Optogenetic and Pharmacogenetic Dissection of the Melanin-concentrating-hormone (MCH) System PDF Download

Author: Sonia Jego
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Languages : en
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Book Description
"Sleep is a fundamental physiological process and sleep-like states have been described in nearly every animal studied to date. Despite the existence of distinct sleep-wake states, our understanding of the mechanism of sleep regulation remains incomplete. The present work focused on a particular hypothalamic neuronal population which expresses melanin-concentrating hormone (MCH). The MCH peptide is thought to have a role in the promotion of sleep. However, all of the evidence supporting a functional role for the MCH system in sleep stems from in vitro and in vivo techniques that have spatial and temporal limitations and involve possible compensatory mechanisms. The present work aimed at clarifying the action of MCH neurons and their co-expressed neurotransmitters on sleep.In our first study, we used optogenetic tools in newly-generated Tg(Pmch-Cre) mice and found that acute optical activation of MCH neurons at the onset of REM sleep extended REM sleep duration whereas MCH neuronal stimulation at NREM sleep onset promoted transition from NREM to REM sleep. In contrast, acute silencing of MCH neurons reduced the frequency and amplitude of the hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory post-synaptic currents in wake-promoting neurons of the tuberomammillary nucleus (TMN), while in vivo activation of MCH neuron terminals in the 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, while their inhibition induced a NREM-to-REM sleep transitional state.Our second study investigated the role of MCH peptide and GABA transmitter, which are thought to be both released by MCH neurons, during acute and semi-chronic optogenetic activation of MCH cells. We used newly-generated mice along with administration of MCH-R1 antagonist SNAP 7941. Our study revealed that the absence of Vesicular GABA Transporter (VGAT) in MCH neurons raises REM sleep mean duration closer to a ceiling value in control condition, masking the REM sleep promoting effect in acute stimulation. Semi-chronic activation of MCH neurons revealed that MCH peptide likely mediates the NREM sleep promoting effect whereas REM sleep promoting effect might involve additional neurotransmitters beside GABA neurotransmission. Together, our results suggest that GABA produced by MCH neurons is playing a crucial role in the basal control of REM sleep. Importantly, these results have confirmed that the mode of MCH activation (acute vs. semi-chronic) has a different effect on sleep, possibly due to the release of various neurotransmitters acting on various targets with different timescales. In the third study, we investigated the effect of pharmacogenetic activation of MCH neurons in the lateral hypothalamus and found that their activation during the resting period (i.e., light period) specifically increased REM sleep whereas a similar activation paradigm during the active period (i.e., dark period) enhanced wakefulness and possibly arousal. These results suggest that subpopulations of MCH neurons exist, and that their modulation of behavior, including sleep, depends on the circadian phase and the physiological and homeostatic need of the animal.Collectively, our results causally demonstrated that MCH neurons are involved in REM sleep regulation, at least during the light phase. Acute activation of MCH neurons significantly promotes REM sleep although this effect is not dependent on MCH peptide release, whereas GABA from MCH neurons is possibly involved in the regulation of basal REM sleep. Our results further suggest that MCH peptide is implicated in the modulation of NREM sleep following semi-chronic activation of MCH soma, consistent with the slow mechanism of action of peptides in the brain. " --