What would it be like if you never forgot — if your brain were able to access your haziest long-term memories as though they had just been freshly made? For the first time, working in rats, researchers have enhanced weak, old memories by tweaking an enzyme in the brain. The findings not only deepen understanding of how memory works, but offer new hope for the development of treatments for Alzheimer’s and other memory-destroying diseases.
The study, led by researchers at Israel’s Weizmann Institute of Science, involved using viruses to ferry genes into specific regions of rats’ brains in order to increase or decrease levels of a substance called protein kinase M zeta (PKMzeta). Inhibition of that enzyme has been shown in past studies to wipe out lab rats’ long-term memory, and the researchers sought to determine what would happen if the protein were overexpressed instead.
“What’s new and exciting and frankly a little unexpected is that [increasing] PKMzeta did what nothing else has ever been shown to do before: take an old, faded, weak memory and make it stronger,” says study co-author Dr. Todd Sacktor, a neurology professor at SUNY Downstate Medical Center and co-author of the study published Thursday in the journal Science.
Usually, specific memories can be altered only while they are being encoded or consolidated in the brain, or when they are being actively recalled. That’s why existing “smart drugs” often used for memory enhancement — such as Ritalin, amphetamine and even caffeine — only aid learning if they are taken while new memories are being formed or immediately thereafter.
Given that no existing compound has been shown to strengthen an old memory, Sacktor and his colleagues had not anticipated their results. They expected that dialing up PKMzeta might prevent memory from fading or even have the opposite effect and wipe it out entirely.
“This is a very important study,” says Joseph LeDoux, professor of neuroscience at New York University and a pioneer of research on memories of fear. “They show that you can enhance long-term memory performance a fairly long time after that memory has been formed. That this enhancement doesn’t require that the memory be explicitly activated is fascinating.”
So what is PKMzeta and how does it affect memory? “It’s an enzyme found only in the brain,” says Sacktor. “Enzymes catalyze chemical reactions and PKMzeta is a really unusual enzyme because once it’s formed, it’s active all the time.”
This ongoing activity may be what allows it to work its long-term memory magic. “Once it’s made, which happens during learning, it can sustain memories for long periods,” Sacktor says.
In their previous work with PKMzeta, Sacktor and his colleagues demonstrated that by introducing a substance called zeta inhibitory peptide (ZIP) — which inhibits PKMzeta — into rats’ brains, they could completely wipe out the animals’ long-term memory without causing any damage to the brain or impairing the rats’ ability to learn new material.
You might call ZIP the “Dollhouse” drug. In the futuristic TV series, an organization uses human beings to carry out various missions, then wipes their minds of any memory of their activities or old lives. (Incidentally, a substance this dangerous could never really be tested on humans: even if villainous rogue chemists could synthesize it, they’d have to be able to do delicate brain surgery in order to delete the story of a person’s life. The compound wouldn’t work orally, and it isn’t likely to get past the blood-brain barrier if injected.)
But tweaking the activity of PKMzeta could hold real promise for the treatment of memory-related conditions. Tuning it up could help enhance memory in conditions like Alzheimer’s, and dialing it down may help loosen the hold of traumatic memories in patients with PTSD.
Sacktor’s group has also in past studies discovered PKMzeta in the tangles that affect neural function in the key areas of the brain damaged by Alzheimer’s. Even if PKMzeta pathology itself doesn’t cause the disorder, restoring appropriate function could potentially retrieve lost memories.
“I think if you [were able to] give the right dose, I would imagine it would increase memory — both in learning something new much more efficiently, and even strengthening a memory that’s old. Basically, your memory’s going to be much better overall,” says Sacktor, discussing the possibilities of a drug that would enhance PKMzeta in humans.
For their new study, Sacktor and his colleagues conditioned rats to connect the taste of saccharin-sweetened water with the feeling of nausea, by injecting the rats with lithium, which induces nausea, immediately after they had been exposed to the sweet stuff. A lithium dose that produces just a little nausea leads to a weak memory and a mild dislike for the associated taste, while higher doses that make rats wretchedly sick will produce strong memories and total avoidance of the sweet liquid.
One week (roughly equivalent to 20 months for a human) after the rats were trained to find saccharin mildly distasteful, researchers infected the insular cortex region of the brain with a virus that increased cells’ ability to make PKMzeta.
Initially Sacktor thought that the excess PKMzeta might wipe out the rats memories. He uses the analogy of a computer, which stores information in codes consisting of 1s and 0s. If you changed a computer’s memory to store only 1s or only 0s, the existing information, which lives within the patterns of the numbers, would be destroyed.
Similarly, the brain holds information within the relative strengths of the connections between cells. So increasing PKMzeta might strengthen all connections in a region indiscriminately, wiping out the memories encoded in the differences. “I had assumed that if you put in too much PKMzeta, you will make all of the synaptic connections stronger and then you would lose memories,” Sacktor says. “It turns out that it goes into some synaptic connections and not others. It seems as if PKMzeta knows where to go, which is just amazing and we don’t understand that biology.”
Instead, PKMzeta strengthened the rats’ weak distaste for saccharin, suggesting that the animals’ old memories had been enhanced. Further, rats that were sequentially trained to dislike salt water and conditioned to avoid saccharin showed strengthening of both memories, suggesting that PKMzeta wasn’'t just enhancing recall of the most recently learned information.
In another experiment, the researchers infused rats brains with a different substance that inhibited PKMzeta instead of increasing it, and, as with the ZIP experiments, this impaired the rats’ memories of taste and nausea.
“It’s a great paper,” says Ryan Parsons, a researcher at Emory University who has also studied PKMzeta. His research found that using substances like ZIP to inhibit PKMzeta in the amygdala — unlike in the insular cortex — doesn’t necessarily erase memory, but temporarily disrupts it. This suggests that memories may be stored in different ways in the various regions of the brain. “It’s not incredible to think that fear-based memories might be a little stronger, or that maybe there is redundant circuitry in the brain that maintains [fear memories], which are obviously very critical to survival,” says Parsons.
“This research could be very important as we search for new ways to improve memory,” says LeDoux.
