): This project represents a multidisciplinary approach to a long-term objective of developing a therapeutic strategy for functionally repairing the dorsal column-dorsal column nuclei sensory pathway in both acute and chronic cervical spinal cord injury (SCI). To improve upper and lower extremity function in humans with cervical SCI, it is hypothesized that injured axons need to regenerate, reinnervate their target sites, and make functional synapses with their target neurons. To test this hypothesis, we are using an adult rat model of mid-cervical SCI and are focusing on ascending primary afferent axons of forelimb dorsal root ganglia (DRG) neurons within the dorsal columns. Our preliminary anatomical and electrophysiological data suggests that some acutely injured forelimb primary afferent axons regenerate through extraspinal peripheral sciatic nerve grafts, reinnervate the brainstem, and make functional synapses with dorsal column nuclei neurons. For the Specific Aims, we will I ) use anatomical techniques to identify strategies for increasing axonal regeneration by acutely injured adult forelimb DRG neurons within sciatic nerve grafts, 2) use anatomical techniques to develop effective strategies for promoting forelimb primary afferent axonal outgrowth from sciatic nerve grafts into their target brainstem dorsal column nuclei, 3) use in vivo and in vitro electrophysiological techniques to evaluate functional synapse formation between regenerating forelimb primary afferent axons and their target dorsal column nuclei neurons as well as conditioned behavioral testing techniques to assess the effects of reconstructing the dorsal column-dorsal column nuclei sensory pathway on forelimb sensorimotor function, and 4) use the best strategies from Aims l and 2, anatomical techniques, electrophysiological techniques, and behavioral testing techniques to examine whether chronically injured forelimb primary afferent axons regenerate and form functional synapses with their target dorsal column nuclei neurons. The significance of this project is that it will delineate a novel treatment strategy for sensory dysfunction in rats with cervical SCI that, if implemented clinically, could lead to enhancement in the quality of life for persons with cervical SCI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040411-03
Application #
6540308
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Kleitman, Naomi
Project Start
2000-06-01
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$216,000
Indirect Cost
Name
University of Louisville
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40292
Beaumont, E; Whitaker, C M; Burke, D A et al. (2009) Effects of rolipram on adult rat oligodendrocytes and functional recovery after contusive cervical spinal cord injury. Neuroscience 163:985-90
Whitaker, Christopher M; Beaumont, Eric; Wells, Michael J et al. (2008) Rolipram attenuates acute oligodendrocyte death in the adult rat ventrolateral funiculus following contusive cervical spinal cord injury. Neurosci Lett 438:200-4
Cothron, Kyle J; Massey, James M; Onifer, Stephen M et al. (2008) Identification of penile inputs to the rat gracile nucleus. Am J Physiol Regul Integr Comp Physiol 294:R1015-23
Massey, James M; Amps, Jeremy; Viapiano, Mariano S et al. (2008) Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Exp Neurol 209:426-45
Kaas, Jon H; Qi, Hui-Xin; Burish, Mark J et al. (2008) Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord. Exp Neurol 209:407-16
Onifer, Stephen M; Nunn, Christine D; Decker, Julie A et al. (2007) Loss and spontaneous recovery of forelimb evoked potentials in both the adult rat cuneate nucleus and somatosensory cortex following contusive cervical spinal cord injury. Exp Neurol 207:238-47
Titsworth, W Lee; Onifer, Stephen M; Liu, Nai-Kui et al. (2007) Focal phospholipases A2 group III injections induce cervical white matter injury and functional deficits with delayed recovery concomitant with Schwann cell remyelination. Exp Neurol 207:150-62
Massey, James M; Hubscher, Charles H; Wagoner, Michelle R et al. (2006) Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. J Neurosci 26:4406-14
Cottrell, Bradford L; Perez-Abadia, Gustavo; Onifer, Stephen M et al. (2006) Neuroregeneration in composite tissue allografts: effect of low-dose FK506 and mycophenolate mofetil immunotherapy. Plast Reconstr Surg 118:615-23; discussion 624-5
Onifer, Stephen M; Zhang, Yi Ping; Burke, Darlene A et al. (2005) Adult rat forelimb dysfunction after dorsal cervical spinal cord injury. Exp Neurol 192:25-38

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