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

髓磷脂促进沿神经细胞轴突的信号传递。它覆盖了超过99%的轴突长度，通过髓鞘的绝缘部分，被称为兰维耶节点的小间隙分开——这是髓鞘轴突信号传递的关键因素。髓鞘是由髓鞘形成细胞紧密包裹在轴突周围形成的致密的多层结构。关于髓鞘组织的大部分已知知识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仍未被探索。紧凑的多层组织显然不利于生存和维持，因为它缺乏细胞质，而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。髓鞘一旦形成，就会终生存在。我们的初步数据表明，在生活条件下，髓磷脂的细胞质通路比目前认为的要宽得多，这可以部分解释髓磷脂的存活。本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突膜的实时相互作用。我们的初步实验表明，髓鞘与Ranvier淋巴结周围轴突膜的接触区域可能发生活动依赖性变化，导致髓鞘的短暂断开，揭示了通常隐藏在髓鞘下的具有离子通道和转运体的轴突区域。我们的目标是通过这些短暂的断开来揭示轴突功能的动态调节机制（“轴突可塑性”）。我们的长期目标是通过髓鞘对生理变化的动态反应来了解轴突功能的调节机制，这对于理解脱髓鞘疾病和脊髓损伤后多发性硬化症或轴突功能障碍等疾病的发生机制也很重要。

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.