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Identifying the cellular correlates of white matter plasticity

Final Report Summary - AXONGLIAPLASTICITY (Identifying the cellular correlates of white matter plasticity)

The aim of this work was to study potential mechanisms of plasticity of function in the white matter, focussing on the node of Ranvier and the myelin sheath. This project has established two novel fundamental mechanisms by which the structure of myelinated axons is formed and may be changed to mediate plasticity of brain function. All work was carried out in accordance with EU and UK legislation on ethics and animal use.

The brain is divided into grey matter “processing nodes” linked by white matter “information superhighways” to minimize conduction delays and energy use. For the white matter, the information propagation speed is increased and the axonal energy cost is reduced by oligodendrocytes wrapping myelin around axons, thus decreasing their capacitance and decreasing the Na+ influx needed at Ranvier nodes to produce an action potential. This arrangement may not just speed action potentials, however, it may also be a previously unsuspected substrate for information storage in the CNS.

Information is generally thought to be stored in the CNS by virtue of grey matter plasticity, i.e. changes in the structure and electrophysiological strength of synapses. However, recently, white matter plasticity has also been suggested to exist, based in part on diffusion tensor magnetic resonance imaging of changes in the brains of people learning to play the piano or juggle. White matter plasticity may adjust action potential arrival times in the CNS, to promote firing of target neurons. Surprisingly, it is unknown which parameters of myelinated axons change to alter the speed. Does white matter plasticity solely reflect changes of myelin thickness, or are there also activity-dependent alterations of Ranvier node Na+ channel density, internode length, or axon diameter at the nodes or internodes? In addition, could alterations of Ranvier node geometry or of the size of the conducting periaxonal space under the myelin be employed to tune the conduction speed of myelinated axons?

First, we demonstrated that spatial variation of the properties of the node of Ranvier and myelin sheath along auditory axons plays a key role in the transmission of information across auditory synapses.This work was published in the high profile journal Nature Communications, with the Fellow as first author.

Next, we identified the node of Ranvier as a potential target for tuning of axonal conduction speed during development and white matter plasticity. We found that, in rat optic nerve and cerebral cortical axons, the node of Ranvier length varies over a 4.4-fold and 8.7-fold range respectively. Strikingly, the variation of node length is much less along axons than between axons. Modelling predicts that these node length differences will alter conduction speed by ~20%, similar to the changes produced by altering the number of myelin wraps or the internode length. For a given change of conduction speed, the membrane area change needed at the node is >270-fold less than that needed in the myelin sheath. Thus, axon-specific adjustment of node of Ranvier length is potentially an energy-efficient and rapid mechanism for tuning the arrival time of information in the CNS. This work was published in the high profile journal eLife with the Fellow as co-first author.

Finally, we investigated how neuronal activity regulates myelination of axons by oligodendrocytes in vivo. Using two-photon imaging, electrophysiology and pharmacology in zebrafish larvae we found that transient elevations of calcium concentration occur in developing myelin sheaths, that neuronal activity raises the frequency of these transients, and that the rate of calcium transients correlates with myelin sheath elongation. These results suggest that intracellular calcium concentration and neuronal activity control myelin sheath development. This work is in the process of being published. Our findings have implications for the development of therapeutic strategies to treat conditions such as stroke and multiple sclerosis, which require remyelination in damaged CNS regions. Understanding how oligodendrocyte calcium transients are generated, and how the dynamics of calcium signaling in oligodendrocytes regulate myelination, may thus open up new therapeutic strategies for treating demyelinating diseases.