Micromechanics of the Neuronal Axon and its Structural and Functional Collapse

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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.