The Lesioned Spinal Cord Is a “New” Spinal Cord: Evidence from Functional Changes after Spinal Injury in Lamprey

Abstract

Finding a treatment for spinal cord injury (SCI) focuses on reconnecting the spinal cord by promoting regeneration across the lesion site. However, while regeneration is necessary for recovery, on its own it may not be sufficient. This presumably reflects the requirement for regenerated inputs to interact appropriately with the spinal cord, making sub-lesion network properties an additional influence on recovery. This review summarizes work we have done in the lamprey, a model system for SCI research. We have compared locomotor behavior (swimming) and the properties of descending inputs, locomotor networks, and sensory inputs in unlesioned animals and animals that have received complete spinal cord lesions. In the majority (∼90%) of animals swimming parameters after lesioning recovered to match those in unlesioned animals. Synaptic inputs from individual regenerated axons also matched the properties in unlesioned animals, although this was associated with changes in release parameters. This suggests against any compensation at these synapses for the reduced descending drive that will occur given that regeneration is always incomplete. Compensation instead seems to occur through diverse changes in cellular and synaptic properties in locomotor networks and proprioceptive systems below, but also above, the lesion site. Recovery of locomotor performance is thus not simply the reconnection of the two sides of the spinal cord, but reflects a distributed and varied range of spinal cord changes. While locomotor network changes are insufficient on their own for recovery, they may facilitate locomotor outputs by compensating for the reduction in descending drive. Potentiated sensory feedback may in turn be a necessary adaptation that monitors and adjusts the output from the “new” locomotor network. Rather than a single aspect, changes in different components of the motor system and their interactions may be needed after SCI. If these are general features, and where comparisons with mammalian systems can be made effects seem to be conserved, improving functional recovery in higher vertebrates will require interventions that generate the optimal spinal cord conditions conducive to recovery. The analyses needed to identify these conditions are difficult in the mammalian spinal cord, but lower vertebrate systems should help to identify the principles of the optimal spinal cord response to injury.

GABA promotes survival and axonal regeneration in identifiable descending neurons after spinal cord injury in larval lampreys

“…The present results provide further support for the idea suggesting that the lesioned spinal cord is a “new spinal cord” 69 and the importance of understanding the changes that occur after SCI in different neurotransmitter systems in the brain and in the spinal cord above and below the site of injury. This study adds to previous work revealing anatomical 37 – 39 , 70 , 71 and physiological 40 , 72 , 73 changes in different neurotransmitter systems above and below the lesion in recovered lampreys and highlights the importance of understanding these changes before applying neuropharmacological interventions in SCI patients.…”

A mathematical model for storage and recovery of motor actions in the spinal cord

“…Complete locomotor recovery occurs spontaneously in the lamprey. While this has been considered to reflect regeneration (Cohen et al 1988), there are also changes in the spinal cord above and below the lesion site that suggest additional recovery factors (Parker 2017), and the need to consider how regenerated inputs interact with the sub-lesion spinal cord to generate the same output using different circuitry with different properties (see Hoffman and Parker 2011). There is an increase in inhibitory activity below, but not above the lesion site.…”

Regenerative capacity in the lamprey spinal cord is not altered after a repeated transection

“…While lampreys recover normal swimming behaviors after spinal cord transection and re-transection, it must be acknowledged that functional recovery is the result of substantial plasticity throughout the central nervous system. That is, the regenerated spinal cord does not return to the original status of an uninjured spinal cord but rather forms new functional circuitry with compensatory network properties (Parker, 2017). This is clearly illustrated by the facts that only a subset of descending axons regenerate in the transected and re-transected spinal cord (Fig.…”

“…Yet, the excitatory postsynaptic potentials, a measure of synaptic strength, can be as strong or stronger than those in the uninjured spinal cord (Mackler and Selzer, 1985, 1987). In addition, using electrophysiological methods, compensatory plasticity has also been documented at regenerated lamprey spinal synapses, as are changes in the intrinsic properties of regenerated axons, which together could boost the synaptic output of regenerated synapses (Cooke and Parker, 2009; Parker, 2017). Given the remarkable consistency of axon, synapse and cytoskeleton distributions (Fig.…”