The rules which determine the response of the immature CNS neurons to damage, the mechanisms which underlie the anatomical and functional reorganization that follows early CNS damage, and the factors which prevent more successful reorganization in the adult CNS are only poorly understood. We have demonstrated that neural tissue transplants modify the response of immature neurons to damage by 1) preventing the massive retrograde cell death of immature axotomized neurons and 2) supporting axonal elongation through the transplant and across the site of a neonatal lesion. The current proposal is designed to examine the mechanisms by which transplants modify the response of the immature CNS to damage. We will grow neural tissue transplants within spinal cord lesions in newborn rats to test the hypothesis that there are three requirements of damaged developing central neurons for survival. The first series of experiments will examine whether transplants provide a) a temporary trophic support for the immature axotomized neurons, b) a terrain which supports axonal elongation, and c) test whether the long-term survival after injury requires that the axotomized neurons establish or re-establish specific synaptic connections. We will determine the extent to which each of these requirements for survival is target specific. After lesions in the developing nervous system, in contrast to the adult, some axons are capable of long distance growth. The second series of experiments in this proposal will test whether this greater capacity for axonal elongation is regulated by factors intrinsic to the developing neurons or whether changes in the environment of the developing spinal cord limit the extent of axonal growth. We will first determine whether the long distance axonal growth in the immature nervous system is continued growth by late-developing axons or regenerative growth by damaged axons. We will test if there is a critical period in the developing spinal cord that permits long distance growth and examine whether immature glia play a role in creating this environment. We will use neuroanatomical tracing techniques (immunocytochemistry, horseradish peroxidase, and fluorescent tracers) at light and electron microscopic levels to address these questions.
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