The hypocretins (orexins) mediate the "phasic" components of REM sleep: A new hypothesis

Abstract

In 1998, a group of phenotypically distinct neurons were discovered in the postero-lateral hypothalamus which contained the neuropeptides hypocretin 1 and hypocretin 2 (also called orexin A and orexin B), which are excitatory neuromodulators. Hypocretinergic neurons project throughout the central nervous system and have been involved in the generation and maintenance of wakefulness. The sleep disorder narcolepsy, characterized by hypersomnia and cataplexy, is produced by degeneration of these neurons. The hypocretinergic neurons are active during wakefulness in conjunction with the presence of motor activity that occurs during survival-related behaviors. These neurons decrease their firing rate during non-REM sleep; however there is still controversy upon the activity and role of these neurons during REM sleep. Hence, in the present report we conducted a critical review of the literature of the hypocretinergic system during REM sleep, and hypothesize a possible role of this system in the generation of REM sleep.

Keywords: Cataplexy; Hypothalamus; MCH; Narcolepsy; Paradoxical sleep; Peptides.

Fig. 1

Hypocretinergic neurons are intermingled with MCHergic neurons in the postero-lateral hypothalamus. (A) Photomicrographs of the postero-lateral hypothalamic area of the cat. The sections were immunostained for hypocretin (black, arrows) and MCH (brown, arrowheads). Sections were processed utilizing the ABC method and the DAB–H₂O₂ reaction to detect peroxidase activity. This reaction was enhanced with nickel to label hypocretinergic cells. Calibration bars: 50 μm. (B) Location of MCHergic and hypocretinergic neurons in the postero-lateral hypothalamus of a representative cat. Camera lucida drawings of MCHergic (on the left, black circles) and hypocretinergic neuronal bodies (on the right, red circles) in the postero-lateral hypothalamus. The neurons are from the same hemi-hypothalamus (reflected in the figure). Camera lucida drawings were obtained from adjacent sections that were immunostained for MCH for Hcrt-2, respectively; these sections were counterstained with Pyronin-Y. The demarcation and nomenclature of cell groups in the cat hypothalamus are based on Berman and Jones, as well as Bleier׳s work . DM, dorsomedial nucleus; EN, entopeduncular nucleus; fx, fornix; HDA, dorsal hypothalamic area; HLA, lateral hypothalamic area; INF, infundibular nucleus; mt, mammillothalamic tract; PAH, paraventricular nucleus; PEH, periventricular complex; PVH, parvocellular nucleus; TCA, area of the tuber cinereum; VM, ventromedial nucleus; ZI, zona incerta; 3V, third ventricle. Modified from . (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Photomicrographs illustrating hypocretin and Fos immunoreactive neurons from the postero-lateral area of the hypothalamus. (A) Hypocretinergic neurons that express c-fos during active wakefulness with motor exploratory activity (arrows). Hypocretinergic neurons are stained in brown. Fos immunoreactivity, which is shown in black, is restricted to nuclei. Hcrt-Fos+ neurons (arrowheads) are also intermingled with Hcrt+Fos+neurons. (B) Group of hypocretinergic neurons during quiet wakefulness. Hypocretinergic neurons did not express c-fos (unfilled arrowheads), although Hcrt-Fos+neurons are intermingled with these neurons (filled arrowheads). All photomicrographs were taken from 20 µm-thick sections and were processed with the diaminobenzidine method enhanced by nickel. Calibration bars: (A and B) 50 µm. Modified from . (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

(A) Polygraphic recording of an episode of REM sleep induced by carbachol microinjection into the nucleus pontis oralis (NPO) in the cat. Arrows signal the beginning of the microinjection of carbachol into the NPO as well as pentobarbital injection for euthanasia. EEG, electroencephalogram; EOG, electro-oculogram; LGN, lateral geniculate nucleus electrogram (PGO waves); EMG, electromyogram. (B–D) Photomicrographs illustrate Fos immunoreactive hypocretinergic neurons (arrows) from the postero-lateral area of the hypothalamus during REM sleep induced by carbachol. Hypocretin immunoreaction is stained in brown. Fos immunoreactivity, which is shown in black, is restricted to the nuclei. Sections were processed employing the ABC method and the DAB–H₂O₂ reaction to detect peroxidase activity. This reaction was enhanced with nickel to label the Fos protein. Calibration bars: (B–D) 10 μm. Modified from . (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Distribution of Fos and hypocretinergic neurons during active wakefulness with motor-exploratory activity, quiet wakefulness and REM sleep induced by the microinjection of carbachol into the nucleus pontis oralis. The camera lucida drawing shows the distribution of Hcrt+Fos+neurons. Each mark indicates one labeled neuron. The percentage of Hcrt+Fos+neurons from the total number of hypocretinergic neurons was on average 79% for active wakefulness, 34% for REM-carbachol and 2% for quiet wakefulness . 3V, third ventricle; Fx, fornix.

Fig. 5

Schema of the working hypotheses 1 and 2. Hypocretinergic neurons not only are correlated with the “phasic” components of REM sleep but also promote its generation.

Fig. 6

The yin and yang is the Taoist symbol used to describe how polar or seemingly contrary forces are interconnected and interdependent in the natural world, and how they give rise to each other in turn. This concept could be applied to the opposite but complementary role of hypocretin and melanin-concentrating hormone (MCH) in the control of wakefulness and sleep. Hypocretin (HCRT) an excitatory neuropeptide, and MCH an inhibitory neuropeptide, interact both at the lateral hypothalamic level as well as in the activating and hypnogenic neuronal areas, in order to regulate the generation of the sleep and wakefulness cycle.