Micromechanics of the Neuronal Axon and its Structural and Functional Collapse

弥漫性轴索损伤是最常见和最重要的创伤性脑损伤之一，当突然的脑运动导致神经元轴突显著变形，导致局部损伤和随后的轴突变性时，就会发生弥漫性轴索损伤。然而，局部性缺陷如何导致轴突的结构和功能完全崩溃尚不清楚。为了回答这个问题，这个项目将从实验和数值上研究调节无髓神经元轴突结构和功能稳定性的主要生物物理机制，并确定导致机械性轴突崩溃的一连串事件。该项目将通过提供对调节轴突损伤的固有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突损伤诊断方案的开发。此外，该项目将向康涅狄格州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，从而使他们受益。外展活动将向高中教师和学生推广工程和科学，并将促进高中中代表性不足的少数族裔学生进入科学技术领域。轴突的机械稳定性是由其周期性轴突质膜骨架支持的，最近发现的周期性轴突质膜骨架由一系列方位环状F-肌动蛋白组成，它们通过αII/βII或αII/βIV谱蛋白四聚体在熵张力下纵向连接，形成了一种正交各向异性材料。在内部，轴突由纵向上相互连接的微管和神经丝组成，这些微管和神经丝附着在细胞器和质膜蛋白上，如Ankyrin G。如果轴突只依赖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，微管可能会通过解聚而断裂并经历不稳定。如果没有PAMS的额外支持，这可能会导致轴索膜塌陷。此外，PAMS的破坏可能会导致微管解聚和轴突变性。因此，PAMS和微管之间的动态平衡在轴突的机械灵活性和持久性方面发挥着非常重要的作用的假设很可能是合理的。最后，轴突变形和损伤过程中，轴突质膜离子通道的分布和迁移率如何受到影响，目前尚不清楚。该项目将确定轴突在动态伸展、弯曲和扭曲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NSF的法定使命，并通过使用基金会的智力优势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.