The impact of myelination on axon sparing and locomotor function recovery in spinal cord injury assessed using diffusion tensor imaging.

The dysmyelinated axons of shiverer mice exhibit impaired conduction characteristics, similar to early postnatal axons before myelination, whereas the patterns of neuronal activity and connectivity are relatively comparable with those of wild-type myelinated axons. This unique dysmyelination pattern is exploited in the present study to determine the role of compact myelin in the loss and recovery of function following traumatic spinal cord injury (SCI). We applied in vivo diffusion tensor imaging (DTI) and post-mortem immunohistochemistry analysis to examine changes in myelin and axonal integrity, and evaluated these changes in concert with the analysis of locomotor function from 1 to 4 weeks following a mid-thoracic contusion injury in homozygous shiverer and heterozygous littermate mice. The DTI biomarkers, axial and radial diffusivities, are noninvasive indicators of axon and myelin integrity in response to SCI of both myelinated and dysmyelinated spinal cord. We show that myelin is critical for normal hind limb function in open field locomotion. However, when the functional outcome is limited during chronic SCI, the extent of recovery is associated with residual axonal integrity and independent of the extent of intact myelin at the lesion epicenter.

L1 cell adhesion molecule is essential for the maintenance of hyperalgesia after spinal cord injury.

Spinal cord injury (SCI) results in a loss of normal motor and sensory function, leading to severe disability and reduced quality of life. A large proportion of individuals with SCI also suffer from neuropathic pain symptoms. The causes of abnormal pain sensations are not well understood, but can include aberrant sprouting and reorganization of injured or spared sensory afferent fibers. L1 is a cell adhesion molecule that contributes to axonal outgrowth, guidance and fasciculation in development as well as synapse formation and plasticity throughout life. In the present study, we used L1 knockout (KO) mice to determine whether this adhesion molecule contributes to sensory dysfunction after SCI. Both wild-type (WT) and KO mice developed heat hyperalgesia following contusion injury, but the KO mice recovered normal response latencies beginning at 4 weeks post-injury. Histological analyses confirmed increased sprouting of sensory fibers containing calcitonin-gene related peptide (CGRP) in the deep dorsal horn of the lumbar spinal cord and increased numbers of interneurons expressing protein kinase C gamma (PKCgamma) in WT mice 6 weeks after injury. In contrast, L1 KO mice had less CGRP(+) fiber sprouting, but even greater numbers of PKCgamma(+) interneurons at the 6 week time point. These data demonstrate that L1 plays a role in maintenance of thermal hyperalgesia after SCI in mice, and implicate CGRP(+) fiber sprouting and the upregulation of PKCgamma expression as potential contributors to this response.

TGF-alpha increases astrocyte invasion and promotes axonal growth into the lesion following spinal cord injury in mice.

Astrocytes respond to environmental cues and play a multifaceted role in the response to trauma in the central nervous system. As the most prevalent contributors to the glial scar, astrocytes are targeted as barriers to regeneration. However, there is also strong evidence that astrocytes are vital for neuroprotection and metabolic support after injury. In addition, consistent with their role during development, astrocytes may be capable of supporting the growth of injured axons. Therefore, we hypothesized that with appropriate stimulation, the reparative functions of endogenous astrocytes could be harnessed to promote axon growth and recovery after spinal cord injury. Transforming growth factor-alpha (TGF-alpha) is a mitogenic growth factor that is active on astrocytes and is poised to contribute to such a strategy. Recombinant TGF-alpha was administered intrathecally to adult C57BL/6 mice for two weeks following a moderate mid-thoracic spinal cord contusion. By three weeks post-injury, TGF-alpha infusion had not affected locomotor recovery, but promoted extensive axon growth and altered the composition of the lesion site. The center of the lesion in the treated mice contained greater numbers of new cells and increased astrocyte invasion. Despite the expression of inhibitory proteoglycans, there was a marked increase in axons expressing neurofilament and GAP-43 immunoreactivity, and the new axons were closely associated with increased laminin expression within and beyond the astrocyte matrix. The results demonstrate that astrocytes are dynamic players in the response to spinal cord injury, and the growth-supportive role of these cells can be enhanced by TGF-alpha infusion.