Different nerve cells in the brain have different roles when it comes to archiving personal experiences. Some nerve cells help in terms of stability and others help when it comes to specificity. 

Researchers from Aarhus University have now proposed a new model of memory postulating that a shared history of cycles of DNA damage and repair organizes individual nerve cells into lasting memory assemblies.

“Inflammation of brain neurons is usually considered to be a bad thing, since it can lead to neurological problems such as Alzheimer’s and Parkinson’s disease,” says Professor Jelena Radulovic from the Department of Biomedicine, who is behind the study.

“But our findings suggest that inflammation in certain neurons in the brain’s hippocampal region is essential for making long-lasting memories.”

The hippocampus has long been known as the brain’s memory center. Professor Radulovic and her colleagues found that a stimulus sets off a cycle of DNA damage and repair within certain hippocampal neurons that leads to stable memory assemblies—clusters of brain cells that represent our past experiences.

“Nerve cells that share some kind of history are believed to form memory assemblies easier than others. Such history can be history of activity, birthdate, immediate early gene response. A shared history of cycles of DNA damage and repair has a particularly important role,” Jelena Radulovic explains.

From shocks to stable memories

The researchers discovered this memory-forming mechanism by giving mice brief, mild shocks sufficient to form a memory of the shock event (episodic memory). They then analyzed neurons in the hippocampal region and found that genes participating in an important inflammatory signaling pathway had been activated.

“We observed strong activation of genes involved in the Toll-Like Receptor 9 (TLR9) pathway,” Jelena Radulovic says. The Tlr9 pathway is a group of molecules that support proper activation of the Tlr9 proteins and downstream signaling.

“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,” she explains.

Brain activity routinely induces small breaks in DNA that are repaired within minutes. But in this population of hippocampal neurons, the DNA damage appeared to be more substantial and sustained.

Triggering inflammation to make memories

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. These organelles are present in the cytoplasm of most animal cells and are essential for coordinating cell division. But in neurons - which don’t divide - the stimulated centrosomes participated in cycles of DNA repair that appeared to organize individual neurons into memory assemblies.

“Cell division and the immune response have been highly conserved in animal life over millions of years, enabling life to continue while providing protection from foreign pathogens,” Jelena Radulovic says.

“It seems likely that over the course of evolution, hippocampal neurons have adopted this immune-based memory mechanism by combining the immune response’s DNA-sensing TLR9 pathway with a DNA repair centrosome function to form memories without progressing to cell division.”

Resisting inputs of extraneous information

During the week required to complete the inflammatory process, the mouse memory-encoding neurons were found to have changed in various ways, including becoming more resistant to new or similar environmental stimuli.

“This is noteworthy,” Jelena Radulovic says.

“Because we’re constantly flooded by information, and the neurons that encode memories need to preserve the information they’ve already acquired and not be ‘distracted’ by new inputs.”

Importantly, the researchers found that blocking the TLR9 inflammatory pathway in hippocampal neurons not only prevented mice from forming long-term memories but also caused profound genomic instability, i.e, a high frequency of DNA damage in these neurons.

“Genomic instability is considered a hallmark of accelerated aging as well as cancer and psychiatric and neurodegenerative disorders such as Alzheimer’s,” she explains.

“Drugs that inhibit the TLR9 pathway have been proposed for relieving the symptoms of long COVID. But caution needs to be shown because fully inhibiting the TLR9 pathway may pose significant health risks.”

Preserving neurocognitive health

Neuron-specific Tlr9 signaling is likely to emerge as a promising preventive and therapeutic target for preserving neurocognitive health.

“Without Tlr9 there is no DNA repair nor memory formation. When dysfunction of Tlr9 can be responsible for some cases of cognitive deficits, then maintaining Tlr9 function would help preserve neurocognitive health,” says Professor Radulovic. 

The research results - more information:

• The study type is basic research on mice.
• Collaborators: University of Göttingen in Germany, Feinberg School of Medicine in Chicago, USA and Albert Einstein College of Medicine in New York, USA.
• External funding: National Institutes of Health and The Lundbeck Foundation.
• Read more in the scientific article: “Formation of memory assemblies through the DNA sensing TLR9 pathway.” (link)

Contact

Professor Jelena Radulovic
Aarhus University, Department of Biomedicine
Mail: jelena.radulovic@biomed.au.dk