The Dorsal Column Lesion Model of Spinal Cord Injury and Its Use in Deciphering the Neuron‐Intrinsic Injury Response

Abstract

The neuron‐intrinsic response to axonal injury differs markedly between neurons of the peripheral and central nervous system. Following a peripheral lesion, a robust axonal growth program is initiated, whereas neurons of the central nervous system do not mount an effective regenerative response. Increasing the neuron‐intrinsic regenerative response would therefore be one way to promote axonal regeneration in the injured central nervous system. The large‐diameter sensory neurons located in the dorsal root ganglia are pseudo‐unipolar neurons that project one axon branch into the spinal cord, and, via the dorsal column to the brain stem, and a peripheral process to the muscles and skin. Dorsal root ganglion neurons are ideally suited to study the neuron‐intrinsic injury response because they exhibit a successful growth response following peripheral axotomy, while they fail to do so after a lesion of the central branch in the dorsal column. The dorsal column injury model allows the neuron‐intrinsic regeneration response to be studied in the context of a spinal cord injury. Here we will discuss the advantages and disadvantages of this model. We describe the surgical methods used to implement a lesion of the ascending fibers, the anatomy of the sensory afferent pathways and anatomical, electrophysiological, and behavioral techniques to quantify regeneration and functional recovery. Subsequently we review the results of experimental interventions in the dorsal column lesion model, with an emphasis on the molecular mechanisms that govern the neuron‐intrinsic injury response and manipulations of these after central axotomy. Finally, we highlight a number of recent advances that will have an impact on the design of future studies in this spinal cord injury model, including the continued development of adeno‐associated viral vectors likely to improve the genetic manipulation of dorsal root ganglion neurons and the use of tissue clearing techniques enabling 3D reconstruction of regenerating axon tracts. © 2018 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 00: 000–000, 2018

Longitudinal assessment of recovery after spinal cord injury with behavioral measures and diffusion, quantitative magnetization transfer and functional magnetic resonance imaging

“…Dorsal column lesion models have been shown to be well-suited for studying neuron-intrinsic regenerative responses. 22 We previously reported the use of diffusion, fMRI and qMT imaging to study plastic changes over a period of months in the spinal cord of nonhuman primates that underwent a unilateral dorsal column transection injury of the cervical spinal cord. 23,24 However, contusion injuries to thoracic and/or lumbar regions are more relevant to those that present clinically in human subjects.…”

The Struggle to Make CNS Axons Regenerate: Why Has It Been so Difficult?

“…Damage to the central branch of the sensory axons alone does not initiate this same pattern of upregulation of gene expression, and neither do lesions to intrinsic CNS axons. The PNS axotomy response and the conditioning effect that it produces has therefore been used as a model for the genetic changes that should drive enhanced regeneration of axons [11].…”

Intrinsic Determinants of Axon Regeneration

“…Axons in peripheral nerves, whether sensory, motor, or autonomic, usually generate a new growth cone and initiate a regenerative response through the permissive Schwann cell environment. This response is backed up by the RAG‐response, a stereotypic set of changes in gene expression that are necessary for successful completion of axon regeneration (Attwell et al, ; Lindner et al, ; Mahar and Cavalli, ). However, cutting the central branch of sensory axons has a very different outcome, with a minimal regenerative response and a gene expression response in the cell body that has only a minimal impact on axon growth (Cartoni et al, ; Chandran et al, ; Mar et al, ; Ylera et al, ).…”

“…Evidence for a role of epigenetic factors in axon outgrowth has been obtained in studies on the developmental decline in axon growth capacity (Venkatesh et al, ; ) as well as in DRG neurons following injury (Finelli et al, , Loh et al, ). The DRG model system is particularly well‐suited to study neuron‐intrinsic differences between PNS and CNS axons (Attwell et al, ). The peripheral and central branch of DRG neurons differ fundamentally in their response to injury despite originating from the same cell body.…”