Cervical spinal injury compromises caudal spinal tissue oxygenation and undermines acute intermittent hypoxia-induced phrenic long-term facilitation

Abstract

An important model of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic burst amplitude following acute intermittent hypoxia (AIH). Moderate AIH elicits pLTF by a serotonin-dependent mechanism known as the Q pathway to phrenic motor facilitation. In contrast, severe AIH (greater hypoxemia) increases spinal adenosine accumulation and activates phrenic motor neuron adenosine 2A receptors, thereby initiating a distinct mechanism of plasticity known as the S pathway. Since the Q and S pathways interact via mutual cross-talk inhibition, the balance between spinal serotonin release and adenosine accumulation is an important pLTF regulator. Spinal injury decreases spinal tissue oxygen pressure (PtO2) caudal to injury. Since AIH is being explored as a neurotherapeutic to restore breathing ability after cervical spinal injury, we tested the hypothesis that decreased PtO2 in the phrenic motor nucleus after C2 spinal hemisection (C2Hx) undermines moderate AIH-induced pLTF, likely due to shifts in the adenosine/serotonin balance. We recorded C3/4 ventral cervical PtO2 with an optode, and bilateral phrenic nerve activity in anesthetized, paralyzed and ventilated rats, with and without C2Hx. In intact rats, PtO2 was lower during severe versus moderate AIH as expected. In chronic C2Hx rats (> 8 weeks post-injury), PtO2 was lower during baseline and moderate hypoxic episodes, approaching severe AIH levels in intact rats. After C2Hx, pLTF was blunted ipsilateral, but observed contralateral to injury. We conclude that C2Hx compromises PtO2 near the phrenic motor nucleus and undermines pLTF, presumably due to a shift in the serotonin versus adenosine balance during hypoxic episodes. These findings have important implications for optimizing AIH protocols in our efforts to restore breathing ability with therapeutic AIH in people with chronic cervical spinal injury.