Genetic analysis of complex traits in the emerging Collaborative Cross.

The Collaborative Cross (CC) is a mouse recombinant inbred strain panel that is being developed as a resource for mammalian systems genetics. Here we describe an experiment that uses partially inbred CC lines to evaluate the genetic properties and utility of this emerging resource. Genome-wide analysis of the incipient strains reveals high genetic diversity, balanced allele frequencies, and dense, evenly distributed recombination sites-all ideal qualities for a systems genetics resource. We map discrete, complex, and biomolecular traits and contrast two quantitative trait locus (QTL) mapping approaches. Analysis based on inferred haplotypes improves power, reduces false discovery, and provides information to identify and prioritize candidate genes that is unique to multifounder crosses like the CC. The number of expression QTLs discovered here exceeds all previous efforts at eQTL mapping in mice, and we map local eQTL at 1-Mb resolution. We demonstrate that the genetic diversity of the CC, which derives from random mixing of eight founder strains, results in high phenotypic diversity and enhances our ability to map causative loci underlying complex disease-related traits.

Interspecies genetics of eating disorder traits.

Family and twin studies have indicated that genetic factors play a role in the development of eating disorders, such as anorexia and bulimia nervosa, but novel views and tools may enhance the identification of neurobiological mechanisms underlying these conditions. Here we propose an integrative genetic approach to reveal novel biological substrates of eating disorder traits analogous in mouse and human. For example, comparable to behavioral hyperactivity that is observed in 40-80% of anorexia nervosa patients, inbred strains of mice with different genetic backgrounds are differentially susceptible to develop behavioral hyperactivity when food restricted. In addition, a list of characteristics that are relevant to eating disorders and approaches to their measurement in humans together with potential analogous rodent models has been generated. Interspecies genetics of neurobehavioral characteristics of eating disorders has the potential to open new roads to identify and functionally test genetic pathways that influence neurocircuits relevant for these heterogeneous psychiatric disorders.

Antinociceptive actions of peripheral glucose administration.

The effects of intraperitoneal (ip) D-glucose administration on antinociception were studied in male Long-Evans rats. Rats were assessed for antinociception using the hot-water tail-withdrawal procedure (54±0.2 °C) to determine if peripheral administration of D-glucose (300, 560, or 720 mg/kg) would enhance morphine-mediated antinociception (MMA) (1.0, 3.0, 4.2, 5.6, and 10.0mg/kg cumulative-dosing regime) and if D-glucose (560, 720, or 1000 mg/kg) alone could produce antinociceptive activity that was naloxone (0.32 mg/kg) reversible. Additionally, the actions of D-glucose on MMA were compared with a stereoisomer, L-glucose, which is not metabolized. The results of these studies demonstrate that peripheral administration of D-glucose significantly enhances MMA and that D-glucose alone produces antinociceptive actions that are potentially mediated by the endogenous opioid system. Furthermore, L-glucose failed to have an effect on MMA suggesting that the alterations in antinociception seen with D-glucose are not due to stressors such as osmolality or injection. The current studies provide evidence that D-glucose alteration of antinociception is not simply a response to taste or gustation.