When confronted with danger, fear spurs a person into defensive actions. This is invaluable as a survival mechanism; however, there is little reason for fear to persist once a threat passes.
The brain neutralizes the memory of that feeling with something called “fear extinction.” This process involves a non-fearful memory with similar circumstances competing with the fear memory to try to suppress it.
A new study finds that the ability to neutralize fear depends on the flexibility of one’s DNA.
“Fear memories need to be plastic. They can be very useful for survival, but they can also get in the way of normal functioning,” says Dr. Paul Marshall of the University of Queensland, Brisbane, Australia. He is the lead author of the study, which the team published in Nature Neuroscience.
There is more than one way in which the strands in DNA’s well-known double-helix structure may twist.
“The most common and most widely recognized form is the ‘B-DNA’ double helix, which twists in a clockwise direction,” says Marshall. “But, with a slight rearrangement of how DNA base-pairs connect with one another, DNA can form other helical structures, such as Z-DNA.”
To understand how this can happen, the researcher offers the following explanation: hold out the hands, palms down, so that the thumbs touch. In this position, the thumbs represent the bases of two DNA strands — and this is how they connect in the B-DNA structure.
Now move the pinkies downward, twisting the wrists so that the thumbs spread apart, the palms face up, and the pinkies touch — this simulates a Z-DNA twist. Continuing to twist the wrists so that the back of the hands face each other and the thumbs once again touch would represent a full twist back into a B-DNA position.
Z-DNA forms less frequently than B-DNA, and only for specific sequences and over a short region. Only recently have scientists begin to figure out why it exists at all.
“We now know that Z-DNA appears wherever genes are being turned on,” says Marshall. He adds, “It’s a marker of gene activity.”
This structure appears to have something to do with memory. “Scientists have also noticed a connection between Z-DNA and certain diseases, including cancer, and high levels of Z-DNA have been found in the brains of people who had Alzheimer’s Disease,” Dr. Marshall says.
Dr. Marshall and senior author Prof. Tim Bredy became intrigued by the brief periods during which Z-DNA structures exist, perhaps because it suggested a possible correspondence with the rapid changes in gene activity seen during the creation of fear-extinction memories.
To investigate further, the researchers took a closer look at an enzyme called ADAR1. Experts know that this enzyme recognizes and attaches to Z-DNA. There is also evidence that it can twist Z-DNA back into B-DNA.
Finally, ADAR1 is involved in RNA editing that influences a cell’s protein functions. Says Dr. Marshall, “ADAR1 is doing a lot of things at once, but that’s what makes it interesting.”
Working with mice, the researchers switched off the gene for ADAR1 in a part of the brain involved in fear-extinction.
Although the mice were still capable of forming fear memories, they could no longer develop their neutralizing counterparts. Turning off ADAR1 broke their capacity for fear extinction.
The scientists also experimented with mutated ADAR1 that no longer functioned very well. This, too, prevented the mice from successfully performing fear extinction.
The researchers conclude that, in mice, Z-DNA quickly forms when they experience fear. Then, during fear extinction, ADAR1 binds to the Z-DNA. This, in turn, increases RNA editing that modifies the cell function and thus the memory. Finally, ADAR1 flips the DNA back into the more normal B-DNA structure.
If the results of the mice experiments also apply to human beings, “It seems that the more easily you can switch between DNA structures,” says Marshall, “the more plastic your memory is.”
“Flexibility of DNA structure, flexibility of memory.”
– Dr. Paul Marshall
Bredy notes that the ability to feel fear and then successfully perform fear extinction is key to avoiding conditions such as PTSD and phobias.
The research suggests that in order to develop effective therapies for such conditions, it is essential to understand fear extinction.
