAC2 protein continued to block production of new memories, keeping the fear-producing memories intact.

The researchers treated the mice experiencing the shocks 30 days earlier with an HDAC2 inhibitor compound and found mice were able to extinguish the painful memory behavior as easily as the mice who experienced the shocks only one day earlier. The team found the HDAC2 inhibitor treatments activated genes in the test mice known as immediate early genes, associated with the plasticity of nerve cells and linked to brain processes involved in learning and drug abuse.

Activation of immediate early genes in the mice then stimulated other genes associated with memory formation. The researchers also found the mice developed more neural connections in the hippocampus, the part of the brain where memories form.

Tsai notes that some HDAC inhibitors are already approved by the FDA to treat cancer, which she hopes will encourage other researchers to advance the drug as a therapy for PTSD. “I hope this will convince people to seriously think about taking this into clinical trials and seeing how well it works,” says Tsai in a university statement.

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