“I Am No Longer Haunted By That Awful Memory” – New Epigenetic Drug Treatment May Erase Painful Memories

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 Is it possible for a drug to dampen a traumatic memory? It may be, as researchers are discovering that a fundamental epigenetic mechanism is responsible for long-term fear memory.

Neuroplasticity, also called brain plasticity, refers to the changes in neural connections such as synapses and neural pathways as a result of changes in behavior, environmental exposure and neural processes (1,2).  While it was once believed that the brain is a physiologically static organ and its networks were fixed, research over the last two decades has revealed that the brain constantly changes and adjusts throughout our lifetime (2). These changes occur during normal brain development through adulthood and also as an adaptive mechanism to environmental pressures such as injury or trauma (1,2).

Histone acetylation is a fundamental epigenetic mechanism that controls brain plasticity by modifying gene expression. Histone acetylation occurs by the enzymatic addition of an acetyl group (COCH3) from acetyl coenzyme A. The process of histone acetylation is tightly involved in the regulation of many cellular processes including chromatin dynamics. Histone acetylation promotes a euchromatic state in which chromatin is more loosely packed and therefore accessible for transcription. Memory plasticity of the brain results in short-term (recent) and long-term (remote) memory. Traumatic experiences, such as physical or psychological abuse, can generate lasting memories associated with fear and anxiety — such as post-traumatic stress disorder (PTSD) — which are difficult to treat and erase.

Recent (short-term) memory fear response has been shown to be effectively treated using exposure-based therapy in which reactivation of the traumatic memory initiates a fixed window of time during which the memory can be modified.  This is called memory reconsolidation. This technique has been shown to be effective in humans and rodents and has successfully been used to treat drug addiction. However, it is not known if this same therapy is effective for treating remote, long-term fear memory.

Scientists at the Massachusetts Institute of Technology in Cambridge found that remote fear memories in mice exposed to trauma could not be altered despite taking advantage of the memory reconsolidation time window.  Instead, their results showed that by inhibiting the enzyme that catalyzes the removal of acetyl groups from histone residues, called histone deacetylases (HDACs), along with exposure-based therapy during memory reconsolidation renews brain neuroplasticity and allows updating of even remote traumatic memories.

Their findings are summarized below:

  • In contrast to recent memory, remote memory recall does not activate nitrosylation of HDAC2 or acetylation-mediated neuronal plasticity in the hippocampus.
  • Nitrosylation of HDAC2, which results in its dissociation from chromatin, is a critical event for effective updating of remote memories during reconsolidation
  • Treatment with an HDAC inhibitor following remote memory recall can compensate for a lack of HDAC2 nitrosylation, allowing acetylation-mediated gene expression and promoting neuroplasticity
  • HDAC inhibitor-supported exposure-based therapy leads to increased neuroplasticity on a functional and structural level.
SEE ALSO:   Epigenetic Regulation and Drug Therapy Could Offer New Treatment for Kidney Stones

Source: Graff et al, Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories, Cell 156, 261-276 (2014).

References: 

1) Neuroplasticity. (2014, January 24). In Wikipedia, The Free Encyclopedia.

2) Brain Plasticity: What Is It?, (2014, January 24)

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