An electro-mechanical mechanism of spike propagation in myelinated axons

有髓轴突中尖峰传播的机电机制

• 批准号: 10194107
• 负责人: RICHARD H KRAMER
• 金额: $ 44.07万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194107
• 关键词: Action Potentials; Automobile Driving; Axon; Brain; Chemicals; Demyelinating Diseases; Development; Drug Targeting; Ensure; Event; Fiber; Fluorescence Resonance Energy Transfer; Frequencies; Genetic Engineering; Glean; Goals; Grant; Ion Channel; Ions; Knockout Mice; Lead; Measures; Mechanics; Membrane; Multiple Sclerosis; Muscle Cells; Myelin Sheath; Names; Nerve; Nervous System Physiology; Nervous system structure; Neurobiology; Neurons; Optics; Photophobia; Physiological Processes; Potassium; Potassium Channel; Process; Ranvier' s Nodes; Shapes; Signal Transduction; Stretching; Structure; Swelling; Synapses; TRAAK channel; Testing; Textbooks; Training; Travel; Water; Work; azobenzene; disabling symptom; drug development; improved; insight; novel; treatment strategy; voltage

Nerve cells send electrical impulses down long fibers called axons. Many axons are surrounded with a layer of insulation called the myelin sheath, a structure that ensures that the impulses propagate very rapidly and reliably. Tiny gaps in the sheath, called nodes of Ranvier, serve to amplify the electrical impulses, driving them forward to the end of the axon, where chemical signals are sent to other neurons or muscle cells at structures called synapses. In multiple sclerosis (MS) and other demyelinating diseases the myelin sheath is damaged and the nodes of Ranvier are disrupted, slowing or even stopping the electrical impulses from reaching the synapse. Our aim is to test a new idea that could fundamentally change our understanding of how electrical impulses are amplified at nodes and how they travel so fast along axons. Instead of the amplification mechanism being purely electrical, we propose a new mechanism, in which physical swelling of the node along a novel molecule that senses swelling, are crucial for amplifying electrical impulses, causing them to propagate faster and more reliably. This idea was spawned by the recent discovery that a specialized mechanically-sensitive ion channel named TRAAK is highly concentrated at nodes. TRAAK is a potassium channel, which are already known to be important for shaping electrical impulses. The presence of TRAAK at nodes raises the possibility that it serves a key electro-mechanical function. This exploratory/developmental project will answer 3 key questions: 1) To what extent do electrical impulses cause swelling of nodes of Ranvier in the brain? 2) Are TRAAK channels necessary for proper electrical impulse propagation in myelinated axon in the brain? 3) Can optical manipulation of a genetically-engineered photo-controlled version of TRAAK restore proper spike propagation in myelinated axons in the brain? Results gleaned from this work will be of great importance for understanding fundamental physiological processes necessary for normal function of the nervous system. These findings will provide new insights into events that occur in demyelinating diseases such as MS, and may lead to new treatment strategies, including the development of drugs for mitigating their debilitating symptoms.

神经细胞将电脉冲沿着称为轴突的长纤维发送。许多轴突 周围有一层叫做髓鞘的绝缘层，这种结构可以确保 脉冲传播得非常迅速和可靠鞘中的微小间隙，称为 兰维尔节点，用于放大电脉冲，将它们向前驱动到 轴突的末端，化学信号被发送到其他神经元或肌肉细胞。 称为突触的结构。多发性硬化症（MS）和其他脱髓鞘疾病 髓鞘被破坏，朗维尔结被破坏，减缓甚至 阻止电脉冲到达突触我们的目的是测试一个新的想法 这将从根本上改变我们对电脉冲 以及它们如何在沿着轴突快速传播。而不是放大 由于机制纯粹是电性的，我们提出了一种新的机制，其中物理 淋巴结沿着一种能感知肿胀的新分子肿胀， 电脉冲，使它们传播得更快，更可靠。这个想法 最近发现一种特殊的机械敏感离子通道 名为TRAAK的节点高度集中。TRAAK是钾离子通道， 已经知道它对形成电脉冲很重要。TRAAK的存在 在节点处提高了它提供关键机电功能的可能性。这 探索性/发展性项目将回答3个关键问题：1）在多大程度上 电脉冲会导致脑部朗维尔淋巴结肿胀吗2)是TRAAK 在有髓鞘轴突中适当的电脉冲传播所必需的通道， 大脑？3)光学操纵基因工程的光控版本 TRAAK恢复大脑中有髓鞘轴突的正常尖峰传播？结果 从这项工作中收集到的信息对理解基本的 神经系统正常功能所必需的生理过程。这些 这些发现将为脱髓鞘疾病的发生提供新的见解， 作为MS，并可能导致新的治疗策略，包括药物的开发， 减轻他们虚弱的症状