Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus

Abstract

Rapid-Eye Movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus (LH). LH melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, however, their action on REM sleep remains unclear. Using optogenetic tools in newly-generated Tg(Pmch-Cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM sleep episode. In contrast, their acute silencing (eNpHR3.0, ArchT) reduced the frequency and amplitude of hippocampal theta rhythm, without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory post-synaptic currents (IPSCs) in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), while in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.

Optogenetic Manipulation of Activity and Temporally Controlled Cell-Specific Ablation Reveal a Role for MCH Neurons in Sleep/Wake Regulation

“…We found that acute activation of MCH neurons significantly increased the time spent in REM sleep in association with decreased NREM sleep. These results were in good agreement with those of a previous study in which ChR2 was expressed in MCH neurons using a Cre-dependent viral vector in prepro-MCH-cre transgenic mice (Jego et al, 2013). Interestingly, NREM rebound was observed after stimulation of MCH neurons.…”

“…A recent study reported that optogenetic stimulation of MCH neurons increased both NREM and REM sleep (Konadhode et al, 2013). These results are consistent with the observation that intracerebroventricular injections of MCH increase both sleep states, but are at variance with results from functional neuroanatomical, pharmacological (Ahnaou et al, 2008), and optogenetic (Jego et al, 2013) studies that specifically indicate a role for MCH neurons in REM sleep regulation.…”

“…To this point, the precise role of MCH neurons in REM sleep regulation remains unclear and the involvement of MCH neurons in NREM sleep is uncertain (Jego and Adamantidis, 2013;Jones and Hassani, 2013;Luppi et al, 2013b;McGinty and Alam, 2013;Pelluru et al, 2013). One potential source of the discrepant results from the optogenetic studies could be the number of MCH neurons transfected with the light-sensitive protein and subsequently stimulated.…”

Neurobiology of Arousal and Sleep: Updates and Insights Into Neurological Disorders

“…Optogenetic activation of MCH neurons during NREM sleep significantly increases the probability of transitions to REM sleep [96]. Mechanisms of MCH REM sleep enhancement involve disinhibition of SLD REM on neurons via MCH/GABA inhibition of REM off neurons in the TMN, vlPAG, DRN, and LC [93,96].…”

Diurnal variation of the melanin-concentrating hormone level in the hypothalamus

“…Fasting is known to increase the expression of MCH mRNA [18]. MCH is also a central player in the promotion and stabilization of sleep [7,[10][11][12]21]. It has been suggested that MCH is affecting the pathophysiology of depression as well [21].…”