New study identifies drug that could improve treatment of post-traumatic stress disorder
Nearly 8 million Americans suffer from posttraumatic stress disorder (PTSD), a condition marked by severe anxiety stemming from a traumatic event such as a battle or violent attack.
Many patients undergo psychotherapy designed to help them re-experience their traumatic memory in a safe environment so as to help them make sense of the events and overcome their fear. However, such memories can be so entrenched that this therapy doesn't always work, especially when the traumatic event occurred many years earlier.
MIT neuroscientists have now shown that they can extinguish well-established traumatic memories in mice by giving them a type of drug called an HDAC2 inhibitor, which makes the brain's memories more malleable, under the right conditions. Giving this type of drug to human patients receiving psychotherapy may be much more effective than psychotherapy alone, says Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory.
"By inhibiting HDAC2 activity, we can drive dramatic structural changes in the brain. What happens is the brain becomes more plastic, more capable of forming very strong new memories that will override the old fearful memories," says Tsai, the senior author of a paper describing the findings in the Jan. 16 issue of Cell.
The new study also reveals the molecular mechanism explaining why older memories are harder to extinguish. Lead authors of the paper are former Picower Institute postdoc Johannes Graff and Nadine Joseph, a technical assistant at the Picower Institute.
Genes and memories
Tsai's lab has previously shown that when memories are formed, neurons' chromatin - DNA packaged with proteins - undergoes extensive remodeling. These chromatin modifications make it easier to activate the genes necessary to create new memories.
In this study, the researchers focused on chromatin modifications that occur when previously acquired memories are extinguished. To do this, they first trained mice to fear a particular chamber - by administering a mild foot shock - and then tried to recondition the mice so they no longer feared it, which was done by placing the mice in the chamber where they received the shock, without delivering the shock again.
This training proved successful in mice that had experienced the traumatic event only 24 hours before the reconditioning. However, in mice whose memories were 30 days old, it was impossible to eliminate the fearful memory.
The researchers also found that in the brains of mice with 24-hour-old memories, extensive chromatin remodeling occurred during the reconditioning. For several hours after the mice were placed back in the feared chamber, there was a dramatic increase in histone acetylation of memory-related genes, caused by inactivation of the protein HDAC2. That histone acetylation makes genes more accessible, turning on the processes needed to form new memories or overwrite old ones.
In mice with 30-day-old memories, however, there was no change in histone acetylation. This suggests that re-exposure to a fearful memory opens a window of opportunity during which the memory can be altered, but only if the memory has recently been formed, Tsai says.
