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

髓磷脂促进信号沿着称为轴突的神经细胞的过程沿着传递。它通过髓鞘的绝缘段覆盖了轴突长度的99%以上，髓鞘被称为朗维尔节点的小间隙隔开，朗维尔节点是有髓鞘轴突中参与信号传输的关键元件。髓鞘是由髓鞘形成细胞紧密包裹在轴突周围形成的紧凑的多层结构。大多数关于髓鞘组织的知识都是基于对组织学处理（死亡和脱水）组织的研究，而其在生活条件下的组织和功能特性在很大程度上尚未探索。紧凑的多层组织对于生存和维持是一个明显的缺点，因为它缺乏细胞质，细胞质是任何活细胞的主要成分，含有参与细胞代谢和自我更新的重要细胞器和分子。一旦形成，髓鞘会持续一生。它的生存可以部分解释我们的初步数据表明，在生活条件下，髓鞘有一个显着更广泛的细胞质访问比目前认为的。拟议的研究将详细分析活髓鞘的组织及其对各种生理信号的反应（轴突活动增加，离子，神经递质，代谢物，激素）。我们还计划研究髓鞘与轴突膜的实时相互作用。我们的初步实验表明，髓鞘与轴突膜周围的朗维尔节点的接触面积可能会发生活动依赖性的变化，导致短暂的髓鞘断开，暴露轴突区域与离子通道和转运蛋白通常隐藏在髓鞘下。我们的目的是揭示轴突功能的动态调制机制（“轴突可塑性”），通过这些短暂的断开。我们的长期目标是了解髓鞘对变化的生理情况的动态反应对轴突功能的调节机制，这对于理解脱髓鞘疾病和病症如多发性硬化或脊髓损伤后轴突功能障碍的起始机制也很重要。

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.