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Drug Permits the Extinction of Distant Traumatic Memories

January 17, 2014. Traumatic memories often plague soldiers and victims of rape and other violent crimes for years, but a new study in mice suggests that drugs known as HDAC inhibitors can help reduce the emotionally troubling aspects of old memories. Led by Li-Huei Tsai of the Massachusetts Institute of Technology, Boston, and published January 16, 2014, in Cell, the findings could serve as the basis for new treatments for anxiety disorders such as post-traumatic stress disorder (PTSD).

A strong emotional component makes the disabling traumatic memories of earlier psychological or physical harm especially enduring and hard to treat. Exposure-based therapeutic approaches, in which the patient is repeatedly re-exposed to the traumatic stimulus in a safe environment, can be helpful for anxiety disorders like PTSD. However, the success of the exposure therapy often depends on the age of the traumatic memory: Older memories are harder to extinguish than newer ones.

Although there is no direct application of these results to schizophrenia, the findings raise hope for the possibility that long-standing psychological problems may be reversible through combinations of drug and behavioral therapy.

Stubborn memories
To determine why exposure-based therapy isn’t as effective for older trauma, first author Johannes Gräff and colleagues employed Pavlovian contextual fear conditioning and extinction paradigms in mice. By repeatedly administering a foot shock in a particular chamber, the researchers trained the mice to associate the box with the trauma, so that later, just being there (even without a shock) elicited a fear response of freezing. The mice were then exposed to an extinction protocol similar to exposure-based therapy: They were repeatedly placed in the chamber but not shocked to see if they could unlearn the association between the two.

The mice successfully lost their fear of the chamber when the extinction protocol was given one day after fear conditioning (modeling recall of a recent traumatic memory) as well as when it was administered one month later (similar to an older memory). However, when tested again one month after the end of the extinction protocol, only the mice who received the "exposure therapy" the day after the fear conditioning had lost their fear of the cage. Those who had spent a month with the memory before the extinction protocol showed a spontaneous recovery of fear.

Absent acetylation
Consistent with the fact that a recall of the traumatic memory was necessary for this process, the uncoupling of the conditioned stimulus and fear is thought to be due to a “reconsolidation window,” a brief period after recall of the traumatic memory when an update to the memory is possible (Monfils et al., 2009). Neuronal plasticity is thought to mediate the updating of a memory with new information during the reconsolidation window (Hartley and Phelps, 2010), so Gräff and colleagues reasoned that there may be more limited neuroplasticity associated with older traumatic memories.

To test their hypothesis, they used immunohistochemistry to measure histone acetylation—an epigenetic modification that appears to be key to some aspects of neuroplasticity—in the hippocampus, a brain area linked to contextual memory formation. Acetylation levels were reduced in the mice that recalled an older memory compared to those with a more recent memory of the shock. This result suggests that the transient hippocampal neuroplasticity (mediated by histone acetylation) underlying the memory modification did not occur during the recall of older memories.

Delving deeper into the underlying mechanism, the researchers found that both the acetylation and expression of a key player in neuronal plasticity, the immediate early gene cFOS, were lower in the older memory recall group than in the recent memory recall group. Further experiments revealed that this acetylation during recent memory recall was due to histone deacetylase 2 (HDAC2) nitrosylation. Administration of a nitric oxide donor before remote memory recall allowed for complete fear extinction, suggesting that the traumatic memory was successfully updated. However, donor administration in conjunction with viral overexpression of a non-nitrosatable form of HDAC2 abolished this effect.

The HDAC advantage
Moving beyond the mechanism underlying the updating of recent but not older memories, Gräff and colleagues found that administration of the HDAC2 inhibitor CI-994 to fear-conditioned mice one hour after remote memory recall permitted an update to the traumatic memory, evidenced by complete fear extinction. In addition to a modified memory, mice treated with CI-994 had higher hippocampal acetylation levels than vehicle-treated controls, along with lower levels of HDAC2 activity. In addition, RNA sequencing showed that nearly 200 genes with putative roles in neuronal plasticity were expressed at higher levels in hippocampal extracts from CI-994 mice.

In fact, the increased expression of neuroplasticity-related genes appeared to correspond to elevated neuronal plasticity in the hippocampus. CI-994-treated mice showed increased metabolic activity in the hippocampus but not in the piriform cortex (an area not involved in the formation of contextual fear memories), as well as improved long-term potentiation (LTP). Structural plasticity of the hippocampus was also enhanced, as demonstrated by a higher number of dendrites and spines, increased dendritic branching, and an increased density of functional synapses.

“Our finding of regained neuroplasticity strongly speaks in favor of a new period of learning during memory extinction,” conclude the authors, and suggests that HDAC inhibitors given during memory reconsolidation may help treat anxiety disorders like PTSD. Importantly, treatment with CI-994 alone, without the extinction protocol, had no effect on older traumatic memory updating, suggesting the HDAC inhibitors would only be effective in combination with exposure-based therapy.—Allison A. Curley.

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 L. Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell. 2014 January 16;156:261-276. Abstract

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