Tension- and Adhesion-Regulated Retraction of Injured Axons.

ABSTRACT

Damage-induced retraction of axons during traumatic brain injury is believed to play a key role in the disintegration of the neural network and to eventually lead to severe symptoms such as permanent memory loss and emotional disturbances. However, fundamental questions such as how axon retraction progresses and what physical factors govern this process still remain unclear. Here, we report a combined experimental and modeling study to address these questions. Specifically, a sharp atomic force microscope probe was used to transect axons and trigger their retraction in a precisely controlled manner. Interestingly, we showed that the retracting motion of a well-developed axon can be arrested by strong cell-substrate attachment. However, axon retraction was found to be retriggered if a second transection was conducted, albeit with a lower shrinking amplitude. Furthermore, disruption of the actin cytoskeleton or cell-substrate adhesion significantly altered the retracting dynamics of injured axons. Finally, a mathematical model was developed to explain the observed injury response of neural cells in which the retracting motion was assumed to be driven by the pre-tension in the axon and progress against neuron-substrate adhesion as well as the viscous resistance of the cell. Using realistic parameters, model predictions were found to be in good agreement with our observations under a variety of experimental conditions. By revealing the essential physics behind traumatic axon retraction, findings here could provide insights on the development of treatment strategies for axonal injury as well as its possible interplay with other neurodegenerative diseases.