Promoting Primary Afferent Collateral Sprouting and Rehabilitation in Improve Forepaw Function after Cervical Spinal Cord Injury

V. Abstract: In Kentucky and thoughout the United States, improvements in safety, emergency medicine, and care after traumatic injury to the adult spinal cord have increased survival, life expectancy, and the number of persons with incomplete injuries. Restoring hand function to perform activities of daily living would significantly improve the quality of life for individuals with quadriplegia after the most frequent incomplete cervical spinal cord injury (SCI). Evidence suggests that promoting collateral sprouting ofaxons remaining within their target sites is a therapeutic approach. Human and rat dorsal root ganglion primary afferents ascending in the spinal cord dorsal columns transmit sensory information from low threshold mechanoreceptors to target thalamic relay neurons in the brainstem cuneate and gracile nuclei. Similar to humans, lesion of the adult rat cervical spinal cord dorsal column primary afferents produces tactile discrimination and forepaw movement deficits during grasp in retrieval tests. Evidence indicates that constitutive and increased chondroitin sulfate proteoglycans (CSPGs) in the extracellular matrix at the SCI site inhibit axon sprouting. We saw that CSPGs increase in the adult rat cuneate and gracile nuclei following lesion of the mid-cervical spinal cord dorsal column primary afferents. We also showed that digestion of CSPGs in the cuneate nucleus by the bacteria-derived enzyme chondroitinase ABC administered acutely then one week following ipsilateral low cervical SCI promoted collateral sprouting of intact forepaw digit primary afferents one week later. Whether collateral sprouting of intact forepaw digit primary afferents within the cuneate nucleus after CSPGs digestion leads to improved function is not known. It also is not known whether forepaw digit primary afferent collateral sprouting requires repeat, single, acute, and/or delayed chondroitinase ABC administration. Specific Aim 1 will test the hypothesis that after incomplete cervical spinal cord injury functional collateral sprouting of forepaw digit primary afferents innervating the cuneate nucleus will occur when chondroitin sulfate proteoglycans in it are digested by chondroitinase ABC. Rehabilitation for hand function is usually performed after cervical SCI. Daily training on a pre-injury acquired, Single Pellet Retrieval Test improved adult rat forelimb performance high cervical SCI. Specific Aim 2 will test the hypothesis that after incomplete cervical spinal cord injury the functional effects of forepaw digit primary afferent collateral sprouting due to chondroitin sulfate proteoglycan digestion will improve with rehabilitation. This project will for the first time show whether dorsal column forepaw primary afferent collateral sprouting in the cuneate nucleus is a strategy to improve adult rat forepaw function after incomplete cervical SCI and whether this therapeutic effect can be improved by rehabilitation.