The corticospinal tract (CST) is key to skilled motor control in humans and many mammals. CST damage in humans during development produces cerebral palsy. Our research program takes a systems approach to study the organization, function, and repair of the developing CST. Our overall goal is to elucidate the functional logic of the developing CST and voluntary motor control. During prior funding periods, we demonstrated the importance of activity-dependent competition in development of CST spinal terminations during a brief postnatal critical period. Imbalance in limb use or the activity of the CST from each hemisphere creates impairments in wiring and visuomotor control. These wiring and control impairments share many similarities with cerebral palsy. During the present funding period we advanced our understanding of CST development in several ways that form the basis of this application. Patterning of CST terminations with spinal neurons requires activity, as shown by our cat studies, and axon guidance.
In Aim 1 we will determine the interplay between activity and axon guidance cues in development of multiple CST circuits to distinct populations of spinal premotor interneuron. We will use the mouse to study activity, as perinatal limb use, and genetic elimination of EphA4-EphrinB3 guidance signals in establishing CST circuits with spinal premotor interneurons. Only in the mouse can CST axon guidance be manipulated genetically. During the present funding period we discovered a novel trophic function of the CST in regulating spinal interneuron development that could underlie rapid development of CST spinal signal transmission. Using our knowledge about how activity drives CST development, we devised ways to repair aberrant CST circuitry and restore visually-guided locomotor function.
In Aim 2 we will determine if manipulation of CST activity steers development and repair of spinal motor circuits that translate CST signals into action. Our discovery of novel activity-dependent regulation of spinal interneurons by the developing CST stimulated us to ask if there is co-development between the CST and the red nucleus, a target of the motor cortex.
In Aim 3 we will determine if development of rubrospinal system control of movement is independent of corticospinal system development.
Our research program is elucidating the logic of descending corticospinal tract control using a developmental model. Our experiments probe the mechanisms of motor impairment in cerebral palsy, a common and devastating developmental motor disorder. Our findings open up new opportunities to accelerate functional development of the corticospinal tract to steer adaptive plasticity after perinatal damage and to help make aberrant corticospinal tract circuits in cerebral palsy more normal, by devising new therapeutic strategies.
