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A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury.

ABSTRACT: Spinal cord injury (SCI) above cervical level 4 disrupts descending axons from the medulla that innervate phrenic motor neurons, causing permanent paralysis of the diaphragm. Using an ex vivo preparation in neonatal mice, we have identified an excitatory spinal network that can direct phrenic motor bursting in the absence of medullary input. After complete cervical SCI, blockade of fast inhibitory synaptic transmission caused spontaneous, bilaterally coordinated phrenic bursting. Here, spinal cord glutamatergic neurons were both sufficient and necessary for the induction of phrenic bursts. Direct stimulation of phrenic motor neurons was insufficient to evoke burst activity. Transection and pharmacological manipulations showed that this spinal network acts independently of medullary circuits that normally generate inspiration, suggesting a distinct non-respiratory function. We further show that this "latent" network can be harnessed to restore diaphragm function after high cervical SCI in adult mice and rats.

SUBMITTER: Cregg JM

PROVIDER: S-EPMC5687843 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury.

Cregg Jared M JM Chu Kevin A KA Hager Lydia E LE Maggard Rachel S J RSJ Stoltz Daimen R DR Edmond Michaela M Alilain Warren J WJ Philippidou Polyxeni P Landmesser Lynn T LT Silver Jerry J

Cell reports 20171001 3

Spinal cord injury (SCI) above cervical level 4 disrupts descending axons from the medulla that innervate phrenic motor neurons, causing permanent paralysis of the diaphragm. Using an ex vivo preparation in neonatal mice, we have identified an excitatory spinal network that can direct phrenic motor bursting in the absence of medullary input. After complete cervical SCI, blockade of fast inhibitory synaptic transmission caused spontaneous, bilaterally coordinated phrenic bursting. Here, spinal co ...[more]

PMID: 29045834

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Project description:BACKGROUND:Propriospinal neurons, with axonal projections intrinsic to the spinal cord, have shown a greater regenerative response than supraspinal neurons after axotomy due to spinal cord injury (SCI). Our previous work focused on the response of axotomized short thoracic propriospinal (TPS) neurons following a low thoracic SCI (T9 spinal transection or moderate spinal contusion injury) in the rat. The present investigation analyzes the intrinsic response of cervical propriospinal neurons having long descending axons which project into the lumbosacral enlargement, long descending propriospinal tract (LDPT) axons. These neurons also were axotomized by T9 spinal injury in the same animals used in our previous study. RESULTS:Utilizing laser microdissection (LMD), qRT-PCR, and immunohistochemistry, we studied LDPT neurons (located in the C5-C6 spinal segments) between 3-days, and 1-month following a low thoracic (T9) spinal cord injury. We examined the response of 89 genes related to growth factors, cell surface receptors, apoptosis, axonal regeneration, and neuroprotection/cell survival. We found a strong and significant down-regulation of ~25% of the genes analyzed early after injury (3-days post-injury) with a sustained down-regulation in most instances. In the few genes that were up-regulated (Actb, Atf3, Frs2, Hspb1, Nrap, Stat1) post-axotomy, the expression for all but one was down-regulated by 2-weeks post-injury. We also compared the uninjured TPS control neurons to the uninjured LDPT neurons used in this experiment for phenotypic differences between these two subpopulations of propriospinal neurons. We found significant differences in expression in 37 of the 84 genes examined between these two subpopulations of propriospinal neurons with LDPT neurons exhibiting a significantly higher base line expression for all but 3 of these genes compared to TPS neurons. CONCLUSIONS:Taken collectively these data indicate a broad overall down-regulation in the genes examined, including genes for neurotrophic/growth factor receptors as well as for several growth factors. There was a lack of a significant regenerative response, with the exception of an up-regulation of Atf3 and early up-regulation of Hspb1 (Hsp27), both involved in cell stress/neuroprotection as well as axonal regeneration. There was no indication of a cell death response over the first month post-injury. In addition, there appear to be significant phenotypic differences between uninjured TPS and LDPT neurons, which may partly account for the differences observed in their post-axotomy responses. The findings in this current study stand in stark contrast to the findings from our previous work on TPS neurons. This suggests that different approaches will be needed to enhance the capacity for each population of propriospinal neuron to survive and undergo successful axonal regeneration after SCI.

Project description:Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality after cervical spinal cord injury (SCI). Upon SCI, inspiratory signals originating in the medullary rostral ventral respiratory group (rVRG) become disrupted from their phrenic motor neuron (PhMN) targets, resulting in diaphragm paralysis. Limited growth of both damaged and spared axon populations occurs after central nervous system trauma attributed, in part, to expression of various growth inhibitory molecules, some that act through direct interaction with the protein tyrosine phosphatase sigma (PTPσ) receptor located on axons. In the rat model of C2 hemisection SCI, we aimed to block PTPσ signaling to investigate potential mechanisms of axon plasticity and respiratory recovery using a small molecule peptide mimetic that inhibits PTPσ. The peptide was soaked into a biocompatible gelfoam and placed directly over the injury site immediately after hemisection and replaced with a freshly soaked piece 1 week post-SCI. At 8 weeks post-hemisection, PTPσ peptide significantly improved ipsilateral hemidiaphragm function, as assessed in vivo with electromyography recordings. PTPσ peptide did not promote regeneration of axotomized rVRG fibers originating in ipsilateral medulla, as assessed by tracing after adeno-associated virus serotype 2/mCherry injection into the rVRG. Conversely, PTPσ peptide stimulated robust sprouting of contralateral-originating rVRG fibers and serotonergic axons within the PhMN pool ipsilateral to hemisection. Further, relesion through the hemisection did not compromise diaphragm recovery, suggesting that PTPσ peptide-induced restoration of function was attributed to plasticity of spared axon pathways descending in contralateral spinal cord. These data demonstrate that inhibition of PTPσ signaling can promote significant recovery of diaphragm function after SCI by stimulating plasticity of critical axon populations spared by the injury and consequently enhancing descending excitatory input to PhMNs.

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A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury.

Publications

A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury.

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