Long-Term Memory Formation Requires DNA Damage and Brain Inflammation, Study Reveals

Inflammation of brain neurons is usually considered a negative thing, since it is linked to diseases such as Parkinson's, Alzheimer's, and neuropsychiatric symptoms like anxiety. A new study, however, puts a different spin on the role of inflammation in the brain, one that can lead to development of drugs that targets inflammatory pathways.

Positive Effect of Brain Inflammation

At Albert Einstein College of Medicine, scientists discovered that long-term memories cannot be formed without DNA damage and brain inflammation. Their study suggests inflammation in certain neurons in the hippocampal region is vital for making long-lasting memories. The surprising findings are discussed in the paper "Formation of memory assemblies through the DNA-sensing TLR9 pathway."

Led by Professor Jelena Radulovic from Dominick P. Purpura Department of Neuroscience, a team of researchers found that a stimulus sets off a cycle of DNA damage and repair within certain hippocampal neurons. This leads to stable memory assemblies, which refer to clusters of brain cells that represent a person's past experiences.

This memory-forming mechanism was discovered by the team by giving brief, mild shocks to mice to form a memory of the shock event, also known as episodic memory. After analyzing neurons in the hippocampal region, they discovered the activation of genes linked to a vital inflammatory signaling pathway.

The scientists observed strong activation of genes involved in the Toll-Like Receptor 9 (TLR9) pathway. This is an inflammatory pathway best known for triggering immune responses by detecting small fragments of pathogen DNA.

At first, the researchers assumed that the TLR9 pathway was activated because the mice suffered from an infection. But after looking more closely, they were surprised to find that TLR9 was activated only in clusters of hippocampal cells that showed DNA damage.

Brain activity routinely produces small breaks in DNA which are repaired within minutes. In this population of hippocampal neurons, however, DNA damage appeared to be more essential and sustained.

Further analysis also indicates that DNA fragments were released from the cell nucleus, leading to activation of the neuron's TLR9 inflammatory pathway. In turn, this pathway stimulated DNA repair complexes to form at the centrosomes of the cell.

READ ALSO: Long-Term Memory: New Discovery Revises Old Theories On Memory Formation

Resisting Information Overload

While completing the inflammatory process, the memory-encoding neurons of mice were found to have changed in different ways. This includes becoming more resistant to new or similar environmental stimuli.

This is noteworthy, according to Radulovic, because we are constantly flooded by extraneous information. In other words, the neurons that encode memories should preserve the information they have already acquired without getting distracted by new inputs.

The research team also discovered that blocking the TLR9 inflammatory pathway in hippocampal neurons not only prevented long-term memory formation, but also caused extreme genomic instability, like a high frequency of DNA damage in these neurons.

Radulovic noted that genomic instability is a hallmark of accelerated aging, cancer, and psychiatric and neurodegenerative disorders like Alzheimer's disease. Additionally, drugs that inhibit the TLR9 pathway have been proposed to relieve the symptoms of long COVID. However, caution must be observed since fully inhibiting the TLR9 pathway can cause significant health risks.

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