This Program Project focuses on mechanisms which account for recovery of locomotor function following spinal injury and on manipulations which can enhance the recovery Our studies carried out during previous granting periods have indicated that restoration of function may not require reestablishment of the original spinal circuitry limited regeneration together with other compensatory responses may suffice. Individual projects in the present Program Project will examine the correlates of motor recovery at the levels of specific molecules, synapses, circuits, and biomechanical systems. In a Project we will examine the mechanisms by which transplants of embryonic spinal cord improve motor function in rats with complete spinal cord transections. The physiologic basis of this recovery will be analyzed quantitatively and manipulated pharmacologically. These studies will allow us to distinguish the contributions to recovery made by supraspinal and propriospinal systems and those made by the reorganizing spinal cord caudal to the transection and transplant. In Tessler's Project we will determine whether identified neurotrophic factors delivered to the injured rat spinal cord by genetically modified cells can enhance the survival and regeneration of axotomized Clarke's nucleus, neurons, and whether transplants can allow these cells to maintain their normal circuitry. In rat vestibulospinal neurons to be studied in Tessler's Project and in goldfish Mauthner cells to be studied in Faber's Project we will examine the relationship between spontaneous regeneration or regeneration assisted by transplants and motor behaviors mediated by identified sets of brainstem neurons. In Fischer's Project parallel in vivo and in vitro experiments will examine the molecular mechanisms by which axotomized adult rat dorsal root ganglion neurons modify the expression and transport of cytoskeletal proteins as their axons change from stable structures to actively growing processes. Understanding these mechanisms will contribute to developing interventions that can enhance the regeneration of CNS axons. These projects together will provide quantitative information on the nature and extent of recovery of function in several different models. examine the extent and constraints on regeneration into the CNS and suggest therapeutic interventions that will enhance recovery.
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