Prolonged acute intermittent hypoxia improves forelimb reach-to-grasp function in a rat model of chronic cervical spinal cord injury.

Repetitive acute intermittent hypoxia (AIH - brief, episodes of low inspired oxygen) elicits spinal motor plasticity, resulting in sustained improvements of respiratory and non-respiratory motor function in both animal models and humans with chronic spinal cord injury (SCI). We previously demonstrated that 7 days of AIH combined with task-specific training improves performance on a skilled locomotor task for at least 3 weeks post-treatment in rats with incomplete SCI. Here we investigated the effect of repetitive AIH administered for 12 wks on a forelimb reach-to-grasp task in a rat model of chronic, incomplete cervical SCI. In a replicated, sham-controlled, randomized and blinded study, male Spraque-Dawley rats were subject to partial hemisection at the 3rd cervical spinal segment, and exposed to daily AIH (10, 5 min episodes of 11% inspired O2; 5 min intervals of 21% O2) or sham normoxia (continuous 21% O2) for 7 days beginning 8 weeks post-injury. Treatments were then reduced to 4 daily treatments per week, and continued for 11 weeks. Performance on 2 pre-conditioned motor tasks, single pellet reaching and horizontal ladder walking, was recorded each week for up to 12 weeks after initiating treatment; performance on spontaneous adhesive removal was also tested. SCI significantly impaired reach-to-grasp task performance 8 weeks post-injury (pre-treatment). Daily AIH improved reaching success by the first week of treatment versus sham controls, and this difference was maintained at 12 weeks (p < 0.0001). Daily AIH did not affect step asymmetry or stride length during ladder walking or adhesive removal time. Thus, prolonged AIH combined with task-specific training improved forelimb reach-to-grasp function in rats with a chronic cervical hemisection, but not off-target motor tasks. This study further supports the idea that daily AIH improves limb function when combined with task-specific training.

Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression.

One of the most promising approaches to improve recovery after spinal cord injury (SCI) is the augmentation of spontaneously occurring plasticity in uninjured neural pathways. Acute intermittent hypoxia (AIH, brief exposures to reduced O2 levels alternating with normal O2 levels) initiates plasticity in respiratory systems and has been shown to improve recovery in respiratory and non-respiratory spinal systems after SCI in experimental animals and humans. Although the mechanism by which AIH elicits its effects after SCI are not well understood, AIH is known to alter protein expression in spinal neurons in uninjured animals. Here, we examine hypoxia- and plasticity-related protein expression using immunofluorescence in spinal neurons in SCI rats that were treated with AIH combined with motor training, a protocol which has been demonstrated to improve recovery of forelimb function in this lesion model. Specifically, we assessed protein expression in spinal neurons from animals with incomplete cervical SCI which were exposed to AIH treatment + motor training either for 1 or 7 days. AIH treatment consisted of 10 episodes of AIH: (5 min 11% O2: 5 min 21% O2) for 7 days beginning at 4 weeks post-SCI. Both 1 or 7 days of AIH treatment + motor training resulted in significantly increased expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) relative to normoxia-treated controls, in neurons both proximal (cervical) and remote (lumbar) to the SCI. All other markers examined were significantly elevated in the 7 day AIH + motor training group only, at both cervical and lumbar levels. These markers included vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and phosphorylated and nonphosphorylated forms of the BDNF receptor tropomyosin-related kinase B (TrkB). In summary, AIH induces plasticity at the cellular level after SCI by altering the expression of major plasticity- and hypoxia-related proteins at spinal regions proximal and remote to the SCI. These changes occur under the same AIH protocol which resulted in recovery of limb function in this animal model. Thus AIH, which induces plasticity in spinal circuitry, could also be an effective therapy to restore motor function after nervous system injury.