We propose to investigate the mechanisms accounting for, limiting and encouraging the recovery of function after spinal cord damage. Recovery, from the level of the neuron to that of the whole animal's behavior will be examined. We wish to determine which aspects of neuronal plasticity, including sprouting and regeneration, may contribute to recovery. A clearer understanding of the nature, extent and regulation of neuronal plasticity should lead to rational strategies for enhancing the extent and quality of recovery from spinal cord injury. Our experimental models are the cat and rat spinal cords. Our experimental approach is multidisciplinary including intra- and extra-cellular recording from axotomized and deafferented neurons; regulation of synthesis of mRNAs coding for proteins in axotomized neurons; the use of neural transplants to enhance regenerative potential; morphological examination of regeneration and sprouting in spinal neurons; and behavioral examination of recovery of motor function following spinal cord damage. Correlative studies include electron microscopic and physiological studies of reinnervation of partially denervated neurons; metabolic and morphological studies of recovery of damaged neurons; morphological, biochemical and physiological studies of the determinants of regeneration; and morphological and behavioral studies of recovery of function. In projects 1 and 2, investigations of physiological and morphological correlates of axotomy and regeneration of spinal and brainstem motorneurons are proposed; the differences in gene expression between regenerating and non-regenerating neurons will be explored in project 3; the increased potential for CNS regeneration elicited by embryonic transplants will be examined in project 4 including an investigation of synapse formation by the regenerating axons; in project 5 light microscopic-electron microscopic correlates of sprouting of spinal systems will be examined quantitatively to learn the rules that determine successful reinnervation; project 6 uses Clarke's nucleus as a model for studying morphological and physiological correlates of recovery of deafferented or axotomized neurons (including physiological consequences of reinnervation and metabolic determinants of survival of damaged cells); in project 7, behavioral and anatomical correlates of recovery of function and lesion-induced sprouting will be explored. Our long-range goal is to find methods that can enhance recovery mechanisms and then determine if these methods improve functional recovery after damage to the spinal cord.
