Human memory may be the result of a 400-million-year-old viral infection

A virus-like protein is believed to be at the root of how our brains store long-term memories – and it may stem back to an ancient infection that occurred hundreds of millions of years ago.

Researchers at the University of Utah Health have been studying a protein called activity-regulated cytoskeleton-associated protein, or Arc. Arc has long been believed to play a critical role in how long-term memories are created and stored in the brain, but little is known about its specific molecular function or evolutionary history.

In a study published in the journal Cell, the researchers show how they captured an image of the protein assembled into large structures with virus-like capsid shells. These structures look remarkably like those of the retrovirus HIV, and this led the scientists to investigate whether Arc is in fact an evolutionary remnant of a very old virus.

In their experiments, they found that several copies of Arc self-assembled into virus-like capsid shells and tucked their own genetic material (mRNA) inside. When the team added these capsids into mouse neurons, grown in a dish, the Arc proteins transferred their genetic cargo into the cells. Much like a virus, the Arc that had been released by mouse brain cells could then subsequently be taken up by another set of neurons, ‘infecting’ cells.

“We went into this line of research knowing that Arc was special in many ways, but when we discovered that Arc was able to mediate cell-to-cell transport of RNA, we were floored,” says the study’s lead author, postdoctoral fellow Elissa Pastuzyn. “No other non-viral protein that we know of acts in this way.”

​Dr Jason Shepherd, senior author of the study, told Alphr that Arc seems to be critical for long-term memory and plasticity. “We had thought Arc was required for processes in the cell it’s made, but these new studies suggest that signaling between cells may also be important,” he said, stressing “we still do not know the role this pathway plays in memory”.

Further work is needed to discern what signals Arc is actually carrying between neurons, and why this intercellular communication is essential for the formation of long-term memory. But given that Arc looks incredible virus-like, does it suggest our capacity to learn and remember is due to an ancient viral infection? “Yes, it does seem like the plasticity and memory capacity in mammals may have arose from this random insertion event,” Shepherd told us.

“While we think that virus infections and outbreaks are a bad thing (and of course they are), these bouts of infection also provide new source material for evolution to create new genes that ultimately become beneficial for the organism.

“It’s also really interesting that despite Arc evolving from an event ~400 million years ago, the biology seems to be preserved. We also think there are other genes in the human genome that contain similar elements of viral origin that may also have preserved properties.”

While a chance encounter around 400 million years ago may have paved the way for mammalian memory, Arc is now a critical part of normal cognition. If the protein is not expressed properly in humans, it can lead to a number of neurodevelopment disorders such as Fragile X and Angelman Syndromes, as well as schizophrenia.

Arc may be the remnant of an ancient virus, but it is now very much at the core of how our brain works.

Image and video credit: Jacobo Lopez, Yi-Chu Su, Hugo Vaca

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