Role of orexin in modulating arousal, feeding, and motivation

Abstract

Orexin deficiency results in narcolepsy in humans, dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. However, orexin neurons are "multi-tasking" neurons that regulate sleep/wake states as well as feeding behavior, emotion, and reward processes. Orexin deficiency causes abnormalities in energy homeostasis, stress-related behavior, and reward systems. Orexin excites waking-active monoaminergic and cholinergic neurons in the hypothalamus and brain stem regions to maintain a long, consolidated waking period. Orexin neurons also have reciprocal links with the hypothalamic nuclei, which regulates feeding. Moreover, the responsiveness of orexin neurons to peripheral metabolic cues suggests that these neurons have an important role as a link between energy homeostasis and vigilance states. The link between orexin and the ventral tegmental nucleus serves to motivate an animal to engage in goal-directed behavior. This review focuses on the interaction of orexin neurons with emotion, reward, and energy homeostasis systems. These connectivities are likely to be highly important to maintain proper vigilance states.

Keywords: feeding behavior; hypothalamus; orexin A; orexin receptors; orexins; reward; sleep.

Figure 1

Orexin and orexin receptors. (A) Structure of mature orexin A and orexin B peptides. The topology of the two intrachain-bonds in orexin A is indicated above the sequence. Amino acid identities are indicated by shading. Mammalian orexin A sequences thus far identified (human, rat, mouse, pig, dog, sheep, and cow) are all identical, while the sequences of orexin B show some differences among species. (B) Schematic representation of orexin system. Orexin A and orexin B are derived from a common precursor peptide, prepro-orexin. The actions of orexins are mediated via two G protein-coupled receptors named orexin-1 (OX₁R) and orexin-2 (OX₂R) receptors. OX₁R is selective for orexin A, whereas OX₂R is a non-selective receptor for both orexin A and orexin B. OX₁R is coupled exclusively to the G_q subclass of heterotrimeric G proteins, whereas OX₂R couples to G_i/o and/or G_q.

Figure 2

Schematic drawing of coronal section and sagittal section through rat brain, summarizing the orexin neuronal system. (A) Prepro-orexin mRNA-containing neurons are shown in black superimposed upon anatomical structures of the hypo- and subthalamic areas. The rectangle designates the area schematized in the figure. Abbreviations: LH, lateral hypothalamic area; PeF, perifornical nucleus; PH, posterior hypothalamic area; Sth, subthalamic nucleus; SubI, subincertal nucleus; ZIV, ventral zona incerta. Additional landmarks include: THAL, thalamus; HAB, habenular complex; ic, internal capsule; opt, optic tract; mt, mammillothalamic tract; f, fornix; mfb, medial forebrain bundle; 3V, third ventricle; Arc, arcuate hypothalamic nucleus; DM, dorsomedial hypothalamic nucleus; and VMH, ventromedial hypothalamic nucleus. (B) Orexin neurons are found only in the lateral hypothalamic area and project to the entire central nervous system. The thickness of arrows represents relative abundance of projections. Abbreviations: 3V, third ventricle; 4V, fourth ventricular; TMN, tuberomammillary nucleus; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine nucleus.

Figure 3

Mechanisms by which orexin system maintains consolidated sleep and wakefulness. The figures represent the functional interaction between orexin neurons, wake-active centers, and sleep-active centers during various states of sleep and wakefulness. Arrows show excitatory and lines show inhibitory input. The thickness of arrows and lines represent relative strength of input. Circle sizes represent relative activities of each group of neurons (A) Awake state. Orexin neurons send excitatory input to wake-active neurons, which send inhibitory feedback projections to orexin neurons. This system might maintain the activity of wake-active neurons. A small decrease in the activity of wake-active neurons results in decreased inhibitory influence to orexin neurons. Orexin neurons, therefore, are disinhibited and increase their excitatory influence on wake-active neurons to maintain their activity. These wake-active neurons send inhibitory projections to the POA sleep center and excitatory projections to the thalamus and cerebral cortex. (B) Sleep state. GABAergic neurons in the sleep center are activated and send inhibitory projections to wake-active neurons and orexin neurons to maintain a sleep state. (C) Model of narcolepsy. Sleep-active neurons in the POA inhibit wake-active neurons and in turn are inhibited by them, thus forming a mutually inhibitory system. This system can cause unnecessary transition between the states, because when either side begins to overcome the other, the switch abruptly turns into the alternative state.

Figure 4

Input and output of orexin neurons at interface of sleep, stress, reward, and energy homeostasis. Orexin neurons in the lateral hypothalamic area (LHA) and posterior hypothalamus (PH) are placed to provide a link between the limbic system, energy homeostasis, the brain stem, and other systems. Arrows show excitatory projections and broken arrows inhibitory projections. Gray semicircles indicate OX₁R and black semicircles indicate OX₂R. Neurotransmitters/modulators are underlined. LC, DR, and TMN are wake-active regions, VLPO is sleep-active region, and LDT/PPT is REM-active region. Orexin neurons promote wakefulness through monoaminergic nuclei that are wake-active. Stimulation of dopaminergic centers by orexins modulates reward systems (VTA). Peripheral metabolic signals influence orexin neuronal activity to coordinate arousal and energy homeostasis. Stimulation of neuropeptide Y neurons by orexin increases food intake. The SCN, the central body clock, sends input to orexin neurons via the DMH. Input from the limbic system (amygdala and BST) might be important to regulate the activity of orexin neurons upon emotional stimuli to evoke emotional arousal or fear-related responses. Abbreviations: BST, bed nucleus of the stria terminalis; VLPO, ventrolateral preoptic area; LC, locus ceruleus; DR, dorsal raphe; TMN, tuberomammillary nucleus; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; VTA, ventral tegmental area; SCN, suprachiasmatic nucleus; DMH, dorsomedial hypothalamus; Arc, arcuate nucleus.