Hill AA, Garcia AJ 3rd, Zanella S, Upadhyaya R, Ramirez JM. Graded reductions in oxygenation evoke graded reconfiguration of the isolated respiratory network. J Neurophysiol 105: 625-639, 2011. First published November 17, 2010 doi:10.1152/jn.00237.2010. Neurons depend on aerobic metabolism, yet are very sensitive to oxidative stress and, as a consequence, typically operate in a low O 2 environment. The balance between blood flow and metabolic activity, both of which can vary spatially and dynamically, suggests that local O 2 availability markedly influences network output. Yet the understanding of the underlying O 2 -sensing mechanisms is limited. Are network responses regulated by discrete O 2 -sensing mechanisms or, rather, are they the consequence of inherent O 2 sensitivities of mechanisms that generate the network activity? We hypothesized that a broad range of O 2 tensions progressively modulates network activity of the preBötzinger complex (preBötC), a neuronal network critical to the central control of breathing. Rhythmogenesis was measured from the preBötC in transverse neonatal mouse brain stem slices that were exposed to graded reductions in O 2 between 0 and 95% O 2 , producing tissue oxygenation values ranging from 20 Ϯ 18 (mean Ϯ SE) to 440 Ϯ 56 Torr at the slice surface, respectively. The response of the preBötC to graded changes in O 2 is progressive for some metrics and abrupt for others, suggesting that different aspects of the respiratory network have different sensitivities to O 2 .