Why Forgetting is Healthy: How Research is Reshaping Our Understanding of How We Forget

When was the last time you forgot something? Maybe it was your keys, a password, or that one item you trekked all the way to the grocery store to buy. Regardless of what it was, chances are, you probably were not too happy about it. People often view forgetting as a negative glitch in normal brain operations, but nonpathological, everyday forgetting is actually essential to healthy cognitive function. Over the last decade, scientists have begun to elucidate exactly how this vital process occurs.

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Graduate student in the Cervantes lab Prachi Shah dissects fruit fly brains, to later stain and identify proteins.

Isaac Cervantes-Sandoval, brain researcher and assistant professor at Georgetown University, is part of a cadre of scientists working to illuminate how the brain forgets. Traditionally seen as a passive fading of memories through natural decay, research in recent years has made neuroscientists rethink that framework. Studies are increasingly characterizing everyday forgetting as an active, well-regulated process. (This is distinct from pathological forgetting in diseases such as Alzheimer’s, in which memory is disrupted by the dying of neurons.)

Dr. Cervantes-Sandoval’s research has helped advance our understanding of the molecular and cellular mechanisms responsible for the process. Active forgetting is important for normal and adaptive cognition, and the inability to forget harmful memories is involved in the pathophysiology of psychiatric disorders.

For one, it helps to reduce information overload and allow the brain to process more efficiently. And crucially, active forgetting also makes those possessing the feature better equipped to respond to a dynamic environment.

“In every animal, you need to have a system…that can be updated continuously, because the conditions are constantly changing,” Dr. Cervantes-Sandoval said. “Forgetting is really important for that because you have to override old memories that become obsolete or are no longer relevant to the new changing situation.”

This behavioral flexibility allows, for example, animals to update their memory of where a food source may be, without previous memories interfering with recalling updated ones of the location.

In addition, forgetting is necessary for generalization — generating concepts from an amalgamation of specific instances. This way, patterns from past experiences can inform responses to new circumstances. Think of it from the perspective of a mouse.

“Now generalization, what it means is that basically you take the gist of what a cat or what a feline is, and then forget the details,” Dr. Cervantes-Sandoval said. “But then you're going to preserve the gist of what the feline is — your model. Even though it's not perfect, it's actually…going to be better to predict that this [new feline] is also dangerous, and you should be running away from it.”

When forgetting doesn’t work properly, it can contribute to the development of psychiatric disorders. Some of these include Autism Spectrum Disorder, schizophrenia, and PTSD.

“So during some neuropsychiatric disorders, you can think about examples of this happening where patients have problems generalizing information. They have problems getting rid of information that is no longer relevant,” he said. “They have obsessive thoughts, for example. That could be a consequence of not understanding that these previous memories are no longer important.”

Despite its importance, understanding of the molecular basis for purposeful forgetting is relatively new, and far from complete. In a 2010 paper, researchers described the first discovered molecular pathway responsible for active forgetting, regulated by the protein Rac1.

Rac1 is a type of G protein, which sits at the inside of the cell membrane and acts as a molecular switch. In this pathway, an activated Rac1 sets off a cascade of enzymes that eventually turn on the protein cofilin. Cofilin breaks down actin cytoskeleton — the structural skeleton in a cell. It’s hypothesized that Rac1 promotes rapid changes to the actin cytoskeleton through this pathway, but the exact mechanism is still unknown.

Memories are stored through structural remodeling at synapses, or junctures between neurons, by making stronger or weaker connections. Activating the Rac1 forgetting pathway essentially reverses these changes, erasing the memory.

Researchers found that in the fruit fly Drosophila, after conditioning them to associate a particular odor with an electric shock (so that they avoid it), inhibiting Rac1 caused the memory to last longer, while increasing Rac1 activity accelerated memory decay. Drosophila are a popular model organism for this kind of research because they are easy to manipulate genetically, and they show remarkable similarity at the molecular and cellular level to human brains.

Dr. Cervantes-Sandoval’s work has tried to uncover essential components in this Rac1 pathway. With collaborators at Scripps, where he worked as a postdoc, the team discovered that a network of dopaminergic neurons — neurons that produce or use dopamine, a chemical messenger of the brain — modulates forgetting. They also found that the dopamine receptor DAMB was required for forgetting.

“Basically, [it] starts with dopamine receptors that are expressed in the cells that are storing the memory — these are called the engram cells,” he said. “There are dopamine receptors in these neurons that basically bind the dopamine that is being released…and that starts a signaling pathway that results in reversing the plasticity that was caused by the learning — or, basically forgetting.”

Dopamine is known for a lot of things, particularly as part of the brain’s reward system. It’s involved in motivation, mood, movement, attention, and other physiological processes. Notably, dopaminergic neurons are also involved in learning and encoding memories. However, memory acquisition uses a different dopamine receptor, dDA1. Which pathway is activated depends on many factors, including timing and the complex cellular context that the signal exists in.

Another important discovery Dr. Cervantes-Sandoval and his collaborators made was the central role of the scaffolding protein Scribble, which is expressed in engram cells. It brings together molecules involved to coordinate their activity.

“[Scribble] basically put[s] together different proteins in a complex that then is going to help to generate this signal that is going to eventually result in memory forgetting,” he said.

The red line shows the performance index (PI) of scrb^RNAi fruit flies with reduced Scribble expression. The black line shows the performance of control flies. Mutant flies show increased memory retention and less decay than control flies in the following 24 hours after aversive training. (Cervantes et al. 2016)

In behavioral experiments, Scribble knock down flies — those with an altered scrb gene that reduces how much Scribble is made — exhibited enhanced memory retention and delayed memory decay compared to normal flies.

Further experiments show that this causes a problem with reversal learning. Flies were taught to associate odor A (but not odor B) with an electric shock. Then, this association was reversed. Most normal flies will avoid the most recent odor associated with the shock because they remember it better. The knock down flies, however, fail to choose.

“What's really happening is that, for these flies, both memories are equal in strength. They're both remembered at the same level,” Dr. Cervantes-Sandoval said. “For them, both odors are as dangerous. So they are actually impaired in this kind of behavioral flexibility. They cannot update their system.”

Dr. Cervantes-Sandoval has continued this pioneering research with his lab at Georgetown. They are currently working on identifying which other proteins bind to Scribble in its signaling complex, and how significantly they affect memory.

These efforts add to a body of work by neuroscientists on active forgetting, research which continues to break conventional wisdom, recasting forgetting as an intentional, coordinated symphony.