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Loss of Snord116 impacts lateral hypothalamus, sleep, and food-related behaviors
Marta Pace, … , Alfonso Urbanucci, Valter Tucci
Marta Pace, … , Alfonso Urbanucci, Valter Tucci
Published May 4, 2020
Citation Information: JCI Insight. 2020;5(12):e137495. https://doi.org/10.1172/jci.insight.137495.
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Research Article Neuroscience

Loss of Snord116 impacts lateral hypothalamus, sleep, and food-related behaviors

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Abstract

Imprinted 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 characterized 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 significant role of this imprinted gene in the function and organization of the 2 main neuromodulatory systems of the lateral hypothalamus (LH) — namely, the orexin (OX) and melanin concentrating hormone (MCH) — systems. We observed that the dynamics between neuronal discharge in the LH and the sleep-wake states of mice with paternal deletion of Snord116 (PWScrm+/p–) are compromised. This abnormal state–dependent neuronal activity is paralleled by a significant reduction in OX neurons in the LH of mutant mice. Therefore, we propose that an imbalance between OX- and MCH-expressing neurons in the LH of mutant mice reflects a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake, and temperature control.

Authors

Marta Pace, Matteo Falappa, Andrea Freschi, Edoardo Balzani, Chiara Berteotti, Viviana Lo Martire, Fatemeh Kaveh, Eivind Hovig, Giovanna Zoccoli, Roberto Amici, Matteo Cerri, Alfonso Urbanucci, Valter Tucci

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Figure 3

Snord116 loss significantly impacts molecular machinery in the hypothalamus.

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Snord116 loss significantly impacts molecular machinery in the hypothal...
(A and B) Venn diagrams illustrating the number of differentially expressed genes (DEGs) that are downregulated (A) and upregulated (B) in the hypothalamus of Prader–Willi syndrome (PWS) PWScrm+/p− mice relative to control mice and that overlap in human patients (29). The results of gene ontology (GO) enrichment analysis of biological processes for the overlapping DEGs are also shown in both A and B. (C) Volcano plots of 637 and 727 DEGs in PWScrm+/p− mice in group 1 (G1; non–sleep deprived). (D) Significantly down- and upregulated genes in the hypothalamus of PWScrm+/p− mutant mice compared with PWScrm+/p+ control mice affected by sleep deprivation (G2 versus G3). (E) GO enrichment analysis of biological processes for 833 (804 down- and 29 upregulated genes in D) DEGs in PWScrm+/p−mutant mice that are significantly affected by sleep deprivation. (F) Heatmap of the relative expression of imprinted genes common in humans and mice assessed in PWScrm+/p− mutant mice compared with the PWScrm+/p+ mice in G1, G2, and G3 (Supplemental Tables 8 and 9). PWScrm+/p− mice and PWScrm+/p+ mice at 3 different time points at ZT 0 (G1; PWS, n = 3, and WT, n = 3), immediately after 6 hours of total SD (G2; PWS, n = 4, and WT, n = 4), and 1 hour after previous SD (G3, n = 4; WT, n = 4).

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