Cyfip1 Haploinsufficiency Increases Compulsive-Like Behavior and Modulates Palatable Food Intake in Mice: Dependence on Cyfip2 Genetic Background, Parent-of Origin, and Sex

Abstract

Binge eating (BE) is a heritable trait associated with eating disorders and involves episodes of rapid, large amounts of food consumption. We previously identified cytoplasmic FMR1-interacting protein 2 ( Cyfip2 ) as a genetic factor underlying compulsive-like BE in mice. CYFIP2 is a homolog of CYFIP1 which is one of four paternally-deleted genes in patients with Type I Prader-Willi Syndrome (PWS), a neurodevelopmental disorder whereby 70% of cases involve paternal 15q11-q13 deletion. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/−) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two Cyfip2 genetic backgrounds, including the BE-prone C57BL/6N ( Cyfip2 N/N ) background and the BE-resistant C57BL/6J ( Cyfip2 J/J ) background. Cyfip1 +/− mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the Cyfip2 N/N background. In contrast, maternal Cyfip1 haploinsufficiency on the BE-resistant Cyfip2 J/J background induced a robust escalation in PF intake in wild-type Cyfip1 J/J males while having no effect in Cyfip1 J/- males. Notably, induction of behavioral phenotypes in wild-type males following maternal Fmr1 +/− has previously been reported. In the hypothalamus, there was a paternally-enhanced reduction in CYFIP1 protein whereas in the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Nochange in FMR1 protein (FMRP) was observed in Cyfip1 +/− mice, regardless of parental origin. To summarize, Cyfip1 haploinsufficiency increased compulsive-like behavior and induced genetic background-dependent, sex-dependent, and parent-of-origin-dependent effects on PF consumption and CYFIP1 expression that could have relevance for neurodevelopmental and neuropsychiatric disorders.

Content and Performance of the MiniMUGA Genotyping Array: A New Tool To Improve Rigor and Reproducibility in Mouse Research

“…A second area of potential research is the expansion of the RCC paradigm beyond the narrow confines of C57BL/6 substrains ( Kumar et al 2013 ; Babbs et al 2019 ; Treger et al 2019 ). A successful RCC requires complete knowledge of the sequence variants shared and private to the set of substrains that will be used in the mapping experiments.…”

“…Two such areas of research are sex chromosome biology and genetic mapping using reduced complexity crosses (RCC; Kumar et al 2013, Bryant et al 2020. RCC are predicated on the idea that if heritable phenotype is variable between a pair of closely related laboratory substrains, then QTL mapping combined with a complete catalog of the few thousand variants that differ among these substrains can lead to the rapid identification of the candidate causal variants (Kumar et al 2013;Babbs et al 2019). The exact number of variants between a pair of substrains, or within a set of substrains, varies substantially but is several orders of magnitude fewer than between classical strains (Mortavazi et al 2020, MTF unpublished) This addresses one of the major limitations of standard mouse crosses, namely the cost in time and resources to move from QTL to quantitative trait variants (Scalzo et al 2008).…”

“…The exact number of variants between a pair of substrains, or within a set of substrains, varies substantially but is several orders of magnitude fewer than between classical strains (Mortavazi et al 2020, MTF unpublished) This addresses one of the major limitations of standard mouse crosses, namely the cost in time and resources to move from QTL to quantitative trait variants (Scalzo et al 2008). The RCC concept have been successfully demonstrated in crosses between C57BL/6J and C57BL/6NJ (Kumar et al 2013;Babbs et al 2019), but existing genotyping platforms do not support extension to other crosses because of the lack of sufficient informative markers to support robust QTL mapping. Identification of such markers requires WGS from all parental substrains used in RCC.…”

Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross

“…F2 mice were previously trained in an intermittent, limited access BLE procedure in a PF conditioned place preference (CPP) paradigm over 22 days (Babbs et al 2018) as described in the Supplementary Information and multiple publications (Babbs et al 2019(Babbs et al , 2020.…”

“…Cyfip2 +/-mice showed reduced BLE on the BLE-prone C57BL/6NJ (B6NJ) background . As subsequent study showed that haploinsufficiency of the closely related gene Cyfip1 also modulated BLE but in a complex manner that depended on C57BL/6 genetic background, sex, and parent-of-origin (Babbs et al 2019). Finally, knockout mice for casein kinase 1-epsilon (Csnk1e), a gene whose deletion enhances behavioral sensitivity to the stimulant, rewarding, and reinforcing responses to opioids and psychostimulants (Bryant et al 2012;Wager et al 2014) and is associated with opioid dependence in humans (Levran et al 2008(Levran et al , 2015, showed a robust, female-specific induction of BLE on the BLE-resistant C57BL/6J (B6J) background .…”