Hand function can be seriously impaired following spinal nerve and cord injuries that partially deafferent the forelimb and fingers, and the deficit will be particularly evident in manual tasks that depend on continuous sensory feedback. Our work in the macaque monkey has shown that somatosensory and motor pathways undergo substantial reorganization following cervical dorsal root and cord lesions, and 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). Our work has shown in monkeys that following a dorsal rhizotomy alone, the motor (M1) CST projection remains robust and may even sprout within the cord, while the somatosensory (S1) CST projection retracts by 40%. This suggests that the M1 CST, not the S1 CST, contributes to recovery following this peripheral injury. In direct contrast, when a central component is combined with the same dorsal rhizotomy, both the S1 and motor CSTs sprout massively and bilaterally, and well beyond their normal range in the cord. This means that the S1 CST, which is generally overlooked, is also a key player in the recovery/compensation observed following some (and perhaps all) SCIs that include a central component. 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 critical that the role played by is different functional subcomponents is understood. This grant will investigate this.
Our specific aims i n summary are as follows: 1. How do the S1 and M1 CSTs each 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 define recovery after spinal injury, how comparable (to the monkey) are the rat motor and S1 CST responses following analogous SCIs? Both rats and monkeys will be tested behaviorally and subchronic and chronic time periods will be examined to determine changes in response over time. We will also track proliferative inflammatory responses in both species 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.
Spinal injury that involves the cervical cord can severely impair hand function in humans and result in loss of independence. We use clinically relevant models of spinal injury in the monkey and rat to study central neural mechanisms responsible for the recovery of hand function. Our findings will provide novel insight into the neuronal reorganization that takes place post-injury, which is needed if patients with peripheral nerve and central spinal deafferentation injuries are to be treated more effectively.
