Nerve cells communicate through short, fleeting pulses of electrical activity. Yet some memories stored in the brain can persist for decades. Research into how the nervous system bridges these two radically different time scales has been going on for decades, and a number of different ideas have picked up some experimental support.
For instance, based on their past activity, nerve cells can dictate which partners they make contact with or increase or decrease the strength of those connections—in essence, rewiring the brain as it develops and processes experiences. In addition, individual cells can make long-term changes in the genes that are active, locking specific behaviors in place. In a paper released by Nature Neuroscience, scientists have looked at the changes in gene expression associated with memories of positive associations and found that they are held in place by chemical modifications of the cells’ DNA.
These chemical modifications fall under the broad (and somewhat poorly defined) category of epigenetic changes. Genetic changes involve alterations of the DNA sequence itself. Epigenetic changes, in contrast, alter how that DNA is processed within cells. They can be inherited as the cell divides and matures and, in rare cases, they’re passed on to the next generation. In some cases, epigenetic changes simply involve how the DNA is packaged inside a cell, which controls how accessible it is to the enzymes that transcribe it for use in making proteins. But in other cases, the DNA itself is chemically modified. That changes how various proteins interact with it.
The most common of these chemical modifications is called methylation, where a single carbon atom is attached at a specific location on one of the DNA bases. A number of studies suggest that methylation changes accompany the formation of long-term memories, so the researchers decided to test this in a well characterized experimental system that dates back to Pavlov: teaching a mouse to associate a sound with having a sugary treat appear in its cage. (Controls included playing the tone in a way that it wasn’t associated with treats and simply providing the tone.)
It only takes mice three tries before they start sniffing around the locations where the treat appears, and by five iterations, the behavior is pretty much locked-in. Past work in other systems has identified areas of the brain that are involved in this process, as well as some of the genes that are required. So, the authors started looking at how these changes came about when the association between the tone and a treat was being formed.
The researchers were able to confirm that the genes identified in past studies were involved in the formation of associative memories, and changes in the gene activity were detectable by the third trial just as behavior started to change. They were also able to detect significant changes in the DNA methylation that occurred at the same time, although only at a specific subset of the areas known to be methylated in that area of the chromosome. They were even able to show that the enzymes responsible for modifying the DNA appeared at these sites at around the time of the third trial.
All of that indicates that methylation changes are associated with the learning process, but it doesn’t get at the issue of cause and effect. So, the team injected a chemical that blocks DNA methylation into the area of the brain that’s involved with this form of associative memory, and they found that it would leave existing memories intact while blocking the formation of new ones. The effect was also specific to injections in this area of the brain. Injecting the drug into a different area, one that is involved in forming the associations involved in addiction, did not affect this particular form of memory.
Overall, the study adds another example to the growing list of cases where epigenetic changes seem to be involved in the process of locking memories into place. This doesn’t mean that the memories are permanent, as there are enzymes that can eliminate methylation as well. Still, it should help maintain the status of the memories for long periods of time—far longer than a brief burst of activity.
But it’s important to note that this sort of methylation is very context dependent: it’s specific to a subset of cells in a single area of the brain. Different methylation patterns—or even the same methylation pattern in a different set of cells—will probably encode something very different.