How does neuronal activity regulate central nervous system myelination?

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Approximately half of the volume of our brain and spinal cord, our central nervous system, is comprised of white matter. White matter is essential for normal brain formation, function and health, and damage to white matter causes the symptoms of many human diseases, such as multiple sclerosis, MS. The "white" in white matter refers to the presence of a fatty substance called myelin, which is made by specialized cells called oligodendrocytes, and which is wrapped around the nerve cables of our brain (called axons). The presence of myelin on axons insulates them and allows our neurons to rapidly transmit electrical impulses over long distances. Myelin also provides nutritional support to axons, essential for their health. Until recently it was though that myelin was a static structure, but in recent years it has become clear that myelin is made throughout our lives, and that it is dynamically regulated by brain activity, perhaps to optimize brain function and repair. Humans make new myelin well into adult life, by the formation of new oligodendrocytes, and, likely, by remodeling of existing myelin. Very interestingly, studies in humans have shown that learning new tasks, e.g. juggling, can stimulate changes in our white matter and investigations in animal models have shown that the learning of new tasks in adulthood requires the formation of new myelin-producing oligodendrocytes. Importantly, the ability of our brain to make new myelin is also key to the regeneration that is observed following the loss of myelin in diseases such as MS. In line with a role for brain function in regulating myelination, own work has shown that the electrical activity of our brain cells stimulates myelin production by oligodendrocytes, and studies by our colleagues have shown that neuronal activity is required for normal myelin regeneration. However, many important questions remain: how do our brain cells tell our oligodendrocytes to promote myelination? Can stimulating brain activity promote regeneration of myelin? We use zebrafish as an animal model to study myelination. Zebrafish produce embryos that are small, transparent, and develop very quickly, and we have made zebrafish where myelin and myelinated axons are fluorescently labelled. These properties of fish together with our tools means that we can directly visualize myelin as it is made, remodelled, and even regenerated over time. To study myelin regeneration (called remyelination), we have recently made a transgenic fish in which we can delete two-thirds of oligodendrocytes in a non-invasive manner, which leads to the loss of myelin (demyelination) from axons. Although the nervous system of both fish and man has the capacity to replace lost myelin through remyelination, this process is imperfect, and ultimately fails in diseases like MS. Therefore it is an important goal of medical research to find ways to promote our endogenous capacity for remyelination. The possibility to directly observe myelination and remyelination in a living animal is a great strength of the system and will be exploited through the work of this proposal. The aim of this proposal is to use zebrafish to directly observe how myelin is made along axons over time in the normal animal, and to assess how this can be regulated by the electrical activity of neurons. We will carry out the first ever (to our knowledge) direct observations of remyelination of single axons over time in a living animal and investigate whether promoting brain function can enhance the regeneration of myelin. This work will provide much needed insight into how our brain builds and regenerates myelin and how brain activity could be manipulated to stimulate myelination in humans in the future.