Lasting memories come at a cost – DNA and brain cell damage

Think back to a truly vivid memory. Maybe it was a special birthday, a terrifying accident, or a life-changing adventure. These memories stick in your brain – the sights, sounds, maybe even smells – far longer than the everyday details of your life. But how does your brain decide what to keep and what to let fade?

Scientists at the Albert Einstein College of Medicine believe the answer lies in something surprising and slightly unsettling: controlled DNA damage and inflammation within your brain cells. It sounds scary, but it might be the secret to how we form lasting memories.

Inflammation is not always the enemy

“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,” explains Dr. Jelena Radulovic, the neuroscientist who led the study. “But our findings suggest that inflammation in certain neurons in the brain’s hippocampal region is essential for making long-lasting memories.”

The hippocampus, a seahorse-shaped structure, nestles deep within your brain, serving as the central command post for memory formation. Now, Dr. Radulovic’s team has revealed a fascinating mechanism at work within this structure.

Brain shocks, DNA damage, and building a memory

The researchers focused on mice, giving them brief, mild shocks. This created a memory of the unpleasant event, known as an episodic memory.

Analyzing the mice’s brains, the scientists discovered something striking – genes involved in an important inflammatory pathway had been activated within the hippocampus.

This pathway, called Toll-Like Receptor 9 (TLR9), is normally part of our immune response. It’s designed to detect bits of foreign DNA from viruses or bacteria, triggering our defenses. But here, it seems to play a different role.

The mild shock caused small breaks in the DNA within certain hippocampal neurons. This kind of routine DNA damage and repair happens all the time. However, in these memory-forming neurons, the damage seemed more significant and long-lasting.

The cell’s nucleus released the broken bits of DNA and other resulting molecules, activating the TLR9 pathway.

Brain’s “rewiring station” of memories

This inflammation response then triggered a cascade of events: DNA repair complexes moved to an unusual location – the centrosomes.

Centrosomes are tiny structures in the cell, usually responsible for helping cells divide. But neurons don’t divide, so what are they doing here?

Dr. Radulovic’s team believes this is where the memory magic happens. The centrosomes, activated by inflammation, become centers for extensive DNA repair.

Memory assembly process

This repair process seems to link these neurons together, creating a ‘memory assembly‘ dedicated to storing that experience.

“Cell division and the immune response have been highly conserved in animal life over millions of years,” Dr. Radulovic says.

“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,” she continued.

Protecting new memories in the brain

Here’s another intriguing part: when these memory-encoding neurons are busy with this inflammatory repair process, they temporarily resist new information.

This makes sense – imagine trying to focus on building something complicated while someone’s constantly interrupting you.

“This is noteworthy,” said Dr. 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 dark side of inflammation

It’s important to note: messing with the brain’s inflammatory pathways is risky business. These scientists discovered that if they fully blocked the TLR9 pathway, it stopped long-term memory formation, and also led to genomic instability – that’s when DNA damage gets out of control.

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

Study implications

This discovery, though still in its early stages, sheds a brilliant light on a previously unexplored avenue for understanding and potentially treating memory disorders.

It paints a hopeful picture of fighting back against diseases known for robbing us of our memories with a new arsenal of therapies one day.

Our understanding of the immune system has evolved. This research suggests that inflammation, carefully controlled and channeled, might hold unexpected power as a collaborator in the complex dance of memory formation and storage.

The implications stretch far and wide. Imagine a future where memory faltering isn’t a foregone conclusion.

How the TLR9 pathway is linked to brain and memories

Our body has a special system called the immune system that helps us fight off germs like bacteria and viruses. As mentioned previously, one important part of this system is the Toll-like receptor 9 (TLR9) pathway, which helps our body recognize and respond to certain types of DNA found in these germs.

What is TLR9 and where is it found?

TLR9 is like a special detector that our body uses to find bad germs. It’s found mainly in two types of immune cells: plasmacytoid dendritic cells (pDCs) and B cells. These cells keep TLR9 inside them until they need to use it to detect germs.

TLR9 looks for specific patterns in the DNA of bacteria and viruses. These patterns are called unmethylated CpG motifs, which are like fingerprints that help TLR9 identify the bad germs. When TLR9 finds these patterns, it grabs onto the DNA and gets ready to sound the alarm.

Once TLR9 grabs onto the germ’s DNA, it recruits a helper called MyD88. MyD88 then calls in more helpers, forming a team that works together to send out signals to other parts of the immune system. These signals are like messages that tell our body to start fighting the germs.

Fighting germs and maintaining balance

When the immune system gets the messages from TLR9 and its helpers, it starts making special proteins called cytokines and interferons. These proteins are like soldiers that help our body fight off the germs.

They do this by activating other immune cells, such as macrophages, natural killer (NK) cells, and T cells, which work together to get rid of the germs.

Our body has to be careful not to overreact to germs, or it might start attacking itself. That’s why the TLR9 pathway has to be well-controlled.

Sometimes, when this control doesn’t work properly, it can lead to problems like autoimmune diseases, where the body starts attacking its own cells.

The TLR9 pathway is like a special alarm system in our body that helps us detect and fight off bad germs. By understanding how this system works, scientists can develop new ways to help our body fight infections and stay healthy.

Next steps in brain and memory research

Of course, transforming all of this knowledge into tangible help for those with memory problems requires years of careful research and clinical trials. This discovery is not the finish line but a promising start.

It has laid a vital foundation for exploring the intricate connection between the immune system and the brain – a connection that might hold the key to safeguarding our most precious memories.

This work, and what scientists build upon it, could open doors to entirely new classes of treatments. It’s a future where we might not just slow down memory-stealing diseases, but potentially restore some of what has been lost.

The full study is published in the journal Nature.

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