The effect of the demyelinating agent cuprizone on binge-like eating of sweetened palatable food in female and male C57BL/6 substrains.

Binge eating is a heritable symptom of eating disorders with an unknown genetic etiology. Rodent models for binge-like eating (BLE) of palatable food permit the study of genetic and biological mechanisms. We previously genetically mapped a coding mutation in Cyfip2 associated with increased BLE of sweetened palatable food in the C57BL/6NJ versus C57BL/6J substrain. The increase in BLE in C57BL/6NJ mice was associated with a decrease in transcription of genes enriched for myelination in the striatum. Here, we tested the hypothesis that decreasing myelin levels with the demyelinating agent cuprizone would enhance BLE. Mice were treated with a 0.3% cuprizone home cage diet for two weeks. Cuprizone induced similar weight loss in both substrains and sexes that recovered within 48 h after removal of cuprizone. Following a three-week recovery period, mice were trained for BLE in an intermittent, limited access procedure. Surprisingly, cuprizone significantly reduced BLE in male but not female C57BL/6NJ mice while having no effect in C57BL/6J mice. Cuprizone also reduced myelin basic protein (MBP) at seven weeks post-cuprizone removal while having no effect on myelin-associated glycoprotein at this time point. C57BL/6NJ mice also showed less MBP than C57BL/6J mice. There were no statistical interactions of Treatment with Sex on MBP levels, indicating that differences in MBP reduction are unlikely to account for sex differences in BLE. To summarize, cuprizone induced an unexpected, significant reduction in BLE in C57BL/6NJ males, which could indicate genotype-dependent sex differences in the biological mechanisms of BLE.

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

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 (Cyfip2N/N) background and the BE-resistant C57BL/6J (Cyfip2J/J) background. Cyfip1+/- mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the Cyfip2N/N background. In contrast, maternal Cyfip1 haploinsufficiency on the BE-resistant Cyfip2J/J background induced a robust escalation in PF intake in wild-type Cyfip1J/J males while having no effect in Cyfip1J/- 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.

Individual differences in functional brain connectivity predict temporal discounting preference in the transition to adolescence.

The transition from childhood to adolescence is marked by distinct changes in behavior, including how one values waiting for a large reward compared to receiving an immediate, yet smaller, reward. While previous research has emphasized the relationship between this preference and age, it is also proposed that this behavior is related to circuitry between valuation and cognitive control systems. In this study, we examined how age and intrinsic functional connectivity strength within and between these neural systems relate to changes in discounting behavior across the transition into adolescence. We used mixed-effects modeling and linear regression to assess the contributions of age and connectivity strength in predicting discounting behavior. First, we identified relevant connections in a longitudinal sample of 64 individuals who completed MRI scans and behavioral assessments 2-3 times across ages 7-15 years (137 scans). We then repeated the analysis in a separate, cross-sectional, sample of 84 individuals (7-13 years). Both samples showed an age-related increase in preference for waiting for larger rewards. Connectivity strength within and between valuation and cognitive control systems accounted for further variance not explained by age. These results suggest that individual differences in functionalbrain organization can account for behavioral changes typically associated with age.