Figure 1.

Hypotheses providing the rationale for experimental design. A, The cumulative stimulus driving pMF mechanisms during hypoxic exposures increases, depending on pattern (sustained > intermittent) and severity (severe > moderate) of hypoxia. Hypoxia causes the following: (1) adenosine accumulation and activation of spinal A_2A receptors, which we illustrate here as increasing with hypoxia “intensity” (solid line); and (2) serotonin (5-HT) release from descending raphe neurons, which reaches a maximum during mASH, with fixed serotonin receptor activation during sAIH and sASH (dashed line). pMF is not observed with mASH because both mechanisms are equal and offsetting due to balanced cross talk inhibition. Overall pMF expression may depend on the relative activation of A_2A versus 5-HT receptors during hypoxia. B, Representative phrenic nerve trace demonstrating experimental protocol. During phrenic nerve recordings, intrathecal drug injections are delivered 12–20 min before exposure to 25 min of mASH or sASH. pMF is observed 60 min after mASH or sASH. C, Experimental conditions are listed for clarification.