There is considerable amount of data on arousal neurons whereas there is a paucity of knowledge regarding neurons that make us fall asleep. Indeed, current network models of sleep- wake regulation list many arousal neuronal populations compared to only one sleep group located in the preoptic area. There are neurons outside the preoptic area that are active during sleep, but they have never been selectively manipulated. Indeed, none of the sleep-active neurons have been selectively stimulated. To close this knowledge gap the proposed studies will use optogenetics to selectively manipulate neurons containing melanin concentrating hormone (MCH). The MCH neurons are located in the posterior hypothalamus intermingled with the orexin arousal neurons. Our very strong preliminary data indicate that optogenetic stimulation of MCH neurons excites sleep active neurons, decreases activity of wake active neurons and increases both non-REM sleep (NREM) and REM sleep (REMS) in wildtype mice (J Neuroscience, 2013), MCH-Cre mice and rats. MCH neuron stimulation increases sleep during the animal's normal active period, which is compelling evidence that stimulation of MCH neurons has a powerful effect in counteracting the strong arousal signal from all of the arousal neurons. Effects of MCH neuron stimulation versus inhibition will be tested in conditions that alter the animal's internal drive to stay awake (24h fasting) or sleep (6h sleep deprivation). In one aim, electrophysiology studies will monitor activity of sleep-active or wake-active neurons in the lateral hypothalamus, preoptic area and pons during normal sleep-wake cycles and during optogenetic stimulation, thereby identifying activity at the single neuron level during natural and optogenetically induced sleep. Neuroanatomy studies will show that MCH neurons project to multiple targets indicating powerful influence of these neurons in orchestrating shifts in vigilance states. The MCH neurons represent the only group of sleep-active neurons that when selectively stimulated induce sleep. From a translational perspective this is potentially useful in sleep disorders, such as insomnia, where sleep needs to be triggered against a strong arousal drive.
These aims will provide a framework for integrating the MCH neurons within an overall model of sleep-wake regulation.
New pharmacological approaches for treating insomnia are needed. The challenge is to discover new phenotypes of neurons that can induce sleep. We have now ascertained that stimulation of MCH neurons robustly increases sleep. What is noteworthy about our results is that sleep was induced in spite of a strong circadian drive to stay awake indicating that MCH neurons are able to inhibit the combined signal of the arousal neurons. This is the first time that selective stimulation of sleep-active neurons has been shown to induce sleep. These results have a strong translational potential for sleep disorders, such as insomnia and jet lag, where sleep needs to be triggered against a strong waking drive.
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