| The central nervous system (CNS) is an intricately evolved organ that requires the precise interplay between neurons, glia and support cells to govern peripheral functions and complex, higher-order central cognition. The brain itself is comprised of roughly one hundred billion neurons, each averaging a thousand synaptic connections that participate in a finely choreographed orchestration of intrinsic and extrinsic cellular factors to provide the fundamental framework for developmental wiring. Through disease or traumatic injury these connections may become severed, resulting in loss of function and vastly amplified rates of morbidity and mortality. Promoting CNS regeneration of previously established circuitry leading to functional recovery after injury or disease provides unique obstacles when compared to those faced during embryonic development. These challenges include diminished rates of intrinsic axon outgrowth capacity, major differences in scale required for re-connection and a largely hostile injury microenvironment. To date, no single therapeutic intervention has produced full restoration after injury in the mammalian CNS, although many molecular, cellular and rehabilitative treatments have been evaluated in both animal and human trials. This written dissertation evaluates mechanisms of chemotropic nerve growth and mechanisms to differentially target convergent pathways for regulating axon growth and fostering the restoration of lost connections due to traumatic injury. |
