Researchers at the University of Queensland have discovered a DNA modification that enhances our ability to extinguish fear. The findings, published in the journal Nature Neuroscience, could help guide the development of new treatments for fear-related anxiety disorders.
Fear extinction works as a counterbalance to fear and involves the creation of new non-fearful memories with similar environmental elements that compete with the original fear memory. The balance between fear and fear extinction is critical to cognitive flexibility, enabling the brain to rapidly adapt to changing conditions.
“You still want to have that memory of ‘there's something dangerous there, I want to be careful,’ but you don't want it to compromise your ability to function normally,” says senior author Timothy Bredy.
According to Bredy, there are tags on DNA bases that can turn gene expression up or down without altering the DNA sequence. He and his team discovered how these chemical tags help regulate fear extinction.
“For a long time, it was thought that only one DNA base—cytosine—could be modified, and that these chemical changes in the brain reduce gene expression,” says first author Xiang Li. “We have now discovered that adenosine, another DNA base, can also be chemically tagged, and that fear extinction memories form thanks to a deoxyadenosine (or adenine) modification that increases the activity of certain genes.”
The researchers made the discovery by placing mice in a box where they heard a particular tone, which was immediately followed by a mild foot-shock. The mice quickly associated the sound with the shock. The mice were then placed in a different box, where they repeatedly heard the same sound but did not receive any foot-shocks. Once returned to the original box, the mice were no longer afraid of the sound.
The team examined the DNA from those mice—particularly the DNA from neurons known to be involved in the fear extinction process—and found modified adenine at more than 2,800 locations, a change that only occurs during the fear extinction process.
To confirm the importance of the adenine modification to fear extinction, they switched off the gene that makes the modification in a group of mice and repeated the experiment. The mice were unable to form fear extinction memories.