The extinction of memories of fear is based on an unusual change in DNA

QBI researchers have discovered a modification of DNA that enhances our ability to extinguish fear.

The results, published in the journal Nature Neuroscience, could help guide the development of new treatments for anxiety disorders linked to fear.

Professor Tim Bredy explains that while fear is an important survival mechanism in which environmental signals encourage us to respond in certain ways, so does the ability to inhibit fear when it occurs. it's not necessary anymore.

"You always want to remember" there is something dangerous out there, I want to be careful ", but you do not want it to compromise your ability to function normally," he says.

The extinction of fear serves as a counterweight to fear. This involves the creation of new non-timorous memories with similar environmental elements that rival the memory of original fear.

According to Professor Bredy, the balance between fear and the extinction of fear is essential to cognitive flexibility, allowing the brain to adapt quickly to changing conditions.

In addition, an essential characteristic of both post-traumatic stress disorder (PTSD) and phobias is an impairment of the extinction of fear.

The key brain region plays a crucial role in extinguishing fear

Research has shown that a small region of the prefrontal cortex plays a vital role in the processes of learning and memorizing the extinction of fear and that the activity of neurons in this region is under narrow epigenetic control.

"Your DNA is not static," says Professor Bredy. "The chemical labels on the DNA act as a dimmer switch that can increase or decrease the expression of a gene."

Yet how the extinction of fear is regulated by such epigenetic changes is still unclear.

For a long time it was thought that cytosine (C) was the only DNA base that could be modified. But it is now clear that adenosine (A) can also be labeled chemically.

It was thought that such epigenetic modifications in the brain were still used to extinguish the dimmer of a gene, thereby reducing gene activity, says Dr. Xiang Li, a researcher at QBI.

In addition, only modifications of cytosine have been observed in badociation with learning and memory, he says.

Professors Bredy, Li and their colleagues have discovered that memories of extinction of fear are formed through a modification of adenosine that increases the activity of certain genes.

In the new study, the mice were placed in a box where they heard a particular tone, which was immediately followed by a slight foot discharge. The mice quickly badociated the sound with the shock of the foot and froze when they heard it.

To encourage the extinction of fear, the mice were then placed in a different box, where they repeatedly heard the same sound, but did not receive a foot shock.

When the mice were returned to the original box, they no longer feared the sound.

The researchers examined the DNA of fear extinction neurons in these mice and discovered the presence of a modified adenosine, N6-methyl-2-deoxyadenosine (m6dA), at over 2800 genome localizations.

In particular, the team found that m6dA accumulates in the brain-derived neurotrophic factor (BDNF) gene, known to promote learning and memory.

Interestingly, m6dA increases the expression of BDNF when extinguishing fear.

"It was thought that m6dA only plays a role in reducing genes," says Professor Bredy, "but we say, no, you have to look with a stronger magnifying glbad."

Look at these very specific neurons, he says, and look at what happens to their DNA when they are actively studying.

Dr. Li agrees. "This study is the first time that people are studying DNA modification, not only in a specific way to a cell type, but also according to the state," he said.

"The most exciting part is that we found that m6dA accumulation at BDNF only occurred in active neurons."

Epigenetic changes in the extinction of scary memories

In other words, this epigenetic change in the genomes of these neurons only occurs during the extinction of fear.

The enzyme responsible for the chemical labeling of adenosine and its transformation into m6dA is well known, and Li felt that he had to be very busy when extinguishing fear.

To confirm this, he deactivated the gene for this enzyme in a group of mice, then repeated the experiment. The mice learned to fear the sound of the tone, but they were unable to form memories of extinction.

In the end, Professor Bredy and Dr. Li want to understand the complete picture of training and memorizing the memory of extinguishing fear in the brain.

This work is an important step in this direction and in the search for effective treatments for a variety of psychiatric disorders, says Dr. Li.

"Understanding the fundamental mechanism of how gene regulation badociated with the extinction of fear could provide future targets for therapeutic intervention in anxiety disorders related to fear."

Provided by
University of Queensland