ZIP protein makes rats forget a month-old memory.
Scientists have erased a long-term memory in the brains of laboratory rats, offering insight into how such memories are stored.
Yadin Dudai and Reut Shema of the Weizmann Institute of Science in Rehovot, Israel, trained rodents to associate a particular smell with illness. Injecting the rat brains up to a month later with a polypeptide called ZIP caused the rats to completely forget the unpleasant memory, they report in Science1.
The study suggests that even though long-term memories can last for years or even for a lifetime, they are constantly maintained by an ever-active process. That goes against previous ideas that long-term memories are simply held in safe, static storage says co-author Todd Sacktor, a neuroscientist at State University of New York Downstate Medical Center in Brooklyn.
"The result is surprising because most people would basically say it's impossible to erase a memory like this," says Sacktor. Most neuroscientists think that relatively permanent changes in the shape and physiology of neurons help store long-term memories, he says.
There's going to be an avalanche of studies following up on this. David Glanzman , University of California, Los Angeles
Researchers already knew that if they caught the formation of a memory within minutes, they could wipe it from the brain's hippocampus with chemicals that stop neurons from making new proteins.
But it was unclear what might happen after this time window passed, when memories are thought to be shunted to another part of the brain - the cortex — for long-term storage. "What's been completely unknown — terra incognita — is what happens next," says Sacktor.
To find out, the team first trained rats to avoid the scent of saccharin by exposing them to the sweet smell, then feeding them lithium — a metal that makes them sick. Rats given this treatment soon learn to avoid water smelling of saccharin.
They then looked to see what would happen if they injected the rat cortex with ZIP, a small protein Sacktor's laboratory previously used to block spatial memories held in the hippocampus. ZIP silences an enzyme called PKM-zeta, which Sacktor thinks is key to perpetuating long-term memory.
The rats given such a shot, even up to a month after learning to avoid saccharin, lost their memory of the bad experience and happily drank the sweet water.
To search for any remaining trace of the memory, the researchers tried reminding the mice of the link by giving them lithium again. But the ZIP-treated mice kept swigging the sweetener-water. "No matter what we did, the memory never came back," says Sacktor.
Spanner in the works
The team suggests that PKM-zeta could maintain memory by creating new receptors for neurotransmitter molecules, says Dudai. A so-far unidentified mechanism that keeps this enzyme active would then be crucial for keeping hold of long-term memories. By blocking PKM-zeta, ZIP may halt this process. "It's like placing a stick in an engine. The minute you stop it the memory collapses," says Dudai.
David Glanzman, a neuroscientist at the University of California, Los Angeles, is not completely convinced that the rats' memories have been fully erased. He says that if experiments show the effect lasts for a year, he would be swayed.
The researchers — who are expecting a lasting effect — are now testing to see whether the memories stay erased for longer periods of time.
"I think there's going to be an avalanche of studies following up on this," Glanzman says.
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Shema, R. et al. Science 317, 951-953 (2007).
University of California, Los Angeles
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Callaway, E. Long-term memory gets wiped. Nature (2007). https://doi.org/10.1038/news070813-10