No 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.

Thermal nociception involves the transmission of temperature-related noxious information from the periphery to the CNS and is a heritable trait that could predict transition to persistent pain. Rodent forward genetics complement human studies by controlling genetic complexity and environmental factors, analysis of end point tissue, and validation of variants on appropriate genetic backgrounds. Reduced complexity crosses between nearly identical inbred substrains with robust trait differences can greatly facilitate unbiased discovery of novel genes and variants. We found BALB/cByJ mice showed enhanced sensitivity on the 53.5°C hot plate and mechanical stimulation in the von Frey test compared to BALB/cJ mice and replicated decreased gross brain weight in BALB/cByJ versus BALB/cJ. We then identified a quantitative trait locus (QTL) on chromosome 13 for hot plate sensitivity (LOD = 10.7; p < 0.001; peak = 56 Mb) and a QTL for brain weight on chromosome 5 (LOD = 8.7; p < 0.001). Expression QTL mapping of brain tissues identified H2afy (56.07 Mb) as the top transcript with the strongest association at the hot plate locus (FDR = 0.0002) and spliceome analysis identified differential exon usage within H2afy associated with the same locus. Whole brain proteomics further supported decreased H2AFY expression could underlie enhanced hot plate sensitivity, and identified ACADS as a candidate for reduced brain weight. To summarize, a BALB/c reduced complexity cross combined with multiple -omics approaches facilitated identification of candidate genes underlying thermal nociception and brain weight. These substrains provide a powerful, reciprocal platform for future validation of candidate variants.