To understand how memory works, how it is formed and gets stored in our brains, neuroscientists are developing new techniques to erase rats’ memories. At first glance, their work can look scary because it seems that for better or worse, our memories build our identity. As a consequence, we can’t help thinking about the implications of such research. Are we assisting in the birth of an Orwellian project? What if one day the techniques fell into the hands of a dangerous political party? What power could it give to the government? More than only accessing memories, they would penetrate into our brain, and manipulate our inner self and deep thoughts.

To get a sense of how random people sitting in cafes between the Fenway area in Boston, and the East and West Villages in New York City, react to the prospect of erasing memory, listen to the audio clips.

- If you had the power to erase memory, would you use it on yourself? On other people? - What specific memory would you first erase? -Where do you think your memories get stored? How do you think it works? -How do you feel about knowing that scientists in their labs are currently erasing rats’ memory?

In October of 2006, I interviewed Jonathan Whitlock, a post-doctorate associate at the Picower Institute at that time. On that day, he lighted up my fascination for memory, and its mechanisms in the human brain. At the end of the interview, he launched that he was erasing rats’ memory. And the whole story began.

Whitlock explained me he had trained a rat to avoid the dark side of a two- compartment box by giving him mild foot shocks whenever he entered that side. After the rat learned that task, Whitlock used an array of electrodes to listen in on many places at the same time in his hippocampus. Once he eavesdrops on the hard-to-detect signal of the memory forming, he manipulated it with the goal of impairing the memory.

“The idea is to watch the initial changes set in motion by learning, and reverse those changes applying the inverse patterned electrical stimulation,” he explained. When Whitlock put the rat back in the box, he said he didn’t remember he had to avoid the dark side. He got trained again and the responses to learning reappeared. His brain was intact and hadn’t been damaged.

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In the 1990’s, Todd Sacktor, neurologist and molecular biologist at the State University of New York Downstate Medical Center, discovered that PKmZeta, persistently expressed and found only in the brain, was the enzyme implicated in the formation of memory. “Basically, I guessed! But it was an educated guest,” he says. Inspired by one of his professors from Columbia University, Sacktor tested PKmZeta on hippocampus slices and it came out to be necessary and sufficient to the formation of memory. More than 15 years of work after, he proved that he was right in live animals. He erased some rats’ memory by inhibiting the role of that specific enzyme.

To prove his hypothesis on live animals, Sacktor had them learned a simple task he knew would be stored in their hippocampus. He trained some rats to avoid a shock zone on a rotating platform. The rats were placed on a slowly spinning circle. One portion of the space was declared the “shock zone” and remained stationary while the rest spun. So the rats had to keep moving to avoid being eventually thrown into the shock zone due to the platform rotation. One day to one month after they learned the task, some rats received an injection of a chemical dubbed ZIP into the hippocampus. While “control animals” who had not receive any injection remembered which areas of their environment to avoid, “inhibitor-injected” animals explored the entire environment, appearing to have no memory of previous training.

Listen to Sacktor explaining his experiment

To get a glimpse of what happened one needs to understand how the gap between two neurons, named the synapse, works. In the brain, neurons spread their tentacles, the axons and the dendrites, to connect to each other. At each connection, the pre-gap side releases some messenger, the neurotransmitters, and on the post-gap side, a receptor traps those transmitters to treat their message. The receptors are floating in and out of the synapse. But when a memory is formed, PkmZeta doubles their number by trapping them for a longer period of time inside the synapse. More transmitters can get trapped and as a consequence, it enhances the strength of the connection between the neurons.

Unlike any other enzyme in the body, PKmZeta action is permanent. Meaning that once it gets activated, it never stop working. To stop its action and erase the memory out of the rats’ brains, Sacktor injected an artificial key, the ZIP drug, to lock the PKmZeta action. The level of receptors went back to normal and the connection between the neurons got weaker. And the ZIP effect was persistent. “What’s remarkable, is that the memory never comes back,” Sacktor says.

However, if the rats were retrained after the drug was eliminated from their bodies, they could learn the task again. “We haven’t damaged the brain or even functionally impaired memory other than wiping out previous long-term memory,” Sacktor explains. Applied to humans, those results could lead to treatments for post-traumatic stress disorders. A doctor could inject a drug in the specific zone of the brain activated by fears. The product would inhibit the action of the protein PmZeta that wakes up every time the memory comes back.

But Dr. David Caplan, neurologist at the Massachsetts General Hospital, doubts that those kinds of treatments could help patients in a foreseeable future and is deeply convinced that the injected drug could also damage other parts of the brain. “Our brain is filled with memories that sometimes we can’t access. Think about them as if they were recorded on videotape. The play head of our brain, the temper lob, is very fragile. I am sure it is today, totally impossible [to erase memory] without damaging the play head of our brain,” he explains over the phone.

Sacktor agrees that his research is not precise enough to erase and pinpoint one specific memory. Right now, the only selectivity has to do with brain anatomy. He can only inject the ZIP drug into a particular part of the brain, and erase all the memories stored there. But he is more optimistic than Caplan as to the future applications of his work in treating humans.

Listen to him talk about potential applications of the ZIP drug on humans.

