The restoration of neurological function after injury to the spinal cord will certainly require a multifaceted genetic, cell biological and pharmacological approach accompanied by precise behavioral and physiological evaluation. Transplantation of fetal neural tissue permits some degree of motor competence to develop in rats and cats after spinal transection when the lesion and graft are made in neonates. We have also shown that grafts of genetically modified fibroblasts improve motor control after partial lesions in adults. Our hypothesis is that grafts of cells modified to secrete bioactive molecules will provide greater development or recovery of function after spinal transection in both neonates and adults because these grafts promote greater regeneration. Recovery after grafting, however, is unlikely to be complete. Pharmacological interventions, specifically with serotonergic agonists, have been shown to enhance recovery mediated by transplants. In these experiments we will continue investigation of pharmacological interventions to determine mechanisms by which these agonists act to improve function in spinal rats. We will also compare fetal transplants with transplants of genetically modified cells made in neonates and adults to determine whether pharmacological agents act synergistically with the transplant mediated effects to improve function further. Alternate strategies including co-grafting a cell line (RN46A-B14) that will secrete 5HT into lumbar cord may produce more long-lasting improvement in function. We will also extend our studies to include catecholaminergic agonists since we believe that the optimal pharmacological strategy may include stimulation of both serotonergic and noradrenergic receptors. Lesions made in neonates and in adults modify circuitry. Introduction of trophic factors into the spinal cord of neonates and adults is also likely to modify circuitry by stimulating growth of systems bearing appropriate receptors. The effects on lumbar circuitry of spinal injury and introduction of trophic factors are not known but must be important in understanding the limits on recovery of function and for developing principled therapeutic strategies. We will focus on changes in the descending monoaminergic systems and the peptidergic afferent systems and their receptor binding sites at the level of the transection/transplantation and in lumbar cord. Regeneration of descending and regeneration (or sprouting) of small caliber dorsal root axons will be studied immunocytochemically and changes in density of their receptor binding sites will be measured. Together these studies should provide significant information about mechanisms of pharmacological stimulation of function that may lead to development of therapies.
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