Scientists Learn Something New About How Memories are Made in the Brain

It involves breaking, then fixing, our DNA

Hiya!

Memories fascinate me. I’ve often wondered why we remember some things but not others or how memories are made in the first place. As for the first, research suggests that our brains prioritize our most useful experiences for future use. Most of these relate to keeping us alive, such as reminding us which person/place/thing is or isn’t safe.

As for my second curiosity, scientists learned that several areas of our brain store memories and know which brain regions are more associated with memory creation, like the hippocampus. But only recently have experts started to figure out how memories are made, and what they’re finding is both incredible and a smidge concerning.

Previous Research

Before I get to the new research, let’s go back to 2015 for a moment. That’s when Li-Huei Tsai, Picower Professor of Neuroscience at the Massachusetts Institute of Technology (MIT) and director of The Picower Institute for Learning and Memory, published a study in Cell demonstrating for the first time that neuron activity in the brain breaks both strands of our DNA double-helix and that they generate rapid gene expression.

When both strands of the DNA double-helix break (known as double-strand breaks, or DSBs), it’s usually associated with diseases, including cancer and a range of neurological ones. Meanwhile, our cells use gene expression to convert instructions stored in our DNA into a functional product, like a protein.

However, Tsai’s findings involved neurons prepared in a lab, which couldn’t fully capture the extent of the activity related to a living animal forming memories. Additionally, Tsai and her colleagues didn’t analyze cells besides neurons.

So in 2021, Tsai and her team published another study, this time in PLoS One, which revealed that DSBs don’t just happen but are widespread throughout the brain. Further, the team was able to link these DNA breaks to learning.

Previously, scientists knew that learning arises thanks to “synaptic plasticity,” which is when neurons change their connections, and that memories are formed when neurons connect to create engrams. The cells that make an engram are like physical traces of individual memories, and they express certain genes after we learn something.

Tsai and her team, including lead author and former graduate student Ryan Stott and co-author and former research technician Oleg Kritsky, used mice for this study.

The researchers issued mice a small electrical zap to their feet when they entered a certain box to condition a fear memory. They then used various methods to analyze the DSBs and gene expression in the mice's brains for 30 minutes afterward, focusing on cells in the hippocampus and prefrontal cortex — both are essential for forming memories and storing conditioned fear memories.

For their control, they also measured the same activity in the brains of mice that didn’t receive the electrical stimulation.

The team found that fear-based memory produced double the number of DSBs in the brains of mice that experienced the slight shock, affecting over 300 genes in both the hippocampus and prefrontal cortex. There were 206 affected genes common to both regions, and the researchers learned that most of them are associated with synapses — the connections neurons make with each other.

The researcher's findings further support that learning arises thanks to synaptic plasticity and that memories are created when engrams form.

Tsai and her team also looked beyond the neurons and found that glia (brain cells that aren’t neurons) also changed the expression of hundreds of genes after fear conditioning.

So, basically, Tsai found that neurons and other brain cells break open DNA in far more locations than previously realized to gain fast access to genetic instructions so memories can form.

Now, another team of researchers picked up where Tsai left off and they found something new.

New Discovery

The new study, published by Nature on March 27, 2024, was completed by Jelena Radulovic, a neuroscientist at the Albert Einstein College of Medicine in New York City, and an international team of scientists from The US, Germany, and Denmark.

While Tsai wasn’t involved in the new research, she told Nature that she thinks the findings are “extremely exciting.”

Since Tsai discovered that DNA breaks are far more common than previously realized and associated them with learning, Radulovic and her colleagues wanted to better understand the process. So, they designed a similar experiment to Tsai’s but analyzed the mice’s gene activity, too, and for longer than 30 minutes.

The researchers zapped the feet of mice when they entered a new environment to create a fear response, similar to Tsai’s experiment. Then, they analyzed the gene activity within neurons in the mice’s hippocampus and were stunned to find some genes related to inflammation were active in some neurons for an astonishing four days after training. By three weeks, the same genes were far less active.

Following the surprising inflammation response, the researchers pinpointed the source — a protein called TLR9, which initiates an immune response when DNA flakes are floating around inside cells.

Radulovic explained to Nature that this response is similar to the immune cells' inflammatory response to fight against invading pathogens. Except, rather than responding to invaders, TLR9 responds to our loose DNA fragments.

TLR9 and its inflammation response weren’t the only surprises Radulovic and her team discovered. Remember when I said previous research suggests that engrams — special groups of neurons — are like physical traces of individual memories and key to memory formation? I also mentioned that engrams express certain genes after we learn something.

Well, Radulovic’s team found that the neurons in the mice’s hippocampus that had the memory-related inflammation response were mostly different from engram neurons.

Engram neuroscientist at Trinity College Dublin, Tomás Ryan, who was not involved in the study, wonders whether neurons encode something distinct from the engram or if the DNA damage and healing might result from engram creation. Ryan told Nature:

“Forming an engram is a high-impact event; you have to do a lot of housekeeping after,” still, he says the research by Radulovic and her team is “the best evidence so far that DNA repair is important for memory.”

So, when we put it all together, Tsai’s earlier research showed that for the brain to create long-term memories, some brain cells are bombarded with electrical activity so intense that it snaps DNA. Now, the new research found that after the DNA breaks, an inflammatory response kicks in to help repair the damage, which cements the memory.

Still, even if the inflammatory response helps repair the DNA damage, breaking DNA — especially as frequently as it seems to happen — feels dangerous. What are the chances something goes wrong in the healing process, and what might the consequences be?

Potential Danger

Tsai is surprised and similarly concerned about the extent of DNA double-strand breaks throughout essential brain areas. After her 2021 discovery, Tsai pointed out that even if the DNA breaks are repaired, the process will likely become fragile and more flawed as we age.

It’s more than an opinion. Research by Tsai from 2020 found a connection between lingering DSBs and cognitive decline and neurodegeneration, ultimately showing that errors can and do occur during the repair process.

This is further supported by other research linking DSBs with neurological and other diseases I mentioned earlier. All of this makes scientists wonder whether a buildup of DSBs might also play a role in diseases like Alzheimer’s.

Looking to the Future

Tsai told Nature she hopes scientists will figure out how the DNA breaks happen and which brain regions are most prone to them.

Meanwhile, a neuroscientist working with Ryan at Trinity College Dublin, Clara Ortega de San Luis, told the journal that she hopes Tsai’s and Radulovic’s research will bring scientific interest back to memory formation. She explained to Nature:

“We know a lot about connectivity [between neurons] and neural plasticity, but not nearly as much about what happens inside neurons.”

So, it seems future research will involve exploring beyond the tiny world of cells and neurons and into the even smaller world within them.

Perspective Shift

I never would have thought that memory creation involves snapping not just one but both strands of our DNA helix. I suppose it’s a decent solution for accessing information within the DNA as quickly as possible, but it still feels risky. I wonder whether experts can figure out the ratio of successful vs unsuccessful repairs.

I also hope scientists learn why we remember what we do. I know the general consensus is that we remember things that could help us survive in the future, but I don’t think that’s the only reason.

I have strong memories of seemingly irrelevant experiences — most of which were moments when I was alone but not lonely. After further reflection, I realized these memories still influenced me, not my survival directly but my understanding of the world. So, eventually, I’ve come to the conclusion that memories form when something leaves an impression on us and shapes our perspective. Alas, I suppose we’ll have to wait to find out.

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