Melanin-concentrating hormone: a new sleep factor?

Abstract

Neurons containing the neuropeptide melanin-concentrating hormone (MCH) are mainly located in the lateral hypothalamus and the incerto-hypothalamic area, and have widespread projections throughout the brain. While the biological functions of this neuropeptide are exerted in humans through two metabotropic receptors, the MCHR1 and MCHR2, only the MCHR1 is present in rodents. Recently, it has been shown that the MCHergic system is involved in the control of sleep. We can summarize the experimental findings as follows: (1) The areas related to the control of sleep and wakefulness have a high density of MCHergic fibers and receptors. (2) MCHergic neurons are active during sleep, especially during rapid eye movement (REM) sleep. (3) MCH knockout mice have less REM sleep, notably under conditions of negative energy balance. Animals with genetically inactivated MCHR1 also exhibit altered vigilance state architecture and sleep homeostasis. (4) Systemically administered MCHR1 antagonists reduce sleep. (5) Intraventricular microinjection of MCH increases both slow wave sleep (SWS) and REM sleep; however, the increment in REM sleep is more pronounced. (6) Microinjection of MCH into the dorsal raphe nucleus increases REM sleep time. REM seep is inhibited by immunoneutralization of MCH within this nucleus. (7) Microinjection of MCH in the nucleus pontis oralis of the cat enhances REM sleep time and reduces REM sleep latency. All these data strongly suggest that MCH has a potent role in the promotion of sleep. Although both SWS and REM sleep are facilitated by MCH, REM sleep seems to be more sensitive to MCH modulation.

Keywords: REM sleep; depression; hypothalamus; orexin; peptides; raphe nuclei.

Figure 1

MCHergic neurons are located in the hypothalamus of the cat. (A) Low magnification photomicrographs that exhibit MCHergic neurons at the tuberal level of the hypothalamus. (B–E) The insets in (A) are shown at higher magnification. These photomicrographs show MCHergic neurons of the dorsal hypothalamic area (B), the perifornical region (C,D), and the lateral hypothalamic area (E). (F) Two MCHergic neurons are shown at high magnification. The photomicrographs were taken from 20-μm-thick sections that were processed for immunofluorescence. FITC was used as fluorescent agent. Fx, fornix; 3V, third ventricle. Calibration bars: (A) 1 mm; (B–E) 100 μm; (F) 20 μm. This figure was modified from Torterolo et al. (2006).

Figure 2

Representative hypnograms illustrating the occurrence of wakefulness and sleep following microinjection of MCH into the dorsal raphe nucleus. The effects of the vehicle (A), and 100 ng of MCH (B) are presented. Comparing to control, the hypnogram corresponding MCH microinjection depicts a substantial increase in the number of REM sleep episodes. This figure was modified from Lagos et al. (2009).

Figure 3

Representative hypnograms illustrating the occurrence of wakefulness and sleep following microinjection of anti-MCH antibodies (immunoneutralization) into the dorsal raphe nucleus. The effects of the vehicle (A) and 1/100 dilution dose of anti-MCH (B) are presented. Comparing to control, the hypnogram corresponding to anti-MCH microinjection depicts a substantial decrease in the number of REM sleep episodes. This figure was modified from Lagos et al. (2011a).

Figure 4

The schematic shows a simple structural model that proposes a tentative mechanism by which MCH promotes sleep. During wakefulness MCHergic neurons may be activated during special conditions such as energy abundance. Inhibiting and facilitating the activating and somonogenic (SWS and REM sleep neuronal networks) respectively, MCH would facilitate and maintain sleep.