Effects of Rehabilitation on Perineural Nets and Synaptic Plasticity Following Spinal Cord Transection.

Epidural electrical stimulation (ES) of the lumbar spinal cord combined with daily locomotor training has been demonstrated to enhance stepping ability after complete spinal transection in rodents and clinically complete spinal injuries in humans. Although functional gain is observed, plasticity mechanisms associated with such recovery remain mostly unclear. Here, we investigated how ES and locomotor training affected expression of chondroitin sulfate proteoglycans (CSPG), perineuronal nets (PNN), and synaptic plasticity on spinal motoneurons. To test this, adult rats received a complete spinal transection (T9-T10) followed by daily locomotor training performed under ES with administration of quipazine (a serotonin (5-HT) agonist) starting 7 days post-injury (dpi). Excitatory and inhibitory synaptic changes were examined at 7, 21, and 67 dpi in addition to PNN and CSPG expression. The total amount of CSPG expression significantly increased with time after injury, with no effect of training. An interesting finding was that γ-motoneurons did not express PNNs, whereas α-motoneurons demonstrated well-defined PNNs. This remarkable difference is reflected in the greater extent of synaptic changes observed in γ-motoneurons compared to α-motoneurons. A medium negative correlation between CSPG expression and changes in putative synapses around α-motoneurons was found, but no correlation was identified for γ-motoneurons. These results suggest that modulation of γ-motoneuron activity is an important mechanism associated with functional recovery induced by locomotor training under ES after a complete spinal transection.

Effects of treadmill training on microvascular remodeling in the rat after spinal cord injury.

INTRODUCTION: The morphological characteristics of skeletal muscles innervated caudal to a spinal cord injury (SCI) undergo dramatic phenotypic and microvascular changes. METHOD: Female Sprague-Dawley rats received a severe contusion at thoracic level 9/10 and were randomly assigned to locomotor training, epidural stimulation, or a combination of the treatment groups (CB). Fiber type composition and capillary distribution were assessed in phenotypically distinct compartments of the tibialis anterior. RESULTS: Spinal cord injury induced a shift in type II fiber phenotype from oxidative to glycolytic (P < 0.05) as well as capillary loss within the oxidative core and glycolytic cortex; the CB treatment best maintained capillary supply within both compartments. DISCUSSION: The angiogenic response of CB training improved capillary distribution across the muscle; capillary distribution became spatially more homogeneous and mean capillary supply area decreased, potentially improving oxygenation. There is an important role for weight-bearing training in maintaining the oxidative phenotype of muscle after SCI. Muscle Nerve 59:370-379, 2019.

Sequential therapy of anti-Nogo-A antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats.

Intense training is the most clinically successful treatment modality following incomplete spinal cord injuries (SCIs). With the advent of plasticity enhancing treatments, understanding how treatments might interact when delivered in combination becomes critical. Here, we investigated a rational approach to sequentially combine treadmill locomotor training with antibody mediated suppression of the fiber growth inhibitory protein Nogo-A. Following a large but incomplete thoracic lesion, rats were immediately treated with either anti-Nogo-A or control antibody (2weeks) and then either left untrained or step-trained starting 3weeks after injury for 8weeks. It was found that sequentially combined therapy improved step consistency and reduced toe dragging and climbing errors, as seen with training and anti-Nogo-A individually. Animals with sequential therapy also adopted a more parallel paw position during bipedal walking and showed greater overall quadrupedal locomotor recovery than individual treatments. Histologically, sequential therapy induced the greatest corticospinal tract sprouting caudally into the lumbar region and increased the number of serotonergic synapses onto lumbar motoneurons. Increased primary afferent sprouting and synapse formation onto lumbar motoneurons observed with anti-Nogo-A antibody were reduced by training. Animals with sequential therapy also showed the highest reduction of lumbar interneuronal activity associated with walking (c-fos expression). No treatment effects for thermal nociception, mechanical allodynia, or lesion volume were observed. The results demonstrate that sequential administration of anti-Nogo-A antibody followed in time with intensive locomotor training leads to superior recovery of lost locomotor functions, which is probably mediated by changes in the interaction between descending sprouting and local segmental networks after SCI.