Timely Motor Learning Promotes Remyelination

Post by D. Chloe Chung

What's the science?

Oligodendrocytes are the important source of myelin sheaths in the brain that wrap around neuronal axons and provide insulation. Since demyelinated axons can be prone to injuries and degeneration, research efforts have focused on developing ways to restore the loss of myelin sheaths in demyelinating diseases such as multiple sclerosis (MS). Oligodendrocyte precursor cells (OPCs) that can differentiate into a new population of oligodendrocytes are known to readily remyelinate axons, but it is still debated whether mature oligodendrocytes can also contribute to remyelination. This week in Nature Neuroscience, Bacmeister and colleagues tracked oligodendrocytes and myelination in live animals to show that properly timed motor learning can lead to the formation of new myelin sheaths in mature oligodendrocytes.

How did they do it?

Mice between 2 and 3 months old were placed inside a box with a window through which they could be trained to reach with their left paw and grab the food pellet located outside the box. These mice were engineered to express green fluorescent protein (GFP) in myelinating oligodendrocytes and myelin sheaths in the cortex. This way, the authors were able to observe if there is any significant change in the production of new oligodendrocytes and already existing myelin sheath as mice are learning a new motor task. Over the course of 2-3 months, the authors used in vivo two-photon microscopy to track nearly 100 oligodendrocytes in the forelimb region of the motor cortex in live animals. To distinguish the effects from motor “learning” and motor “performance”, oligodendrocytes and myelin sheaths were monitored when mice were being trained for the task (“learning”) and when mice repeated the task 1 month after the initial training (“performance”). Also, to test the effects of motor learning in the context of myelin repair, mice were fed with food containing cuprizone that can induce oligodendrocyte death and demyelination.

What did they find?

When mice were learning the forelimb reach motor task, the rate of new oligodendrocyte production in the cortex temporarily decreased. After the learning period, however, the rate increased again at two times the rate of mice without training, accompanied by noticeable changes in myelin sheath lengths. Importantly, these changes were not observed when mice were repeating the task, meaning that oligodendrocyte formation and myelin sheath dynamics were altered specifically by motor learning, and not by motor performance. To further evaluate this phenomenon in a disease setting, the authors put mice on a cuprizone diet which killed almost 90% of existing oligodendrocytes in the cortex and suppressed the formation of new oligodendrocytes. When mice stopped receiving cuprizone, they robustly produced new oligodendrocytes which, interestingly, myelinated not only the axons that lost myelin sheaths, but also previously unmyelinated axons, ultimately changing the myelination pattern in the brain. The authors trained these cuprizone-fed mice for the same motor task either 3 days (“early learning”) or 10 days (“delayed learning”) after the last cuprizone treatment. Surprisingly, delayed learning increased the formation of new oligodendrocytes and stimulated mature oligodendrocytes that survived the earlier cuprizone treatment, which together promoted robust remyelination. In contrast, mice with early learning failed to properly learn the motor task and showed temporary impairment in new oligodendrocyte formation, suggesting that motor learning can enhance remyelination in a timing-dependent manner.

What's the impact?

This study used real-time imaging in mouse brains to highlight the importance of motor learning and its appropriate timing in inducing remyelination. This study showed that mature oligodendrocytes have the capacity to remyelinate, expanding our knowledge of oligodendrocyte biology. Importantly, this is the first study to demonstrate that motor learning can transiently suppress the formation of new oligodendrocytes, which provides interesting insights on oligodendrocyte differentiation. Given that behavioral interventions are often used to help demyelinating disease patients with their motor functions, findings from this study will be valuable in optimizing therapeutic strategies against demyelination in debilitating disorders such as MS.

Bacmeister et al. Motor learning promotes remyelination via new and surviving oligodendrocytes (2020). Access the original scientific publication here.