The hypocretins/orexins: integrators of multiple physiological functions

Abstract

The hypocretins (Hcrts), also known as orexins, are two peptides derived from a single precursor produced in the posterior lateral hypothalamus. Over the past decade, the orexin system has been associated with numerous physiological functions, including sleep/arousal, energy homeostasis, endocrine, visceral functions and pathological states, such as narcolepsy and drug abuse. Here, we review the discovery of Hcrt/orexins and their receptors and propose a hypothesis as to how the orexin system orchestrates these multifaceted physiological functions.

Keywords: addiction; anxiety; arousal; hypothalamus; narcolepsy; neuropeptide; sleep; stress.

Figure 1

The six schematic drawings show the representative nuclei (or nucleus) involved in the corresponding functions, namely, the structure involved in regulation of sensory information [the posterior hypothalamic area, (PH)], in locomotion [the cuneiform nucleus (CNF) and lateral vestibular nucleus (LVN)], in cognition [the prefrontal cortex (PFC) and hippocampus (Hip)], in energy homeostasis [the arcuate nucleus (ARC)], in endocrine [the paraventricular nucleus of hypothalamus (PVH)] and in visceral functions [the ventrolateral medulla (VLM), pontine Kölliker-Fuse nucleus (KF) and dorsal motor nucleus of the vagus (DMV)].

Figure 2

Effect of orexins (Hcrt) on structures involved in locomotion and sensory systems (pain). This diagram summarizes the effects of orexin (Hcrt) on structures involved in locomotion and pain. Orexin regulates locomotor activities and muscle tone. Notably, especially in terms of muscle tone, these regulations are bidirectional, namely, orexin facilitates muscle tone or inhibits it depending on the region. We consider regulation of pain as representative of sensory systems. Both the cuneiform nucleus (CNF) and pedunculopontine tegmental nucleus (PPT) are parts of the so called mesencephalic locomotor region (MLR), and nucleus pontis oralis (PnO) contains the alleged pontine inhibitory area. Abbreviations: AccSh, nucleus accumbens shell; LC, locus coeruleus; LVN, lateral vestibular nucleus; Mo5, motor trigeminal nucleus; MVMR, medioventral medullary region; PAG, periaqueductal gray matter; PH, posterior hypothalamic area; PVH, paraventricular nucleus of hypothalamus; PVT, paraventricular nucleus of thalamus; rLH, rostrolateral hypothalamus; SNc, substantia nigra pars compact; SNr, substantia nigra pars reticulate.

Figure 3

Effects of orexin (Hcrt) on arousal and cognition areas. This diagram summarizes the effects of orexin on nuclei involved in arousal and cognition (including learning). It should be noted that a role for the medial temporal lobe (MTL) and striatum [i.e. caudate putamen (CPu)] in these effects of orexin were suggested by a human study, in addition to the prefrontal cortex (PFC) and thalamus suggested from animal and human studies. The medial septum and diagonal band of Broca (MSDM) is included in the basal forebrain (BF); the MTL consists of the hippocampus, entorhinal cortex (EC), peri- and postrhinal cortex, subiculum, and pre- and parasubiculum (Pr-PaS). Abbreviations: CA1, Cornu Ammonis area 1; DG, dentate gyrus; DR, dorsal raphe nuclei; LC, locus coeruleus; LDT/PPT, laterodorsal tegmental nucleus/pedunculopontine tegmental nucleus; Th, thalamus; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray matter.