Spinal injury disrupts connections between the brain and spinal cord, causing life-long paralysis. Most spinal injuries are incomplete, leaving spared neural pathways to motor neurons that initiate and coordinate movement. One therapeutic strategy to induce functional motor recovery is to harness plasticity in these spared neural pathways. Chronic intermittent hypoxia (CIH) (72 episodes per night, 7 nights) increases synaptic strength in crossed spinal synaptic pathways to phrenic motoneurons below a C2 spinal hemisection. However, CIH also causes morbidity (e.g., high blood pressure, hippocampal apoptosis), rendering it unsuitable as a therapeutic approach to chronic spinal injury. Less severe protocols of repetitive acute intermittent hypoxia may elicit plasticity without associated morbidity. Here we demonstrate that daily acute intermittent hypoxia (dAIH; 10 episodes per day, 7 d) induces motor plasticity in respiratory and nonrespiratory motor behaviors without evidence for associated morbidity. dAIH induces plasticity in spared, spinal pathways to respiratory and nonrespiratory motor neurons, improving respiratory and nonrespiratory (forelimb) motor function in rats with chronic cervical injuries. Functional improvements were persistent and were mirrored by neurochemical changes in proteins that contribute to respiratory motor plasticity after intermittent hypoxia (BDNF and TrkB) within both respiratory and nonrespiratory motor nuclei. Collectively, these studies demonstrate that repetitive acute intermittent hypoxia may be an effective and non-invasive means of improving function in multiple motor systems after chronic spinal injury.

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.

Although systemic inflammation occurs in most pathological conditions that challenge the neural control of breathing, little is known concerning the impact of inflammation on respiratory motor plasticity. Here, we tested the hypothesis that low-grade systemic inflammation induced by lipopolysaccharide (LPS, 100 μg/kg ip; 3 and 24 h postinjection) elicits spinal inflammatory gene expression and attenuates a form of spinal, respiratory motor plasticity: phrenic long-term facilitation (pLTF) induced by acute intermittent hypoxia (AIH; 3, 5 min hypoxic episodes, 5 min intervals). pLTF was abolished 3 h (vehicle control: 67.1 ± 27.9% baseline; LPS: 3.7 ± 4.2%) and 24 h post-LPS injection (vehicle: 58.3 ± 17.1% baseline; LPS: 3.5 ± 4.3%). Pretreatment with the nonsteroidal anti-inflammatory drug ketoprofen (12.5 mg/kg ip) restored pLTF 24 h post-LPS (55.1 ± 12.3%). LPS increased inflammatory gene expression in the spleen and cervical spinal cord (homogenates and isolated microglia) 3 h postinjection; however, all molecules assessed had returned to baseline by 24 h postinjection. At 3 h post-LPS, cervical spinal iNOS and COX-2 mRNA were differentially increased in microglia and homogenates, suggesting differential contributions from spinal cells. Thus LPS-induced systemic inflammation impairs AIH-induced pLTF, even after measured inflammatory genes returned to normal. Since ketoprofen restores pLTF even without detectable inflammatory gene expression, “downstream” inflammatory molecules most likely impair pLTF. These findings have important implications for many disease states where acute systemic inflammation may undermine the capacity for compensatory respiratory plasticity.