Intermittent Hypoxia Enhances Connectivity between Cervical Spinal Interneurons

Abstract

Intermittent hypoxia is a potent initiator of spinal plasticity and a promising rehabilitative modality to enhance respiratory and non‐respiratory motor function in certain cases of neurologic dysfunction. Current models of intermittent hypoxia‐induced spinal plasticity have focused exclusively on motoneurons, and nothing is known about how cervical spinal interneurons are impacted by intermittent hypoxia. Prior work has established that most cervical spinal interneurons alter discharge rates during acute hypoxia, and that some spinal interneurons are synaptically coupled with phrenic motoneurons. We hypothesize that acute intermittent hypoxia triggers “network level” spinal plasticity which manifests as an increase in the prevalence of temporally related discharge of spinal interneurons. To test this hypothesis, bilateral phrenic motor output was recorded in N=12 anesthetized and ventilated adult rats and a 16‐channel multi‐electrode array was used to record mid‐cervical neuron activity during and following three, 5‐min episodes of hypoxia (11% O2). To evaluate “functional connectivity” among spinal interneurons, cross‐correlation histograms were constructed for all possible pairs of simultaneously recorded neurons. A positive correlogram “peak” > 3 stdev above the mean was taken to indicate an excitatory connection. The current analysis focused on post‐hypoxia discharge, and data were included for 319 neuronal pairs in which a correlogram peak was detected during any post‐hypoxia period. A correlogram peak was present in 24% of neuronal pairs during the pre‐hypoxia baseline. This value tended to increase during hypoxia (Hypoxia‐1: 34%; Hypoxia‐2: 30%; Hypoxia‐3: 34%), but this did not reach statistical significance (all P>0.05 vs. baseline). In contrast, the number of excitatory connections, as reflected by positive correlogram peaks, were significantly increased following each bout of hypoxia (Hypoxia‐1: 60%; Hypoxia‐2: 53%; Hypoxia‐3: 50%) (all P<0.05 vs. baseline). This is the first demonstration that intermittent hypoxia alters the connectivity of spinal networks and we therefore conclude that the spinal impact of intermittent hypoxia extends beyond phrenic motoneurons. These data support the hypothesis that neuroplasticity in spinal networks contributes to sustained changes in respiratory and/or autonomic output following intermittent hypoxia.Support or Funding InformationNIH: 1F32NS095620‐01 (KS); 1R01NS080180‐01A1 (DF); and T32‐ND043730 (MS). Department of Defense W81XWH‐14‐1‐0625 (PR).