MCH neurons: vigilant workers in the night.

1783 Critical Topics Forum—Jego and Adamantidis Since the discovery of the MCH peptide1 and the identification of its receptor(s),2 experimental and clinical studies have demonstrated a role for the MCH peptide in many hypothalamic functions, from energy homeostasis and stress response to learning and memory, stress/anxiety, LTP, and sleep.3 This heterogeneity of functions is consistent with the broad distribution of MCH terminals4 and MCH receptors5 throughout the brain and suggests a modulatory mode of action. Whether this heterogeneity of brain functions results from the existence of subpopulations of MCH neurons or distinct terminal domains remains unknown. Over the last decade, experimental studies based on correlative, lackor gain-of function evidence led to the consensus that MCH peptide facilitates NREM and REM sleep, suggesting a “MCH hypnogenic hypothesis.” Importantly, juxtacellular recordings showed that MCH neurons are silent during wakefulness, while their discharge rate progressively increases during NREM sleep to be maximal during REM sleep.6 Unfortunately, genetic deletion models partially confirmed the hypnogenic hypothesis (see below), leaving the question about the precise role of MCH neurons (or MCH peptide) in regulating NREM or REM sleep unanswered. Thus, we and other have started to investigate the mechanisms underlying the control of sleep states by MCH neurons by combining optogenetic with electrophysiology and genetic engineering in mice. The four commentaries7-10 included in this critical forum all converge to four major points of discussion. Those include (1) the causality of the targeting networks in promoting or maintaining particular sleep-wake states, (2) the dynamics of peptide vs. transmitters release and their implication in sleep behavior, (3) the functional wiring of a single sleep circuit, and (4) its functional relevance in the complex sleep-wake networks of the brain. Those points are discussed below according to the three papers included in this forum, as well as experimental studies reported over the last years.