A surprising discovery by researchers at the Albert Einstein College of Medicine suggests that brain inflammation and DNA damage are critical elements in the formation of long-term memories. The study, published in the journal Naturechallenges the conventional idea that brain inflammation is only detrimental.
“Inflammation of neurons in the brain is generally considered a bad thing because it can lead to neurological problems such as Alzheimer’s disease and Parkinson’s disease,” said Jelena Radulovic, MD, Ph.D., director of the study, professor in the Dominick P. Purpura department. of neuroscience, professor of psychiatry and behavioral sciences, and Sylvia and Robert S. Olnick Professor of Neuroscience at Einstein. “But our results suggest that inflammation of certain neurons in the hippocampal region of the brain is essential for the creation of lasting memories.”
To study 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 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 memory-inducing shocks, researchers focused on the hippocampus, a critical region of the brain involved in memory processing. They used advanced genetics and molecular biology techniques to analyze neurons in this region. One of the main techniques used was massive RNA sequencing, which allowed researchers to examine the expression of thousands of genes simultaneously.
They found that the Toll-Like Receptor 9 (TLR9) inflammatory pathway was strongly activated in these neurons. This pathway is usually 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 hippocampal neurons rather than infection.
The results provide evidence that 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, mice could not form long-term memories, indicating its essential role in this process.
To investigate further, the researchers looked at DNA damage and repair processes within these neurons. They found that fragments of DNA and other molecules resulting from the damage were released from the nucleus. This release triggered activation of the TLR9 pathway, which then stimulated DNA repair mechanisms at centrosomes – organelles usually involved in cell division. In neurons, which do not divide, centrosomes play a different role, helping to organize neurons into stable memory assemblies necessary for long-term memory formation.
“Cell division and the immune response have been highly conserved in animal life for millions of years, allowing life to continue while providing protection against foreign pathogens,” Radulovic explained. “It seems likely that during evolution, hippocampal neurons adopted this immune-based memory mechanism by combining the TLR9 DNA-sensing pathway of the immune response with centrosomal function of DNA repair to form memories without progressing toward cell division.”
Another important finding is that during the week-long inflammatory process, neurons coding for memory became more resistant to new or similar stimuli. This resistance is important because it allows the information already acquired to be preserved, thus preventing these neurons from being distracted by new inputs. This resistance ensures the stability of the memories formed over time.
“This is remarkable,” Radulovic said, “because we are constantly inundated with information and the neurons that encode memories must preserve the information they have already acquired and not be ‘distracted’ by new input.”
The study also highlighted the potential risks associated with total inhibition of the TLR9 pathway. The researchers observed that blocking this pathway not only prevented memory formation, but also led to profound genomic instability in 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 although modulation of the TLR9 pathway may have therapeutic potential, it should be performed 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 disease,” Radulovic said. “Drugs that inhibit the TLR9 pathway have been proposed to relieve symptoms of long COVID. But caution should be exercised, as complete inhibition of the TLR9 pathway can pose significant health risks.
The use of animal models, such as mice, in scientific research offers significant advantages, including the ability to tightly control experimental conditions and the ability 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 such as memory formation and brain function. There are, however, notable pitfalls, including differences in brain complexity and cognitive abilities between mice and humans, which may limit the direct applicability of the findings.
Future research should focus on validating these findings in humans to determine whether similar mechanisms of DNA damage and inflammation are involved in human memory formation. Additionally, exploring the molecular details of the TLR9 pathway in different neuron types could learn more about its role in memory and neurodegenerative diseases. Investigating potential therapeutic interventions that may modulate this pathway without causing genomic instability could also provide new treatments for memory-related disorders.
The study titled “Formation of memory assemblies via the TLR9 DNA-sensing 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.