Delivery of neurotrophins to the spinal cord is a promising technique to re-engage the locomotor circuitry following spinal cord injury and their use may augment the recovery obtained with body-weight supported treadmill training. The mechanism by which neurotrophins promote locomotor recovery is unknown, but our modeling work suggests that plasticity in the afferent system transmission is involved in recovery.
Aim 1 will obtain information about the changes in afferent transmission to motoneurons and interneurons following neurotrophin delivery to the spinal cord and compare those to the ones obtained with body-weight supported treadmill training. Acquiring this information will provide new insights into the neural mechanisms associated with recovery after SCI and serve as a novel outcome measure for new therapies. We propose to use intracellular and multiunit recording techniques to characterize and compare the changes in afferent transmission obtained with body-weight supported treadmill training or neurotrophin producing cellular transplants. In addition, we will characterize the interneuronal activity patterns and afferent effects on this activity following to thetiA/otreatment modalities. We hypothesize that afferent transmission to motoneurons and interneurons is modified by neurotrophin transplants in a manner similar to the way it is affected by body-weight supported treadmill training, but that the effects are more widespread in the neurotrophin treated animals due to a wider distribution of the neurotrophins with this methodology. In our second aim, we intend to refine our transplant technique to the point where neurotrophin producing transplants could be attempted in the clinic with minimal risks for the patient. We hypothesize that neurotrophins can be delivered via lumbar puncture injection of autologous cells modified to express neurotrophins and that these cells will promote the recovery of plantar weight-bearing stepping without the need for training in acutely and chronically injured animals.

Public Health Relevance

The aims of this project are consistent with the NINDS'mission of reducing the burden of neurological diseases and will further our understanding of the mechanism by which neurotrophins promote locomotor recovery and establish the efficacy of a clinically translatable application of this treatment therapy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Drexel University
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Ollivier-Lanvin, Karen; Fischer, Itzhak; Tom, Veronica et al. (2015) Either brain-derived neurotrophic factor or neurotrophin-3 only neurotrophin-producing grafts promote locomotor recovery in untrained spinalized cats. Neurorehabil Neural Repair 29:90-100
Lee, Seung Joon; Kalinski, Ashley L; Twiss, Jeffery L (2014) Awakening the stalled axon - surprises in CSPG gradients. Exp Neurol 254:12-7
Jin, Ying; Bouyer, Julien; Haas, Christopher et al. (2014) Behavioral and anatomical consequences of repetitive mild thoracic spinal cord contusion injury in the rat. Exp Neurol 257:57-69
Singh, Anita; Krisa, Laura; Frederick, Kelly L et al. (2014) Forelimb locomotor rating scale for behavioral assessment of recovery after unilateral cervical spinal cord injury in rats. J Neurosci Methods 226:124-31
Graziano, Alessandro; Foffani, Guglielmo; Knudsen, Eric B et al. (2013) Passive exercise of the hind limbs after complete thoracic transection of the spinal cord promotes cortical reorganization. PLoS One 8:e54350
Houle, John D; Cote, Marie-Pascale (2013) Axon regeneration and exercise-dependent plasticity after spinal cord injury. Ann N Y Acad Sci 1279:154-63
Haas, Christopher; Fischer, Itzhak (2013) Human astrocytes derived from glial restricted progenitors support regeneration of the injured spinal cord. J Neurotrauma 30:1035-52
Liu, Gang; Detloff, Megan Ryan; Miller, Kassi N et al. (2012) Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury. Exp Neurol 233:447-56
Keeler, Benjamin E; Liu, Gang; Siegfried, Rachel N et al. (2012) Acute and prolonged hindlimb exercise elicits different gene expression in motoneurons than sensory neurons after spinal cord injury. Brain Res 1438:8-21
Ketschek, A R; Haas, C; Gallo, G et al. (2012) The roles of neuronal and glial precursors in overcoming chondroitin sulfate proteoglycan inhibition. Exp Neurol 235:627-37

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