Paternally expressed imprintedSnord116andPeg3regulate hypothalamic orexin neurons

Abstract

words: 186; words count: 9525; figures: 4; Supplementary material: figures 6; table 8Conflict of Interest: each author discloses the absence of any conflicts of interest relative to the research covered in the submitted manuscript. Highlights• Snord116 regulates neuronal activity in the lateral hypothalamus (LH), which is time-locked with cortical states of sleep.• Loss of Snord116 reduces orexin neurons in the LH and affects sleep homeostasis and thermoregulation in mice.• Snord116 and Peg3 independently control orexin expression in the LH.• Paternally expressed alleles maximize the patrilineal effects in the control of REM sleep by the LH in mammals. AbstractImprinted genes are highly expressed in the hypothalamus; however, whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at chromosome 15q11-q13, is characterised by hypothalamic insufficiency. Here, we investigate the role of the paternally expressed Snord116 gene within the context of sleep and metabolic abnormalities of PWS, and we report a novel role of this imprinted gene in the function and organisation of the two main neuromodulatory systems of the lateral hypothalamus (LH), namely, the orexin (OX) and melanin concentrating hormone (MCH) systems. We observe that the dynamics between neuronal discharge in the LH and the sleep-wake states of mice with paternal deletion of Snord116 (PWScr m+/p-) are compromised. This abnormal state-dependent neuronal activity is paralleled by a significant reduction in OX neurons in the LH of mutants. Therefore, we propose that an imbalance between OX-and MCH-expressing neurons in the LH of mutants reflects a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake and temperature control.