New Myelin Required to Learn a New Task

When neuroscientists talk about the process of learning, they usually discuss neurons sprouting new connections, or beefing up the ones they already have. Glia, it has long seemed, are passive bystanders. But new research published this week in Science (McKenzie et al., 2014) suggests that glia, specifically oligodendrocytes, play an active role in the learning of a new motor skill.

Using a method to block the maturation of oligodendrocyte precursor cells (OPCs) without affecting existing oligodendrocytes or myelin, researchers tested the ability of mice to pick up a novel motor task—in this case, running on a wheel with irregularly spaced rungs. Mice whose OPCs were prevented from maturing had a more difficult time learning the task. If the mice were allowed to learn the task before receiving the OPC maturation block, they were able to recall the running strategy with no problems.

The data suggest that functioning, mature oligodendrocytes are critical players in acquiring new motor-based skills. This study and others may also add some pieces to the puzzle of maturational arrest of OPCs in patients with MS.

The study

The researchers targeted myelin regulatory factor (MyRF), a transcription factor that is only expressed in oligodendrocytes and is critical for initiating myelination. Using tamoxifen—a drug typically used to treat breast cancer but also used to modulate gene expression in mice—the researchers inactivated the MyRF allele in the OPCs of mice, preventing them from maturing into oligodendrocytes. The treatment did not affect preexisting oligodendrocytes or myelin.

The researchers then allowed the mice to learn to use the complex wheel. The complex wheel is modified from a regular running wheel by removing rungs at random intervals. Normally, wild-type mice take approximately a week to develop an effective strategy to use the wheel.

“When a normal mouse runs on a normal wheel, what it does is it reaches forward with its left front paw, and then it brings its left rear paw up and grabs the rung immediately behind its front paw,” said the study’s corresponding author, Bill Richardson, Ph.D., of University College London, in an interview with MSDF. But when the mouse runs on the complex wheel and brings its hind paw forward, the rung might not be there. “They very quickly learn to adapt and they grab the same rung as their forepaw. They learn general strategies, they don’t just memorize the pattern,” Richardson said.

[This video begins with a wild-type mouse on its first introduction to the complex wheel. Initially, the mice are clumsy and inefficient. The second piece of footage is of an experimental mouse who learned the task within 7 days. The key strategy is that the mouse brings its hind paw to the same rung as its forepaw to advance the wheel. (MacKenzie et al., Science/AAAS 2014)].

Mice that were exposed to the tamoxifen treatment had a much more difficult time learning and adopting this strategy, even though their performance improved over time. However, mice that were allowed to learn the complex wheel before the treatment were able to recall the strategy for running on the wheel after the treatment, suggesting that oligodendrocyte differentiation and myelination are critical for learning rather than recall.

Kicking learning into gear

Richardson said that his work was part of a growing body of literature suggesting that glial cells play an important role in learning. Previous MRI studies showed that learning is accompanied by changes that are more apparent in white matter than gray matter. “Which was unexpected, because learning has always been thought to be the preserve of neurons and neurons are what you find in gray matter. White matter is just the connections between the neurons,” he said.

“In this [study, the researchers] show the important participation of oligodendrocytes in creating new myelin to allow acquisition of new information,” Gabriel Corfas, Ph.D., of Boston Children’s Hospital said in an interview with MSDF. Corfas also co-authored an accompanying commentary in the same issue of Science (Long and Corfas, 2014).

Other studies show that myelin is important in cognitive faculties of the brain as well. Corfas mentioned a study done by his own group wherein they observed hypomyelination in animals that had been isolated from the rest of the group (Makinodan et al., 2012; Liu et al., 2012).

Richardson thinks that OPCs exert their effects on learning through direct interactions with naked axons. “Every time an action potential passes along an unmyelinated axon, the oligodendrocyte precursor gets a little ‘kick.’ And maybe, we think, if the precursor gets enough ‘kicks,’ it will stimulate that precursor to divide and differentiate and form a myelin segment.”

Sarah Kucenas, Ph.D., “Head Fish Whisperer” of the University of Virginia, studies glial biology. She echoed Richardson’s sentiment in an interview with MSDF, saying that it made sense that the oligodendrocytes would have a “push you, pull me” relationship with axons to promote myelination.

Richardson speculated that some aspects of the “push you, pull me” relationship between axons and OPCs may be dysfunctional in patients with MS. He said that it’s currently unknown whether demyelinated axons in patients with MS even form synapses with the OPCs nearby. He told MSDF that his group plans to investigate this question in collaboration with the lab of Robin Franklin, Ph.D., of the University of Cambridge in London.

The bridge to MS

“This is part of a new wave of studies showing that myelin is more plastic than we believed before,” Corfas said. “It’s giving us hope that we can harness this plasticity to enhance repair and recover function in demyelinating disorders, such as MS.” However, Corfas also emphasized that more work needs to be done in this area before a true connection to MS can be made.

“There are many reasons to think that there is a connection between myelin and movement, not the least of which is that in multiple sclerosis, one of the functions that is very frequently affected is movement and motor control,” Richardson said.

David Rowitch, M.D., Ph.D., of the UCSF Benioff Children’s Hospital San Francisco agreed that the study was both very interesting and elegant. In an interview with MSDF, he said that while the study’s applications to MS research and therapy might be a few steps removed, it could explain some phenomena seen in MS patients. Since the onset of MS typically occurs in young adults, Rowitch speculated that most of their myelinated learning would have already occurred.

“What it doesn’t reassure us about is future learning. If a young adult with MS has compromised learning, does that mean they’ll have difficulty learning tasks in the active phases of the disease? It could help some patients explain their experience,” he said.

However, the paper has direct implications for another class of demyelinating diseases: leukodystrophies. These are genetic disorders in which children never develop myelin. “These kids have profound neurodevelopmental delay and learning problems. I think what this paper does help us understand is the nature of the learning problem in leukodystrophy,” Rowitch said.

And he concluded by pointing out that the study demonstrates yet another important role for glia and myelin in maintaining the healthy function of the brain. Though it’s a few steps away from bridging the gap between understanding glia and developing pro-myelinating therapies, the study underscores the importance of protecting myelin and restoring it in patients with demyelinating diseases.

Key open questions

• How might MS researchers make use of this new information and better examine the interaction between glial cells and axons in myelination?
• How useful will patients find this information in describing their experiences?
• Could these findings be of use to examining rehabilitation strategies for patients with motor-related disabilities?

Disclosures and sources of funding

Richardson’s study received support from the European Research Council (grant agreement 293544), the U.K. Medical Research Council, the Wellcome Trust, and Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology. In the paper, Richardson noted that he received an Invitation Fellowship from the Japan Society for Promotion of Science.

Corfas, Kucenas, and Rowitch had no disclosures.