Recently, researchers at the Albert Einstein College of Medicine in the United States have found that without DNA damage and brain inflammation, long-term memory cannot be formed. This surprising discovery was published online in the journal Nature on March 28th.
During the learning process, damage to the nucleus DNA of neurons releases DNA (large white dots on the right), histones (purple), and transcription factors (red and green). Image source: Albert Einstein College of Medicine.
Researchers suggest that inflammation in brain neurons is typically seen as detrimental, possibly leading to neurological issues like Alzheimer's and Parkinson's diseases. However, a new discovery indicates that inflammation in certain hippocampal neurons is essential for the formation of enduring memories. Stimulation triggers a cycle of DNA damage and repair in specific hippocampal neurons, resulting in stable memory ensembles, representing clusters of brain cells reflecting past experiences.
By subjecting mice to brief, mild electric shocks to induce memory formation (episodic memory), researchers uncovered this mechanism of memory formation. They then analyzed the neurons in the hippocampus and found genes involved in important inflammatory signaling pathways to be activated.
Researchers observed strong activation of genes related to the Toll-like receptor 9 (TLR9) pathway. This inflammatory pathway can trigger an immune response by detecting small fragments of pathogenic DNA, leading researchers initially to hypothesize that TLR9 activation was due to infection in the mice. However, upon closer inspection, they were surprised to find that TLR9 was only activated in hippocampal neuron clusters exhibiting DNA damage.
Brain activity typically causes minor DNA breaks, which are repaired within minutes. But in these hippocampal neurons, DNA damage appears to be more severe and prolonged.
Further analysis revealed that other molecules generated by DNA damage are released from the cell nucleus, subsequently activating the neuron's TLR9 inflammatory pathway. This pathway, in turn, stimulates the formation of DNA repair complexes in an unusual location, namely the centrosome. Centrosomes are present in the cytoplasm of most animal cells and are crucial for coordinating cell division. However, in neurons, which do not divide, stimulated centrosomes are involved in the cycle of DNA repair, seemingly organizing individual neurons into memory components.
Importantly, researchers also found that blocking the TLR9 inflammatory pathway in hippocampal neurons not only prevents mice from forming long-term memories but also leads to severe genomic instability, indicating a high frequency of DNA damage in these neurons. Genomic instability is considered a hallmark of aging, cancer, and neurodegenerative diseases like Alzheimer's.
(Original title: Study Suggests Forming Long-Term Memories is Indeed "Brain-Straining")
