The purpose of the proposed research is to elucidate the rules which determine the response of immature CNS neurons to damage, the mechanisms which underlie the anatomical and functional reorganization that follows early CNS damage, and the factors which permit more successful reorganization i the neonate than in the adult CNS. We have demonstrated previously that embryonic neural tissue transplants modify the response of the immature spinal cord to damage by rescuing immature axotomized neurons from retrograde cell death and by supporting the growth of axons from the host CNS into the transplant. Spinal cord to spinal cord (homonymous) transplants support the persistent survival of axotomized neurons and elongation of their axons, whereas heteronymous (non-spinal cord) transplants only temporarily support this reorganization. Thus permanent reorganization resulting in recovery and/or sparing of function is a target-specific effect of the transplant. The current proposal is designed to identify cellular and molecular mechanisms underlying neuronal survival and axonal elongation after injury in the developing nervous system. We will determine the degree to which the capacity of immature CNS neurons for survival and axonal elongation after injury is regulated by factors intrinsic to the developing neuronal systems (for example the presence of axonal collaterals, ongoing synthesis of growth associated proteins) and the degree to which extrinsic environmental conditions (such as the presence of particular extracellular matrix components) regulate survival and growth and the degree to which intrinsic and extrinsic factors interact. Our model system (spinal cord injury at birth) allows us to study the effect of transplants on the development of undamaged axons in the corticospinal tract and on the survival of axotomized brainstem-spinal tract cells and subsequent re-growth of their axons. We will use quantitative methods to compare developing and regenerating neuronal populations to determine the extent to which their requirements for survival and axonal elongation differ and the extent to which they are similar. We will use neural tissue transplantation n vivo, neuroanatomical tracing (immunocytochemistry, horseradish peroxidase, and florescent tracers) at light and electron microscopic levels and in vitro tissue culture techniques to address these questions.
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