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| Credit: Ted Kinsman/Science Photo Library |
Background
Our memories form when certain neurons in the hippocampus, the area responsible for memory, change over time in response to the things we experience.
This process requires a lot of energy and involves significant biochemical changes inside the cells. These molecular changes are believed to cause breaks or “damage” in our DNA.
A new study in mice, published on the 27th of March in Nature, shows that:
“When long-term memory is forming, certain neurons undergo a surge of electrical activity intense enough to break their DNA. Then, an inflammatory response initiates, facilitating the repair of this damage and solidifying the memory.”
Typically, when you hear DNA “damage” you would think about diseases such as cancer. However, in this case, the cycle of DNA damage and repair presents a potential explanation for the formation of memories.
The Experiment & The Results
In their experiment to understand how DNA damage plays a role in memory formation, researchers put mice in a new environment and then electrically shocked them to make the mice associate this new environment with a feeling of pain.
So when the animals were once again put into that environment, they would ‘remember’ the experience and show signs of fear, such as freezing in place.
After that, researchers examined the gene activity in the brain area associated with memory which is the hippocampus to find out that some genes responsible for inflammation were active in a set of neurons four days after training.
Further analysis showed that DNA fragments, along with other molecules resulting from the DNA damage, were released from the nucleus. After which the neurons’ TLR9 inflammatory pathway was activated; this pathway in turn stimulated DNA repair complexes to form at an unusual location: the centrosomes.
“We observed strong activation of genes involved in the Toll-Like Receptor 9 (TLR9) pathway,” — said Dr. Radulovic, director of the Psychiatry Research Institute at Montefiore Einstein (PRIME).
The team explained that the cause of this inflammation was a protein called TLR9.
“This inflammatory pathway is best known for triggering immune responses by detecting small fragments of pathogen DNA. So at first we assumed the TLR9 pathway was activated because the mice had an infection. But looking more closely, we found, to our surprise, that TLR9 was activated only in clusters of hippocampal cells that showed DNA damage.” — said Dr. Radulovic
This protein triggers an immune response when DNA is broken into fragments floating around the insides of cells.
It is the same inflammatory response that our body uses to fight off infections and foreign bodies that enter our systems, however, in this case, neurons used this inflammatory response to their own DNA damage.
The protein TLR9 was most active in the hippocampal neurons in which DNA breaks resisted repair.
In these cells, DNA repair machinery accumulated in an organelle called the centrosome, which is often associated with cell division and differentiation.
However, mature neurons don’t divide, which was surprising for the researchers to see centrosomes participating in DNA repair.
In other words, during damage-and-repair cycles, neurons might encode information about the event that triggered the DNA damage which originally is associated with a memory.
To emphasize the role of TLR9, researchers deleted the gene encoding its transcription in some mice and the results were as follows:
The animals could not recall long-term memories about their training: they froze much less often when placed into the “Painful” environment where they had previously been shocked than did mice that had the gene intact.
Caution With TLR9 Inhibitors
The risks and benefits of TLR9 inhibitors depend on various factors, including the specific context of their use and the individual’s health condition.
Here’s a simplified breakdown:
- Reduced Immune Response: TLR9 inhibitors may weaken the body’s ability to fight infections by suppressing immune responses mediated by TLR9.
- Potential Side Effects: Like any medication, TLR9 inhibitors could have side effects such as gastrointestinal issues, allergic reactions, or other adverse effects.
- Impact on Memory Formation: Since TLR9 plays a role in memory formation, inhibiting it could potentially affect cognitive functions and memory formation processes.
Benefits:
- Treatment of Autoimmune Disorders: TLR9 inhibitors might be beneficial in managing autoimmune disorders by reducing excessive immune responses that lead to inflammation and tissue damage.
- Therapeutic Potential for Neurodegenerative Diseases: Inhibiting TLR9 could offer therapeutic potential in neurodegenerative diseases by modulating inflammatory responses associated with these conditions.
- Cancer Treatment: TLR9 inhibitors may have a role in cancer treatment by modulating immune responses against tumor cells and enhancing the effectiveness of cancer therapies.
Conclusion
In short, the research discovered that our “Learning process” can start a chain reaction of DNA damage and repair in the brain, thanks to TLR9. This process helps certain groups of brain cells in the hippocampus to form memories.
The inflammatory responses mediated by TLR9 have a vital role in memory formation, and impairments in TLR9 function could be implicated in cognitive, neurodegenerative, and psychiatric disorders.