Graded Reductions in Oxygenation Evoke Graded Reconfiguration of the Isolated Respiratory Network

Abstract

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 .

Fatal breathing dysfunction in a mouse model of Leigh syndrome

“…KO mice had abnormal responses when exposed to low levels of O 2 or high levels of CO 2 . Although changes in oxygen and pH are thought to be primarily detected in the arterial blood by the carotid bodies (39), the CNS is also sensitive to changes in central levels of O 2 and CO 2 (27,31,40,41). In the absence of carotid bodies, hypoxia still triggers a ventilatory response (42).…”

“…The preBötzinger complex (preBötC) in the ventral medulla is critical for respiratory rhythm generation (25,26) and may play a role in the hypoxic response (27,28). Extracellular recordings of brain stem slices containing the preBötC were obtained from P8-P10 KO mice and their control littermates.…”

Ion Channel Regulation by the LKB1-AMPK Signalling Pathway: The Key to Carotid Body Activation by Hypoxia and Metabolic Homeostasis at the Whole Body Level

“…However, it is now clear that although mitochondrial activities may vary between cell types, their local environment may be a key regulatory factor. Firstly, intracellular O 2 gradients, and possibly ATP gradients, occur at the cellular level (Jones 1986 ) and such gradients may vary between and within tissues due to "local" metabolic activity within multicellular preparations (Hill et al 2011 ) . Moreover, there are tissue-speci fi c differences with respect to mitochondrial function that have been attributed to cell-speci fi c O 2 supply, substrate availability and other intracellular variables (including ADP and ATP demand), which may modulate many aspects of mitochondrial function including the af fi nity of cytochrome c oxidase for O 2 (Gnaiger et al 1998 ;Cooper and Brown 2008 ;Brown 1992 ) .…”

“…However, the question of how type I cells sense and respond to hypoxia remains a contentious issue (Peng et al 2010 ;Peers et al 2010 ;Evans et al 2011 ;Chandel 2010 ) . The mechanism is likely common to all O 2 −sensing cells, including carotid body type I cells, pulmonary arterial smooth muscle and endothelial cells, neonatal adrenomedullary chromaf fi n cells and specialised neurons of the respiratory network within the brainstem; all of which have been de fi ned by their acute sensitivity to "activation" by graded changes in p O 2 lying within the physiological range (Eyzaguirre and Koyano 1965a ;Hill et al 2011 ;Dipp and Evans 2001 ;Thompson et al 1997 ) .…”

Modulation of network pacemaker neurons by oxygen at the anaerobic threshold

“…In superfused brain slices, there is a steep gradient in PO 2 from the surface to the core of the slice (Jiang et al 1991;Mulkey et al 2001;Hill et al 2011), such that the majority of the superficial slice tissue may be hyperoxic, while the core may remain hypoxic, particularly in thick slices. Although the use of arterially perfused brain preparations potentially could ameliorate this problem, normal physiological PO 2 levels are usually not used in such experiments (Paton 1996;Wilson et al 2001).…”