After publishing an especially challenging quantum mechanics article, it's not uncommon to hear some of our readers complain that their head hurts. Presumably, they mean that the article gave them a (metaphorical) headache. But it is actually possible that challenging your brain does a bit of physical damage to the nerve cells of the brain. Researchers are reporting that, following situations where the brain is active, you might find signs of DNA damage within the cells there. The damage is normally restored quickly, but they hypothesize that the inability to repair it quickly enough may underlie some neurological diseases.

This research clearly started out as an attempt to understand Alzheimer's disease. The authors were working with mice that were genetically modified to mimic some of the mutations associated with early-onset forms of the disease in humans. As part of their testing, the team (based at UCSF) looked for signs of DNA damage in the brains of these animals. They generally found that the indications of damage went up when the brains of mice were active—specifically, after they were given a new environment to explore.

That might seem interesting on its own, but the surprise came when they looked at their control mice, which weren't at elevated risk of brain disorders. These mice also showed signs of DNA damage (although at slightly lower levels than the Alzheimer's-prone mice).

The DNA damage in question is called a "double strand break," which occurs when both sides of the double helix undergo a rupture, cleaving a single DNA molecule into two parts. This was first detected by looking for a chemical modification of a DNA packaging protein (the proteins are called histones) that tend to label sites of double strand breaks. The researchers found another protein that tends to localize to these sites, but another commonly used assay that looks for the breaks themselves (called TUNEL, for the biologists among us) came up blank.

To sort out the differences between these results, the authors isolated the DNA itself from the mouse brains. This confirmed that breaks in the DNA were more common in animals that have been put in an enriched environment. As many as 40 percent of their cells had DNA that showed signs of damage.

Much of the rest of the paper is focused on figuring out what's going on. The authors tested whether neural activity alone was sufficient to cause this by shining light into the animal's eye while they were anesthetized; that worked too. So did activating neural activity in the brain itself. So, it's pretty clear that the double strand breaks were an outcome of neural activity. By using various inhibitors, the researchers even narrowed it down to a single neural signaling molecule, called glutamate.

The obvious question here is why nerve cells end up picking up DNA damage when doing what is, effectively, their job. One hypothesis is that the nerve cells can't help it. Nerve activity is inherently energy-intensive, and high metabolic activity tends to create oxygen radicals that can damage DNA. But treatment with antioxidants didn't stop the breaks from occurring, which seems to suggest we need to look elsewhere for an explanation. The authors suggest it may be a consequence of the changes in gene activity that follow nerve firing.

Could this result in long-term damage? As far as the researchers could tell, the breaks were repaired within a day, which suggests that any problems should be transient. And a number of other studies have shown that remaining mentally active helps protect you from the common forms of mental decline that occur with old age. So, all of that argues this isn't something to keep you up at night. Nevertheless, the authors suggest that the additional damage associated with a disease state—in their case, Alzheimer's—could overwhelm the repair system and contribute to the disease's progression.

Nature Neuroscience, 2013. DOI: 10.1038/nn.3356 (About DOIs).

Listing image by flickr user: rikishi