Genetic link to fear memories found hidden in ‘junk DNA’ of mice

Using a powerful new sequencing technique, researchers have discovered genes in mice that help quell fear-related memories. These genes are hidden in relatively unknown regions of the mammalian genome that we have termed “junk DNA”.

“It’s like harnessing the power of the Hubble telescope to peer into the unknown of the brain,” said University of Queensland neuroepigeneticist Timothy Bredy, describing a new technique that can zoom in on areas of the genome that have escaped scrutiny. review so far.

Genes may be involved in fear disorders such as phobias and post-traumatic stress disorder (PTSD), which affect 15 million adults in the United States each year.

We all have those memories that send jolts of terror up our spine, that make us avoid a subject (spiders, heights) or certain situations (public speaking). It is a healthy learning response, heavily selected because it protects us physically or socially.

But in normal situations, repetitive exposure to these fear signals, without anything bad happening, should, over time, decondition your fear response.

Fear and its extinction take place in the infralimbic prefrontal cortex of our brain, and recent research has traced this process back to the transcriptional machinery and epigenetics – changes around DNA that alter the way it is expressed. but not the DNA sequence itself.

For some of us though, this downregulation of fear never happens.

Fears stubbornly get bogged down, becoming a mind killer that prevents our brains from letting us rationally deal with these things or move on from scary events.

Using fear-conditioned mice and a novel RNA sequencing technique, the researchers took a take a closer look at molecules called long non-coding RNA (lncRNA) that have previously been implicated as regulatory genes linked to conditions such as drug addiction, depression, schizophrenia and anxiety. Forty percent of the lncRNAs identified so far are found at higher concentrations in neurons.

The researchers found that a class of these genes, which they called eRNAs, expressed in the infralimbic prefrontal cortex of mice, are involved in linking our experiences to the regulation of gene expression.

A gene, called ADRAM (activity-dependent lncRNA associated with memory), appears to function both as a scaffold that allows other molecules access to a gene for expression and to coordinate other molecules, including eRNAs, which express a gene that helps quell fears. .

When ADRAM expression was knocked out in mice before they were deconditioned from their fear, they showed no difference in their fear downregulation training sessions compared to controls.

However, the knockout mice remained fearful later, suggesting that their fear extinction memory was impaired. Their other fear and anxiety behaviors remained normal.

“These data demonstrate that the effect of [the gene knockouts] on fear extinction is due to its influence on cognition rather than nonspecific physiological indicators of generalized anxiety,” the researchers wrote in their paper.

The team cautions that it is not yet known whether ADRAM plays a greater role in learning and this study only found these specific effects in male mice. But many of these fundamental molecules are conserved across species, and these findings suggest that this class of lncRNA genes warrants further investigation.

“Our results suggest that long non-coding RNAs provide a bridge, connecting dynamic environmental cues to mechanisms that control how our brain responds to fear,” Bredy explained.

“With this new understanding of gene activity, we can now work to develop tools to selectively target long non-coding RNAs in the brain that directly alter memory and hopefully develop a new therapy for PTSD. and phobia.”

This research was published in Cell reports.

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