Enhanced phrenic motor neuron BDNF expression elicited by daily acute intermittent hypoxia is undermined in rats with chronic cervical spinal cord injury

Abstract

Acute intermittent hypoxia (AIH) elicits spinal neuroplasticity and is emerging as a potential therapeutic modality to improve respiratory and non-respiratory motor function in people with chronic incomplete spinal cord injury (SCI). Brain-derived neurotrophic factor (BDNF) is necessary and sufficient for moderate AIH-induced phrenic long-term facilitation, a well-studied form of respiratory motor plasticity. Repetitive daily AIH (dAIH) enhances BDNF expression within the phrenic motor neurons of normal rats, but its effects on BDNF after chronic cervical spinal cord injury (cSCI) are unknown. In contrast to AIH, chronic intermittent hypoxia (CIH), simulating that experienced during sleep apnea, elicits neuropathology and undermines plasticity. Here, we tested the hypothesis that daily AIH vs CIH differentially regulate phrenic motor neuron BDNF expression in spinally intact and injured rats. Rats with and without C2 hemisection (C2Hx; 8 weeks post-injury) were exposed to 28 days of: 1) sham normoxia (Nx, 21 % O₂); 2) daily AIH (dAIH: 10, 5 min episodes of 10.5 % O₂ per day; 5 min normoxic intervals); 3) mild CIH (CIH5/5: 5 min of 10.5 % O₂, 5 min intervals, 8 hrs/day); or 4) moderate CIH (CIH2/2: 2 min of 10.5 % O₂, 2 min intervals, 8 hrs/day). After 28 days of daily exposure (i.e., 12 weeks post-injury), BDNF immunoreactivity was assessed within phrenic motor neurons identified via retrograde cholera toxin B fragment labeling. In intact rats, daily AIH increased BDNF protein levels in phrenic motor neurons (∼31 %) but not in rats with C2Hx. CIH had no effects on phrenic motor neuron BDNF levels in intact rats, although there was a trend towards increased phrenic motor neuron BDNF after C2Hx, suggesting the need for further study. Since dAIH effects on phrenic motor neuron BDNF are not observed in rats with chronic cervical SCI, the potential of dAIH to enhance BDNF-dependent phrenic motor plasticity may be suppressed by conditions prevailing with chronic cSCI.