Traumatic events generate some of the most enduring forms of memories. Extreme physical or psychological harm often leads to the development of PTSD or other fear and anxiety-related disorders. Not only are these memories intensely painful, they are also extremely difficult to treat with behavioral therapy. A recent study by a group of researchers based at Harvard and MIT suggests that therapeutic modulation of epigenetic enzymes may reduce suffering from long term traumatic memories.
The most effective treatment for fear/anxiety disorders is exposure-based psychotherapy. Repeated exposure to the original traumatic memory in a safe environment allows the memory to be newly interpreted as neutral or safe, a process known as memory reconsolidation. However, memory reconsolidation only works for very recent memories; if too much time passes before intervention, the painful memories are there for good, no longer viable to memory reconsolidation.
So just how does the brain determine whether a memory is too old for reconsolidation?
In a study published in this week’s edition of Cell, a group of researchers led by Li-Huei Tsai and Stephen Haggarty at the Massachusetts Institute of Technology and Harvard, respectively, describe how epigenetic modifications of chromatin – specifically acetylation of histone 3 on lysine residues 9 and 14 – regulate neuroplasticity related gene expression that dictates whether a memory is too old for reconsolidation in mice. Further, they showed that administering a drug that increases the level of this epigenetic modification – an HDAC inhibitor – gives old memories a face-lift, making them appear new, and thus, much more susceptible to reconsolidation through psychotherapy.
Using Pavlovian fear conditioning, researchers instilled traumatic memories in mice by placing them in an unfamiliar cage and giving them an electrical shock. The mice quickly became terrified of the cage and when returned to the setting, they froze in anticipation of the shock. Mice that were repeatedly returned to the cage one day later with no shock stopped reacting in fear. However, those that were returned to the cage 30 days after the initial shock still reacted even after repeated tries, their memories too old for reconsolidation.
Prior work in mice had shown that neuroplasticity was regulated by histone acetylation, and Tsai and her collaborators hypothesized that this epigenetic control mechanism might determine whether a memory is amenable to modification through therapy. They tested an inhibitor of histone deacetylase 2 (HDAC2), and found that, along with decreased histone acetylation levels in their hippocampi, treated mice were able to overcome their long term, entrenched memories of fear through exposure based therapy; i.e., their memories became plastic again, and susceptible to reconsolidation.
Furthermore, they identified nitrosylation of HDAC2, and its resulting dissociation from chromatin as a possible mechanism for controlling its activity. Thus, nitrosylation of HDAC 2 may serve as a sort of on-off switch that denotes the age of a memory.
According to the researchers, this is the first study to attenuate older, more remote fear memories in an animal model. If the findings apply to humans, the potential uses of HDAC inhibitors would be innumerable. Combining psycotherapy with a drug that augments memory retrieval could aid in the treatment of PTSD, panic disorder, phobias, and numerous other anxiety and fear-related disorders.