Loss of Snord116 impacts lateral hypothalamus, sleep, and food-related behaviors
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
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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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 2

Homeostatic regulation and thermoregulatory response.

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Homeostatic regulation and thermoregulatory response. (A) REM distributi...
(A) REM distribution in PWScrm+/p+ and PWScrm+/p– mice over a 24-hour (LD:12/12). Baseline (BL), 6 hours sleep deprivation (SD), and 18 hours rebound (RB) are shown. Data are shown as 2-hour bin percentages. Conditions: 22°C and 30°C (TNZ). REM differences across the 2 cohorts (2-way ANOVA; time, F[20,160] = 8.66, P ≤ 0.0001; genotypes, F[8, 160] = 3.33, P ≤ 0.001); at TNZ (2-way ANOVA; time, F[11, 88] = 11.61, P ≤ 0.0001). PWScrm+/p– mice showed an increase in REM sleep (F[1.85,4.74]= 18.06, P = 0.0082). Theta power in REM increased in mutants (2-way ANOVA; F[11,88]= 3.08, P ≤.001 “time”; F(1,8) = 8.04,P = 0.02 “genotypes”). (B) PWScrm+/p+ mice displayed an increased delta from ZT6 to ZT10 (2-way ANOVA: F[11,88]= 28.77 P ≤ 0.0001 “interaction”), while mutants showed a mild increase at ZT 6 (2-way ANOVA; F[11,88] = 12.25 P ≤ 0.0001 “interaction”). PWScrm+/p– mice showed lower delta than PWScrm+/p+ mice in RB (unpaired t test: t[8] = 2.31, P = 0.04). PWScrm+/p– mice (n = 10, 5 mice at 22°C and 5 mice at 30°C) and PWScrm+/p+ mice (n = 10, 5 mice at 22°C and 5 mice at 30°C). (C) T-tail, Heat loss index (HLI), and body temperature profiles are expressed as 2-hour mean ± SEM. Mutants showed increased body temperature at ZT 6 at 22°C (2-way ANOVA: F[11,88] = 3.53, P = 0.0004 “time”; F[11,88] = 7.86, P ≤ 0.0001 “genotypes”). At 30°C, T-tail (2-way ANOVA; F[11,88] = 2.68, P ≤ 0.0001; “interaction”) and HLI (2-way ANOVA; main effect of time of day, F[11,88] = 4.72, P ≤ 0.0001 “interaction”) were increased in PWScrm+/p+ mice. PWScrm+/p– mice (n = 10, 5 mice at 22°C and 5 mice at 30°C) and PWScrm+/p+ mice (n = 10, 5 mice at 22°C and 5 mice at 30°C). (D) PWScrm+/p– mice showed an increase in Ppox (unpaired t test; t[8] = 2.49, P = 0.03). (E) Cell count distribution of OX immunoreactive neurons (upper) and MCH immunoreactive neurons (below) in the lateral hypothalamus. Coronal sections were stained with OX- and MCH-specific antibodies, counterstained with DAPI, and scored. PWScrm+/p– mice (n = 4) and PWScrm+/p+ mice (n = 4). OX+ neurons were reduced in the PWScrm+/p– mutants (unpaired t test; t[33] = 3.85, P = 0.0005). Values are expressed as the percentage of positive neurons relative to all stained nuclei (mean ± SEM). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001.