The interrelation of neuronal function and oxidative metabolism of the brain is most incisively studied by optical techniques in vivo. When O2 becomes limited the respiratory chain becomes reduced, extracellular potassium activity is increased, the EEG is depressed and excitability declines, all as expected. Under mildly hyperoxic conditions however, the opposite responses occur, which indicate an absence of a critical tissue Po2 and a continuum of dependence on the O2 concentration, including levels well above the limits for maximal activity of the respiratory chain in isolated mitochondria in vivo. The unexpectedly high steady state of reduction of cytochrome a, a3 provides the basis for a new hypothesis of an extra energy conservation site between cytochrome a3 and O2 and leads to a consideration of a reaction mechanism of O2 with four electrons and four H+ ions occurring at an enzymically active centre of cytochrome a, a3. A special function of the cytochrome a, a3 complex is implied in regulating cellular K+ transport and thus excitability.