Repetitive Intermittent Hypoxia Induces Respiratory and Somatic Motor Recovery after Chronic Cervical Spinal Injury

Abstract

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.

A Murine Model of Cervical Spinal Cord Injury to Study Post-lesional Respiratory Neuroplasticity

“…Thus, the endpoint of the model is a weight drop of 30% of the initial body weight in a week. Approximately one week post-surgery, the animals slowly recover a partial locomotion allowing them the ability to feed themselves and regain weight (see Lovett-Bar et al 24 for the locomotor recovery study).…”

“…The spinal structural changes (implication of substitutive pathways 34 and the involvement of spinal interneurons 8 ) or the ultrastructural changes at the diaphragm motor end plate 4 also actively participate in the spontaneous restoration of the respiratory activity following a C2 SCI. The most studied topic on the C2 SCI model is the physiological consequences of the initial injury on the entire respiratory system (Tidal volume, frequency in non-anesthetized animals 24 ) and its subsequent spontaneous recovery (on anesthetized preparations i.e. phrenic nerve activity 17 , diaphragm activity 16,17 and more recently, the intercostal activity 35 ).…”

“…phrenic nerve activity 17 , diaphragm activity 16,17 and more recently, the intercostal activity 35 ). This C2 SCI murine model has also been used to study hindlimb impairment and the subsequent spontaneous recovery and induced recovery following a non-invasive strategy (Intermittent hypoxias 24 ).…”

Intermittent Hypoxia-Induced Spinal Inflammation Impairs Respiratory Motor Plasticity by a Spinal p38 MAP Kinase-Dependent Mechanism

“…Separate rats were injected intrapleurally with cholera toxin b subunit bilaterally (25 g/side; Calbiochem) to retrogradely label phrenic motoneurons (Mantilla et al, 2009;Guenther et al, 2010;Dale-Nagle et al, 2011;Golder et al, 2011;Dale et al, 2012;Lovett-Barr et al, 2012). Three days later, rats were exposed to IH-1 (n ϭ 6) or normoxia (n ϭ 6) and then transcardially perfused (16 h after IH-1) with cold PBS (0.01 M, pH 7.4; Thermo Fisher Scientific) followed by 4% paraformaldehyde (PFA; Thermo Fisher Scientific).…”

Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset

“…Given that the progressive RGC injury occurring in glaucoma is characterized by a multifactorial pathology putatively involving a host of excitotoxic, inflammatory, immune, vascular, biomechanical, and other factors [58][59][60], and that the mechanisms dictating RGC soma and RGC axon loss may be quite distinct [61][62][63], the epigenetic changes induced by RH-Post will likely be extensive in order to account for the magnitude of the protection achieved. It is also worth noting that, although exposures to intermittent systemic hypoxia may not ultimately be adopted as a clinical treatment for glaucoma patients, this very stimulus has established a strong record for protection against a variety of acute and chronic diseases in the CNS [27][28][29][30][64][65][66][67], and other tissues [68][69][70], and may not be easily mimicked by a pharmacologic, monotherapy approach.…”