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 environmental. We will use transplantation, neuroanatomical tracing (immunocytochemistry, horseradish peroxidase, and fluorescent tracers) at light and electron microscopic levels and tissue culture techniques to address these questions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Modified Research Career Development Award (K04)
Project #
5K04NS001356-03
Application #
3075099
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Georgetown University
Department
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
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Howland, D R; Bregman, B S; Goldberger, M E (1995) The development of quadrupedal locomotion in the kitten. Exp Neurol 135:93-107
Howland, D R; Bregman, B S; Tessler, A et al. (1995) Development of locomotor behavior in the spinal kitten. Exp Neurol 135:108-22
Joosten, E A (1994) Developmental expression of N-CAM epitopes in the rat spinal cord during corticospinal tract axon outgrowth and target innervation. Brain Res Dev Brain Res 78:226-36
Kunkel-Bagden, E; Dai, H N; Bregman, B S (1993) Methods to assess the development and recovery of locomotor function after spinal cord injury in rats. Exp Neurol 119:153-64
Joosten, E A; Bar, P R; Gispen, W H et al. (1993) Transient projections from rat occipital cortex are able to respond to a spinal target derived diffusible factor in vitro. Neurosci Lett 164:85-8
Bernstein-Goral, H; Bregman, B S (1993) Spinal cord transplants support the regeneration of axotomized neurons after spinal cord lesions at birth: a quantitative double-labeling study. Exp Neurol 123:118-32
Kunkel-Bagden, E; Dai, H N; Bregman, B S (1992) Recovery of function after spinal cord hemisection in newborn and adult rats: differential effects on reflex and locomotor function. Exp Neurol 116:40-51
Bregman, B S; Bernstein-Goral, H (1991) Both regenerating and late-developing pathways contribute to transplant-induced anatomical plasticity after spinal cord lesions at birth. Exp Neurol 112:49-63