To understand how memory works, how it is formed and gets stored in our brains, neuroscientists are developing new techniques to erase rats’ memories. At first glance, their work can look scary because it seems that for better or worse, our memories build our identity. As a consequence, we can’t help thinking about the implications of such research. Are we assisting in the birth of an Orwellian project? What if one day the techniques fell into the hands of a dangerous political party? What power could it give to the government? More than only accessing memories, they would penetrate into our brain, and manipulate our inner self and deep thoughts.

Martine Berrebi, a French psychologist in Paris, is convinced that an individual’s past builds his identity, helps him advance and look forward. “Erasing a memory would make a hole in our personal history,” she says. And even if that research could lead to treatment for Post-Traumatic Stress Disorder patients, Berrebi assumes that a trauma has to be processed verbally in order to heal. “It will be reflected in the body. And the memory will resurface when a certain event brings it back to the forefront.” She strongly believes that it all has to do with something more than only neurological phenomena.

To get a sense of how random people sitting in cafes between the Fenway area in Boston, and the East and West Villages in New York City, react to the prospect of erasing memory, listen to the audio clips.

- If you had the power to erase memory, would you use it on yourself? On other people? - What specific memory would you first erase? -Where do you think your memories get stored? How do you think it works? -How do you feel about knowing that scientists in their labs are currently erasing rats’ memory?

Marco Nguyen, a French cartoonist, drew his interpretation of the neuroscientists’ work.

Look at larger sizes here.

Two main questions drive scientists’ quest in understanding how memory get formed and stored in the brain: how does learning occur? And how does memory last for several years or even a life-time?

In the 1970s’, scientists proposed an artificial model, the Long Term Potentiation, that would mimic the brain plasticity, its capacity to reorganize after new experiences. They realized that an electrical shock induced in a rabbit’s hippocampus last for just a second, but gave a long term change in the brain: the connections between the neurons got stronger. But is LTP really important, or are scientists just fooling themselves? Even though it is a very artificial thing, it is hoped that by studying it, it could reveal the mechanism of memory storage.

Today, scientists are not sure yet that LTP is what happens when a memory is formed, but it has the properties everyone expect memory to have: it is triggered by a lot of electrical activity, which happens during learning, and the consequences of that is a persistent strengthening.

Sam Cooke took over Whitlock’s work at the Picower Institute. “Jonathan Whitlock’s study was important because he showed that LTP occurs when learning occurs. But he didn’t show that this was necessary or sufficient for information to be stored in the brain,” Cooke says. And that’s what Cooke aims at.

The first step to show that LTP is necessary to form memory is to try to erase memory. Scientists know that during the critical period of around half an hour after LTP is induced, its effect can be reversed. So if LTP is a key mechanism in information storage then, Cooke should be able to form a memory, and use another artificial process, the Long Term Depotentiation (LTD), to erase that memory. “In simple terms, LTP and LTD are just the opposite process,” Cooke adds.

To do so, Cooke trains animals and observes the changes in the connections between the neurons in their hippocampus. To record the changes, he implants 16 tiny electrodes in a rat hippocampus, which is not bigger than 2 mm deep and 6 mm long. Once equipped, the rat explores objects made out of LEGO with different textures on them. He learns what this objects he has never seen look like, and smell like. Then, Cooke removes one of the objects and replaces it with a new object. The fact that the rat doesn’t explore a familiar object demonstrates that he remembers it. “The rat is just interested in new things he’s never seen before,” Cooke says. At that point, he knows a memory has been formed.

To erase it, he applies a low-frequency stimulation into the rat hippocampus. In doing so, Cooke hopes to mismatch, or disassociate the connections between the neurons involved in that specific memory the rat has just formed. As fast as two fingers clapping, the memory could be erased. But Cooke is only at the beginning of his study and hasn’t published any peer-reviewed article yet. More reserved than Whitlock, he knows his research requires a long set of experiments before he can tell any definitive result about his work.

Scientists know from experiments made in the 1950’s that the hippocampus plays a role in memory formation. Listen to Cooke’s thoughts on that bean-shaped part of the brain.

The plasticity of the brain is its lifelong ability to reorganize neural pathways based on new experience. Imagine making an impression of a coin in a lump of clay. In order for the impression of the coin to appear in the clay, the shape of the clay changes as the coin is pressed into it. Similarly, the neural circuitry in the brain must reorganize in response to experience or sensory stimulation. Neurologists all agree that memories are formed in the hippocampus, a bean-shaped area of the brain, involved in learning. But the mechanism had been an assumption for more than three decades.

credits Marco Nguyen

In 1949, Donald Hebb, a psychologist from Nova Scotia, had suggested that information in the nervous system was probably stored as changes in the connections between neurons. Twenty-four years later, two Norwegian researchers demonstrated a cellular phenomenon that mimicked exactly what Hebb had imagined. Between 1966 and 1973, in Per Anderson’s Laboratory in Oslo, Norway, Timothy Bliss and Terje Lømo were applying patterns of electrical frequencies to a rabbit’s hippocampus and found that when stimulating the rabbit’s brain with very specific electrical patterns, they were inducing changes in the connection between the neurons. Bliss and Lømo called this strengthening long-term potentiation (LTP). Those changes in the hippocampus proved that the brain had remarkable plastic capabilities.

It wasn’t until August 2006 that Jonathan Whitlock, researcher at the Picower Institute, added the missing piece to the puzzle. He showed that the types of changes, Bliss and Lømo could induce in the brain, actually happened naturally.