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

髓鞘促进了沿着神经细胞突起的信号传递。它覆盖了99%以上的轴突长度，由被称为Ranvier结点的小间隙隔开的髓鞘段隔开--Ranvier结节是参与有髓轴突信号传递的关键元件。髓鞘是一个紧凑的多层结构，由髓鞘形成的细胞紧紧地包裹在轴突周围。关于髓鞘组织的大部分已知是基于对组织学处理(死亡的和脱水的)组织的研究，而其在活体条件下的组织和功能特性在很大程度上仍未被探索。这种紧密的多层组织结构对生存和维护是一个明显的劣势，因为它缺乏细胞质，细胞质是任何活细胞的主要组成部分，包含参与细胞新陈代谢和自我更新的重要细胞器和分子。一旦形成，髓鞘就会终身存在。我们的初步数据表明，在生活条件下，髓鞘具有比目前认为的更广泛的细胞质通路，这可以部分解释它的存活。这项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(轴突活动增加、离子、神经递质、代谢物、激素)的反应。我们还计划研究髓鞘与轴索膜的活体相互作用。我们的初步实验表明，兰维尔结节周围髓鞘与轴索膜的接触区域可能发生活性依赖性的变化，导致髓鞘一过性断开，使轴突区域暴露出通常隐藏在髓鞘下的离子通道和转运体。我们的目的是通过这些暂时性的连接中断来揭示轴突功能(“轴突可塑性”)的动态调节机制。我们的长期目标是了解髓鞘对生理环境变化的动态反应对轴突功能的调节机制，这对于理解脊髓损伤后多发性硬化症或轴突功能障碍等脱髓鞘疾病的发病机制也是重要的。

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.