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Dissertation
Promoting descending and ascending axonal outgrowth from peripheral nerve grafts after spinal cord injury
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2012
DOI:
https://doi.org/10.17918/00000451
Abstract
After a spinal cord injury volitional muscle control, sensory feedback, and autonomic function is impaired or lost. Recovery is hindered by poor regeneration of mature neurons, decrease in trophic support, and formation of glial scar tissue. Injured axons readily grow into intraspinal peripheral nerve grafts (PNGs) but most do not extend beyond the distal graft end. The goal of this project was to increase axonal outgrowth and promote functional recovery after spinal cord injury. Adult female Sprague-Dawley rats received a complete lower thoracic transection and two branches of pre-degenerated sciatic nerve were apposed to each side of the lesion cavity to support descending axon regeneration (dPNG) or ascending axon regeneration (aPNG). There was an approximate delay of one week before axons entered the PNG and axons extended to the distal end (~15mm) by 30 days. In Aim 1 anatomical and biochemical features of PNGs during axon regeneration were characterized followed by assessment of changes in neurotrophic factor (NTF) expression in PNGs and adjacent spinal cord tissue. Expression of mRNA for the NTF glial cell line-derived neurotrophic factor (GDNF) was significantly higher in the PNG compared to injured spinal cord, suggesting a possible attractive effect that restricts axons from extending beyond the PNG. This information was used in Aim 2 to test whether over-expression of GDNF at the distal graft-spinal cord site, in combination with matrix modification to digest inhibitory factors of glial scar tissue, would enhance axonal outgrowth and functional recovery. Transected animals received a dPNG or an aPNG, microinjection of a lentiviral vector to overexpress GFP (control) or GDNF and PBS (control) or chondroitinase treatment to digest inhibitory proteoglycans of the glial scar. GDNF treated animals did not develop hyper-reflexia in response to sensory stimuli and showed moderate improvements in hindlimb locomotor function. Anterograde labeling of regenerated axons indicated that over-expression of GDNF failed to increase axonal outgrowth from PNGs and electrophysiology experiments did not detect an increase in synaptic function between regenerating axons and spinal cord neurons. These results indicate that further manipulation is required to promote functional recovery after injury beyond a local increase in neurotrophic factor.
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Details
- Title
- Promoting descending and ascending axonal outgrowth from peripheral nerve grafts after spinal cord injury
- Creators
- Arthi Amarnath Amin
- Contributors
- Michel A. Lemay (Advisor)John D. Houle (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xix, 206 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; College of Medicine; Drexel University
- Other Identifier
- 991014970202404721