Spinal cord injury (SCI) is a debilitating condition that results in significant loss of motor function and reduction in quality of life for the approximatel 265,000 Americans affected. For many years, a dogma held by those studying SCI was that long-range regeneration of descending tracts was the key to regaining function. However, more recent research has shown that functional recovery is due to local rewiring of these tracts to propriospinal neurons and plasticity of spared neural tissue within the spinal cord. To better understand how this regeneration occurs, we need to identify which neuronal populations are involved in these local rewiring events after SCI. While the local circuitry that contributes to locomotion via central pattern generators is well defined in model organisms, the full details of the interneuron (IN) circuitry contributing to rhythm generation and frequency modulation are still being defined in mammals. Currently, very few examples exist with firm links between developmental identity, as assessed by molecular and/or transcription factor profiles, and functional identity, as assessed by electrophysiology and/or connectivity patterns. New tools are needed to better understand the role of different spinal INs populations in functional recovery after SCI and to develop potential interventions to target these populations. This project will develop tools to isolate and culture ventral spinal neuron populations. We will develop an in vitro platform that will allow us to study connectivity between INs, motoneurons (MNs), and cortical neurons in a model system and to define cues that promote functional connectivity of these networks. Finally, we will examine the contributions of transplanted spinal MN and IN populations to functional recovery in a rat model of spinal cord injury.
Statement Spinal cord injury is a major clinical problem; about 12,000 new injuries are added annually to the approximately 265,000 spinal cord injury patients in the United States. Mechanistic knowledge gained and therapeutic approaches developed in this study may contribute to future clinical therapies for spinal cord injury patients Transplantation approaches using spinal cord neurons developed in this project may also be useful for other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS).
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