Neural mechanisms underlying REM sleep regulation by MCH neurons

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Understanding the neural mechanisms controlling rapid eye movement sleep (or paradoxical sleep; PS) is critical considering the dysregulation of PS in many neuropsychiatric disorders (e.g. major depressive disorder and post-traumatic stress disorder) and the adverse health consequences of PS suppression. In the lateral hypothalamus (LH), neurons expressing melanin concentrating hormone (MCH) are thought to play an integral role in PS regulation but their precise role in this function is unclear. The proposed work is aimed to address this question and to delineate the neuronal circuitry MCH neurons impact in order to regulate PS. To demonstrate the specific role of MCH neurons in PS control, in Aim 1, we will selectively activate and silence the MCH neurons using a novel pharmacogenetic tool - Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) - and study the changes in baseline PS and PS rebound following selective PS deprivation (PS homeostasis). Because MCH neuronal activation increases PS and MCH neurons are inhibitory in nature, we hypothesize that the MCH neurons inhibit PS suppressing neurons in the ventrolateral periaqueductal grey (vlPAG)/lateral pontine tegmentum (LPT) to facilitate PS. We will test this hypothesis, in Aim 2, by studying the changes in PS a) following i vivo optogenetic stimulation of the MCH terminals in the vlPAG/LPT and b) following optogenetic inhibition of the MCH terminals in the vlPAG/LPT with concurrent stimulation of MCH cell bodies by DREADDs. Finally, in order to identify the neurochemically distinct subset of vlPAG/LPT neurons that relay MCH PS promoting inputs to the SLD, we will activate and silence a) the vlPAG/LPT neurons specifically projecting to the SLD and b) glutamatergic and GABAergic neurons in the vlPAG/LPT using DREADDs and study the changes in PS and PS homeostasis (Aim 3). We predict, based on our preliminary results that GABAergic neurons in the vlPAG/LPT projecting to the SLD are critically involved in PS suppression and hence their inhibition by MCH neurons may promote PS.