Inactivity‐Induced Phrenic Motor Facilitation underlies Spontaneous Recovery of Ventilation and Diaphragm EMG activity Following Cervical Spinal Injury

Abstract

Cervical spinal injury disrupts neural pathways to phrenic motor neurons, thereby causing diaphragm paresis and paralysis and diminished breathing capacity. Some spontaneous functional recovery in the capacity to generate phrenic nerve or diaphragm activity is observed days‐to‐months post‐injury via mechanisms that not understood. We have previously found that prolonged reductions in spinal synaptic inputs to phrenic motor neurons in uninjured rats results in a PKCz‐dependent, rebound enhancement of phrenic burst amplitude, a form of spinal plasticity known as inactivity‐induced phrenic motor facilitation (iPMF). Little is known regarding the role for iPMF in the control of breathing. Here, we tested the hypothesis that mechanisms giving rise to iPMF underlie spontaneous recovery of ventilation and diaphragm EMG activity following a high cervical spinal injury. Sprague Dawley rats (Harlan colony 217, 12–16 weeks old) chronically instrumented with radiotelemetry for bilateral diaphragm electromyogram (EMG) recordings received small interfering RNAs directed against PKCz or non‐targeting siRNAs in the interpleural space (100pg/side) three days prior to a C3 midline contusion. Three days following contusion, EMG and plethysmography were recorded in unanesthetized rats breathing room air (FIO2/FICO2=0.21/0.0, NX) or with maximal chemoreceptor stimulation (FIO2/FICO2= 0.105/0.07, MCS). In injured rats receiving control injections, tidal volume under both inspired gas concentrations and diaphragm EMG during MCS showed minimal change from baseline conditions (TV NX: 99%, TV MCS: 90%, diaphragm EMG right: 95%, left: 100%). By contrast, in injured rats receiving siPKCz, tidal volume during normoxia and MCS (63% NX, 90% MCS) and electrical activity of the diaphragm during MCS (right: 85%, left: 80%) were reduced from pre‐injury levels, suggesting that impairment of iPMF prevented spontaneous recovery of phrenic motor output (and hence, diaphragm EMG activity) following spinal injury. Thus, we speculate that iPMF is a form of compensatory plasticity that senses and responds to reductions in spinal synaptic inputs to phrenic motor neurons to maintain stable phrenic motor output following spinal injury.Support or Funding InformationSupported by NIH R01‐HL105511, DoD SC120226 and NIH T32‐OD010423‐09