Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis

The finding of orexin (hypocretin) deficiency in patients with narcolepsy suggests that this hypothalamic neuropeptide plays a crucial role in regulating and maintaining sleep/wakefulness states and energy homeostasis. Orexin might be especially important for stabilization of behavioral states, because the major symptom in narcolepsy is instability of each behavioral state, which results in sleep/wakefulness fragmentation. The efferent and afferent systems of orexin neurons suggest interactions between these cells and arousal/sleep-wakefulness centers in the brainstem as well as important feeding centers in the hypothalamus. Electrophysiological studies have shown that orexin neurons are regulated by monoamines and acetylcholine as well as metabolic cues, including leptin, glucose, and ghrelin. Thus, orexin neurons have the requisite functional interactions with hypothalamic feeding pathways and monoaminergic/cholinergic centers, and provide a critical link between peripheral energy balance and the central mechanisms that coordinate sleep/wakefulness and motivated behavior such as food seeking.