Intermittent hypoxia induces spinal plasticity in rats with cervical spinal cord injury

Abstract

Many experimental therapies have been used in the search for effective approaches to improve recovery after spinal cord injury (SCI). One of the most promising approaches 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) elicits plasticity in respiratory and non-respiratory spinal systems in experimental animals. AIH treatment has also been shown to improve walking abilities in persons with chronic incomplete SCI. In this thesis, I first examined the effect of AIH treatment, alone or in combination with motor training, on functional recovery in a rat model of incomplete cervical SCI. Second, I examined the effect of AIH on the expression of plasticity- and hypoxia-related proteins in the spinal cords of SCI rats. In a randomized, blinded, normoxia-controlled study, rats were trained to cross a horizontal ladder and footslip errors were measured before surgery for SCI, 4 wks post-surgery, each day of daily AIH treatment, and 1, 2, 4 and 8 weeks after treatment. dAIH treatment consisted of 10 episodes of AIH: (5 min 11% O2: 5 min 21% O2) for 7 days beginning at 4 wks post-SCI. AIH-treated rats made fewer footslips on the ladder task compared to normoxia-treated control rats after 4 days of treatment and this improvement was sustained for 8 wks post-treatment. Importantly, daily ladder training was required for AIH treatment to facilitate recovery. AIH treatment + motor training also increased the expression of Hypoxia-inducible factor-1α (HIF-1α), Vascular endothelial growth factor (VEGF), Brain-derived neurotrophic factor (BDNF), tyrosine kinase B receptors (trkB) and phospho-trkB in spinal motor neurons in SCI rats compared to normoxia-treated SCI rats. In particular these hypoxia- and plasticity-related proteins were differentially expressed both temporally and spatially in the spinal cord during AIH treatment. These findings demonstrate that AIH + motor training can augment neural plasticity and improve motor recovery in an animal model of SCI. Taken together with the promising findings from human SCI studies, the results of this thesis suggest that AIH has potential as an effective therapy to restore motor function after nervous system injury.