Modulation of lumbar motor circuitry after an above-level SCI and NT-3 gene therapy

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Spinal cord injury (SCI) is a severe medical problem experienced by humans with high mortality and long term morbidity. Unfortunately, there has been no effective treatment available for SCI patients. The lumbar motoneurons (MNs) are the final common pathway for motor output to the hindlimbs. Any impairment of these MNs can cause hindlimb paralysis and muscle atrophy. When SCI occurs above the lumbar level, namely above-level injury, the lumbar MNs are not directly damaged by the trauma, but they undergo profound dendritic atrophy and synaptic stripping. While most SCI studies to date have focused on the regeneration or protection of the injured spinal cord at the injury site, few studies have explored how modulation of lumbar MN circuitry would affect pathological and functional consequences after an above-level SCI. Our goal is to develop a beneficial restorative treatment targeting lumbar MNs after an above-level SCI and to functionally dissect out how individual afferent pathways affect lumbar MN remodeling and functional recovery. In this application, we propose a central hypothesis that increasing local NT-3 levels at lumbar MN pools will stimulate the recruitment of spared axons from distinct afferent pathways and enhance their synaptic formation onto lumbar MNs. Thus, reestablishment of neural circuitry at the lumbar level forms the anatomical basis for hindlimb functional recovery after an above-level SCI. Accordingly, three specific aims are proposed to investigate the three major afferent pathways to influencing lumbar MNs function to determine their roles in NT- 3-mediated remodeling of lumbar motor circuitry and hindlimb recovery after a thoracic SCI. These pathways include the descending reticulospinal tracts (RetST), the descending propriospinal tracts (dPST), and the dorsal roots (DR) afferents. Once the functional role of each specific pathway is defined, we will used combinational approaches to target multiple pathways to maximize the treatment effect. This will be done u sing an adult mouse thoracic 9 (T9) contusive SCI model and an AAV2-NT-3 gene transfer approach to increase the level of NT-3 in MNs.