The hypocretins as sensors for metabolism and arousal

Abstract

Sleep disturbances are associated with hormonal imbalances and may result in metabolic disorders including obesity and diabetes. Therefore, circuits controlling both sleep and metabolism are likely to play a role in these physiopathological conditions. The hypocretin (Hcrt) system is a strong candidate for mediating both sleep and metabolic imbalances because Hcrt neurons are sensitive to metabolic hormones, including leptin and ghrelin, and modulate arousal and goal-orientated behaviours. This review discusses the role of Hcrt neurons as a sensors of energy balance and arousal and proposes new ways of probing local hypothalamic circuits regulating sleep and metabolism with unprecedented cellular specificity and temporal resolution.

Figure 1. Hypothalamic circuits regulate energy homeostasis

A, schematic drawing of a coronal section through the entire rat brain showing the lateral hypothalamus (LH) and the zona incerta (ZI) and a magnification of the arcuate nucleus showing neuropeptide Y (NPY)/agouti-related protein (AgRP) and proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons. Peripheral signals (leptin, ghrelin) directly regulate the activity of arcuate nucleus through the median eminence, which lacks a brain blood barrier. Leptin inhibits NPY/AgRP neurons and activates POMC/CART neurons whereas ghrelin has the opposite effect (Abizaid & Horvath, 2008). These neurons project to mutiple brain regions including the lateral hypothalamus where signal is further processed and integrated into coherent feeding behaviour. B, schematic drawing of a saggital section through the rat brain showing the neuroanatomical organization of the Hcrt system. Dots indicate the relative location and abundance of Hcrt-expressing cell bodies. Arrows point out some of the more prominent terminal fields including the (noradrenergic cells of the LC), histaminergic neurons of the posterior hypothalamus, cholinergic cells of the basal forebrain, serotonine-procuding neurons of the raphe and dopaminergic neurons of the VTA. Abbreviations used: Amy, amygdala; Ctx, cortex; Hipp, hippocampus; LC, locus coeruleus; ME, median eminence; OB, olfactory bulb; OT, olfactory tubercule; PP, posterior pituitary; Sp Ch, spinal chord; Th, thalamus; VTA, ventro-tegmental area; LH, lateral hypothalamus; V, 3rd ventricle; ZI, zona incerta.

Figure 2. Hcrt system as a sensor of metabolism

Hcrt neurons are inhibited by leptin and activated by ghrelin and glucose. In addition, they received indirect circadian inputs that are integrated with metabolic signals to modulate sleep and metabolism. Chronic short sleep perturbation induces metabolic changes including lowering leptin levels and increasing ghrelin levels that directly increase the activity of the Hcrt system. This increase in Hcrt activity promotes consummatory behaviours (food, drug), energy expenditure (via higher locomotor activity and metabolic rate) and sleep-to-wake transitions. Consequently, activation of the Hcrt system inhibits sleep and energy conservation. Triggering activity of the Hcrt neuronal circuit by circulating metabolic factors may then result in a positive feedback loop, which worsens existing sleep perturbation symptoms. This positive loop is inhibited by increasing sleep pressure (a consequence of sleep demand) and may result in a stabilization of the sleep–wake cycle. V: 3rd ventricle.

Figure 3. Optical deconstruction of Hypothalamus local circuits

Schematic drawing of a coronal section through the rat showing hypothalamic neuronal populations involved in sleep and metabolism. Hcrt neurons are the targets of projections from multiple brain areas, including NPY/AgRP and POMC/CART neurons of the arcuate nucleus. Although the interplay between hypothalamic nuclei in regulating energy homeostasis remains unclear, NPY/AgRP neurons inhibit Hcrt cells, which in turn activate NPY/AgRP cells and inhibit POMC/CART neurons. Complex hypothalamic circuits can be functionally deconstructed with high temporal and spatial resolution using optogenetics. Genetic targeting of ChR2 or NpHR into defined classes of hypothalamic neurons (e.g. Hcrt as shown in the figure) allow bimodal manipulation of specific circuit activity without inadvertent activation/inhibition of neighbouring cells (e.g. grey neuronal populations as shown in the figure). Combination of optogenetics with imaging of fluorescent calcium sensors (Ca²⁺) or voltage sensitive dyes (VSD) of identified neuronal populations (e.g. NPY/AgRP as shown in the figure) in brain slices will reveal synaptic function and plasticity associated with metabolism and arousal. In addition, bath application of metabolic factors (leptin, ghrelin, glucose), variation of environmental parameters (temperature, pH, CO₂) and the use of animal models for neurological disorders (narcoleptic mice, ob/ob obese mice, etc.) may model pathophysiological conditions.