Brain oxygen responses induced by arousing stimuli and fentanyl: generalized or structure-specific?

Brain oxygen levels fluctuate with changes in neural activity and systemic physiology, yet it remains unclear whether oxygen responses to salient stimuli are structure-specific or reflect generalized brain activation. Using oxygen sensors coupled with high-speed amperometry in freely moving rats, we compared oxygen dynamics in three structures with markedly different neuronal firing properties: nucleus accumbens, medial thalamus, and substantia nigra pars reticulata, along with simultaneous measurements in the subcutaneous space. Natural arousing stimuli produced rapid oxygen increases in all brain sites coupled with robust subcutaneous oxygen decreases, though there are minor differences in magnitude. In contrast, intravenous fentanyl (30 µg/kg) induced uniform hypoxic responses in all brain sites, consisting of a rapid and strong decrease followed by a weaker posthypoxic rebound, with low between-site variability. These findings show that physiological oxygen increases during arousal are largely generalized and likely dominated by systemic mechanisms such as peripheral vasoconstriction, cerebral vasodilation, and global increases in cerebral blood flow, whereas fentanyl-induced hypoxia reflects purely systemic effects induced by respiratory depression. Overall, these results indicate that brain oxygen dynamics are shaped predominantly by systemic physiology rather than local neuronal firing properties, highlighting important constraints on interpreting oxygen-based signals as markers of neuronal activity.NEW & NOTEWORTHY Brain oxygenation is often used to infer local neuronal activity, but the extent to which it reflects local versus brain-wide processes remains unclear. By comparing oxygen dynamics across several brain regions and peripheral tissue in awake rats, we found that arousing stimuli evoke similar brain oxygenation increases dominated by systemic physiological mechanisms. In contrast, fentanyl induces uniform hypoxia reflecting respiratory depression. These findings show brain oxygenation largely reflects systemic states rather than local neuronal firing.