Micromechanics of the Neuronal Axon and its Structural and Functional Collapse

弥漫性轴索损伤是一种最常见和最重要的创伤性脑损伤，它发生在突然的脑运动导致神经元轴突明显变形，导致局部损伤和随后的轴突变性。然而，局部缺陷如何导致轴突结构和功能的完全崩溃尚不清楚。为了回答这个问题，本项目将通过实验和数值研究调节无髓鞘神经元轴突结构和功能稳定性的主要生物物理机制，并确定引起机械诱导轴突崩溃的级联事件。该项目将通过提供对调节轴索损伤的先天机制的更好理解而产生更广泛的影响，并可能导致新的弥漫性轴索损伤诊断方案的发展。此外，该项目将通过向康涅狄格大学的本科生和研究生介绍虚拟现实作为一种交互式应用力学工具，使他们受益。这些拓展活动将向高中教师和学生推广工程和科学，并将促进高中少数族裔学生参与科学和技术。轴突的机械稳定性由其周期性轴突质膜骨架（PAMS）支持，该骨架最近被发现由一系列方位环状的f -肌动蛋白组成，在纵向上由αII/βII或αII/βIV谱聚体在熵张力下连接，形成正交异性材料。在内部，轴突包括纵向定向的相互连接的微管和神经丝，它们附着在细胞器和质膜蛋白（如锚蛋白g）上。如果轴突仅依靠相对刚性的细胞骨架细丝（如微管）来保持机械稳定性，那么在弯曲应力下，微管可能会断裂并通过解聚发生不稳定。如果没有PAMS的额外支持，这可能导致轴突膜崩溃。此外，PAMS的破坏可能导致微管解聚和轴突退化。因此，PAMS和微管之间的动态平衡对轴突的机械柔韧性和耐久性起着非常重要的作用的假设可能是正确的。最后，目前尚不清楚在轴突变形和损伤过程中，轴突质膜中离子通道的分布和迁移是如何受到影响的。该项目将确定轴突在动态伸展、弯曲和扭转下的结构和功能行为，以及机械诱导轴突崩溃期间的级联事件和对动作电位的影响。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

One of the most common and important traumatic brain injuries is the diffuse axonal injury which happens when abrupt brain movements lead to significant deformations of neuronal axons resulting in localized damage and subsequent axonal degeneration. However, how localized defects can cause complete structural and functional collapse of the axon is not known. To answer this question, this project will investigate experimentally and numerically the main biophysical mechanisms that regulate structural and functional stability of the unmyelinated neuronal axon and determine the cascade of events causing mechanically induced axonal collapse. The project will have a broader impact by providing an improved understanding of innate mechanisms that regulate axonal injury and it could lead to development of novel diffuse axonal injury diagnosis protocols. In addition, the project will benefit undergraduate and graduate students at UCONN by introducing them to virtual reality as an interactive applied mechanics tool. The outreach activities will promote engineering and science to high school teachers and students and will advance participation of high school underrepresented minority students into science and technology. The mechanical stability of the axon is supported by its periodic axon plasma membrane skeleton (PAMS), which was recently discovered to comprise a series of azimuthal ring-like F-actins connected longitudinally by αII/βII or αII/βIV spectrin tetramers held under entropic tension forming an orthotropic material. Internally, an axon comprises longitudinally oriented interconnected microtubules and neurofilaments, which are attached to organelles and to plasma membrane proteins such as Ankyrin G. If the axon only counts on relative rigid cytoskeletal filaments, such as microtubules, for mechanical stability, then under bending stress, microtubules will likely break and undergo instability via depolymerization. This can cause the axon membrane to collapse if there is not additional support by the PAMS. Furthermore, disruption of PAMS could potentially lead to microtubules depolymerization and axon degeneration. It is then likely that the hypothesis that dynamic equilibrium between PAMS and microtubules play a very important role in mechanical flexibility and durability of the axons is justified. Finally, it is currently unknown how distribution and mobility of ion channels in the axon plasma membrane is affected during axonal deformation and injury. The project will determine the structural and functional behavior of an axon under dynamic extension, bending, and twisting, and the cascade of events during a mechanically induced axonal collapse and effect on action potential.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.