Abstract
Despite limited regeneration capacity, partial injuries to the adult mammalian spinal cord can elicit variable degrees of functional recovery, mediated at least in part by reorganization of neuronal circuitry. Underlying mechanisms are believed to include synaptic plasticity and collateral sprouting of spared axons. Because plasticity is higher in young animals, we developed a spinal cord compression (SCC) injury model in the neonatal mouse to gain insight into the potential for reorganization during early life. The model provides a platform for high-throughput assessment of functional synaptic connectivity that is also suitable for testing the functional integration of human stem and progenitor cell-derived neurons being considered for clinical cell replacement strategies. SCC was generated at T9–T11 and functional recovery was assessed using an integrated approach including video kinematics, histology, tract tracing, electrophysiology, and high-throughput optical recording of descending inputs to identified spinal neurons. Dramatic degeneration of axons and synaptic contacts was evident within 24 hours of SCC, and loss of neurons in the injured segment was evident for at least a month thereafter. Initial hindlimb paralysis was paralleled by a loss of descending inputs to lumbar motoneurons. Within 4 days of SCC and progressively thereafter, hindlimb motility began to be restored and descending inputs reappeared, but with examples of atypical synaptic connections indicating a reorganization of circuitry. One to two weeks after SCC, hindlimb motility approached sham control levels, and weight-bearing locomotion was virtually indistinguishable in SCC and sham control mice. Genetically labeled human fetal neural progenitor cells injected into the injured spinal cord survived for at least a month, integrated into the host tissue and began to differentiate morphologically. This integrative neonatal mouse model provides opportunities to explore early adaptive plasticity mechanisms underlying functional recovery as well as the capacity for human stem cell-derived neurons to integrate functionally into spinal circuits.
Highlights
Adaptive plasticity in the spinal cord has become an important focus in spinal cord injury (SCI) research due to increasing evidence that spinal networks in the injured spinal cord of rodents and cats can reorganize spontaneously following an injury [1,2,3,4,5,6,7,8], and that this reorganization can be promoted by experimental manipulation [2,3,9,10,11,12]
We demonstrate much greater behavioral recovery after thoracic compression injuries than after complete thoracic transections, we use immunohistochemistry, electron microscopy and tract tracing to characterize the extent of damage after compression injury, and we use electrophysiological and high-throughput optical recording to characterize the recovery of functional synaptic connections from specific descending tracts onto specific subpopulations of lumbar motoneurons
One of our working hypotheses in developing a neonatal SCI model is that the envelope of plasticity exhibited by the neonatal spinal cord encompasses the plasticity of which the adult spinal cord is capable
Summary
Adaptive plasticity in the spinal cord has become an important focus in spinal cord injury (SCI) research due to increasing evidence that spinal networks in the injured spinal cord of rodents and cats can reorganize spontaneously following an injury [1,2,3,4,5,6,7,8], and that this reorganization can be promoted by experimental manipulation [2,3,9,10,11,12]. Post-injury plasticity in the spinal cord involves the sprouting of spared axons and the formation of novel synaptic connections and may or may not promote functional recovery, depending on whether it is adaptive or maladaptive [13]. The adaptive plasticity exhibited by the adult brain and spinal cord in connection with learning, memory and recovery from injury is believed to involve at least in part the same mechanisms that underlie the plasticity of the developing nervous system [15,16]. Insight into the mechanisms governing adaptive plasticity following injury in the adult spinal cord may be gained by characterizing adaptive plasticity following injury in the immature spinal cord. Very little is known about the pathogenetic processes involved in pediatric SCI and its potential recovery, providing an additional incentive to investigate mechanisms of adaptive plasticity in the immature spinal cord
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