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Remembering and forgetting.

Lost years of infancy.

Text: Fabienne Hübener

Our earliest childhood memories are buried deep within us. But a number of clues indicate that we continue to store them throughout our lives. Why, then, are we unable to recall them? Flavio Donato and his team are hot on the trail of early memories in the brain.

small boy with fireworks
(Symbolic image: Priscilla du Preez, unsplash)

In the beginning, there was E.T. At least that’s how Flavio Donato remembers it. Back in 1986, at the tender age of three, he was excitedly awaiting the return of his elder brother, who always brought back a gift for Flavio when he was away on extended trips. This time, his brother pulled a tiny figurine from his bag. It was E.T., the Extra-Terrestrial. Donato is 38 years old now and a neuroscientist at Basel University’s Biozentrum, and that is his earliest memory.

Many people’s first memories are of a particularly emotional event that took place when they were between the ages of two and five. Anything before that feels as if it has been erased. Researchers refer to the phenomenon as “childhood amnesia”. “Our experiences from early childhood can influence us for the rest of our lives,” explains Donato. “And yet we don’t even remember them. I find that fascinating.”

Donato’s research is based on two groundbreaking discoveries. Around 20 years ago, research teams learned that young children who had had half of their brain removed as a treatment for epilepsy were still largely capable of living normal lives. Young brains are so plastic that they can compensate for even serious defects. The second breakthrough was lauded with the 2014 Nobel Prize in Physiology or Medicine. Scientists May-Britt Moser, Edvard Moser and John O’Keefe identified specialized nerve cells in the brain that are responsible for creating a map of the environment. With this insight, the researchers paved the way to understanding how experiences are encoded deep within the brain through the activity of ensembles of nerve cells.

Stellate cells control brain development

Flavio Donato experienced that second discovery up close and in person; starting in 2013, he spent around six years working in the laboratory of May-Britt Moser and Edvard Moser in Trondheim, Norway. It was there that he first observed that during the early stages of brain development, the nerve cells charged with creating a universal map of the environment drive the maturation of those forming memories.

This switch allows for different classes of nerve cells to mature according to a regulated process. The maturation procedure is directed by “stellate cells”, star-shaped cells located in an important hub for memory tucked between the cortex and the hippocampus. Donato’s study, published in Science, earned him the renowned Eppendorf & Science Prize for Neurobiology in 2017. In 2019, he returned to Basel, where he founded his own working group at the Biozentrum. Aided by a Starting Grant of 1.5 million euros from the European Research Council, he continued his research into early childhood memory through studies on mice. “My plan is to label the nerve cells involved in memory formation during the early stages of development and track them as they mature,” explains Donato.

Artificial memory

Scientists have already partially pieced together the process by which memories are made in adult brains: An experience activates a group of nerve cells in the brain and leaves behind a physiological mark, a network of new connections also known as an “engram”. Our memory is made up of countless millions of such engrams working in concert. The more frequently we repeat an experience, the stronger the connections between the nerve cells in this network become, and a seldom-trodden footpath is transformed into a bustling street.

To trace the path of a memory through a developing brain until it reaches maturity, researchers must first locate the specific engram in question. For example, they may start by taking mice that are just a few days old and allowing them to begin gathering experiences. The animals might learn that they hear an unpleasant sound whenever they sit in a dark corner.

Days or weeks later, researchers observe the behavior of the mouse as it approaches the dark corner. The mouse’s demeanor – whether it appears hesitant or assertive – helps the scientists gauge how well the animal remembers the initial experience. Normally, a mouse that is no more than a few days old forgets the unpleasant event after only one or two days. When scientists artificially stimulate the nerve cells involved in the creation of the memory, however, the mouse hesitates to explore the dark corner.

This stimulation reactivates the engram, thus reviving a lost memory. Astonishingly, the nerve cell that has been artificially stimulated does not even have to be a central part of the engram in question. The memory also can be triggered via a back alley, so to speak. Earlier studies involving this type of research have led to the hypothesis that these early memories are not lost after all, even in humans. We are simply unable to access them under normal circumstances.

Two paths to memory

Based on that hypothesis, Donato and his team have spent the last couple of years studying whether there are differences in the way young and mature brains form memories. It turns out that the process displays both qualitative and quantitative differences depending on age. Young brains, for example, recruit different nerve cells and require less stimulation to establish a memory pathway. “We were surprised to see how little information young mice need in order to learn effectively,” reports the neuroscientist. The brains of young animals and adult animals may also process information differently.

But there are still a few missing pieces left in the puzzle when it comes to understanding the way memories form in the young brain. “We’re still putting the pieces together, and we’ve already come to some surprising conclusions,” reveals Donato. But he and his team want to be completely certain of their results before taking them public. They are currently conducting comprehensive control trials. If their findings prove to be correct, they will provide a solid foundation for charting the course of early childhood memories all the way to the adult brain.

More articles in the current issue of  UNI NOVA.

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