Using a powerful new sequencing technique researchers have tracked down genes within mice that work towards soothing fear-related memories. These genes are hidden within relatively unknown regions of the mammalian genome we’d written off as ‘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 into areas of the genome that have evaded scrutiny so far.
The genes could be involved in fear disorders such as phobias and post-traumatic stress disorder (PTSD), which impacts 15 million adults in the US each year.
We all have those memories that send jolts of terror down our spines, that make us avoid a subject (spiders, heights) or certain situations (public speaking). This is a healthy learning response, strongly selected for since it keeps us physically or socially safe.
But in normal situations, repetitive exposure to these fear cues, without anything bad happening should, in time, decondition your fear response.
The fear and the extinction of it takes place in the infralimbic prefrontal cortex of our brains, and recent research has traced this process to transcriptional machinery and epigenetics – modifications around DNA that change how it is expressed but not the DNA sequence itself.
For some of us though, that downregulation of fear never arrives. The fears get stubbornly stuck, becoming a mind-killer that prevents our brains from letting us deal with these things rationally or move on from the fearful events.
Using fear-conditioned mice and a new RNA sequencing technique, researchers took a closer look at molecules called long noncoding RNA (lncRNA) that have already been implicated as regulating genes linked to conditions including drug addiction, depression, schizophrenia, and anxiety. Forty percent of the lncRNA identified so far are found in greater concentrations within neurons.
Researchers found a class of these genes, which they’ve called eRNAs, expressed in the mice’s infralimbic prefrontal cortex are involved in linking our experiences to regulation of gene expression.
One gene, dubbed ADRAM (activity-dependent lncRNA associated with memory), appears to work both as a scaffold that allows other molecules access to a gene for its expression and to coordinate other molecules, including eRNAs, that express a gene which helps dull fears.
When the expression of ADRAM was knocked out in the mice before they were deconditioned of their fear, they showed no difference within their fear downregulation training sessions compared to the controls.
However, the knockout mice later remained fearful – suggesting 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 on non-specific physiological indicators of generalized anxiety,” the researchers wrote in their paper.
The team cautions that they do not yet know if ADRAM plays a more extensive role in learning and this study only found these specific effects within male mice. But many of these fundamental molecules are conserved across species and these findings do suggest this class of lncRNA genes deserves a closer examination.
“Our findings suggest that long non-coding RNAs provide a bridge, linking dynamic environmental signals with the mechanisms that control the way our brains respond to fear,” Bredy explained.
“With this new understanding of gene activity, we can now work towards developing tools to selectively target long non-coding RNAs in the brain that directly modify memory and hopefully, develop a new therapy for PTSD and phobia.”
Image credit: Tom Gent © 2019 Circle of Death
Study published in Cell Reports (DOI:10.1016/j.celrep.2022.110546) with support from the Brain & Behaviour Research Foundation (NARSAD), the National Institutes of Health (NIH), the Australian Research Council, and the Westpac Bicentennial Foundation.