You can't make long-term memories without damaging your brain cells

Brain inflammation is considered a bad thing: it can lead to neurological problems such as Alzheimer's and Parkinson's disease. However, this new study suggests that inflammation in specific neurons in the brain's hippocampal region is essential for making long-lasting memories.

The brain's memory center has long been recognized to be the hippocampus. According to research by Dr. Radulovic and her colleagues, specific hippocampal neurons undergo a cycle of DNA damage and repair that results in stable memory assemblies or groups of brain cells that symbolize our past experiences.

The scientists discovered how memories are made in mice by giving them small shocks. They looked at brain cells in the hippocampal region. They found that specific genes related to inflammation were turned on.

In particular, this gene activation was involved in the Toll-Like Receptor 9 (TLR9) pathway. The primary function of this inflammatory pathway is to detect tiny pieces of pathogen DNA and initiate immune responses. Thus, initially, scientists thought the mice's infection was the reason the TLR9 pathway was triggered. Upon closer inspection, however, scientists were shocked to discover that TLR9 was exclusively active in hippocampus cell clusters exhibiting DNA damage.

Typically, brain activity results in small breaks in DNA that are swiftly repaired. Yet, the damage was more extensive and persisted longer in these hippocampus neurons.

Upon closer inspection, they discovered that the nucleus was leaking materials from DNA damage and DNA fragments. This set off the TLR9 inflammatory pathway in neurons, which led to the assembly of DNA repair teams at the centrosomes, an unanticipated location. These structures aid in cell division and are typically found in the cytoplasm of cells. However, these active centrosomes aided in rounds of DNA repair in neurons, which do not divide. This is to group individual neurons into the groupings that make up memories.

Study leader Jelena Radulovic, M.D., Ph.D., professor in the Dominick P. Purpura Department of Neuroscience, professor of psychiatry and behavioral sciences, said, "Cell division and the immune response have been highly conserved in animal life over millions of years, enabling life to continue while protecting from foreign pathogens. It seems likely that throughout 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."

The mice's memory-encoding neurons underwent changes in the week it took for the inflammation to subside. They toughened against unfamiliar or comparable events occurring in their environment. According to Dr. Radulovic, this is significant since our brains are constantly inundated with fresh information. Memory-storing neurons must maintain current information and avoid becoming distracted by incoming data.

Most importantly, scientists found that blocking the TLR9 inflammatory pathway in hippocampal neurons prevented mice from forming long-term memories and caused profound genomic instability, i.e., a high frequency of DNA damage in these neurons.

Dr. Radulovic said, "Genomic instability is considered a hallmark of accelerated aging as well as cancer and psychiatric and neurodegenerative disorders such as Alzheimer's. Drugs that inhibit the TLR9 pathway have been proposed for relieving the symptoms of long-term COVID-19. But caution needs to be shown because fully inhibiting the TLR9 pathway may pose significant health risks."

Journal Reference:

1. Jovasevic, V., Wood, E.M., Cicvaric, A. et al. Formation of memory assemblies through the DNA-sensing TLR9 pathway. Nature 628, 145-153 (2024). DOI: 10.1038/s41586-024-07220-7