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Long-Term Memory Formation Requires Nerve Cell Damage

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Inflammation in the brain is rarely seen as a good thing; research has linked it to diseases including Alzheimer’s, Parkinson’s and neuropsychiatric symptoms such as anxiety. But a new study from Albert Einstein College of Medicine scientists puts a different spin on inflammation’s role in the brain, one that could have implications for drugs that target inflammatory pathways.

The research, published in Nature, suggests that DNA damage and inflammation in hippocampal neurons are critical for long-term memory formation, at least in mice.

Memory formation in the brain

The hippocampus is well-known for its role in memory formation, organization and storage. It’s in this part of the brain that our individual experiences are represented as neural assemblies in hippocampal and cortical circuits. How these assemblies form – and are maintained – has been the focus of much research and debate in neuroscience.

The most widely accepted mechanism is stimulus-induced long-term potentiation of synaptic activity; put simply, this means that neuronal connections become stronger after repeated stimulation over a long period of time, which underlies memory formation and retainment. Other mechanisms of action have also been proposed that suggest memory is influenced by built-in cellular programs that are present within individual neurons from the early stages of development.

The research team behind the Nature study wanted to explore whether an overarching process – one that integrates stimulus-dependent and pre-existing mechanisms – could be involved in memory formation and maintenance. The research was led by Dr. Jelena Radulovic, MD, professor in the Dominick P. Purpura Department of Neuroscience, professor of psychiatry and behavioral sciences and the Sylvia and Robert S. Olnick Chair in Neuroscience at Einstein.

Fear conditioning activates inflammatory pathway

Radulovic and colleagues subjected male and female mice to contextual fear conditioning (CFC), where mice were placed in a novel environment for three minutes before receiving a brief, mild electric shock to the foot. This assay is designed to induce episodic memory; when the animal is returned to the environment, it typically demonstrates a freezing response if it remembers the environment and associates it with the electric shock.

Using techniques including bulk RNA-sequencing (RNA-seq) and immunofluorescent labeling, Radulovic and colleagues analyzed gene expression and DNA breaks in hippocampal neurons. The neurons had been extracted from the mice either 96 hours or 21 days after CFC. “We previously reported that the 21-day gene expression repertoire revolved around cilium and extracellular matrix genes needed for PNN formation, but the 96-hour gene expression profiles associated with the shaping of recent memory representations remained unexplored,” the authors said.

After CFC, genes involved in inflammatory signaling were, to the researcher’s surprise, upregulated. “We observed strong activation of genes involved in the Toll-like receptor 9 (TLR9) pathway,” said Radulovic, who is also director of the Psychiatry Research Institute at Montefiore Einstein (PRIME).

The TLR9 pathway is typically triggered by the presence of small fragments of pathogenic DNA. “At first we assumed the TLR9 pathway was activated because the mice had an infection,” said Radulovic. “But looking more closely, we found, to our surprise, that TLR9 was activated only in clusters of hippocampal cells that showed DNA damage.”

DNA damage can be triggered by brain activity, but it’s often repaired within just a few minutes. In the hippocampal neurons analyzed in the study, double strand (ds) DNA breaks persisted, and were substantial. When dsDNA breaks were at a maximal level, the researchers observed nuclear envelope ruptures, which allowed for other molecules produced by DNA damage to be released into the cytoplasm, activating the TLR9 pathway.

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This pathway triggered the formation of DNA repair complexes at an unexpected location – the centrosomes. Centrosomes are membrane-free organelles that, in dividing cells, help to coordinate the process of cell division. Neurons, however, do not divide. Instead, it appears that the DNA complexes forming at the centrosomes in neurons are helping 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,” Radulovic explained. “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.”

An important finding of the study – in Radulovic’s opinion – is that, during the week whereby this inflammatory process was ongoing, hippocampal neurons became resistant to new or similar environmental stimuli: “This is noteworthy 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,” she said.

“The recruitment of individual neurons to assemblies is essential not only for encoding individual memories, but also for protecting them from streams of incoming information over time, ensuring stability and persistence of memory representations. On the basis of the evidence presented here, we suggest that in distinct populations of hippocampal CA1 excitatory neurons, this is achieved through learning-induced TLR9 signalling linking DNA damage to DDR,” the authors said in the paper.

Is caution needed when inhibiting the TLR9 pathway?

In knock-out experiments, blocking the TLR9 inflammatory pathway in hippocampal neurons impaired long-term memory formation, and triggered a high frequency of DNA damage.

This data could have implications for drugs that inhibit TLR9, 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 COVID. But caution needs to be shown because fully inhibiting the TLR9 pathway may pose significant health risks.” 

Reference: Jovasevic V, Wood EM, Cicvaric A, et al. Formation of memory assemblies through the DNA-sensing TLR9 pathway. Nature. 2024. doi: 10.1038/s41586-024-07220-7

This article is a rework of a press release issued by the Albert Einstein College of Medicine. Material has been edited for length and content.