Brain inflammation and DNA damage: Unexpected keys to long-term memory

A surprising discovery by researchers at the Albert Einstein College of Medicine suggests that brain inflammation and DNA damage are essential components in the formation of long-term memories. The study, published in the journal Nature, challenges the conventional view that inflammation in the brain is solely detrimental.

“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,” said study leader Jelena Radulovic, M.D., Ph.D., 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. “But our findings suggest that inflammation in certain neurons in the brain’s hippocampal region is essential for making long-lasting memories.”

To investigate memory formation, the researchers conducted their study using a controlled experimental setup with mice. They began by subjecting the mice to mild, brief shocks, a method known as contextual fear conditioning. This approach is used to create an episodic memory, which is a type of memory associated with specific events. The shocks were designed to be strong enough to form a memory without causing significant harm to the animals.

Following the memory-inducing shocks, the researchers focused on the hippocampus, a critical region of the brain involved in memory processing. They used advanced genetic and molecular biology techniques to analyze the neurons within this region. One of the primary techniques used was bulk RNA sequencing, which allowed the researchers to examine the expression of thousands of genes simultaneously.

They discovered that the Toll-Like Receptor 9 (TLR9) inflammatory pathway was highly activated in these neurons. This pathway is typically involved in the immune response, detecting DNA fragments from pathogens. However, the researchers found that the TLR9 pathway was activated due to DNA damage in the hippocampal neurons rather than an infection.

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The results provide evidence that the activation of the TLR9 pathway in response to DNA damage is crucial for memory formation. This finding was unexpected, as this pathway is generally known for its role in immune responses rather than memory processes. The researchers found that when the TLR9 pathway was blocked, the mice could not form long-term memories, indicating its essential role in this process.

To delve deeper, the researchers examined the DNA damage and repair processes within these neurons. They found that DNA fragments and other molecules resulting from the damage were released from the nucleus. This release triggered the activation of the TLR9 pathway, which then stimulated DNA repair mechanisms at the centrosomes — organelles usually involved in cell division. In neurons, which do not divide, the centrosomes played a different role, aiding in organizing neurons into stable memory assemblies necessary for long-term memory formation.

“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.”

Another significant finding was that during the week-long inflammatory process, the memory-encoding neurons became more resistant to new or similar stimuli. This resistance is important because it helps preserve the information already acquired, preventing these neurons from being distracted by new inputs. This resistance ensures the stability of the formed memories over time.

“This is noteworthy,” said Radulovic, “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.”

The study also highlighted the potential risks of fully inhibiting the TLR9 pathway. The researchers observed that blocking this pathway not only prevented memory formation but also led to profound genomic instability in the hippocampal neurons. Genomic instability is a condition characterized by a high frequency of DNA damage and is associated with accelerated aging and various neurological disorders, including Alzheimer’s disease. This finding suggests that while modulating the TLR9 pathway could have therapeutic potential, it must be done with caution to avoid adverse effects on genomic stability.

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

Using animal models, such as mice, in scientific research offers significant benefits, including the ability to control experimental conditions tightly and the opportunity to conduct invasive procedures that would be unethical in humans. Mice share many genetic and physiological similarities with humans, making them excellent models for studying complex biological processes like memory formation and brain function. However, there are notable pitfalls, including the differences in brain complexity and cognitive abilities between mice and humans, which can limit the direct applicability of findings.

Future research should focus on validating these findings in humans to determine if similar mechanisms of DNA damage and inflammation are involved in human memory formation. Additionally, exploring the molecular details of the TLR9 pathway in different types of neurons could uncover more about its role in memory and neurodegenerative diseases. Investigating potential therapeutic interventions that can modulate this pathway without causing genomic instability could also provide new treatments for memory-related disorders.

The study, “Formation of memory assemblies through the DNA-sensing TLR9 pathway,” was authored by Vladimir Jovasevic, Elizabeth M. Wood, Ana Cicvaric, Hui Zhang, Zorica Petrovic, Anna Carboncino, Kendra K. Parker, Thomas E. Bassett, Maria Moltesen, Naoki Yamawaki, Hande Login, Joanna Kalucka, Farahnaz Sananbenesi, Xusheng Zhang, Andre Fischer, and Jelena Radulovic.