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The interaction between genotype and environment is recognized as an important source of experimental variation when complex traits are measured in the mouse, but the magnitude of that interaction has not often been measured. From a study of 2448 genetically heterogeneous mice, we report the heritability of 88 complex traits that include models of human disease (asthma, type 2 diabetes mellitus, obesity, and anxiety) as well as immunological, biochemical, and hematological phenotypes. We show that environmental and physiological covariates are involved in an unexpectedly large number of significant interactions with genetic background. The 15 covariates we examined have a significant effect on behavioral and physiological tests, although they rarely explain >10% of the variation. We found that interaction effects are more frequent and larger than the main effects: half of the interactions explained >20% of the variance and in nine cases exceeded 50%. Our results indicate that assays of gene function using mouse models should take into account interactions between gene and environment.

The effects of timed food restriction on the circadian rhythm of mice kept in a 12:12 light-dark cycle are investigated. Calorie-restricted subjects exhibited nocturnal behavior one hour earlier than did normal controls. Further, varying hypocaloric feeding at 2, 10, 14 and 22 hours after the onset of the light cycle advanced the onset of nocturnal activities by 1, 3, 1 and 1 hour, respectively.

The Wistar Kyoto (WKY) rat is hyperreactive to stress and exhibits depressive-like behavior in several standard behavioral tests. Because patients with depressive disorders often exhibit disruptions in the circadian rhythm of activity, as well as altered secretory patterns of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid hormones, we tested the hypothesis that these phenomena occur in the WKY rat. Plasma ACTH and corticosterone levels remained significantly higher after the diurnal peak for several hours in WKY rats relative to Wistar rats. Also, plasma levels of thyroid-stimulating hormone were significantly higher in WKY relative to Wistar rats across the 24-h period, despite normal or slightly higher levels of 3,5,3'-triiodothyronine. In addition, under constant darkness conditions, WKY rats exhibited a shorter free running period and a decreased response to a phase-delaying light pulse compared with Wistar rats. In several ways these results are similar to those seen in other animal models of depression as well as in depressed humans, suggesting that the WKY rat could be used to investigate the genetic basis for these abnormalities. hypothalamic-pituitary-adrenal axis; hypothalamic-pituitary-thyroid axis; forced swim test