Although axon regeneration is limited in the central nervous system, partial lesions of the spinal cord induce neuroplasticity processes that can lead to spontaneous functional improvement. To determine whether such compensatory mechanisms occur in the respiratory system, we analyzed the incidence of partial injury of the cervical spinal cord on diaphragm activity in adult rats. We show that a section of the lateral area of the C2 cervical spinal cord induces complete phrenic nerve inactivation and ipsilateral hemidiaphragm paralysis, whereas medial or dorsolateral sections had only a moderate effect on respiratory activity. In the case of lateral hemisection, activity of the ipsilateral phrenic nerve was partially restored after a lapse of 3 months. No spontaneous diaphragm recovery was observed, however, even after a lapse of several months in the case of hemisection or lateral section. Ipsilateral hemidiaphragm activity could however be restored after transection of the contralateral phrenic nerve, by activation of the "crossed phrenic phenomenon" (involving activation of previously latent respiratory contralateral pathways crossing the midline). These data suggest that the respiratory system develops important long-term plasticity processes at the level of phrenic motoneuron innervation. However, they do not by themselves allow substantial diaphragm recovery, underscoring the continued need for developing repair strategies. These studies also validates the use of the respiratory system as a model to evaluate the functional incidence of repair strategies not only after hemisection but also after more limited sectioning restricted to the lateral side of the cervical cord.
After disruption of the descending respiratory pathways induced by unilateral cervical spinal cord injury (SCI) in rats, the inactivated ipsilateral (ipsi) phrenic nerve (PN) discharge may partially recover following some specific experimental procedures [such as contralateral (contra) phrenicotomy (Phx)]. This phrenic reactivation involves normally silent contra pathways decussating at the level of the phrenic nucleus, but the mechanisms of this crossed phrenic activation are still poorly understood. The present study investigates the contribution of sensory phrenic afferents to this process by comparing the acute effects of ipsi and contra Phx. We show that the phrenic discharge (recorded on intact PNs) was almost completely suppressed 0 h and 3 h after a lateral cervical SCI, but was already spontaneously reactivated after 1 week. This ipsi phrenic activity was enhanced immediately after contra Phx and was completely suppressed by an acute contra cervical section, indicating that it is triggered by crossed phrenic pathways located laterally in the contra spinal cord. Ipsi phrenic activity was also abolished immediately after ipsi Phx that interrupts phrenic sensory afferents, an effect prevented by prior acute ablation of the cervical dorsal root ganglia, indicating that crossed phrenic activation depends on excitatory phrenic sensory afferents but also putatively on inhibitory non-phrenic afferents. On the basis of these data, we propose a new model for crossed phrenic activation after partial cervical injury, with an essential role played by ipsi-activating phrenic sensory afferents.
Spinal cord injury (SCI) triggers a complex cellular response at the injury site, leading to the formation of a dense scar tissue. Despite this local tissue remodeling, the consequences of SCI at the cellular level in distant rostral sites (i.e., brain), remain unknown. In this study, we asked whether cervical SCI could alter cell dynamics in neurogenic areas of the adult rat forebrain. To this aim, we quantified BrdU incorporation and determined the phenotypes of newly generated cells (neurons, astrocytes, or microglia) during the subchronic and chronic phases of injury. We find that subchronic SCI leads to a reduction of BrdU incorporation and neurogenesis in the olfactory bulb and in the hippocampal dentate gyrus. By contrast, subchronic SCI triggers an increased BrdU incorporation in the dorsal vagal complex of the hindbrain, where most of the newly generated cells are identified as microglia. In chronic condition 90 days after SCI, BrdU incorporation returns to control levels in all regions examined, except in the hippocampus, where SCI produces a long-term reduction of neurogenesis, indicating that this structure is particularly sensitive to SCI. Finally, we observe that SCI triggers an acute inflammatory response in all brain regions examined, as well as a hippocampal-specific decline in BDNF levels. This study provides the first demonstration that forebrain neurogenesis is vulnerable to a distal SCI.
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