Abstract
The hypothalamus monitors body homeostasis and regulates various behaviors such as feeding, thermogenesis, and sleeping. Orexins (also known as hypocretins) were identified as endogenous ligands for two orphan G-protein-coupled receptors in the lateral hypothalamic area. They were initially recognized as regulators of feeding behavior, but they are mainly regarded as key modulators of the sleep/wakefulness cycle. Orexins activate orexin neurons, monoaminergic and cholinergic neurons in the hypothalamus/brainstem regions, to maintain a long, consolidated awake period. Anatomical studies of neural projections from/to orexin neurons and phenotypic characterization of transgenic mice revealed various roles for orexin neurons in the coordination of emotion, energy homeostasis, reward system, and arousal. For example, orexin neurons are regulated by peripheral metabolic cues, including ghrelin, leptin, and glucose concentration. This suggests that they may provide a link between energy homeostasis and arousal states. A link between the limbic system and orexin neurons might be important for increasing vigilance during emotional stimuli. Orexins are also involved in reward systems and the mechanisms of drug addiction. These findings suggest that orexin neurons sense the outer and inner environment of the body and maintain the proper wakefulness level of animals for survival. This review discusses the mechanism by which orexins maintain sleep/wakefulness states and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis.
Highlights
The hypothalamus plays a critical role in maintaining energy homeostasis by coordinating behavioral, metabolic, and neuroendocrine responses (Bernardis and Bellinger, 1996)
Dense projections of orexin neurons are observed in the serotonergic dorsal raphe nucleus (DR), Abbreviations: AgRP, agouti-related peptide; Arc, arcuate nucleus; BAT, brown adipose tissue; BST, bed nucleus of the stria terminalis; CTB, cholera toxin B subunit; DR, dorsal raphe nucleus; DREADD, designer receptors exclusively activated by designer drugs; FEO, food-entrainable oscillator; GPCRs, G-protein-coupled receptors; ICV, intracerebroventricular; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; LHA, lateral hypothalamic area; NMDAR, N -methyl-D-aspartate receptor; Neuropeptide Y (NPY), neuropeptide Y; OX1R, orexin receptor 1; OX2R, orexin receptor 2; PPT, pedunculopontine tegmental nucleus; PTX, pertussis toxin; PVN, paraventricular thalamic nucleus; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; TTC, C-terminal fragment of tetanus toxin; VLPO, ventrolateral preoptic nucleus; VTA, ventral tegmental area
CONCLUDING REMARKS the name orexin is derived from the word orexigenic after its function in feeding, mounting evidence has revealed various physiological roles for orexin other than feeding, such as maintenance of sleep, autonomous regulation, and reward processing
Summary
Orexins ( known as hypocretins) were identified as endogenous ligands for two orphan G-protein-coupled receptors in the lateral hypothalamic area They were initially recognized as regulators of feeding behavior, but they are mainly regarded as key modulators of the sleep/wakefulness cycle. Orexin neurons are regulated by peripheral metabolic cues, including ghrelin, leptin, and glucose concentration This suggests that they may provide a link between energy homeostasis and arousal states. Orexins are involved in reward systems and the mechanisms of drug addiction These findings suggest that orexin neurons sense the outer and inner environment of the body and maintain the proper wakefulness level of animals for survival. This review discusses the mechanism by which orexins maintain sleep/wakefulness states and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis
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