FUNCTIONAL INTEGRATION OF TRANSPLANTS

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The long-term objectives of this study are to define the physiological and anatomical responses of spinal cord motoneurons (MN) to spinal cord-injury (SCI) in the adult rat, and to determine if interventive actions, such as neurotransplantation procedures, can lead to restoration of spinal cord function. Experiments are designed to evaluate the consequences of interruption of descending input to MNs after complete transection of the spinal cord and to test whether a fetal spinal cord (FSC) transplant alone, or in combination with hindlimb exercise, will reverse or limit the expected hyperreflexia resulting from SCI. Additional experiments are designed to evaluate the influence of neural tissue transplants on return of spinal cord function after a partial injury either rostral or caudal to the cervical enlargement. Changes in the H-reflex in hindlimbs and induction of hindlimb locomotion following stimulation of the mesencephalic locomotor region (MLR) will be tested. Aim I of this proposal will examine temporal changes in spinal cord MN reflex circuitry and functional interaction with hindlimb muscles after a complete transection lesion to provide a baseline for the physiological responses to injury, against which all interventive treatments can be compared. Aim II will investigate short- and long-term changes caudal to a complete transection lesion in the distribution of afferent fibers, dendritic morphometry and MN size to provide an anatomical correlation to the functional changes detected-in Aim I. These measures will be made using immunocytochemical and image analysis procedures. Aim III will investigate the acute and chronic effects of a partial SCI on physiological properties of MNs, as determined by H-reflex testing. Initial hemisection lesions (at C2 or T1) will provide one side per animal displaying chronic effects, while enlargement of the lesion to a complete transection just prior to testing will provide one side displaying acute effects. Reflex modifications resulting from transplantation intervention(s) will be determined. In Aim IV, the capacity for neural tissue transplants to restore locomotor control to the spinal cord below the level of a partial cervical SCI will be examined. Differences in the level of injury (C2 or T1) will test for the importance of an intact cervical central pattern generator for inducing locomotion of the hindlimbs.