The cure for fear
The key to controlling fear may be hidden in the "junk" DNA
Daniil Sukhinov, Naked Science
According to a new study by an international team of scientists, a fragment of "junk" DNA that does not encode any proteins may be the key to suppressing fear-related memories in people suffering from post-traumatic stress disorder (PTSD) and phobias.
An article with the results of the study was published in the journal Cell Reports (Wei Wei et al., ADRAM is an experience-dependent long non-coding RNA that drives fear extinction through a direct interaction with the chaperone protein 14-3-3).
Conditioned fear (or conditioned fear reflex) is a reaction acquired by a person or animal and produced by some neutral (conditional) signal, which is usually followed by an unpleasant or painful stimulus. Often this reaction is modeled on the example of mice, when, before transmitting to them an electrical stimulus (bringing discomfort, but not pain), researchers turn on a conditional light or sound signal, with which this feeling of discomfort will then be associated in rodents.
The extinction of conditional fear manifests itself in a decrease in the reaction to a frightening signal, which occurs when this signal is repeatedly presented to the subject without any painful or uncomfortable consequences for him. Both phenomena are evolutionarily conserved behavioral adaptation, which is crucial for 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 in order not to feel a sense of fear "in vain".
Like other forms of learning, the extinction of long—term memory of conditioned fear depends on coordinated changes in the expression of many genes, especially in the infralimbic prefrontal cortex (ILPFC) - the area of the brain in the anterior part of the frontal lobes. An international research project led by Timothy Bredy, associate professor at the Queensland Brain Institute (Australia), has discovered new genes whose expression is enhanced 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. Genes located in this region do not encode protein sequences, but sometimes they are expressed anyway. As a result, long non-coding RNAs (DNCRNAS) with a length of more than 200 nucleotides are synthesized, with an often unknown function.
"Until recently, scientists thought that most of our genome consists of junk DNA, which, in fact, does nothing," explains Dr. Brady. "But when researchers started studying these areas, they realized that this part of the genome is active and transcribed."
The proposed mechanism of action of the long non-coding RNA ADRAM on the expression of the Nr4a2 gene, necessary for the extinction of the memory of conditional fear. Blue hexagon is a chaperone protein, CBP is a protein that enhances the expression of Nr4a2, HDAC is a protein that blocks the expression of Nr4a2. Figure from the article by Wei Wei et al.
Using a powerful new sequencing approach, Dr. Brady's team identified 434 DNCRNAS from relatively unknown regions of the human genome. From this number, the authors identified and studied only one dncRNA, which was called ADRAM (activity-dependent dncRNA associated with memory). This dncRNA is notable for acting as a conduit for special regulatory proteins (chaperones) that control gene transcription. In particular, the researchers found that chaperone proteins directed by ADRAM contribute to the expression of the Nr4a2 gene, which is necessary for the extinction of conditioned fear memory.
"Our results show that long non—coding RNAs form a bridge linking dynamic environmental signals with mechanisms that control how our brain reacts to fear," comments Brady on the results of the study. "With a new understanding of gene activity, we can now begin developing tools for selective exposure to dncRNA in the brain and hopefully develop a new therapy for post—traumatic stress disorder and phobias."
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