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

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 1

Loss of paternal Snord116 alters neuronal dynamics in the LH associated with sleep and food.

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Loss of paternal Snord116 alters neuronal dynamics in the LH associated ...
(A) The cartoon shows mice chronically implanted with a microwire array of 16 channels and with an EEG-EMG wireless transmitter. The correct placement of the SUA electrode was histologically verified by 40-μm Nissl-stained coronal brain sections (bregma, –1.10/–1.90). (B) The experimental design used to record SUA and the sleep-wake cycle. (C) An example of sleep stages (wakefulness in gray; sleep, including both NREM and REM sleep stages, in orange) aligned with the firing rate recorded in the LH. The heatmaps show the response firing rate in spikes/second from 0 Hz (blue) to 20 Hz (red). (D) The heatmaps show the response firing rate used to classify neurons before and after food consumption (firing rate in spikes/second from 0 Hz [blue] to 20 Hz [red]). (E) Violin plots of classified units according to the sleep-wake cycle according to ANOVA followed by post hoc Bonferroni’s correction (P < 0.05). (F) Violin plots of classified units according to their discharge related to food consumption (paired Student’s t test of the firing rate between before and after the pellet was released, binned at 50 ms, P < 0.05). (G) The pie chart represents the distribution of recorded neurons according to the sleep-wake stage: wake (W-max, in green), sleep (both NREM and REM sleep, S-max, in blue), and not responding (ws, yellow). Food-related neurons are classified as Type I neurons, in gray; Type II neurons are in green; and Type III neurons are in red. Differences between the 2 genotypes are indicated by $, while differences within groups across time points are indicated by §. Significance was computed with the χ2 test; for details on the statistical analysis, see Supplemental Tables 2–4. The 2 genotypes investigated were PWScrm+/p− mice (n = 4) and PWScrm+/p+ mice (n = 4).