Differential spinal tissue oxygen profile during moderate and severe acute intermittent hypoxia

Abstract

Plasticity is a hallmark of the neural system controlling breathing. A frequently studied model of respiratory motor plasticity is phrenic long‐term facilitation (pLTF), a persistent increase in phrenic burst amplitude induced by acute intermittent hypoxia (AIH). Two independent mechanisms underlie pLTF, depending on details of the AIH protocol. For example, moderate AIH (3, 5 min hypoxic episodes of moderate arterial PO2 with 5 min intervals) elicits a form of pLTF that requires intact carotid bodies, raphe neuron spinal serotonin release, and phrenic motor neuron serotonin type 2 receptor activation; this mechanism is known as the Q pathway to phrenic motor facilitation. The same protocol with more severe hypoxic episodes elicits a distinct cellular mechanism known as the S pathway; severe AIH leads to spinal adenosine accumulation and phrenic motor neuron adenosine 2A receptor activation, initiating the S pathway to pLTF. Since these pathways interact via mutual cross‐talk inhibition, intermediate AIH protocols fail to elicit pLTF since the Q and S pathways cancel one another. Thus, the balance of raphe serotonergic neuron activation (fast) versus spinal tissue hypoxia (slower) is a key determinant in regulating pLTF expression. Since the specific levels of spinal tissue hypoxia tipping this balance are not known, we compared spinal tissue oxygen profiles between moderate (PaO2 40 – 50 mmHg) vs severe AIH (PaO2 25 – 30 mmHg). Ventral cervical spinal tissue oxygen pressure (PtO2) and phrenic nerve activity were recorded in anesthetized, paralyzed and ventilated rats (IFO2 = 60%). As reported before, severe AIH elicited greater short‐term hypoxic phrenic responses and pLTF vs moderate AIH. Severe AIH elicited greater decreases in PtO2, reaching a nadir below ~5 mmHg. Following each episode, a transient overshoot in PtO2 was observed, reaching 90 mmHg above baseline conditions. Following the third hypoxic episode, PtO2 remained above baseline for at least 15 minutes post AIH (~ 10 mmHg). With moderate AIH, tissue hypoxia was less severe (PtO2 nadir ~ 16 mmHg), and post‐hypoxia overshoots far less prominent. In summary, spinal tissue oxygen dynamics are complex during AIH protocols; differences in PtO2 profiles likely underlie mechanistic differences in pLTF observed with moderate vs severe AIH. Understanding these dynamics (including the post‐AIH PtO2 “memory”) may help understand how to optimize AIH protocols to maximize plasticity and, potentially, functional benefits when harnessing AIH to restore breathing deficits with neural injury and/or disease.Support or Funding InformationNIH HL147554 and HL148030