Corinna Jane Darian-Smith, PhD - US grants

DESCRIPTION (provided by applicant): Injuries of the cervical dorsal roots in humans and other primates can severely impair hand function - particularly the performance of manipulative tasks that depend on sensory feedback. Such injuries are relatively common following accidents and trauma in humans, and are typically difficult to repair surgically. Some recovery of function has been demonstrated that has been linked to reorganization within the sensory neocortex and subcortical structures. This application is a systematic examination of behavioral, physiological and structural changes that occur following damage to the sensory neurons that supply feedback from the hand to the brain. Although reorganization has been demonstrated, we still know relatively little about the neural basis for it, where it occurs, and how such changes mediate behavioral recovery or compensation. Without this knowledge we cannot target realistic therapeutic strategies to the appropriate regions. We will use a unique model that allows us to select and block sensory input from a discrete part of the non-human primate hand- namely the index finger and thumb and surrounding regions. We will use physiological and anatomical analyses to determine changes in the somatosensory neuronal circuitry and correlate these results with the behavioral deficit and recovery of manual dexterity over a period of several months. The specific aims are inter-dependent, and can be summarized by the following questions. 1. How does the spontaneous recovery of precision grip relate to the extent of the dorsal root section? Over a period of several months we evaluate the ability to perform a precision grip task. We will then correlate this function with the size of the lesion to provide an indication of the sensory feedback required for some recovery of hand function. 2. Do subcortical somatosensory neuron populations contribute to cortical reactivation and recovery of hand function? We will evaluate electrophysiological changes at different levels of the neuraxis to identify where functional reorganization is concentrated. This information will identify regions where therapy could be targeted. 3. Do primary afferents that 'sprout' into the spinal dorsal horn and cuneate nucleus during the post-lesion months form functional synapses on cuneothalamic and spinothalamic cells? This question arises from the results of a preliminary study. We will use neuroanatomical and ultrastructural techniques to directly identify functional synapses and to reconstruct changes in the primary afferent circuitry that occur following the dorsal root lesion. The proposed studies will contribute important new insight into the central neural mechanisms responsible for the behavioral adaptations that are observed during the months following a well defined dorsal root injury. In addition they will provide insight into the mechanisms of adult neuronal dorsal root avulsion injuries in humans which are debilitating. A better understanding of the post-lesion reorganization of the somatosensory pathways is needed if patients with avulsed spinal dorsal roots are to be treated more effectively.

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.

? DESCRIPTION (provided by applicant): 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 in 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.