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; 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.

神经细胞将电脉冲向下降低长纤维，称为轴突。许多轴突是 周围环绕着一层称为髓鞘的绝缘层，这种结构可确保 冲动非常迅速，可靠地传播。鞘中的微小间隙，称为 Ranvier的节点，用于扩大电脉冲，将其推向前进 轴突的末端，该轴突将化学信号发送到其他神经元或肌肉细胞处 结构称为突触。在多发性硬化症（MS）和其他脱髓鞘疾病中 髓鞘受损，Ranvier的节点被破坏，放慢甚至 阻止电脉冲到达突触。我们的目标是测试一个新想法 这可能从根本上改变了我们对电动冲动的理解 在节点上放大以及它们如何沿轴突如此快速行驶。而不是放大 机制是纯电气的，我们提出了一种新机制，其中物理机制 沿着新的分子的肿胀，感知肿胀，对于放大至关重要 电脉冲，使它们更快，更可靠地传播。这个想法是 最近发现，专门的机械敏感离子通道产生了 命名的Traak高度集中在节点上。 Traak是一个钾通道，是 已经知道对于塑造电脉冲很重要。 Traak的存在 在节点上，它可以发挥关键的电力机械功能。这 探索/发展项目将回答3个关键问题：1） 电脉冲会导致大脑中兰维尔的淋巴结肿胀？ 2）是traak 在髓鞘的轴突中适当的电脉冲传播所需的通道 脑？ 3）可以光学操纵基因设计的照片控制版本 traak恢复大脑中髓鞘轴突中适当的尖峰繁殖？结果 从这项工作中收集到的理解将非常重要 神经系统正常功能所需的生理过程。这些 调查结果将为脱髓鞘疾病中发生的事件提供新的见解 作为MS，并可能导致新的治疗策略，包括开发 减轻他们的衰弱症状。