"Unlocking Memories: The Intriguing Science of DNA Repair"

In a groundbreaking study, scientists have discovered that the formation of long-term memories is linked to the breaking and repairing of DNA in nerve cells, a process that is facilitated by an inflammatory response.

The researchers found that when a long-term memory is formed, certain brain cells experience a surge of electrical activity that causes DNA damage. This damage is then repaired by an inflammatory response, which helps to cement the memory in place.

The findings, published in the journal Nature, suggest that this DNA damage-and-repair cycle plays a crucial role in the formation and durability of memories.

"These results provide the best evidence so far that DNA repair is important for memory," said Tomás Ryan, an engram neuroscientist at Trinity College Dublin. "But it's still unclear whether the DNA damage is a consequence of engram creation, or if it encodes something distinct from the engram."

The researchers trained mice to associate a small electric shock with a new environment, and then examined gene activity in neurons in the hippocampus, a brain area crucial for memory. They found that some genes responsible for inflammation were active in a set of neurons four days after training, but were much less active three weeks later.

Further investigation revealed that the cause of the inflammation was a protein called TLR9, which triggers an immune response to DNA fragments floating inside cells. In this case, the nerve cells were responding to their own DNA, rather than to invading pathogens.

The researchers found that TLR9 was most active in a subset of hippocampal neurons where DNA breaks resisted repair. These neurons also had accumulations of DNA repair machinery in the centrosome, an organelle that is typically associated with cell division and differentiation. However, mature neurons do not divide, so it is unclear why the centrosome is participating in DNA repair.

When the researchers deleted the gene encoding the TLR9 protein from mice, the animals had trouble recalling long-term memories about their training. These findings suggest that "we are using our own DNA as a signalling system" to "retain information over a long time," said study co-author Jelena Radulovic.

The study also raises the possibility that this DNA damage-and-repair cycle might be faulty in people with neurodegenerative diseases such as Alzheimer's, leading to a build-up of errors in a neuron's DNA.

"These results bring much-needed attention to mechanisms of memory formation and persistence inside cells," said Clara Ortega de San Luis, a neuroscientist who works with Ryan at Trinity College Dublin. "We know a lot about connectivity between neurons and neural plasticity, but not nearly as much about what happens inside neurons."

Source:

<https://www.nature.com/articles/d41586-024-00930-y>