Orexin neurons track temporal features of blood glucose in behaving mice

Does the brain track how fast our blood glucose is changing? Knowing such a rate of change would enable the prediction of an upcoming state and a timelier response to this new state. Hypothalamic arousal-orchestrating hypocretin/orexin neurons (HONs) have been proposed to be glucose sensors, yet whether they track glucose concentration (proportional tracking) or rate of change (derivative tracking) is unknown. Using simultaneous recordings of HONs and blood glucose in behaving male mice, we found that maximal HON responses occur in considerable temporal anticipation (minutes) of glucose peaks due to derivative tracking. Analysis of >900 individual HONs revealed glucose tracking in most HONs (98%), with derivative and proportional trackers working in parallel, and many (65%) HONs multiplexed glucose and locomotion information. Finally, we found that HON activity is important for glucose-evoked locomotor suppression. These findings reveal a temporal dimension of brain glucose sensing and link neurobiological and algorithmic views of blood glucose perception in the brain's arousal orchestrators.