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Repetitive acute intermittent hypoxia (rAIH) increases growth/trophic factor expression in respiratory motor neurons, thereby eliciting spinal respiratory motor plasticity and/or neuroprotection. Here we demonstrate that rAIH effects are not unique to respiratory motor neurons, but are also expressed in non-respiratory, spinal alpha motor neurons and upper motor neurons of the motor cortex. In specific, we used immunohistochemistry and immunofluorescence to assess growth/trophic factor protein expression in spinal sections from rats exposed to AIH three times per week for 10 weeks (3 × wAIH). 3 × wAIH increased brain-derived neurotrophic factor (BDNF), its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and phosphorylated TrkB (pTrkB) immunoreactivity in putative alpha motor neurons of spinal cervical 7 (C7) and lumbar 3 (L3) segments, as well as in upper motor neurons of the primary motor cortex (M1). 3 × wAIH also increased immunoreactivity of vascular endothelial growth factor A (VEGFA), the high-affinity VEGFA receptor (VEGFR-2) and an important VEGF gene regulator, hypoxia-inducible factor-1α (HIF-1α). Thus, rAIH effects on growth/trophic factors are characteristic of non-respiratory as well as respiratory motor neurons. rAIH may be a useful tool in the treatment of disorders causing paralysis, such as spinal injury and motor neuron disease, as a pretreatment to enhance motor neuron survival during disease, or as preconditioning for cell-transplant therapies.

We tested the hypotheses that: 1) long-term facilitation (LTF) following acute intermittent hypoxia (AIH) varies among three inbred rat strains: Fischer 344 (F344), Brown Norway (BN) and Lewis rats, and 2) ventral cervical spinal levels of genes important for phrenic LTF (pLTF) vary in association with pLTF magnitude. Lewis and F344, but not BN rats exhibited significant increases in phrenic and hypoglossal burst amplitude 60 min post-AIH that were significantly greater than control experiments without AIH, indicating strain differences in phrenic (98%, 56% and 20%, respectively) and hypoglossal LTF (66%, 77% and 5%, respectively). Ventral spinal 5-HT2A receptor mRNA and protein levels were higher in F344 and Lewis versus BN, suggesting that higher 5-HT2A receptor levels are associated with greater pLTF. More complex relationships were found for 5-HT7, BDNF and TrkB mRNA. BN had higher 5-HT7 and TrkB mRNA versus F344; BN and Lewis had higher BDNF mRNA levels versus F344. Genetic variations in serotonergic function may underlie strain differences in AIH-induced pLTF.

Repetitive acute intermittent hypoxia (AIH) elicits respiratory motor plasticity and increases growth/trophic factor expression in respiratory motor neurons (Satriotomo et al., 2007; Dale et al., 2007). Here, we tested the hypothesis that repetitive AIH similarly affects neurons involved in non‐respiratory motor behaviors. Growth/trophic factor protein levels were examined via immunofluorescence in sections from perfused rats exposed to thrice weekly AIH (3xwAIH; 10 episodes,10.5% O2, 5 min duration, 5 min interval, 3x per week, 10 weeks). Upper motor‐neurons of primary and secondary motor cortex (M1‐M2) and alpha motor neurons in the cervical (C7) and lumbar (L3‐4) ventral horns were investigated. Compared to sham rats, neurons in all three areas exhibited increased expression of: 1) brain derived neurotrophic factor (BDNF) and its high affinity receptor (TrkB); 2) vascular endothelial growth factor (VEGF) and VEGF receptor‐2; and 3) an important VEGF gene regulator, hypoxia‐inducible factor‐1α. Thus, 3xwAIH regulates endogenous levels of important growth/trophic factors critical for motor neuron survival and plasticity, even in regions of the CNS associated with somatic (versus respiratory) motor control. 3xwAIH may be a useful tool in the treatment of disorders leading to partial paralysis, including spinal injury and motor neuron disease.(NIH HL080209 and NS057778).

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