Glucose-inhibited neurons orchestrate behavior and metabolism according to body energy levels, but how glucose inhibits these cells is unknown. We studied glucose inhibition of orexin/hypocretin neurons, which promote wakefulness (their loss causes narcolepsy) and also regulate metabolism and reward. Here we demonstrate that their inhibition by glucose is mediated by ion channels not previously implicated in central or peripheral glucose sensing: tandem-pore K(+) (K(2P)) channels. Importantly, we show that this electrical mechanism is sufficiently sensitive to encode variations in glucose levels reflecting those occurring physiologically between normal meals. Moreover, we provide evidence that glucose acts at an extracellular site on orexin neurons, and this information is transmitted to the channels by an intracellular intermediary that is not ATP, Ca(2+), or glucose itself. These results reveal an unexpected energy-sensing pathway in neurons that regulate states of consciousness and energy balance.

Hypothalamic orexin/hypocretin neurons recently emerged as key orchestrators of brain states and adaptive behaviors. They are critical for normal stimulation of wakefulness and breathing: Orexin loss causes narcolepsy and compromises vital ventilatory adaptations. However, it is unclear how orexin neurons generate appropriate adjustments in their activity during changes in physiological circumstances. Extracellular levels of acid and CO 2 are fundamental physicochemical signals controlling wakefulness and breathing, but their effects on the firing of orexin neurons are unknown. Here we show that the spontaneous firing rate of identified orexin neurons is profoundly affected by physiological fluctuations in ambient levels of H ؉ and CO2. These responses resemble those of known chemosensory neurons both qualitatively (acidification is excitatory, alkalinization is inhibitory) and quantitatively (Ϸ100% change in firing rate per 0.1 unit change in pH e). Evoked firing of orexin cells is similarly modified by physiologically relevant changes in pHe: Acidification increases intrinsic excitability, whereas alkalinization depresses it. The effects of pHe involve acid-induced closure of leak-like K ؉ channels in the orexin cell membrane. These results suggest a new mechanism of how orexin/hypocretin networks generate homeostatically appropriate firing patterns.arousal ͉ hypocretin ͉ hypothalamus ͉ pH ͉ breathing

Brain glucose sensing is critical for healthy energy balance, but how appropriate neurocircuits encode both small changes and large background values of glucose levels is unknown. Here, we report several features of hypothalamic orexin neurons, cells essential for normal wakefulness and feeding: (i) A distinct group of orexin neurons exhibits only transient inhibitory responses to sustained rises in sugar levels; (ii) this sensing strategy involves time-dependent recovery from inhibition via adaptive closure of leak-like K ؉ channels; (iii) combining transient and sustained glucosensing allows orexin cell firing to maintain sensitivity to small fluctuations in glucose levels while simultaneously encoding a large range of baseline glucose concentrations. These data provide insights into how vital behavioral orchestrators sense key features of the internal environment while sustaining a basic activity tone required for the stability of consciousness.brain ͉ glucose ͉ hypocretin ͉ orexin ͉ hypothalamus T o survive, living organisms need to vary their behavior according to internal energy levels. In mammals, this involves translating the hormone and nutrient content of the extracellular fluid into appropriate combinations of brain states such as hunger, arousal, and motivation (1). This translation critically relies on neurons producing the peptide neurotransmitters orexins/ hypocretins (orexin neurons) (2, 3). Orexin neurons are located in the hypothalamus but innervate most of the brain, with major inputs to arousal and reward centers, where orexins are released and act on two specific G protein coupled receptors (4, 5). The firing of orexin neurons promotes wakefulness (6) and is so important for maintaining normal consciousness that loss of orexin cells causes severe narcolepsy/cataplexy (7,8). Orexins are also a powerful stimulus for reward-seeking behavior, and destruction of orexin neurons prevents fasting from stimulating foraging (9-12). Besides promoting wakefulness and reward-seeking, orexin cells are involved in memory, stress, and cardiovascular control (reviewed in ref. 5).Recent data show that orexin neurons are not only key effectors of vital behaviors but are also specialized sensors of the body's internal environment. In particular, they act as electrical detectors of glucose, a fundamental signal informing the brain of changes in body energy reserves (12-14). Small physiological rises in ambient [glucose] are sufficient to trigger large K ϩ currents in orexin cell bodies, causing hyperpolarization and suppression of action potential firing (15). Presumably, it is this combination of critical ''sensor'' and ''effector'' tasks that makes the orexin system such a prominent link between body energy status and behavior (12). However, this multitasking also poses an unsolved paradox. If orexin cells are shut down by even a small rise in glucose and loss of their activity causes narcolepsy, how is narcolepsy-free consciousness maintained after a meal or during diabetic hyperglycemia? One theoretical solu...

Narcolepsy is characterized by chronic sleepiness and cataplexy - episodes of profound muscle weakness that are often triggered by strong, positive emotions. Narcolepsy with cataplexy is caused by a loss of orexin (also known as hypocretin) signaling, but almost nothing is known about the neural mechanisms through which positive emotions trigger cataplexy. Using orexin knockout mice as a model of narcolepsy, we found that palatable foods, especially chocolate, markedly increased cataplexy and activated neurons in the medial prefrontal cortex (mPFC). Reversible suppression of mPFC activity using an engineered chloride channel substantially reduced cataplexy induced by chocolate but did not affect spontaneous cataplexy. In addition, neurons in the mPFC innervated parts of the amygdala and lateral hypothalamus that contain neurons active during cataplexy, and that innervate brainstem regions known to regulate motor tone. These observations indicate that the mPFC is a critical site through which positive emotions trigger cataplexy.