Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice

Abstract

Currently available evidence indicates that neurons containing melanin-concentrating hormone (MCH) in the lateral hypothalamus are critical modulators of sleep-wakefulness, but their precise role in this function is not clear. Studies employing optogenetic stimulation of MCH neurons have yielded inconsistent results, presumably due to differences in the optogenetic stimulation protocols, which do not approximate normal patterns of cell firing. In order to resolve this discrepancy, we 1) selectively activated the MCH neurons using a chemogenetic approach (Cre-dependent hM3Dq expression) and 2) selectively destroyed MCH neurons using a genetically targeted diphtheria toxin deletion method, and studied the changes in sleep-wake in mice. Our results indicate that selective activation of MCH neurons causes specific increases in rapid eye movement (REM) sleep without altering wake or non-REM (NREM) sleep. On the other hand, selective deletions of MCH neurons altered the diurnal rhythm of wake and REM sleep without altering their total amounts. These results indicate that activation of MCH neurons primarily drives REM sleep and their presence may be necessary for normal expression of diurnal variation of REM sleep and wake.

Melanin-concentrating hormone neurons promote rapid eye movement sleep independent of glutamate release

“…The firing rate of MCH neurons is maximal during REMs and minimal during wake suggesting that the MCH neurons may belong to a ‘REMs-on’ type (Hassani et al 2009). Consistent with these observations, optogenetic and chemogenetic activation of MCH neurons led to substantial increases in REMs without significantly altering other sleep-wake states in mice (Jego et al 2013; Tsunematsu et al 2014; Vetrivelan et al 2016). These evidences strongly suggest that MCH neurons may specifically promote REMs.…”

“…These evidences strongly suggest that MCH neurons may specifically promote REMs. In addition, loss of MCH neurons produced a significant increase in the diurnal variation of REMs without altering the daily total amounts (Vetrivelan et al 2016), suggesting that MCH neurons may be necessary for maintaining the diurnal pattern of REMs.…”

“…Loss of MCH neurons induced a robust increase in LMA without increasing the time spent in wake in mice indicating a hyperactivity phenotype (Vetrivelan et al 2016; Whiddon and Palmiter 2013). Moreover, a moderate hyperthermia (~0.5°C), especially during the dark period, was observed after the loss of MCH neurons (Vetrivelan et al 2016). Therefore, we studied the changes in LMA and Tb after the deletion of Vglut2 from MCH neurons, as well as after the activation of MCH neurons lacking Vglut2, to assess the potential contribution of glutamate in the regulation of LMA and Tb.…”

Neural Circuitry of Wakefulness and Sleep

“…These cells innervate the SLD and many other regions, and they fire maximally during REM sleep (Hassani et al, 2009b). Several studies show that photoactivation or chemoactivation of the MCH neurons increases REM sleep (Jego et al, 2013; Tsunematsu et al, 2014; Vetrivelan et al, 2016). Whether the MCH neurons promote NREM sleep is debated as this has been reported by only one group (Konadhode et al, 2013).…”

Neuroscience: A Distributed Neural Network Controls REM Sleep

“…We now know, for example, that lateral hypothalamic cells that contain melanin concentrating hormone (MCH) play a role in promoting REM sleep, possibly through inhibition of REM-off neurons in the vlPAG/LPT [16,110,111]. The synaptic mechanism by which MCH cells regulate the vlPAG/LPT remains unclear, but could be directly through MCH or GABA release or indirectly through glutamate-mediated feedforward inhibition [16,112].…”