Over a lifetime, the human brain stores countless memories. Some are mundane and practical, others are subjective, and some influence our thinking and behaviour. Not all of them are good.
Post-traumatic Stress Disorder (PTSD) encompasses intrusive traumatic memories, which dictate behavior. Currently, PTSD is treated with antidepressants and cognitive therapy, but it is often treatment resistant, and dropout rates are consistently high. Consequently, exposure-based therapies have been developed to reconstruct memories in order to elicit less distress. However, research has focused on recent traumas, leaving it unclear whether reconsolidation treatments would be effective for distant memories, which are more stable and enduring than recent ones, and so more difficult to reinterpret. Recent rodent research suggests that it may be possible to develop a drug that facilitates reconsolidation, allowing exposure therapy to be more effective for remote traumas.
Using typical Pavlovian fear conditioning and extinction paradigms, the researchers first investigated the disparity between recent and remote memories. They showed that extinction training was significantly less effective amongst mice that had received fear conditioning 30 days ago than amongst those that had been conditioned the previous day. Mice with remote memories also showed recovery of the fear memory, indicating that the extinction training was unsuccessful.
To investigate what made the remote memories more robust, post-mortem chemical analyses were carried out. By definition, successful memory reconsolidation induces a degree of neuronal plasticity, as the memory is represented differently. Therefore, if extinction training was successful, chemical indicators of plasticity should be observable. A potential indicator was the acetylation of histone proteins in the hippocampus, which sets off several reactions causing long-term changes to gene expression, consistent with an enduring memory alteration. Indeed, mice with recent traumatic memories, for whom extinction training was successful, had higher levels of histone acetylation than mice with remote memories.
These results led the researchers to test whether increasing the likelihood of acetylation would affect the outcome of extinction training. Histone Deacetylase Inhibitors (HDACis) were administered for this purpose. This time, mice with remote memories showed consistent, successful extinction and other, related indicators of plasticity that were not seen in the original remote memory group. Incidental metabolic effects on extinction were ruled out. Importantly, administering the HDACis did not attenuate the traumatic memory by itself – extinction training was always necessary.
Inevitably, however, as this was a preclinical trial using mice, this research has several shortcomings. It is unclear whether HDACis would evoke similar effects in humans, and developing a targeted drug without serious side effects will take time. Other brain areas may make unexpected contributions in humans. Also, in this study, memory recall was achieved by placing mice in the environment in which the memory was formed. Conversely, exposure therapy relies on patients being able and willing to mentally recall the event, and any emotional detachment from patients may limit the drug’s effect.
Nonetheless, this is a promising avenue of research, which not only offers the possibility of better treatments for PTSD, but advances our understanding of how memories are represented in the brain.
Written by Lexie Thorpe
Gräff J., Joseph N., Horn M., Samiei A., Meng J., Seo J., Rei D., Bero A., Phan T. & Wagner F. & (2014). Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories, Cell, 156 (1-2) 261-276. DOI: 10.1016/j.cell.2013.12.020
Schottenbauer M.A., Glass C.R., Arnkoff D.B., Tendick V. & Gray S.H. (2008). Nonresponse and Dropout Rates in Outcome Studies on PTSD: Review and Methodological Considerations, Psychiatry: Interpersonal and Biological Processes, 71 (2) 134-168. DOI: 10.1521/psyc.2008.71.2.134
Images made by Jooyeun Lee.