Open any neuroscience textbook and you'll find mention of myelin. This white, fatty protein is the stuff that gives white matter its color as well as its name. Historically, myelin has been discussed mainly as a simple neural insulator, a somewhat ubiquitous and uniformly distributed lipid that supports the critical signaling work of the more functional gray matter. New research out of Harvard University, though, challenges that notion-demonstrating varying distribution profiles of the substance in different parts of the cortex and promoting the idea that white matter plays a more sophisticated role in brain function than previously thought.
Battling historical notions
Myelin is an outgrowth of oligodendrocytes, one of the types of glial cells that make up the brain's so-called white matter. It covers the axons of nerve cells like a sausage casing. That covering, called the myelin sheath, helps to increase the speed of electrochemical signals across the brain. Diseases like multiple sclerosis (MS) damage the sheath; that damage, as well as the related signaling issues, result in a range of debilitating physical, sensory, and cognitive problems such as muscle weakness, ataxia, visual problems, and chronic pain.
"The general consensus in the field was that myelin was static. That it never changed structure unless it was diseased or damaged," says R. Douglas Fields, chief of the nervous system development and plasticity section of the National Institutes of Health (NIH). "As with many things in science, that was just a historical artifact of the way people were thinking. The concept that there could be plasticity in myelin-and that myelin could be more than insulation-was just really foreign to most people."
It was also believed that the protein was uniformly distributed across all nerve cells. But Paola Arlotta, a scientist at Harvard University's prestigious Stem Cell Institute, wondered if that were really the case. While the field generally accepted that idea, technology had only recently advanced to the point where it could be directly tested.
Arlotta and colleagues used high-throughput electron microscopy to create the first high-resolution map of myelin distribution in the mouse cortex. Using software to create three-dimensional reconstructions of neurons and their myelination patterns, the group found that not all brain cells are myelinated in the same fashion. In fact, in examining cells in the prefrontal regions of the cortex, the most evolved region of the brain, the group found not only less myelin than other neurons, but also a distinct intermittent pattern along their axon tracts.
"We saw the myelin was placed a little bit here, and a little bit there, on some cells. And there were also neurons that had no myelin and others that had a lot of it. It was really an 'A-ha!' moment for us. These are the cells that have a much more sophisticated function. And they seem to be using myelin differently," says Arlotta. "So it seems that different neurons may actually talk to oligodendrocytes in very different ways. This is an important thing to know, especially in disease, because if it is true that some neurons have more or a better ability to tell oligodendrocytes how to myelinate them, then I would argue that those are the neurons one should study so they can understand what molecules they are using to send those messages. It might help us better understand the demyelination we see in a disease like MS, for example."
Arlotta proposes that these different myelin distributions may be the key to understanding how different networks of neurons work together as well.
"It may be more than just a cell saying 'I want to send my signal from point A to point B.' Some of these cells may be using myelin in a much more creative way," she says. "They place myelin in specific positions and this allows the different neurons to modulate the speed in which the signal travels so everyone can work together. So it's not about 'Let's try to communicate as fast as we can,' but maybe 'Let's try to modulate the speed of this signal so that all these different cells can synchronize and work together to do this job.'"
A shift in thinking
Robyn Klein, a neurobiologist at the Washington University School of Medicine who studies neuroinflammation and demyelination, says that this finding adds a new layer of complexity in understanding demyelinating diseases like MS. It may also make finding effective treatments more complicated as well.
"Currently, we don't really think much about oligodendrocytes in terms of their ability to contribute to these diseases. There's certainly some evidence already that they do play a role," she says. "But I believe we're going to have to focus more on the way myelin functions in the context of its environment-and not just look at the neurons they are insulating-if we're going to make a real difference."
Fields agrees-and he's happy that people in the neuroscience and medical fields are opening up to the idea that both gray matter and white matter can be critical to brain function, and emphasizes that we need to look beyond disease states to fully understand it.
"What's so intriguing about this whole story is that it's just another example of how you can be led astray by preconceptions you have," says Fields. "It's a big change in thinking. We're just on the cusp of this insight that white matter is really important, as important as the gray matter. We don't know yet the extent to which something like myelin might be involved in learning or cognition and what the mechanisms are. But we're definitely far away from the old view that myelin is static and only changes in disease-and that gives us a real opportunity to start figuring it out."