Hand use and neuronal plasticity after spinal cord injury

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DESCRIPTION (provided by applicant): Spinal nerve and cord injuries that result in the partial deafferentation of the forelimb and hand can severely impair hand function, especially the execution of manual tasks that depend on continuous sensory feedback. Our studies in the macaque monkey have shown that somatosensory and motor pathways undergo substantial reorganization following a dorsal root lesion, and that this reorganization contributes to the recovery of hand function (which can be dramatic). The corticospinal tract (CST) is the major descending pathway mediating hand function in the primate and its response following spinal injury is widely used as a biomarker of recovery. In the macaque monkey (and human), this pathway originates from at least 9 functional cortical subdivisions. Each has a different spinal projection, and only 30% of the total CST originates from the motor cortex. Despite this, the motor component of the tract is often the only part considered following spinal cord injury (SCI). We have recently demonstrated in monkeys that following a dorsal rhizotomy, the motor CST projection sprouts within the cord, while the somatosensory (S1) CST projection retracts by 40%. This suggests it is the motor CST, not the S1 CST that contributes to recovery following this peripheral injury. However, preliminary studies in the monkey show a very different story when a central component is added to the same dorsal rhizotomy. When this occurs, both the S1 and motor CSTs sprout massively and bilaterally, well beyond their normal range in the cord. This means that the S1 CST, which is generally overlooked, may also be a key player in the recovery /compensation observed following SCI. Since CST sprouting is used as an anatomical biomarker of hand/paw recovery following SCI (from rats to primates), as well as a target in therapeutic development, it is imperative that the role played by its different functional subcomponents is understood. This grant will investigate this. Our specific aims in summary are as follows: 1. How do the different corticospinal tract components respond to well defined models of peripheral and central SCI in the monkey? 2. Do the injury induced CST terminal sprouts form functional synapses, and if so, with what?, and 3. Since the CST is used extensively in the rat to determine recovery after spinal injury, how comparable (to the monkey) are the rat motor and S1 CST responses following analogous SCIs? All animals will be tested behaviorally and subchronic and chronic time periods will be examined to determine any transience/permanence of response. We will also track proliferative inflammatory responses so that these can be correlated with behavior and terminal sprouting. The lesion models to be used are well defined, involve both peripheral and central components, and as such are clinically relevant. We use powerful multifactorial statistical modeling to assess changes within and between species. Our findings will improve our understanding of the changes that occur in clinical injuries, and better enable the future development of effective treatments for people with spinal cord injury.