We have developed an association-based approach using classical inbred strains of mice in which we correct for population structure, which is very extensive in mice, using an efficient mixed-model algorithm. Our approach includes inbred parental strains as well as recombinant inbred strains in order to capture loci with effect sizes typical of complex traits in mice (in the range of 5 % of total trait variance). Over the last few years, we have typed the hybrid mouse diversity panel (HMDP) strains for a variety of clinical traits as well as intermediate phenotypes and have shown that the HMDP has sufficient power to map genes for highly complex traits with resolution that is in most cases less than a megabase. In this essay, we review our experience with the HMDP, describe various ongoing projects, and discuss how the HMDP may fit into the larger picture of common diseases and different approaches.

Background-Behavioral inflexibility is a feature of schizophrenia, attention deficithyperactivity disorder, and behavior addictions that likely results from heritable deficits in the inhibitory control over behavior. Here, we investigate the genetic basis of individual differences in flexibility, measured using an operant reversal learning task.

Rationale Various dimensions of impulsivity have been linked to substance abuse and dependence, both as consequences of, and as predisposing factors to addiction. With respect to the latter, they may be quantitative indicators of liability for substance use disorders (SUD) and aid in determining underlying genetic influences. We have previously determined that inhibitory control over impulsive responding, as measured by a reversal learning task, is heritable and under substantial genetic control, however their role as explaining variables for aspects of SUD have not been well explored. Objective The aim of this study was to test for an association between genetically-determined differences in inhibitory control and addiction-related phenotypes, such that phenotypes of poor inhibitory control would predict propensity for elevated operant drug-seeking and –taking behaviors. Methods Mice from BxD strains with either good reversal learning (GRL) or poor reversal learning (PRL) ability were tested for intravenous cocaine self-administration under FR1, FR2, and FR5 reinforcement schedules. Additionally, locomotor responses to experimenter-delivered cocaine were assessed. Results Compared to GRL strains, PRL strains acquired self-administration behavior more rapidly and administered cocaine at greater rates under all schedules of reinforcement, without any differences in discrimination index. In addition, PRL mice also exhibited increased responding during time-out periods. PRL strains also showed larger locomotor responses to 10 or 20 mg/kg injections of cocaine. Conclusions These studies demonstrate that heritable strain differences in inhibitory control do influence drug self-administration, thus suggest that genetically-driven impulsivity of this type may predispose susceptibility to drug abuse and addiction.

Increased bone fragility was observed in chickens fed diets containing less than 1 ppm copper. Using a device that was designed to measure torsion during fracture, it could be demonstrated that bone from copper-deficient chicks fractured with less deformation and torque than bone from control chicks. The collagen of bone from copper-deficient chicks appeared to contain fewer cross-links than normal bone. The introduction of artificial cross-links into collagen from copper-deficient chick bone by formaldehyde and NaBH4 treatments improved bone strength and strain (deformation) so that it was comparable with normal bone. Copper deficiency blocks the formation of cross-links in collagens and elastin from various tissues. It is felt that the bone fragility related to nutritional copper deficiency is the result of decreased bone collagen cross linking. Arterial elastin metabolism was also investigated. By radioactively labeling arterial soluble elastin (tropoelastin) in vivo by an intraperitoneal injection of [G-3H]valine, it could be demonstrated that copper deficiency appeared to reduce its rate of metabolic turnover. Soluble elastin or tropoelastin is assumed to be the precursor of mature or insoluble elastin. The observations presented here are consistent with the view that by retarding the steps associated with elastin cross-link formation, the incorporation of soluble elastin into mature elastin may be retarded as well.

Background: The relative growth of the neocortex parallels the emergence of complex cognitive functions across species. To determine the regions of the mammalian genome responsible for natural variations in cortical volume, we conducted a complex trait analysis using 34 strains of recombinant inbred (Rl) strains of mice (BXD), as well as their two parental strains (C57BL/6J and DBA/2J). We measured both neocortical volume and total brain volume in 155 coronally sectioned mouse brains that were Nissl stained and embedded in celloidin. After correction for shrinkage, the measured cortical and noncortical brain volumes were entered into a multiple regression analysis, which removed the effects of body size and age from the measurements. Marker regression and interval mapping were computed using WebQTL.