Elsevier

Neuroscience Research

Volume 62, Issue 3, November 2008, Pages 147-154
Neuroscience Research

Training improves the electrophysiological properties of lumbar neurons and locomotion after thoracic spinal cord injury in rats

https://doi.org/10.1016/j.neures.2008.07.003Get rights and content

Abstract

The aim of the present study was to evaluate the effect of a stepping-based rehabilitation program in voluntary wheel cages on the functional recovery and electrophysiological properties of neurons in the rat lumbar spinal cord after compressive thoracic (T10) spinal cord injury (SCI). A significant decrease in stance/swing duration and the number of limbs simultaneously in the stance phase was seen in trained compared to sedentary rats at 28 days after SCI (p < 0.05). These kinematic improvements were associated with a significant increase in the amplitude of extracellular recordings from the tibial motoneuron pool in response to descending neuronal drive as well as significant amelioration of electrophysiological properties assessed from intracellular recordings. In fact, electrophysiological properties were not significantly different between uninjured controls and SCI-trained rats. Brain-derived neurotrophic factor (BDNF) levels were significantly elevated in the lumbar spinal cord of SCI-trained rats compared to SCI-sedentary controls. The data support a therapeutic role of increased neuromuscular activity in promoting functional recovery and suggest that it might occur via the beneficial effects of neurotrophic factors on neuronal plasticity.

Introduction

Disruption of the lateral, ventrolateral or ventral white matter tracts at the thoracic level in adult rats induces alterations in their motor behavior, as assessed by tests such as the Basso, Beattie and Bresnahan open field locomotor scale and grid-walking tasks (Miller et al., 1971, Jankowska et al., 1974, Noble and Wrathall, 1989, Basso et al., 1995, Loy et al., 2002, Schucht et al., 2002). Most research efforts in this area have focused on corticospinal, propriospinal, vestibulospinal and reticulospinal axons that are known to participate in various aspects of forelimb and hindlimb function (Matsuyama and Drew, 2000, Schmidt and Jordan, 2000, Jordan and Schmidt, 2002). For instance, after thoracic spinal cord hemisection, locomotion recovery occurs in parallel with increased numbers of collaterals from spared reticulospinal fibers entering the intermediate lamina below the injury at L2 (Ballermann and Fouad, 2006). A recent study showed that long propriospinal neurons are part of a new intraspinal circuit that, following spinal cord injury (SCI), appears to relay output from the cortex to its original spinal targets below the injury site (Bareyre et al., 2004). These observations regarding the role of spared descending fibers in recovery give credence to the suggestion that actual neuronal regeneration across an injury site to re-innervate the lumbar spinal cord may not be necessary to achieve substantial improvements in function after SCI (Jordan and Schmidt, 2002, Bareyre et al., 2004, Ballermann and Fouad, 2006).

Neuronal afferent inputs that are activated during stepping may project intersegmentally to modulate the activity of spared descending fibers, in addition to their direct segmental input to the lumbar neuronal pool. It is therefore noteworthy that, after contusive SCI, an increased daily level of neuromuscular activity, which provides supplementation of neuronal afferent inputs to the spinal cord, has been shown to promote locomotion recovery in rodents (Engesser-Cesar et al., 2005, Smith et al., 2006). In a rat thoracic compressive SCI model, we investigated, as a first objective of the present study, the effects of spontaneous locomotor activity (weight-bearing rehabilitation) on connectivity between the descending neuronal tracts and the lumbar neurons, with the expectation that it is improved by such rehabilitation.

We reported previously (Beaumont and Gardiner, 2002, Beaumont and Gardiner, 2003) that increased chronic activity in the form of daily voluntary or forced treadmill training in healthy rats exerts a demonstrable impact on the biophysical properties of tibial motoneurons, notably enhancing firing frequency–current (F–I) slopes in response to depolarizing current injections, whereas opposite changes occur in motoneurons distal to thoracic spinal cord transection (Beaumont et al., 2004). A second expectation put to the test in the present study was that, after SCI, the responsiveness of spinal neurons is improved by weight-bearing activity in trained versus sedentary animals.

Augmentation of neuromuscular activity level increases the production of endogenous brain-derived neurotrophic factor (BDNF), which has been suggested to augment the level of synaptic plasticity and recovery of function (Gomez-Pinilla et al., 2002, Griesbach et al., 2004, Ying et al., 2005). A third objective was, therefore, to investigate the effect of weight-bearing rehabilitation on BDNF protein expression in spinal cord tissue at the infralesional (lumbar) versus supralesional (cervical) levels.

Section snippets

Animal surgery

Thirty adult female Sprague–Dawley rats (n = 30, 225–250 g, Charles River, St-Constant, Quebec, Canada) were used in this study. First, the rats were placed on a feedback-controlled heating blanket to prevent a drop in temperature during surgery. Ophthalmic ointment was placed on the eyes to prevent drying. Each animal was given a 5-ml injection of sterile saline before and after surgery to prevent dehydration. They also received antibiotic prophylaxis (gentamicin, 50 mg/kg, i.m.) immediately after

Results

SCI-trained rats progressively increased their daily running distances during the first week from 1 to ∼10 km per day. During the 2nd and 3rd weeks of training, they ran an average distance of 9.8 ± 2.2 km of wheel activity (n = 9). This group was compared to uninjured sham-operated controls (n = 10) and SCI-sedentary rats (n = 11).

Discussion

In this study, we have demonstrated that spontaneously performed locomotor activity after SCI is beneficial in maintaining locomotor patterns similar to those in uninjured rats. Moreover, the data suggest that the recovery of hindlimb muscle function was mediated, at least in part, by (i) increased connectivity between neurons originating above the low thoracic lesion site and the lumbar spinal cord and (ii) improved electrophysiological properties and firing characteristics of the tibial

Conclusion

It is difficult to determine from the present study if amelioration of the locomotor pattern after a stepping-based rehabilitation program is mostly attributable to plasticity between the supraspinal-lumbar spinal cord axis or to the preservation of hindlimb motoneuron properties. Both of them most likely contribute to locomotion recovery. Neuronal plasticity after training could be induced, at least in part, by an increase in the amount of trophic factors, suggesting that exogenous

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