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.

神经细胞沿着称为轴突的长纤维发送电脉冲。许多轴突是 周围有一层称为髓鞘的绝缘层，这种结构确保 脉冲传播非常快速且可靠。护套上的微小间隙称为 Ranvier 节点，用于放大电脉冲，驱动它们前进到 轴突末端，化学信号在此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 髓鞘受损，Ranvier结被破坏、减慢甚至 阻止电脉冲到达突触。我们的目标是测试一个新想法 这可能会从根本上改变我们对电脉冲如何产生的理解 在节点处放大以及它们如何沿着轴突如此快速地移动。而不是放大 机制是纯电气的，我们提出了一种新机制，其中物理 沿着感知肿胀的新型分子的节点肿胀对于放大至关重要 电脉冲，使它们传播得更快、更可靠。这个想法是 最近的发现催生了一种专门的机械敏感离子通道 名为 TRAAK 的节点高度集中。 TRAAK 是钾通道， 众所周知，它对于塑造电脉冲很重要。 TRAAK的存在 在节点处增加了它发挥关键机电功能的可能性。这 探索性/开发性项目将回答 3 个关键问题：1）在多大程度上 电脉冲会导致大脑中的朗飞结肿胀吗？ 2) 是TRAAK 有髓轴突中适当的电脉冲传播所必需的通道 脑？ 3）可以对基因工程光控版本进行光学操纵吗 TRAAK 能恢复大脑中有髓鞘轴突的正常尖峰传播吗？结果 从这项工作中收集到的信息对于理解基本原理非常重要 神经系统正常功能所必需的生理过程。这些 研究结果将为脱髓鞘疾病中发生的事件提供新的见解，例如 作为多发性硬化症，可能会带来新的治疗策略，包括开发治疗多发性硬化症的药物 减轻他们的衰弱症状。