A fatty insulating layer called myelin wraps around nerve fibres in the brain, and new evidence shows it actively reshapes itself as animals learn. Researchers at the MRC are training mice to run on wheels with irregularly spaced rungs to watch how myelin changes on the neurons that control that skill. The problem is that scientists know myelin helps the brain adapt to new experiences, but they do not understand the mechanism. The team hypothesises that specialised cells called oligodendrocytes sense which neurons are active during a behaviour and add or remodel myelin on those specific cells, fine-tuning their electrical signals and rewiring neural circuits. This is fundamental science with no immediate practical application. The project will use genetic manipulations to block the pathways that might let oligodendrocytes detect neuronal activity, then test whether mice can still learn the motor skill. Disrupting new myelin formation will reveal how it alters connectivity between neurons. If the work succeeds, it will illuminate a basic mechanism of brain plasticity. That deeper understanding could eventually inform strategies to maintain cognitive function in healthy ageing or to improve recovery after brain injury or disease—but those applications remain distant.
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In the vertebrate brain and spinal cord, cells called "oligodendrocytes" construct a fatty insulating layer around "axons" - long filamentous extensions of "neurons", the electrically excitable cells. This insulation, called "myelin", greatly speeds up the electrical signals sent by nerve cells as well as providing energetic support to neurons and their axons. Recently it has been demonstrated that oligodendrocytes and the myelin that they make also help the brain to adapt to new experiences, contributing to learning and memory formation. How exactly myelin influences learning is still not well understood. Our hypothesis is that oligodendrocytes can sense the neurons that are activated by specific behaviours, resulting in the formation or remodelling of myelin on those active neurons. We predict that this process will fine-tune electrical signals and alter the connectivity of the active neurons leading to the development of new neuronal circuits responsible for new behaviours. In this project we will train mice to learn a new motor skill (running on a wheel with irregularly spaced rungs) and observe how the myelin on activated neurons changes with learning. We will then use a number of different genetic manipulations to disrupt pathways that may enable oligodendrocytes to sense neuronal activity and determine if these mice maintain the ability to learn motor skills. We will also disrupt the formation and maintenance of new myelin that is formed during skill learning to ask how this process changes neuronal connectivity. Our experiments will help illuminate the general mechanisms underpinning one of the fundamental functions of the brain - the ability to adapt - and may provide insights into how better to maintain cognitive ability during healthy aging, or to aid recovery of brain function following disease or injury.
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