Whenever you’re living out a new and exciting experience — even if it’s something as simple as trying a new glass of wine during a summer picnic, there are neurons actively at work, however leisurely everything around you may seem. These neurons, known as “engram” cells, act in a similar way to pixels in a digital camera, encoding the colors of the sights, the smells, even the feelings of the blanket and grass around you, and rendering the entire thing to your memory. Whenever you recall this particular day — whether it’s next week, a month or a year from now, your brain reactivates these same engram cells to reconstruct the whole thing from scratch.
Now, thanks to a recent study from MIT, we understand a bit more about how this process works. It’s actually the brain remodeling on a grand scale using the cells’ chromatin — the packaging within our chromosomes that consists of DNA and proteins. This remodeling, which unlocks the engram cells and activates them, is a lengthy process that takes several days to complete, altering both the density and arrangement of chromatin. Then histones, a tightly compact structure of DNA and insular proteins sends coded signals to specific genes within each cell.
The paper, authored by MIT postdoc Asaf Marco, was published by Nature Neuroscience and may be a trailblazer of a kind. “This paper is the first to really reveal this very mysterious process of how different waves of genes become activated, and what is the epigenetic mechanism underlying these different waves of gene expression,” said his adviser, Dr. Li-Huei Tsai, the director of MIT’s Picower Institute for Learning and Memory who is also the head coordinator of the study. In other words, it could be our first shot at understanding how chemical bonds impact the formation and recreation of memory, bringing trauma and nightmares into the realm of physical medicine.
You might be wondering where these engram cells come from, as we are often quick to assume that particular regions of the brain assume full responsibility for each task. They are found primarily in the hippocampus — the region of the brain associated with memory formation, as well as learning and emotional processing, but they are also located in networks throughout the brain. Some recent neuroscience literature demonstrates that engram cells create their own neural networks that revolve around different memories, and these networks then become activated when you recall a particular memory. The specific workings of molecular mechanisms that encode and then access these memories however, are not quite fully understood.
What neuroscientists do understand is that within the initial stages of memory formation, genes referred to as immediate early genes become activated within the engram cells, but shortly after, they go back to their normal activity levels. The MIT team led by Tsai was curious as to how the process picked up when it came to facilitating the long-term storage of one’s memories.
“The formation and preservation of memory is a very delicate and coordinated event that spreads over hours and days, and might be even months — we don’t know for sure,” says Marco. This is why memories aren’t always entirely reliable, and sometimes insignificant details can crop up each time we recall a specific episode of our lives. The replay is never 100% identical to the way it ran last time. “During this process, there are a few waves of gene expression and protein synthesis that make the connections between the neurons stronger and faster.”
Tsai and Marco began to suspect that the movements of these waves could be manipulated with something called an “epigenomic” modification, with molecular alterations of the chromatin that control access to particular genes. In his previous work, Tsai demonstrated that when enzymes cutting off access to the chromatin become overly active, they can impact the brain’s ability to create a new memory.
For their test subjects, Tsai and Marco selected genetically engineered mice whose engram cells were tagged with fluorescent proteins. The mice were given a mild foot shock when placed in a cage, and learned to associate the cage with the shock. As their memory of the cage formed, the hippocampal engram cells of their brain produced a yellow fluorescent marker — indicating activity was taking place as they learned.
“Then we can track those neurons forever, and we can sort them out and ask what happens to them one hour after the foot shock, what happens five days after, and what happens when those neurons get reactivated during memory recall,” says Marco of the procedure.
During the earliest part of the initial stage, just after the memory has been formed, there’s a great deal of modifications happening with the chromatin — in DNA strands throughout its heavy layers. As the DNA altered, the researchers found the chromatin had loosened, making the DNA more accessible. What Marco and Tsai didn’t expect to find, however, was that the loosening happened in stretches of chromatin where no genes were available — regions that geneticists refer to as “enhancers.” These portions of the DNA strand interact with genes, giving them signals to become active. In the earliest stages, the chromatin modifications had no effect on gene expression.
Five days after memory formation, the researchers looked at the cells again. As these memories consolidated, the 3D structure of the chromatin wrapped around the enhancers was altered, with the enhancers moving closer to their target genes. This didn’t mean they were now activated, but they were in the prime spot to be expressed when the subjects recalled their memory. It was time to put the mice back in the experimental cage. When they received the mild shock a second time, their earlier memories were again activated. The primed enhancers routinely interacted with the target genes and the genes were heavily expressed.
During memory recall, the majority of the genes being activated play a role in encouraging protein synthesis at the synapses between neurons — solidifying the connectivity between each neuron. Their team also learned that the dendrites of each neuron, which are branches reaching from each neuron to gather input from other neurons, began to develop more spines, a significant piece of evidence suggesting that memory recollection strengthens these connections.
Where Do We Go From Here?
Their study is the first to demonstrate that memory formation requires priming enhancers within the brain to stimulate gene expression whenever a certain piece of sensory information — a sound, sight, or smell, inadvertently takes us back to the past.
“This is the first work that shows on the molecular level how the epigenome can be primed to gain accessibility. First, you make the enhancers more accessible, but the accessibility on its own is not sufficient. You need those regions to physically interact with the genes, which is the second phase,” says Marco, anticipating the road ahead when it comes to future research. “We are now realizing that the 3D genome architecture plays a very significant role in orchestrating gene expression.”
Marco’s team has yet to determine how long the epigenomic modifications last after the memory is fully digested, but Marco says it’s possible for them to linger for weeks or possibly even months. Alzheimer’s disease is an important factor he’s taken into consideration — how the neurodegenerative disorder that has become an unfortunate staple in so many of our lives could be affected by it. His next study will focus directly on how engram cells are altered, if at all, by Alzheimer’s disease, and earlier efforts from Tsai have shown potential to restore lost memories in mice using an HDAC (histone deacetylase) inhibitor to unlock the chromatin shield. If this treatment were to become successful with human subjects, it could allow millions to produce and hold onto memories well into their golden years.
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