Academic journal article Genetics

Working-for-Food Behaviors: A Preclinical Study in Prader-Willi Mutant Mice

Academic journal article Genetics

Working-for-Food Behaviors: A Preclinical Study in Prader-Willi Mutant Mice

Article excerpt

(ProQuest: ... denotes formulae omitted.)

PRADER-WILLI syndrome (PWS) is a rare neurodevelopmental disorder that is caused by genomic imprinting defects within the small nuclear ribonucleoprotein N (SNPRN) cluster of the human chromosome region 15q1113. PWS is characterized by developmental delays, feeding problems, hyperphagia, behavioral disorders, and sleep-wake disturbances (Peters 2014; Tucci 2016). In preclinical investigations, mouse models with different deletions at the orthologous locus on mouse chromosome 7C have shown the main features of the human syndrome, such as growth retardation (Rozhdestvensky etal. 2016), hyperphagia (Davies etal. 2015), and sleep abnormalities (Lassietal. 2016). Small nucleolar RNA 116 (Snord116, also called MBII-85), a paternally expressed noncoding gene that modifies other small nuclear RNAs (snoRNAs), is considered one of the key players in PWS (Peters 2014). Expression studies of the snoRNAs MBI-36, MBII-85 (Snord116), MBII-52 (Snord115), and MBII-13 show that these snoRNAs are either exclusively or prevalently expressed in the brain (Cavaillé et al. 2000). Yet, it has been demonstrated that MBII-52, MBII-85, and MBII13 are imprinted in the mouse brain. However, no analysis of the imprinting status of Snord116 in different areas of the brain has yet been conducted. Mice that maternally inherit the Snord116 deletion are phenotypically similar to wild type (Skryabin et al. 2007); thus, the paternal inheritance of the mutation is the critical heterozygous pattern to be investigated. However, several studies have indicated that the investigation of homozygous mutants may also be needed to fully understand the role of Snord116 (Wolf et al. 2008; Qi et al. 2016). Biallelic deletion of Snord116 in mice produces classical developmental phenotypes associated with reduced body weight and growth; however, as mutant mice enter adulthood, hyperphagia is observed, and the balance between energy intake and expenditure is altered (Qi et al. 2016). The regulatory processes involved in maintaining body weight homeostasis through daily food intake and expenditure include a proper balance between thermoregulation and physiological states (Overton and Williams 2004; Florant and Healy 2012), and between behavior and cognitive processes (Chen et al. 2016; Higgs 2016). Recently, we studied the link between thermogenesis and sleep in PWScrm+/p2 mutant mice, reporting a significant increase in the circadian variations of body temperature that disrupt sleep in mutants (Lassi et al. 2016).The latter study suggests that Snord116 is involved in sleep-wake regulation, and in the daily control of body temperature. Thermogenesis plays an important role in adjusting metabolism both during sleep, when energy expenditure is reduced owing to resting, and during wakefulness, when the individual is searching for food and engaging in physical activity (Schmidt 2014). Food intake is governed by at least two important motivations, the need for calories, and the hedonic value of food (Challet and Mendoza 2010). However, food intake is also structured by fundamental cognitive/behavioral processes, such as clock-dependent mechanisms (Mistlberger 2011). By studying the PWSICdel mouse line, Davies et al (2015) reported that hyperphagia in these PWS mutant mice is due to a constant need for calories, and that the related behavior is not due to an increased hedonic value of food intake. In particular, the PWSICdel mice presented similar behavioral licking responses compared to control mice toward palatable food. That study concluded that the hyperphagic trait in mutant mice is due mainly to one of two motivational systems; it remains to be understood whether the specific need for calories influences behavioral or cognitive processes in mutants as they access food during the day. Therefore, here, we explored fundamental aspects of the behavioral and cognitive systems associated with food-intake (i.e., working-for-food behavioral strategies) in the mouse mutant model PWScrm+/p2 (Skryabin et al. …

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