Orexin cells efficiently decode blood glucose dynamics to drive adaptive behavior

Abstract

The brain needs to track body energy state to optimize physiology and behavior. Important information about current and future energy states is contained in minute-to-minute fluctuations in blood glucose. However, it is unclear whether brain glucose sensors are capable of responding to this temporal structure to extract such information. In behaving mammals, hypothalamic hypocretin/orexin neurons (HONs) control arousal and are proposed to sense energy balance, yet recent studies show that HON activity varies rapidly (over seconds) with locomotion. It remains unknown if and how HONs reflect blood glucose fluctuations. Here, for the first time, we co-monitored HON activity and blood glucose in behaving mice, uncovering inhibition of HONs by rising blood glucose. Surprisingly, peak HON signals (population waves) anticipated peak glucose deviations by several minutes. In multivariate analysis of diverse HON activity correlates (locomotion, metabolic variables), the glucose temporal gradient (negative first derivative) emerged as prime predictor of HON population activity on the minute timescales, thereby explaining this anticipatory response. Furthermore, 2-photon imaging of >900 individual HONs revealed parallel communication of absolute blood glucose values and their derivatives in distinct HON subsets. Thus, HONs transmit multiplexed slowly and rapidly changing information, and, in the slow bandwidth, extract temporal features from blood glucose dynamics that suggest a hybrid of anticipatory and proportional logic in brain responses to blood glucose.

Eat, seek, rest? An orexin/hypocretin perspective

“…The intragastric infusions were performed via an implanted catheter, for precise control over volume and composition of ingested nutrients, and to avoid any caveats from oral taste receptors that may activate HONs. In the fast frequency domain (seconds), HON activity of behaving mice was dominated by rapid behaviours such as running, as expected from previous data and from the brain‐wide direct neural inputs to HONs 10,49,55,59,88 . However, in the slower frequency domain (minutes), HONs displayed differential responses to some of the intragastrically administered nutrients.…”

“…While functional subpopulations of HONs most likely exist, 45,57,58 multiphoton imaging of 1000s of HONs in vivo indicates that rapid dynamics of HONs in vivo is typical of most, if not all, HONs, though not all HONs (in)activate together and some do so in antiphase with each other 55,59,60 . Furthermore, optogenetic evidence implies that this HON activity contributes to the initiation of locomotion.…”

“…Thus, HONs have direct access to these nutrients, which in theory can be used for direct sensing. The ability of HONs to distinguish between ingested nutrients has recently been examined by monitoring HON activity using HON‐targeted cytosolic calcium indicators and fiberoptic fluorescence imaging in behaving mice, in combination with direct intragastric infusions of different dietary macronutrients 59,88 . The intragastric infusions were performed via an implanted catheter, for precise control over volume and composition of ingested nutrients, and to avoid any caveats from oral taste receptors that may activate HONs.…”

“…Intragastric infusions of glucose produced a very different HON response 59 . HONs were rapidly inhibited following the intragastric glucose infusion 59,88 .…”

“…Intragastric infusions of glucose produced a very different HON response 59 . HONs were rapidly inhibited following the intragastric glucose infusion 59,88 . Unlike amino acids, glucose level deviations are rapidly counter‐regulated inside the body.…”