Forgotten Memories May Remain Intact in the Brain

Forgetting is a fact of life—one that many people find frustrating. But mounting evidence pushes back at the notion that a slip or lapse in our recollection is inherently bad. Indeed, forgetting can sometimes help people cope psychologically or let go of useless knowledge. In a new study, neuroscientist Tomás Ryan of Trinity College Dublin and his colleagues have examined the fundamental biology underlying a form of forgetting we experience every day. Their work suggests that when we can’t recall an old phone number or a high school teacher’s name, those details are not necessarily lost. As Ryan explained to Mind Matters editor Daisy Yuhas, forgetting may be an active process that the brain uses to support learning. He also discussed how dementia may ultimately reflect disordered forgetting more than lost memories.

[An edited transcript of the interview follows.]

You study an idea that some people may find counterintuitive: forgetting can be part of learning. How so?

We often think of forgetting as a deficit of the brain or a limitation. Memory loss from dementia or brain trauma, for example, can be devastating.

But we also experience “everyday forgetting” as we go about our lives—because there’s just so much going on. We’re expected to learn and retain many things in order to function in modern society. Some are quite arbitrary, such as having to memorize facts you’ll never need again for school exams. Others are not so arbitrary but are still quite demanding, such as the knowledge you build to become a practicing doctor.

Although we may think of forgetting as a nuisance, and it often is, it could be a feature of the brain rather than a bug. A growing body of research in neuroscience is beginning to examine the idea that forgetting is adaptive rather than limiting.

So forgetting comes in many forms?

There are different kinds that people generally consider distinct. We may use the word amnesia for a kind of forgetting that most people would agree is neither adaptive nor beneficial. Some forms of amnesia make it difficult to form new memories. Others make it difficult to recall memories formed before an injury.

But everyday forgetting is different. If you forget where you parked your car, nobody calls that amnesia. Or if you don’t do very well on your finals, you don’t get to tell your professor, “Oh, sorry, I had amnesia that day.” These cases represent a form of forgetting where you don’t have a ready grasp of desired memories for that context.

In your new study, you examine everyday forgetting in rodents. What did these mice have to learn?

Mice are very curious creatures. We trained them to associate an object with a room or an environment. So we presented the mice with objects—such as a tube or a cone—that they had never seen before in a given context.

Then, the next day or a week later, we asked the mice to inspect two objects: one that had been associated with that context and another that had not. Usually the animals would inspect the novel object for a given context. But if they had forgotten the association, both objects seemed new, and the mice explored both equally.

We also studied fear conditioning, where the animals received a very mild electric shock—it did them no harm—for a few seconds in a particular context. They later showed a freezing behavior in that same environment, provided that they remembered it. If the mice froze less in that context, they had forgotten the association.

How did you encourage them to forget?

Natural forgetting is believed to occur for many reasons. Memories may simply fade over time. But forgetting can also be caused by “retroactive interference,” which is when you experience two events that are quite similar close in time. The memory of one interferes with the other.

This is a very well-studied effect and one we can control in our own experiments, which is why we used this approach with the mice. So for example, after presenting mice with objects in context A, they were placed in context B with identical objects. That second experience made it harder for them to remember associations from context A.

You also monitored memory formation in the brain. How, exactly, did you do so?

The brain is different before and after learning information. That difference is accounted for by physical or chemical changes in the brain’s structure. We call a brain change that occurs during learning and that is required for memory an engram.

In the past 10 years, the ability to label and manipulate specific engrams in the rodent brain has really transformed the memory field—and, by extension, the forgetting field. Identifying where an engram is located is like looking for a needle in a very, very large haystack. The human brain, for example, has billions of neurons and trillions of synapses, and there is change going on all the time. Some of it has nothing to do with memory.

To find an engram, we use genetic techniques to hijack what are called immediate early genes, which express themselves only when a particular neuron is active. The result is that we can genetically label those cells in a permanent way. By doing this, we essentially tag cells that we know are active in a given time window—such as when the brain is forming a memory.

[Read more about the search for engrams]

By putting these methods together, you had a way to both watch as mice learned or forgot associations and observe the brain cells linked to memories. What did that reveal?

We were able to show that in cases of retroactive interference, memories survived this type of forgetting and could be reexpressed. Nothing was wrong with those original memories, even though the mice had failed to recall them. Not only were the engrams there, but they were also healthy and functional.

In addition to tagging engram cells, we labeled cells with optogenetic receptors, which are ion channels that are activated by light. This combination allowed us to turn specific memory engrams on and off. When we did that, we found we could get mice to recall forgotten memories just by stimulating these engram cells.

We also found that if we optogenetically blocked the engram cells at the same time that we put mice in situations that would interfere with memory formation, the mice did not forget. In other words, you need activity in engram cells for forgetting to occur.

Does that mean our brain is suppressing a memory to help us learn?

Forgetting may be caused by competition between different memories. Therefore, you could say that forgetting is a form of learning and decision-making. The animal’s brain creates a competing engram, and then the brain must decide which engram to express in a given environment and moment.

How does this fit into studies of memory loss linked to trauma or dementia?

When I was a postdoc at the Massachusetts Institute of Technology, my colleagues and I did one of the first studies that integrated optogenetics and engram labeling. We studied amnesia both with drugs that impair memory consolidation and with genetically altered mice that serve as models of early Alzheimer’s disease. There, too, we found we could optogenetically stimulate the engrams for forgotten memories—and the memories were recalled.

Since then, other research groups have found the same thing for models of Alzheimer’s, age-related memory loss, stress-related memory loss and sleep-deprivation-induced amnesia. In every case, the engram survives—but the memory can only be retrieved with optogenetic activation.

In the recent study done in my lab in Dublin, we looked at natural forgetting using engram manipulation for the first time. In addition, we found that a short reminder training session, for example, could help animals reaccess those same engram cells.

You can’t do that in the Alzheimer’s mouse model. If you retrain those mice on the same behavior, they can learn it, but they make a new engram for it.

Could your new study inform how we look at dementia?

Even though our study did not involve people with Alzheimer’s or any disease model, it may open up some interesting doors. What might be happening in diseases such as Alzheimer’s is that natural forgetting processes—including retroactive interference—may be misactivated. As a result, engrams are surviving but not being expressed in the right way.

In other words, instead of the disease causing memory loss because it has somehow degraded the engrams, it may be triggering a very natural process of forgetting but for maladaptive reasons. If so, some of that memory loss may even be reversible because the engrams are intact. That would be a very different way of thinking about pathological memory loss, and it’s something that we hope to test in the future.

Are you a scientist who specializes in neuroscience, cognitive science or psychology? And have you read a recent peer-reviewed paper that you would like to write about for Mind Matters? Please send suggestions to Scientific American’s Mind Matters editor Daisy Yuhas at [email protected].

This is an opinion and analysis article, and the views expressed by theauthor or authors are not necessarily those of Scientific American.


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