A Perspective on the Biology of Forgetting

Ron Davis, Ph.D., Professor and Chair of Neuroscience at The Scripps Research Institute (TSRI) in Jupiter, Florida, teamed up with Yi Zhong, Ph.D., Professor of Life Sciences at Tsinghua University in Beijing, China, to pen a call to action published this week in the journal Neuron. The article reveals surprising new insights into how the brain manages memory storage.

Like many neuroscientists, the researchers have spent years working to understand the molecular mechanisms behind learning and memory, but about five years ago, they shifted their focus to the mechanisms behind forgetting. In the review, the pair presents evidence that our brains actively use molecular mechanisms to erode memories. “We're laying out to the scientific community the evidence that we have and the rationale for the brain being designed to forget,” says Davis.

While most scientists agree that our brains use molecular mechanisms that alter the structure and function of certain neurons in order to learn and store memories, some researchers are skeptical that our brains would eventually alter those neurons in such a way that could effectively erase those memories. T

Many psychologists believe that the memory engram—the set of cells and molecules involved in encoding a given memory—never goes away, but that as memories are used less, people struggle to retrieve them. Davis and Zhong say that while there are instances in which people struggle to retrieve intact memory engrams, our brains also use active forgetting—a series of molecular changes that degrades a memory engram and gradually removes it completely—to make room for new memories.

The pair asserts that active forgetting is a mechanism for maintaining homeostasis in the brain. Our bodies employ homeostatic control mechanisms to maintain healthy internal temperatures, glucose levels and more. We are bombarded with information all day long, and there may be a limit to the resources the brain can use to store memories at a given time, and active forgetting of unused and unimportant memories frees up the resources needed to encode important new memories. Davis and Zhong believe disruption of this process could be involved in a variety of neuropsychiatric disorders, such as autism spectrum disorders and post-traumatic stress disorder.

There are likely dozens of different ways the brain approaches the task of molecularly erasing unused memories. In the article, the team describes what they and others have found about certain molecules involved in forgetting. The best-understood mechanism thus far is RAC1-dependent forgetting. They posit that the RAC1 molecule is involved in at least four different types of forgetting, which they have studied in the olfactory memories of Drosophila. RAC1 is known to be involved in chemical and structural changes that allow neurons to encode memories. The researchers develop arguments that when activated by a particular type of dopamine receptor, RAC1 is involved in a cascade that remodels the cell’s actin cytoskeleton to erode those memories. But this is only one piece of the puzzle—although the researchers have identified several other molecules involved in the RAC1-dependent mechanism, there are many steps left to elucidate in the process.

Scientists have a long way to go to fully understand how our brains forget unused and unimportant memories and make space for new ones. One of the main challenges, explains Davis, is the same obstacle that makes the research so exciting. There really isn’t a library of information on the topic, since so few researchers have studied active forgetting—meaning there aren’t a lot of clues to drive their questions. “It’s a whole new window into the learning and memory mechanisms,” he says. “We’re doing experiments that have never been done before and examining brain processes that have never been examined before.”

Research in the Zhong laboratory is supported by grants 2013cb835100 from the 973 program of the Ministry of Science and Technology of China, 91332207 from the National Science Foundation of China, and No. Z161100002616010 from Beijing Municipal Science & Technology Commission. Research on forgetting in the Davis laboratory is supported by grants 4R37NS019904, 5R01NS052351 and 1R35NS097224 from the NINDS.

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