Summary: Researchers unveiled a groundbreaking discovery that DNA damage and brain inflammation are vital processes for forming long-term memories, particularly within the brains hippocampus.

Contrary to previous beliefs associating inflammation with neurological diseases, this study highlights inflammations critical role in memory formation through the activation of the Toll-Like Receptor 9 (TLR9) pathway following DNA damage in hippocampal neurons.

These findings not only challenge conventional views on brain inflammation but also caution against indiscriminate inhibition of the TLR9 pathway, given its importance in memory encoding and the potential risks of genomic instability.

Key Facts:

Source: Albert Einstein College of Medicine

Just as you cant make an omelet without breaking eggs, scientists atAlbert Einstein College of Medicinehave found that you cant make long-term memories without DNA damage and brain inflammation.

Their surprising findings were published online today in the journalNature.

Inflammation of brain neurons is usually considered to be a bad thing, since it can lead to neurological problems such as Alzheimers and Parkinsons disease, said study leaderJelena Radulovic, M.D., Ph.D., professor in theDominick P. Purpura Department of Neuroscience, professor of psychiatry and behavioral sciences, and the Sylvia and Robert S. Olnick Chair in Neuroscience at Einstein.

But our findings suggest that inflammation in certain neurons in the brains hippocampal region is essential for making long-lasting memories.

The hippocampus has long been known as the brains memory center. Dr. 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 assembliesclusters of brain cells that represent our past experiences. Elizabeth Wood, a Ph.D. student, and Ana Cicvaric, a postdoc in the Radulovic lab, were the studys first authors at Einstein.

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, said Dr. Radulovic, who is also director of thePsychiatry Research Institute at Montefiore Einstein(PRIME).

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.

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 neuronswhich dont dividethe 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, Dr. Radulovic said.

It seems likely that over the course of evolution, hippocampal neurons have adopted this immune-based memory mechanism by combining the immune responses 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, said Dr. Radulovic, because were constantly flooded by information, and the neurons that encode memories need to preserve the information theyve 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 Alzheimers, Dr. Radulovic said.

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.

The study is titled Formation of memory assemblies through the DNA sensing TLR9 pathway. Other Einstein authors are: Hui Zhang, Ph.D., Zorica Petrovic, B.A., Anna Carboncino, Ph.D., Kendra K. Parker, B.A., Thomas E. Bassett, Ph.D., Xusheng Zhang, M.S.

The other contributors are: co-first author Vladimir Jovasevic, Ph.D., at Northwestern University, Chicago, IL; Maria Moltesen, Ph.D., Naoki Yamawaki, Ph.D., Hande Login, Ph.D., Joanna Kalucka, Ph.D., all at Aarhus University, Aarhus, Denmark; Farahnaz Sananbenesi, and Andre Fischer, Ph.D., at University Medical Center, Gttingen, Germany.

Author: Elaine Iandoli Source: Albert Einstein College of Medicine Contact: Elaine Iandoli Albert Einstein College of Medicine Image: The image is credited to Neuroscience News

Original Research: Open access. Formation of memory assemblies through the DNA sensing TLR9 pathway byJelena Radulovic et al. Nature

Abstract

Formation of memory assemblies through the DNA sensing TLR9 pathway

As hippocampal neurons respond to diverse types of information, a subset assembles into microcircuits representing a memory. Those neurons typically undergo energy-intensive molecular adaptations, occasionally resulting in transient DNA damage.

Here we found discrete clusters of excitatory hippocampal CA1 neurons with persistent double-stranded DNA (dsDNA) breaks, nuclear envelope ruptures and perinuclear release of histone and dsDNA fragments hours after learning.

Following these early events, some neurons acquired an inflammatory phenotype involving activation of TLR9 signalling and accumulation of centrosomal DNA damage repair complexes.

Neuron-specific knockdown ofTlr9impaired memory while blunting contextual fear conditioning-induced changes of gene expression in specific clusters of excitatory CA1 neurons.

Notably, TLR9 had an essential role in centrosome function, including DNA damage repair, ciliogenesis and build-up of perineuronal nets.

We demonstrate a novel cascade of learning-induced molecular events in discrete neuronal clusters undergoing dsDNA damage and TLR9-mediated repair, resulting in their recruitment to memory circuits.

With compromised TLR9 function, this fundamental memory mechanism becomes a gateway to genomic instability and cognitive impairments implicated in accelerated senescence, psychiatric disorders and neurodegenerative disorders.

Maintaining the integrity of TLR9 inflammatory signalling thus emerges as a promising preventive strategy for neurocognitive deficits.

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DNA Damage and Inflammation Key to Memory Formation - Neuroscience News