A neuron-glia circuit anticipates hypoxia to regulate organismal oxygen use

Organisms must regulate metabolic resources such as oxygen (O₂) and nutrients despite environmental variability and the energetic costs of their own actions^1-3. Such regulation can occur reactively, through homeostatic corrections of recent imbalances, or predictively, through allostatic adjustments that anticipate future demand^4,5. Predictive regulation is particularly important because metabolic resources often continue to be consumed for seconds to minutes after motor actions cease as tissues repay incurred costs, making it advantageous to prevent depletion before it occurs⁶. However, the cellular and circuit mechanisms for allostatic control remain largely unknown^5,7,8. Using whole-brain neuronal and astroglial imaging and O₂ measurements in behaving zebrafish, we identified a noradrenergic-astroglial circuit that detects, anticipates, and prevents internal O₂ depletion. We found that swimming exacerbated internal hypoxia with a multi-second delay, but behavioral adaptations occurred before such selfgenerated hypoxia manifested, suggesting predictive control, confirmed using computational modeling. Noradrenergic neurons in the nucleus of the solitary tract directly detected brain hypoxia and received efference copies of swimming actions; these inputs summed at the level of membrane voltage to increase spiking and norepinephrine release when actions and resource scarcity co-occurred. Astroglia integrated noradrenergic input into prolonged Ca²⁺ elevation that tracked the O₂ cost of recent actions and thereby predicted O₂ debt relative to O₂ availability, rising ~8 s before O₂ fell. This astroglial prediction reorganized brain-wide activity to suppress locomotion and promote respiration, preempting O₂ depletion. Silencing noradrenergic neurons or astroglial signaling abolished these hypoxia coping behaviors, whereas selective activation evoked them. This neuronal-astroglial mechanism constitutes a predictive control system that integrates physiological state with behavioral intent to avert metabolic crisis, revealing a cellular substrate for proactive energy management.