The long range goal of this research program is to identify the requirements of developing and mature CNS neurons for survival and axonal regeneration after injury and to identify ways to enhance axonal sprouting and regenerative growth after spinal cord injury at birth or at maturity. Studies during the previous period of support using neural tissue transplantation techniques after spinal cord injury indicate that I) CN5 neurons (like their peripheral counterparts) are dependent upon target derived trophic support for neuronal survival and axonal elongation after injury, 2) particular populations of neurons have very specific requirements for survival and for tonal elongation after injury and 3) survival and axonal elongation are regulated independently. At present, little is known about the effects of exogenous trophic support on neuronal survival and axonal elongation in vivo. We are in a situation to test in vivo for CNS neurons for the first time many of the principles of neurotrophic influences CNS pathways during development and after injury which to date have been inaccessible to experimental manipulation. We will test the influence of members of the neurotrophin family (BDNF,NT-3, NT-4, NLF) and the injury related neurotrophic factor (CNTF) on CNS pathways during development, at maturity and after spinal cord injury. The studies proposed will examine systematically 3 representative classes of neurons: descending corticospinal neurons, descending brainstem spinal neuron and ascending neurons to determine the extent to which their requirements for survival and regrowth after injury are similar and the extent to which they differ. It is likely that CNS neurons require trophic support from their target not only during development but also in the adult, or that a lesion makes them dependent again in an immature fashion. We will use spinal cord lesions and transplants in newborn and adult rats and the administration of exogenous neurotrophic support to determine the requirements of CNS neurons for survival and growth after spinal cord injury and to identify ways to enhance that growth. We will use neural tissue transplantation, neuroanatomical tracing (anterograde and retrograde transport of horseradish peroxidase and fluorescent tracers, retrograde transport of neurotrophic factors, in situ hybridization, immunocytochemistry), quantitative morphometrics, and tissue culture techniques to address the specific aims. The experiments proposed will test the hypothesis that the admintration of exogenous trophic agents Bill increase the survival of innnature axotomized CNS neurons, prevent the atrophy of mature axotomized CNS neurons and increase the capacity of both mature and in immature neurons for regenerative growth after spinal cord injury and transplantation in neonatal and adult operates. We predict that particular strategies will enhance the survival, plasticity and regenerative growth of particular pathways after spinal cord injury during development and at maturity.
Showing the most recent 10 out of 35 publications
