Genetic differences in the behavioral organization of binge eating, conditioned food reward, and compulsive-like eating in C57BL/6J and DBA/2J strains

Abstract

Binge eating (BE) is a heritable symptom of eating disorders associated with anxiety, depression, malnutrition, and obesity. Genetic analysis of BE could facilitate therapeutic discovery. We used an intermittent, limited access BE paradigm involving sweetened palatable food (PF) to examine genetic differences in BE, conditioned food reward, and compulsive-like eating between C57BL/6J (B6J) and DBA/2J (D2J) inbred mouse strains. D2J mice showed a robust escalation in intake and conditioned place preference for the PF -paired side. D2J mice also showed a unique style of compulsive-like eating in the light/dark conflict test where they rapidly hoarded and consumed PF in the preferred unlit environment. BE and compulsive-like eating exhibited narrow-sense heritability estimates between 56 and 73 percent. To gain insight into the genetic basis, we phenotyped and genotyped a small cohort of 133 B6J x D2J-F2 mice at the peak location of three quantitative trait loci (QTL) previously identified in F2 mice for sweet taste (chromosome 4: 156 Mb), bitter taste (chromosome 6: 133 Mb) and behavioral sensitivity to drugs of abuse (chromosome 11: 50 Mb). The D2J allele on chromosome 6 was associated with greater PF intake on training days and greater compulsive-like PF intake, but only in males, suggesting that decreased bitter taste may increase BE in males. The D2J allele on chromosome 11 was associated with an increase in final PF intake and slope of escalation across days. Future studies employing larger crosses and genetic reference panels comprising B6J and D2J alleles will identify causal genes and neurobiological mechanisms.

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

“…Mice were trained in an intermittent, limited access, conditioned place preference ( CPP ) procedure to detect genetic differences in BE (Babbs et al 2018; Goldberg et al 2017; Kirkpatrick et al 2017). All mice on the Cyfip1 ,2 N/N background were experimentally naïve prior to BE training.…”

“…Cages were assigned to either the PF or Chow group in a counterbalanced design in order to ensure equal distribution across Sex, Genotype, Treatment, and PO. On D23, mice were assessed for compulsive eating and associated behaviors, as previously described (Babbs et al 2018; Kirkpatrick et al 2017). (Supplementary Material).…”

“…Slope analyses of food intake across days were calculated to detect escalation in consumption as a measure of BE-like behavior (Babbs et al 2012; Babbs et al 2018; Kirkpatrick et al 2017) using GraphPad Prism 7 (GraphPad Software, La Jolla, CA USA). Linear regression was employed to fit a line for each group, to calculate the slope and y-intercept, and to determine whether each slope was significantly different from zero.…”

“…We previously mapped the gene homolog Cyfip2 in BE (Kirkpatrick et al 2017). Because CYFIP1 deletion and reduced CYFIP1 expression are associated with more severe PWS (Type I) and hyperphagia in the PWP (FXS) and conversely, because gene duplication and thus, increased expression of CYFIP1 are associated with restrictive eating (Chang et al 2019), in this study, we tested the hypothesis that Cyfip1 haploinsufficiency would increase premorbid compulsive-like behavior and increase consumption of palatable food ( PF ) in our BE paradigm (Babbs et al 2018; Goldberg et al 2017; Kirkpatrick et al 2017). We tested the effect of Cyfip1 haploinsufficiency on two different Cyfip2 genetic backgrounds.…”

“…2009). Finally, because OC behaviors are associated with BE (Kessler et al 2016; Moore et al 2017; Wilfley et al 2016) and hyperphagia in PWS (Griggs et al 2015), we employed a battery of tests to assess anxiety-like and compulsive-like behaviors and post-BE training behaviors in Cyfip1 haploinsufficient mice, including compulsive-like eating and concomitant behaviors in the light/dark conflict test (Babbs et al 2018; Kirkpatrick et al 2017).…”