Traumatic memories can last a lifetime. One common method for treating individuals with haunting memories is a form of cognitive behavioral therapy called exposure-based therapy, which involves repeatedly exposing patients to the original fear-inducing thought or event in a safe environment. In a process called memory reconsolidation, the reactivated memory becomes susceptible to disruption and can be overwritten by new memories that do not cause anxiety. But exposure-based therapy is not always effective in patients with anxiety disorders such as post-traumatic stress disorder (PTSD).
In a study published January 16th in Cell, Li-Huei Tsai of the Massachusetts Institute of Technology and her collaborators found that compounds called histone deacetylase inhibitors (HDACis) can weaken long-term fear memories in mice when combined with exposure-based therapy (1). These compounds interfere with the function of histone deacytalases—enzymes that remove acetyl groups from histones, allowing them to wrap DNA more tightly. The loosening of the chromatin caused by HDACis increases the access of transcription-initiating enzymes to genes involved in memory and learning. This epigenetic process could have stable, broad, and long-lasting effects on gene expression, potentially making it suitable for permanently modifying traumatic memories.
“This study is a very important step towards developing additional treatments for PTSD, which would prove crucial in helping more people who suffer from this disorder,” said Marie-H. Monfils, a fear memory expert at the University of Texas at Austin, who was not involved in the research.
In the new study, Tsai and her team repeatedly exposed mice to a tone paired with a foot shock so that the animals would later freeze in fear upon hearing the tone by itself. Using an extinction paradigm, which is analogous to exposure-based therapy, the researchers then repeatedly exposed the mice to the tone without delivering the foot shock. When the extinction paradigm took place one day after the mice were exposed to the tone-shock pairing, it was effective at reducing the fear response to the tone. But this protocol was not effective when it occurred one month after the mice learned to associate the tone with the shock.
On the other hand, exposure-based therapy combined with HDACi treatment was effective at reducing fear, even when given one month after the mice were exposed to the tone-shock pairing. Moreover, HDACi treatment increased the expression of genes that affect the communication between neurons in the hippocampus—a brain region that plays a crucial role in learning and memory. However, HDACi treatment alone did not produce these changes in gene expression or behavioral benefits in mice with one-month-old fear memories, highlighting the importance of combining cognitive behavioral and pharmacological strategies to effectively treat the most enduring traumatic memories.
“This is the first report of a successful effort to attenuate remote fear responses in an animal model of fear memories,” said Gary Kaplan, a PTSD expert at the Veterans Affairs Boston Healthcare System and the Boston University School of Medicine, who was not involved in the research. “The novelty of the findings is that the authors focused on the molecular and circuit-level mechanisms of remote fear memories and targeted novel treatment approaches towards erasing them. This is an exciting preclinical finding that could potentially have a large translational impact.”
1. Gräff J, Joseph NF, Horn ME, Samiei A, Meng J, Seo J, Rei D, Bero AW, Phan TX, Wagner F, Holson E, Xu J, Sun J, Neve RL, Mach RH, Haggarty SJ, Tsai LH. 2014. Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories. Cell 156(1-2):261-76. doi: 10.1016/j.cell.2013.12.020.