Analysis of Neuronal Growth Dynamics and Control

9612054 Buettner The growth of neuronal axons represents a fundamental step in nerve development: axons grow out from individual neurons in or near the brain and spinal cord to make synaptic connections with innervation targets throughout the body. Multiple axons projecting to the same target become bundled together to form a nerve supplying function to that site. The remote location of most targets from the initiation sites of the axons innervating them, and the complex pathways along which axonal growth occurs, poses a demanding navigational challenge for the growing axons - one which they meet with remarkable success under normal developmental conditions. However, the repair of postnatal injury to a nerve requires repetition of the same axonal growth and navigation process for the affected axons, and the lack of success of this axonal regeneration typically leads to incomplete recovery of nerve function or paralysis. To better understand the principles underlying axonal growth and navigation (often referred to collectively as 'pathfinding') and how they may be altered during regeneration, this investigation addresses the quantitative dynamics of the axonal growth cone, the sensory-motile leading tip of the axon which controls where and how the axon grows. The primary focus of this study will be to develop a computer simulation model of growth cone motion based on the molecular forces generated within the growth cone during its migration. Particular emphasis will be placed on the role of actin, a major structural component of the growth cone cytoskeleton and long believed to play a central role in the motility not only of growth cones but of many other cell types as well. Another important factor to be considered is the interaction of the growth cone with the extracellular environment. This work should have multidisciplinary impact, with both biological and technological implications. In neuroscience, it will provide a new mea ns of testing hypotheses about the forces responsible for growth cone locomotion and the mechanisms underlying growth cone pathfinding. It will also provide insight into strategies for manipulating growth cone migration, of importance in nerve repair and the formation of biological neural networks. In mathematical science and engineering, the simulation of growth cone processing of instructional cues will be used to suggest new paradigms for controlling both biological and nonbiological systems.