Key to fear control may be hidden in junk DNA

(ORDO NEWS) — A fragment of junk DNA that does not code for any proteins may be the key to suppressing fear-related memories in people with post-traumatic stress disorder (PTSD) and phobias, according to a new study by an international team of scientists.

Conditioned fear (or a conditioned fear reflex) is a reaction acquired by a person or animal and developed to some neutral (conditioned) signal, which is usually followed by an unpleasant or painful stimulus.

Often, this response is modeled using mice as an example, when, before giving them an electrical stimulus (which brings discomfort, but not pain), researchers turn on a conditioned light or sound signal, with which this feeling of discomfort will then be associated in rodents.

The extinction of conditioned fear is manifested in a decrease in the reaction to a frightening signal that occurs when this signal is repeatedly presented to the subject without any painful or uncomfortable consequences for him.

Both phenomena are evolutionarily conserved behavioral adaptations that are critical to survival. After all, if a person or an animal has learned to be afraid of something when a preliminary signal appears, then it should be able to unlearn it so as not to experience a feeling of fear “in vain”.

Like other forms of learning, long-term conditioned fear memory fading depends on coordinated changes in the expression of multiple genes, especially in the infralimbic prefrontal cortex (IPFC), the brain region at the front of the frontal lobes.

An international research project led by Timothy Bredy, Associate Professor at the Brain Institute in Queensland (Australia) , has discovered new genes whose expression is upregulated in ILPFC neurons in response to learning associated with the development of conditioned fear and its disappearance.

Oddly enough, these genes are located in a part of the genome called junk (non-coding) DNA. The genes in this region do not code for protein sequences, but are sometimes expressed anyway. As a result, long non-coding RNAs (lncRNAs) over 200 nucleotides in length are synthesized, with often unknown function.

“Until recently, scientists thought that most of our genome was made up of junk DNA, which, in fact, does nothing,” explains Dr. Brady. “But when researchers started studying these regions, they realized that this part of the genome is active and transcribed.”

Key to Fear Control May Be Hidden in Junk DNA 2Proposed mechanism of action of the long non-coding ADRAM RNA on the expression of the Nr4a2 gene, which is necessary for the fading of conditioned fear memory. The blue hexagon is a chaperone protein, CBP is a protein that enhances Nr4a2 expression, HDAC is a protein that blocks Nr4a2 expression

Using a powerful new sequencing approach, Dr. Brady’s team has identified 434 dncRNAs from relatively unknown regions of the human genome. Of these, the authors isolated and studied only one dncRNA, which they called ADRAM (activity-dependent dncRNA associated with memory).

This dncRNA is remarkable in that it acts as a conductor for special regulatory proteins (chaperones) that control gene transcription. In particular, the researchers found that ADRAM-directed chaperone proteins promote the expression of the Nr4a2 gene, which is necessary for conditioned fear memory fading.

“Our results show that long non-coding RNAs form a bridge that connects dynamic environmental cues to mechanisms that control how our brains respond to fear,” says Brady.

“With this new understanding of gene activity, we can now begin developing tools to target DNARNA selectively in the brain and hopefully develop new therapies for post-traumatic stress disorder and phobias.”


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