Melanin-Concentrating Hormone Neurons Promote and Stabilize Sleep

This was not an industry supported study. The authors have indicated no financial conflicts of interest. The neurochemical mechanisms responsible for sleep induction remain speculative. The prevailing theory is that GABAergic neurons in the ventrolateral preoptic area are the driving force behind sleep induction.1,2 However, three new landmark studies recently identified a central role for melanin-concentrating hormone (MCH) in the promotion and stabilization of sleep.3–5 The following commentary is designed to describe and highlight what these studies found and discuss how they impact the field of sleep medicine and biology. MCH cells are located in the hypothalamus and are intermingled with orexin (hypocretin) neurons. However, unlike their wake-promoting orexinergic neighbors, MCH neurons are hypothesized to promote sleep. Indeed, MCH neurons are functionally, chemically and anatomically positioned for sleep promotion. MCH neurons are sleep active. Not only do they express c-Fos during sleep,6,7 they also discharge action potentials during both NREM and REM sleep.8 However, MCH neurons are preferentially active during REM sleep,8 suggesting they primarily function to control this sleep state. MCH neurons heavily innervate arousal-promoting regions such as the tuberomammillary nucleus (TMN), basal forebrain, locus coeruleus (LC), ventrolateral periaqueductal gray, and dorsal raphe.9,10 Since they also release GABA, MCH neurons may promote sleep by inhibiting wake-promoting circuits. In addition, sleep amounts increase when MCH is applied to arousal-promoting regions,6 whereas, sleep duration decreases when MCH receptors are either pharmacologically blocked11 or genetically deleted.12 Despite the strong link between the MCH neurons and sleep promotion, there was no direct evidence indicating that the MCH system naturally functions to promote sleep. Recently, in one of the most remarkable and elegant sleep studies, Blouin et al. provide a rare glimpse into the chemical mechanism of the human brain during natural behavior. They show that MCH release is directly correlated with sleep onset in behaving humans.3 They did this by placing microdialysis probe directly into the amygdala of epileptic patients in order to collect and quantify levels of MCH released during different sleep-wake behaviors. They nicely showed that MCH levels rise sharply at sleep onset, suggesting that the MCH system functions to initiate sleep. Conversely, they found that orexin levels peak at wake onset, indicating that the orexinergic system could be responsible for promoting wakefulness. Blouin et al. suggest that together MCH and orexin form a biochemical circuit that controls behavioral arousal states, with MCH functioning to promote sleep and orexin acting to facilitate arousal. However, their results are correlative in nature, which makes it difficult to establish causality. For example, is MCH release actually promoting sleep, or is sleep itself promoting MCH release? The second paper under discussion nicely addresses and answers this question.4 Konadhode and colleagues provide the first functional evidence indicating that MCH neurons per se act to induce sleep.4 Using novel optogenetic techniques, they were able to genetically target and selectively stimulate only MCH neurons in order to determine how they specifically impact sleep-wake behavior. This novel strategy represents a major advance in the field because conventional neuroscience techniques (e.g., receptor pharmacology) were unable to specifically identify the role of MCH neurons in sleep control. Konadhode and coworkers made several seminal observations, but their most important and relevant finding was that chronic stimulation of MCH neurons shortened sleep onset, reduced the duration of waking bouts, and triggered marked increases in both NREM and REM sleep. Interestingly, stimulation of MCH cells did not affect the duration of sleep periods, suggesting that MCH is involved in the initiation, but not the maintenance of sleep states. Importantly, they found that activation of MCH cells promotes sleep during the dark phase when mice are typically active and alert, suggesting that MCH functions as a powerful somnogenic agent. Finally, they showed that MCH neurons innervate wake-promoting regions such as the histaminergic TMN cells and the noradrenergic LC cells, and they hypothesized that MCH induces sleep by inhibiting these circuits. The final paper in this discussion is particularly important because it identified potential mechanisms by which MCH neurons promote sleep.5 Jego and coworkers also capitalized on the advantages of optogenetics in order to determine the functional role of MCH cells in sleep promotion. But, unlike Konadhode et al., they used optical methods that allowed selective stimulation or inhibition of MCH cells during defined sleep states. This strategy provided them the resolution needed to identify how MCH neurons function to generate particular sleep states. Jego and coworkers made several notable observations. First, they found that MCH cell activation markedly increased the duration of REM sleep, but it did not directly impact NREM sleep itself, which is consistent with the fact that MCH cells are most active during REM sleep. In contrast, acute silencing of MCH cells did not reduce REM sleep duration; its only effect was to slow REM sleep theta rhythm. Last, Jego et al. wanted to identify the potential targets by which MCH cells promote REM sleep. In series of in vitro and in vivo experiments, they found that MCH potentially drive REM sleep by inhibiting cells in the TMN and medial septum, through a release of GABA. Together, their results suggest that MCH neurons may function to stabilize REM sleep through inhibition of arousal circuits. In summary, these studies provide a fundamentally new framework for understanding the biochemical control of sleep regulation. The first study from Dr. Siegel's group3 is biologically important because it demonstrates that MCH is released in a pattern consistent with its role in sleep promotion. The second study from Dr. Shiromani's group4 is biologically important because it shows that selective optogenetic stimulation of MCH cells triggers rapid onset of sleep, demonstrating a clear somnogenic role for MCH. And the last study by Dr. Adamantidis's group5 is physiologically significant because it nicely demonstrates that MCH neurons promote and stabilize REM sleep by inhibiting wake-promoting circuitry. Collectively, these new findings illustrate that the MCH system plays a central role in sleep induction. They also raise the enticing possibility that MCH could be used as an effective and natural agent for alleviating insomnia.

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