Long‐term reorganization of respiratory pathways after partial cervical spinal cord injury

Abstract

High cervical spinal cord injury (SCI) interrupts bulbospinal respiratory pathways innervating phrenic motoneurons, and induces an inactivation of phrenic nerves (PN) and diaphragm. We have previously shown that the ipsilateral (ipsi) PN was inactivated following a lateral C2 SCI, but was spontaneously partially reactivated 7 days post-SCI. This phrenic reactivation depended on contralateral (contra) descending pathways, located laterally, that cross the spinal midline. We analysed here whether long-term post-lesional changes may occur in the respiratory network. We showed that ipsi PN reactivation was greater at 3 months compared with 7 days post-SCI, and that it was enhanced after acute contra phrenicotomy (Phx), which also induced a substantial reactivation of the ipsi diaphragm (not detected at 7 days post-SCI). At 3 months post-SCI (compared with 7 days post-SCI), ipsi PN activity was only moderately affected by ipsi Phx or by gallamine treatment, a nicotinic neuromuscular blocking agent, indicating that it was less dependent on ipsi sensory phrenic afferents. After an additional acute contra SCI (C1) performed laterally, ipsi PN activity was abolished in rats 7 days post-SCI, but persisted in rats 3 months post-SCI. This activity thus depended on new functional descending pathways located medially rather than laterally. These may not involve newly recruited neurons as retrograde labelling showed that ipsi phrenic motoneurons were innervated by a similar number of medullary respiratory neurons after a short and long post-lesional time. These results show that after a long post-lesional time, phrenic reactivation is reinforced by an anatomo-functional reorganization of spinal respiratory pathways.

Decreased spinal synaptic inputs to phrenic motor neurons elicit localized inactivity-induced phrenic motor facilitation

“…For example, within days-weeks following high cervical SCI, an initially paralyzed hemidiaphragm caudal to injury often spontaneously (partially) recovers in humans (Axen et al, 1985; Hoh et al, 2013; McKinley et al, 1996; Oo et al, 1999; Strakowski et al, 2007) and rodents (Baussart et al, 2006; El-Bohy et al, 1998; Fuller et al, 2006; Golder et al, 2011; Golder and Mitchell, 2005; Lane et al, 2009; Vinit et al, 2007), although the extent of this spontaneous recovery depends on injury severity. This return of ipsilateral diaphragm activity post-injury may be due to remodeling of phrenic circuits (Darlot et al, 2012; Goshgarian, 2009; Lane et al, 2009) or strengthening of spared ipsilateral pathways (Vinit et al, 2008; Vinit and Kastner, 2009), possibly via mechanisms of iPMF. Consistent with this interpretation, cervical spinal injury is associated with a rapid increase in TNFα (Yune et al, 2003) and aPKC activity caudal to injury (Guenther et al, 2012).…”

Degeneration of Phrenic Motor Neurons Induces Long-Term Diaphragm Deficits following Mid-Cervical Spinal Contusion in Mice

“…Following partial lateral C2 hemisection, long-term ipsilateral phrenic activity depends on this alternative descending respiratory pathway, independently of the lateral crossed phrenic pathway. [39][40][41] In our model, the spared ventromedial region might mediate respiratory plasticity leading to functional network reorganization and consequent long-term modification of diaphragm EMG activity. Although not explored in the current study, these long-term diaphragm changes could also be caused by mechanisms such as morphological plasticity and changes in intrinsic excitability and inhibitory synaptic input to spared ipsilateral phrenic motor neurons, as well as plasticity in respiratory interneuron populations of the cervical spinal cord.…”

Distinct Expression of c-Jun and HSP27 in Axotomized and Spared Bulbospinal Neurons After Cervical Spinal Cord Injury

“…These crossed pathways are normally ineffective after an acute cervical hemisection but are potent after a time-lapse of several hours to several days (Vinit et al 2007), depending at least in part on synaptic remodeling (Goshgarian 2003). One can presume that the observed cell body response of bulbospinal neurons with spared axons may contribute to the development of these synaptic plasticity processes involving contralateral crossing axons and perhaps also to long-term anatomo-functional network reorganizations which occur in chronic post-lesion conditions in the respiratory and reticulospinal locomotor system (Vinit et al 2008;Ballermann and Fouad 2006).…”

“…To test the hypothesis that c-Jun up-regulation in spared medullary neurons may be related to the functional deficit engendered by the injury (Vinit et al 2008(Vinit et al , 2009a rather than to neuronal damage by itself, we have analyzed the expression of phospho-c-Jun in the rVRG in rats (FG-Phx rats) which have received a section of the left phrenic nerve 1 week before in order to inactivate the ipsilateral diaphragm. In these rats, we did not detect any phosphoc-Jun immunolabeling in the rVRG, suggesting that the lack of respiratory function did not by itself engender c-Jun up-regulation in the rVRG (not shown).…”

“…To label retrogradely neurons with spared axons projecting to the phrenic nucleus area (in FG-C4 rats), the rats received, immediately after the lateral section and after C3-C4 laminectomy and removal of the dura, two injections of FG in the area of the ipsi phrenic nucleus, beneath C3 and C4 dorsal roots, respectively ( Fig. 1a) (Vinit et al 2008). The injections of 0.15 μl each were performed using a 33-gauge internal cannula (C-315 I, Plastics One, Roanoke, VA, USA) connected to a 10-μl Hamilton syringe.…”