How does Adaptive Myelination Re-shape Neural Circuits During Learning?

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.

Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system (CNS). Myelin surrounds and electrically insulates axons, greatly speeding up the propagation of electrical impulses and also providing the wrapped axon with substrates for energy production. OLs are generated throughout life from OL progenitor cells that reside throughout the CNS. Preventing OL production in adult mice has been shown to reduce their ability to learn motor and cognitive tasks and to form new long-term memories in a process termed adaptive myelination. The mechanisms that determine adaptive myelination and how this influences neuronal circuits to permit effective learning and memory formation in the adult brain are still not known.

Using a transgenic reporter mouse line that labels active neurons during a specific time frame, we will specifically focus on changes to myelination on axons that are activated and required during behaviour paradigms e.g. running on a wheel with irregularly spaced rungs. We will determine if new myelin is formed preferentially on behaviour-activated axons, if existing myelin changes on these axons and using various conditional knockout mice investigate the mechanisms underpinning these processes. Finally, we will investigate how adaptive myelination influences the changes in neuronal engagement and synaptic plasticity that are required for efficient learning.

This project will provide insight into one of the mechanisms underpinning the ability of the CNS to adapt to enable learning and memory formation.