The regulation of sleep and wakefulness by the hypothalamic neuropeptide orexin/hypocretin

Abstract

Orexins, also known as hypocretins, are neuropeptides that are exclusively expressed by neurons in the lateral hypothalamic area. Although originally recognized as regulators of feeding behavior, orexins are now mainly regarded as key modulators of the sleep/wakefulness cycle. In addition, anatomical studies of neural networks and analyses of transgenic mice have revealed integrated roles for orexin neurons in the coordination of emotion, energy homeostasis, and the reward system. A functional link between the limbic system and orexin neurons may be important for increasing vigilance in response to emotional stimuli. These findings suggest that orexin neurons relay information about an organism's environment to maintain the proper amount of sleep and wakefulness in animals.

Fig. 1

Schematic representation of orexins and orexin receptors. Prepro-orexin is proteolyzed into two mature neuropeptides, orexin-A and orexin-B. Orexin-A acts on both OX₁R and OX₂R, while orexin-B mainly acts on OX₂R. OX₁R is coupled exclusively to the Gq subclass of G proteins, whereas OX₂R is coupled to either Gi or Gq.

Fig. 2

A schematic diagram illustrating the integrative physiological roles of orexin neurons. Orexin neurons regulate the hypothalamic nuclei involved in feeding behavior. At the same time, they promote wakefulness through monoaminergic nuclei and other sleep-related nuclei in the brain stem. Energy levels influence orexin neuronal activity to coordinate arousal and energy homeostasis. Input from the limbic system may be important for regulating the activity of orexin neurons to evoke emotional arousal or fear-related responses. Abbreviations: 5-HT, serotonin; ACh, Acetylcholine; Arc, arcuate nucleus; BST, bed nucleus of the stria terminalis; DA, dopamine; DR, dorsal raphe nucleus; GABA, gamma-aminobutyric acid; HA, histamine; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; NA, noradrenaline; NPY, neuropeptide Y; POA, preoptic area; POMC, proopiomelanocortin; PPN, pedunculopontine tegmental nucleus; TMN, tuberomammillary nucleus; VTA, ventral tegmental area