As long-term memories take shape, certain brain cells undergo such intense electrical activity that it leads to DNA breakage. A mouse study published in Nature on March 27th reveals that an inflammatory response kicks in to repair this damage, aiding in the consolidation of memory.
Neurons Repair DNA Breaks During Memory Formation
Neurons repair broken DNA strands during the process of memory formation, according to a study illustrated by Ted Kinsman from Science Photo Library. Dr. Li-Huei Tsai, a neurobiologist at the Massachusetts Institute of Technology who was not involved in the study, called this discovery "very exciting," supporting the notion that forming memories is a "risky business."
Typically, breaks in the double helix DNA molecule's two strands are associated with diseases including cancer. However, in this scenario, the cycle of DNA damage and repair provides an explanation for how memories are formed and sustained.
"This also suggests a possibility: that this cycle may be defective in patients with neurodegenerative diseases such as Alzheimer's disease, leading to the accumulation of errors in neuronal DNA," said Jelena Radulovic, the lead author of the paper and a neuroscientist at the Albert Einstein College of Medicine in the United States.
This isn't the first time DNA damage has been linked to memory. In 2021, Tsai and colleagues demonstrated that double-strand DNA breaks are common in the brain and associated with learning ability.
To better understand the role of these DNA breaks in memory formation, Radulovic and her team trained mice to associate mild shocks with a new environment. When placed back into the new environment later, the mice "remembered" the experience and exhibited signs of fear, such as freezing in place.
The researchers then examined the gene activity in the hippocampus, a critical area of the brain for memory. They found that after four days of training, some genes responsible for inflammation were active in a group of neurons. After three weeks of training, the same gene activity significantly decreased.
The team identified the cause of the inflammation - a protein called TLR9, which triggers an immune response to floating DNA fragments inside cells. Radulovic explained that this reaction is similar to the inflammatory response immune cells use to defend against invading pathogens carrying genetic material.
However, the researchers found that in this case, neurons didn't react to invaders but rather to their own DNA. TLR9 was most active in a subset of hippocampal neurons resistant to repairing DNA breaks. In these cells, DNA repair mechanisms accumulated in a cellular organelle called the centrosome, typically associated with cell division and differentiation. However, mature neurons do not divide. Radulovic noted that seeing the centrosome involved in DNA repair was surprising.
Radulovic wonders whether memory is formed through a mechanism similar to how immune cells adapt to foreign substances they encounter. "In other words, neurons may encode information about events that trigger DNA breaks during the damage and repair cycle of memory formation," she said.
When researchers deleted the gene encoding the TLR9 protein from mice, they struggled to recall long-term memories of the training. Placed back in the previously shocked environment, they froze much less frequently than normal mice. Radulovic said these findings suggest, "we are using our own DNA as a signaling system to preserve information long-term."
How these findings align with other discoveries about memory formation, such as the crucial role of a subset of hippocampal neurons known as engram cells, remains unclear. These cells are thought to be physical traces of individual memories, expressing certain genes after learning events. However, the group of neurons associated with memory-related inflammation observed by Radulovic and colleagues differs from engram neurons in many ways.
Tomas Ryan, a neuroscientist at Trinity College Dublin in Ireland, said the study provides the "strongest evidence to date that DNA repair is important for memory." However, he questions whether neurons encode something different from engrams. Instead, he believes DNA damage and repair might be a consequence of engram formation.
Tsai hopes future research will explore how double-strand DNA breaks occur and whether they also occur in other regions of the brain.
For more information, see the related paper: https://doi.org/10.1038/s41586-024-07220-7
