Collaborative Research: Dynamic Regulation of Axonal Morphology by Neurofilament Transport

神经细胞延伸出又长又细的突起，称为轴突，它定义了神经系统的线路模式。轴突允许神经细胞彼此之间以及与全身其他细胞进行电通信。每个轴突都包含一个微小的内部支架，由填充空间的蛋白质组成，称为神经丝，由分子运动蛋白沿着轴突不断穿梭；它们决定了轴突的形状和大小。神经丝在发育过程中积累，增加轴突直径，使电活动传播得更快；过度积累（如发生在许多神经退行性疾病）可导致通信异常和轴突变性。本项目验证了神经丝运输速率决定轴突直径、形状和功能的假设。这项工作将由经验丰富的生物学家和物理学家组成的跨学科团队进行，将创新的生物成像技术与数学和计算方法相结合，以研究这些重要问题。从这项研究中获得的见解对于理解健康的大脑功能至关重要，也可以为许多神经退行性疾病中观察到的轴突问题提供重要见解。该项目的物理科学和生命科学的学员将在主要研究人员的监督下组成团队工作，并将通过跨学科的互动扩大他们的技能，增加物理和生命科学界面的熟练研究人员。为了将拟议研究的影响扩展到K-12水平，该项目的物理学家和生物学家将主持重点小组研讨会，旨在为初中和高中教师提供思想和工具，以活跃他们在细胞生物学和算法思维领域的教学，并介绍免费提供但功能强大的学习工具，他们可以在课堂上应用。神经系统的功能取决于动作电位沿轴突的传播速度，这种速度与神经系统的生理功能有关。这个速度取决于轴突的大小和形状。脊椎动物轴突大小和形状的主要决定因素是填充空间的细胞骨架聚合物，称为神经丝。神经丝也是沿微管轨道移动的轴突运输的货物。因此，神经丝定义轴突形态，但它们也在不断变化。拟议的研究解决了这个有趣的和生理上重要的关系。中心假设是神经丝运输的动力学决定了轴突神经丝的含量，这反过来又决定了轴突的直径和功能。具体目标是确定在整个轴突直径规格下神经丝运输速度和通量之间的动态相互作用，以及神经丝如何在Ranvier节点处导航局部收缩。为了实现这些目标，研究人员将采用计算和数学方法与外周神经髓鞘轴突的创新活体成像紧密结合，这些成像来自一种新的转基因小鼠，该小鼠在神经元中表达一种光激活的神经丝蛋白。

Nerve cells extend long, thin protrusions called axons that define the wiring pattern of the nervous system. Axons allow nerve cells to communicate electrically with each other and with other cells throughout the body. Each axon contains a microscopic, internal scaffold of space-filling proteins called neurofilaments that are constantly shuttled along the axon by molecular motor proteins; these define axon shape and size. Neurofilaments accumulate during development, increasing axon diameter and allowing electrical activity to travel more quickly; excessive accumulation (as occurs in many neurodegenerative diseases) can lead to communication abnormalities and axonal degeneration. This project tests the hypothesis that the rate of neurofilament transport determines the diameter, shape and function of axons. The work will be conducted by a seasoned interdisciplinary team of biologists and physicists, combining innovative biological imaging techniques with mathematical and computational methods to investigate these important questions. The insights gained from this research will be critical for understanding healthy brain function and could also provide important insights into the axonal problems observed in many neurodegenerative diseases. Trainees on this project from both the physical and life sciences will work in teams supervised by the principal investigators, and will expand their skills through interdisciplinary interaction, adding to the skilled research workforce at the interface of the physical and life sciences. To extend the impact of the proposed research to the K-12 level, the physicists and biologists on this project will host focused, small-group workshops that will seek to empower middle and high school teachers with ideas and tools to invigorate their instruction in the areas of cell biology and algorithmic thinking, and introducing freely available but powerful learning tools that they can apply in their classrooms.The function of nervous systems is dependent on the propagation of action potentials along axons at a velocity that is specific to their physiological function. This velocity is dependent on axon size and shape. A principal determinant of axon size and shape in vertebrates are space-filling cytoskeletal polymers called neurofilaments. Neurofilaments are also cargoes of axonal transport that move along microtubule tracks. Thus, neurofilaments define axonal morphology, but they are also in constant flux. The proposed research addresses this intriguing and physiologically important relationship. The central hypothesis is that the kinetics of neurofilament transport determines axonal neurofilament content, which in turn specifies axonal caliber and function. The specific goals are to determine the dynamic interplay between neurofilament transport velocity and flux in the specification of overall axon caliber, and how neurofilaments navigate local constrictions at the nodes of Ranvier. To accomplish these goals, the investigators will employ a tight integration of computational and mathematical methods with innovative live imaging of myelinated axons in peripheral nerves ex vivo from a new transgenic mouse that expresses a photoactivatable neurofilament protein in neurons.