The living myelin sheath: functional organization and role in dynamic modulation of axonal function in CNS

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Myelin facilitates signal transmission along the processes of the nerve cells called axons. It covers over 99% of axonal length by insulating segments of myelin sheath, separated by small gaps known as nodes of Ranvier - the key elements involved in signal transmission in myelinated axons. The myelin sheath is a compact multilayer structure formed by the myelin-forming cell tightly wrapped around the axon. Most of what is known about the organization of myelin sheath is based on studies of histologically processed (dead and dehydrated) tissue, while its organization and functional properties in living conditions remain largely unexplored. The compact multilayer organization is an obvious disadvantage for survival and maintenance because it lacks cytoplasm, the main component of any living cell containing vital organelles and molecules involved in the cell metabolism and self-renewal. Once formed, the myelin sheath persists for lifetime. Its survival can be partially explained by our preliminary data suggesting that in living conditions myelin has a significantly wider cytoplasmic access than currently thought. The proposed study will analyze in detail the organization of living myelin sheath and its responses to various physiological signals (increased axonal activity, ions, neurotransmitters, metabolites, hormones). We also plan to study the live interactions of myelin sheath with axonal membrane. Our preliminary experiments revealed that the contact areas of myelin sheath with axonal membrane around the nodes of Ranvier may undergo activity-dependent changes resulting in transient disconnections of myelin, unmasking axonal areas with ion channels and transporters normally hidden under the myelin sheath. Our aim is to uncover the mechanisms of dynamic modulation of axonal function ("axonal plasticity") through these transient disconnections. Our long-term goal is to understand the mechanisms of regulation of axonal function by dynamic responses of the myelin sheath to changing physiological situations, which is also important for understanding of the mechanisms of initiation of demyelinating diseases and conditions such as multiple sclerosis or axonal dysfunction after spinal cord injury.