The lateral hypothalamus (LH) controls energy balance. LH melanin-concentrating-hormone (MCH) and orexin/hypocretin (OH) neurons mediate energy accumulation and expenditure, respectively. MCH cells promote memory and appropriate stimulus-reward associations; their inactivation disrupts energy-optimal behaviour and causes weight loss. However, MCH cell dynamics during wakefulness are unknown, leaving it unclear if they differentially participate in brain activity during sensory processing. By fiberoptic recordings from molecularly defined populations of LH neurons in awake freely moving mice, we show that MCH neurons generate conditional population bursts. This MCH cell activity correlates with novelty exploration, is inhibited by stress and is inversely predicted by OH cell activity. Furthermore, we obtain brain-wide maps of monosynaptic inputs to MCH and OH cells, and demonstrate optogenetically that VGAT neurons in the amygdala and bed nucleus of stria terminalis inhibit MCH cells. These data reveal cell-type-specific LH dynamics during sensory integration, and identify direct neural controllers of MCH neurons.

SummaryIn humans and rodents, loss of brain orexin/hypocretin (OH) neurons causes pathological sleepiness [1, 2, 3, 4], whereas OH hyperactivity is associated with stress and anxiety [5, 6, 7, 8, 9, 10]. OH cell control is thus of considerable interest. OH cells are activated by fasting [11, 12] and proposed to stimulate eating [13]. However, OH cells are also activated by diverse feeding-unrelated stressors [14, 15, 16, 17] and stimulate locomotion and “fight-or-flight” responses [18, 19, 20]. Such OH-mediated behaviors presumably preclude concurrent eating, and loss of OH cells produces obesity, suggesting that OH cells facilitate net energy expenditure rather than energy intake [2, 21, 22, 23]. The relationship between OH cells and eating, therefore, remains unclear. Here we investigated this issue at the level of natural physiological activity of OH cells. First, we monitored eating-associated dynamics of OH cells using fiber photometry in free-feeding mice. OH cell activity decreased within milliseconds after eating onset, and remained in a down state during eating. This OH inactivation occurred with foods of diverse tastes and textures, as well as with calorie-free “food,” in both fed and fasted mice, suggesting that it is driven by the act of eating itself. Second, we probed the implications of natural OH cell signals for eating and weight in a new conditional OH cell-knockout model. Complete OH cell inactivation in adult brain induced a hitherto unrecognized overeating phenotype and caused overweight that was preventable by mild dieting. These results support an inhibitory interplay between OH signals and eating, and demonstrate that OH cell activity is rapidly controllable, across nutritional states, by voluntary action.

OBJECTIVE-Glucose sensing by specialized neurons of the hypothalamus is vital for normal energy balance. In many glucoseactivated neurons, glucose metabolism is considered a critical step in glucose sensing, but whether glucose-inhibited neurons follow the same strategy is unclear. Orexin/hypocretin neurons of the lateral hypothalamus are widely projecting glucoseinhibited cells essential for normal cognitive arousal and feeding behavior. Here, we used different sugars, energy metabolites, and pharmacological tools to explore the glucose-sensing strategy of orexin cells. RESEARCH DESIGN AND METHODS-We carried out patchclamp recordings of the electrical activity of individual orexin neurons unambiguously identified by transgenic expression of green fluorescent protein in mouse brain slices. RESULTS-Weshow that 1) 2-deoxyglucose, a nonmetabolizable glucose analog, mimics the effects of glucose; 2) increasing intracellular energy fuel production with lactate does not reproduce glucose responses; 3) orexin cell glucose sensing is unaffected by glucokinase inhibitors alloxan, D-glucosamine, and N-acetyl-D-glucosamine; and 4) orexin glucosensors detect mannose, D-glucose, and 2-deoxyglucose but not galactose, L-glucose, ␣-methyl-D-glucoside, or fructose. CONCLUSIONS-Our new data suggest that behaviorally critical neurocircuits of the lateral hypothalamus contain glucose detectors that exhibit novel sugar selectivity and can operate independently of glucose metabolism. Diabetes 57:2569-2576, 2008 H ypothalamic neurons maintain body energy balance by sensing energy status and initiating compensatory adjustments in food intake and energy expenditure (1,2). A key signal informing the brain of energy levels is the concentration of extracellular glucose (3,4). Specialized glucose-sensing (glucosensing) hypothalamic neurons respond to changes in ambient glucose levels with increases (glucose-excited neurons) or decreases (glucose-inhibited neurons) in their firing frequency (5,6). These responses are considered critical for orchestrating changes in hormone release, appetite, and food-seeking behavior that control body energy stores and blood glucose levels (4,7,8). Impaired hypothalamic glucosensing can lead to diabetes and obesity (9). It is thus important to understand how glucosensing neurons operate.Until now, most studies examining the link between fluctuations in glucose levels and neuronal electrical activity have focused on glucose-excited neurons. There is now strong evidence that in most of these cells, extracellular glucose is carried into the cytosol by GLUT, phosphorylated by glucokinase, and subsequently metabolized to generate ATP, which closes membrane ATP-sensitive K ϩ channels (K ATP channels) and so electrically excites the cell (7,8,10). In contrast, glucose-inhibited neurons remain much less understood. Although the final effectors mediating glucose-induced inhibition have been recently defined as K ϩ or Cl Ϫ channels (11,12), the nature of glucosensing events upstream of these channels is unclear. There...

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