Spinal cord injury was once deemed irreversible and untreatable but recent repair approaches have shown great promise in facilitating axon regeneration across the lesion site and functional recovery. One promising repair strategy is the transplantation of growth-promoting olfactory ensheathing glia (OEG). Our preliminary data and all proposed studies combine the therapies of OEG transplantation with 6 months of treadmill step training to promote axon regeneration following complete spinal cord transection in adult rats. Initial data suggest that these two repair strategies result in functional recovery of hindlimb stepping and substantial regeneration of serotonergic (5-HT) and noradrenergic (NA) axons across the lesion and into the caudal stump. The proposed experiments will determine the potential of these repair strategies, alone or in combination, and examine the mechanisms by which motor function improves.
Specific aim 1 will determine if the recovery of hindlimb locomotion following both treatments is due to the regeneration of 5-HT and/or NA axons across the lesion. By pharmacologically blocking 5-HT and/or NA receptors linked to locomotion, the contribution of each of these neurotransmitter systems will be tested. Light and electron microscopy will be used to determine the number and length of the 5-HT and NA axons that cross the lesion site and if they form structurally identifiable synaptic contacts on neurons in the caudal stump.
Specific aim 2 will use electrophysiological and pharmacological methods to compare functional connectivity between supraspinal neurons and the lumbosacral motor networks in rats with and without OEG injections and step training. It will also determine if these functional connections use serotonin or noradrenaline for neurotransmission.
Specific aim 3 will use retrograde tracing techniques to identify the supraspinal neurons that regenerate their axons across the lesion site and determine whether these retrogradely labeled neurons are serotonergic and/or noradrenergic. Our long term goal is to regain voluntary control of hindlimb stepping after a complete midthoracic spinal cord injury in an adult animal.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
Zip Code
Khankan, Rana R; Griffis, Khris G; Haggerty-Skeans, James R et al. (2016) Olfactory Ensheathing Cell Transplantation after a Complete Spinal Cord Transection Mediates Neuroprotective and Immunomodulatory Mechanisms to Facilitate Regeneration. J Neurosci 36:6269-86
Khankan, Rana R; Wanner, Ina B; Phelps, Patricia E (2015) Olfactory ensheathing cell-neurite alignment enhances neurite outgrowth in scar-like cultures. Exp Neurol 269:93-101
Takeoka, Aya; Jindrich, Devin L; Muñoz-Quiles, Cintia et al. (2011) Axon regeneration can facilitate or suppress hindlimb function after olfactory ensheathing glia transplantation. J Neurosci 31:4298-310
Ziegler, Matthias D; Hsu, Derek; Takeoka, Aya et al. (2011) Further evidence of olfactory ensheathing glia facilitating axonal regeneration after a complete spinal cord transection. Exp Neurol 229:109-19
Shields, Shannon D; Moore, Katherine D; Phelps, Patricia E et al. (2010) Olfactory ensheathing glia express aquaporin 1. J Comp Neurol 518:4329-41
Takeoka, Aya; Kubasak, Marc D; Zhong, Hui et al. (2010) Noradrenergic innervation of the rat spinal cord caudal to a complete spinal cord transection: effects of olfactory ensheathing glia. Exp Neurol 222:59-69
Ziegler, Matthias D; Zhong, Hui; Roy, Roland R et al. (2010) Why variability facilitates spinal learning. J Neurosci 30:10720-6
Takeoka, Aya; Kubasak, Marc D; Zhong, Hui et al. (2009) Serotonergic innervation of the caudal spinal stump in rats after complete spinal transection: effect of olfactory ensheathing glia. J Comp Neurol 515:664-76
Edgerton, V Reggie; Roy, Roland R (2009) Activity-dependent plasticity of spinal locomotion: implications for sensory processing. Exerc Sport Sci Rev 37:171-8
Munoz-Quiles, Cintia; Santos-Benito, Fernando F; Llamusi, M Beatriz et al. (2009) Chronic spinal injury repair by olfactory bulb ensheathing glia and feasibility for autologous therapy. J Neuropathol Exp Neurol 68:1294-308

Showing the most recent 10 out of 12 publications