“ DNA also plays a role in memory storage", reveals to Science and Future neuroscientist Johannes Gräff, who led new research published in the journal Nature GeneticsIn the brains of mice, researchers were able to manipulate memories through epigenetic modification – the activation markers of DNA. This "epigenetic switch" was capable of suppressing and then restoring a memory.
“ For about 20 years, it has been known that learning and memory are accompanied by epigenetic modifications“, explains Johannes Gräff. “ But we didn't know if the reverse was true, if these modifications could change memory"Each time a memory is recorded—a process called 'encoding'—specific neurons associated with that information are activated. This population of cells forms what scientists call an engram. It will be activated again when the memory needs to be recalled."
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The formation of a memory requires contortions of DNA.
In the laboratory, mice are subjected to an unpleasant experiment. At a specific location in their cage, they receive a moderate electric current on their paws. In their brains, an engram encodes the memory of this unpleasant experience. The neurons involved in this engram have undergone modifications to their DNA: not in its code itself, but in its spatial structure. While DNA is often represented as a long, free strand or, conversely, compacted as an X-shaped chromosome, its position in space is actually highly variable, depending on whether the proteins around which it is wrapped expose or conceal certain sequences. Thus, by contorting the DNA strand in the right way, two initially distant sequences can come into contact and trigger the activation of a gene.
For many, these genes, activated during engram formation, help strengthen the connection between neurons. We now realize that the 3D architecture of the genome plays a very important role in orchestrating gene expression." , concluded researcher Asaf Marco in a statement, regarding his works published in 2020.
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An epigenetic switch that reversibly activates and deactivates a memory
Among the genes activated during engram formation, Johannes Gräff's team is particularly interested in the best-known ARC gene. ARC is an extremely important gene for synaptic plasticity"That is to say, the reorganization of connections between neurons," the neuroscientist explains. "If the encoding of the memory of the electric shock relies on the activation of ARC, then its inactivation could erase it," the researchers reason.
And that's exactly what's happening! Scientists are combining the CRISPR gene-editing tool—a protein capable of pinpointing the desired location in DNA—with enzymes that can open or close the sequence containing the ARC gene. It's a veritable epigenetic switch designed to act only in the neurons of the engram of the electric shock that was administered to the mice.
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“ Opening and increasing ARC resulted in improved memory, while closing and decreasing ARC resulted in memory loss.“,” summarizes Johannes Gräff, surprised to find that a single modification across the entire genome and in very few cells was enough to induce a change in behavior. When faced with the location previously associated with an electric shock, the mice in which ARC was rendered inaccessible exhibited significantly less of the characteristic fear-induced freeze. But when ARC was opened again, they hesitated once more, just like the unmodified mice. Their memory had returned.
While this research is only the beginning, scientists hope it will one day lead to a better understanding of memory disorders and pathologies, such as post-traumatic stress disorder or dementia. And perhaps, to tools that can help those who suffer from these conditions make their memories more or less accessible to their owners.
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