Activity-Dependent Increase in Neurotrophic Factors Is Associated with an Enhanced Modulation of Spinal Reflexes after Spinal Cord Injury

Abstract

Activity-based therapies such as passive bicycling and step-training on a treadmill contribute to motor recovery after spinal cord injury (SCI), leading to a greater number of steps performed, improved gait kinematics, recovery of phase-dependent modulation of spinal reflexes, and prevention of decrease in muscle mass. Both tasks consist of alternating movements that rhythmically stretch and shorten hindlimb muscles. However, the paralyzed hindlimbs are passively moved by a motorized apparatus during bike-training, whereas locomotor movements during step-training are generated by spinal networks triggered by afferent feedback. Our objective was to compare the task-dependent effect of bike-and step-training after SCI on physiological measures of spinal cord plasticity in relation to changes in levels of neurotrophic factors. Thirty adult female Sprague-Dawley rats underwent complete spinal transection at a low thoracic level (T12). The rats were assigned to one of three groups: bike-training, step-training, or no training. The exercise regimen consisted of 15 min/d, 5 days/week, for 4 weeks, beginning 5 days after SCI. During a terminal experiment, H-reflexes were recorded from interosseus foot muscles following stimulation of the tibial nerve at 0.3, 5, or 10 Hz. The animals were sacrificed and the spinal cords were harvested for Western blot analysis of the expression of neurotrophic factors in the lumbar spinal cord. We provide evidence that bike-and step-training significantly increase the levels of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4 in the lumbar enlargement of SCI rats, whereas only step-training increased glial cell-derived neurotrophic factor (GDNF) levels. An increase in neurotrophic factor protein levels that positively correlated with the recovery of H-reflex frequency-dependent depression suggests a role for neurotrophic factors in reflex normalization.

Elliptical exercise improves fatigue ratings and quality of life in patients with multiple sclerosis

“…To verify this idea, researchers could measure somatosensoryevoked potentials to investigate whether spinal conduction speeds improved. In animal models of spinal cord injury, exercise has been shown to increase the release of brain-derived neurotrophic factor, which promotes reflex normalization [42], and to increase action of microRNAs, which help regulate apoptosis after injury [43]. Fisher et al showed that when neurologically damaged rats were exposed to treadmill training, their walking performance returned to the level of nondisabled control subjects within 30 days [44].…”

Peripheral Nerve Grafts Support Regeneration after Spinal Cord Injury

“…Delaying distal end apposition of each PNG allows the separation of descending regeneration in the rostrally apposed PNG from ascending regeneration in the caudally apposed PNG. Currently we are examining the effects of exerciseinduced increase in neurotrophic factors in the spinal cord above and below the level of injury [50] to determine if a local increase in endogenous factors might improve axonal regeneration into, and possibly out of, these differently apposed PNGs.…”

“…Extension of regenerated axons beyond the distal PNG-spinal cord interface was observed by anterograde tracing experiments and electrical stimulation of the PNG promoted cFos expression in distal spinal neurons, which was indicative of synaptic activity by regenerated axons exiting the graft. Currently we are performing this grafting approach in combination with hind limb training (either bicycling or stepping) for rats [50], to assess changes in motoneuron excitability after SCI and the possibility of attracting regenerating axons towards the CPG of the lumbar spinal cord in response to the rhythmic activity during training.…”

Gene expression analysis of neurotrophins, Trk receptors, and associated regulatory molecules after contusive spinal cord injury.

“…This phenomenon has been described in both animal (Edgerton VR 2008) and human (Harkema SJ 2008) studies of spinal cord injury. Neurotrophins have been associated as playing a key role in induction of such changes (Hutchinson KJ 2004;Boyce VS 2007;Côté MP 2011;Boyce VS 2012). However, activity-dependent changes in locomotion often manifest at times later than those examined in studies of post-SCI expression of neurotrophins and trk receptors ; (Table 3).…”

“…Additionally, the type and amount of sensory input can influence spontaneous recovery after SCI (Grau, Washburn et al 2004;Ollivier-Lanvin, Keeler et al 2010;Caudle, Brown et al 2011;Grau, Huie et al 2012) and also influence the effectiveness of physical therapy (Bouyer and Rossignol 1998;Bouyer and Rossignol 2003;Gomez-Pinilla, Ying et al 2004;Edgerton, Courtine et al 2008;Frigon and Rossignol 2009;Ollivier-Lanvin, Keeler et al 2010), all of which may involve neurotrophin signaling (Gomez-Pinilla, Hutchinson, Gomez-Pinilla et al 2004;Boyce, Tumolo et al 2007;de Leon 2007;Côté MP 2011;Boyce, Park et al 2012). Further, autonomic dysreflexia (AD), a maladaptive condition frequently observed in patients with cervical or high thoracic SCI, is often triggered by nociceptive sensory input (Maiorov, Fehlings et al 1998;Krassioukov and Fehlings 1999;Garstang and Miller-Smith 2007), and sprouting of central terminals of nociceptive neurons, thought to be NGF-dependent, is a proposed mechanism that contributes to AD (Weaver, Cassam et al 1997;Krenz, Meakin et al 1999;Marsh, Wong et al 2002;Cameron, Smith et al 2006;Ackery, Norenberg et al 2007).…”