Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades

Abstract

If we conduct the same experiment in two laboratories or repeat a classical study many years later, will we obtain the same results? Recent research with mice in neural and behavioral genetics yielded different results in different laboratories for certain phenotypes, and these findings suggested to some researchers that behavior may be too unstable for fine-scale genetic analysis. Here we expand the range of data on this question to additional laboratories and phenotypes, and, for the first time in this field, we formally compare recent data with experiments conducted 30-50 years ago. For ethanol preference and locomotor activity, strain differences have been highly stable over a period of 40-50 years, and most strain correlations are in the range of r = 0.85-0.98, as high as or higher than for brain weight. For anxiety-related behavior on the elevated plus maze, on the other hand, strain means often differ dramatically across laboratories or even when the same laboratory is moved to another site within a university. When a wide range of phenotypes is considered, no inbred strain appears to be exceptionally stable or labile across laboratories in any general sense, and there is no tendency to observe higher correlations among studies done more recently. Phenotypic drift over decades for most of the behaviors examined appears to be minimal.

Fig. 1.

Correlations between means of inbred strains observed in different laboratories. The dashed line indicates identical results for two laboratories, and the gray line is the best fit of data from the y axis to data on the x axis, plotted for the actual range of data. When this line is above the dashed line, the means scores in laboratory Y were generally greater than for the corresponding strains tested in laboratory X. Numbers 1–21 correspond to strains shown at the bottom of the figure, with the most common strains shown as colored numerals. Effect sizes from the ANOVAs are shown for the strain main effect and strain-by-laboratory interaction. The significance (P) of the interaction effect is also indicated. NS denotes an interaction not significant at P = 0.05. (A) Brain weight measured in the Edmonton laboratory versus four other laboratories. Data for Edmonton and Portland were collected in 2002 and published in ref. . (B) Preference for 10% ethanol solution versus tap water. Nine additional strains not studied in the D.W. and J.C.C. laboratories were included in this set of comparisons (22, BALB/cJ; 23, BUB/BnJ; 24, C57BLKS/J; 25, CBA/J; 26, CE/J; 27, I/LnJ; 28, LP/J; 29, RIIIS/J; 30, SEA/GnJ). (C) Locomotor activity in Edmonton versus four other laboratories, scaled to centimeters per minute.

Fig. 2.

Percent time spent exploring the two open arms of the elevated plus maze. Lines, effect sizes, and strain numbers in A and B have the same meanings as in Fig. 1. (A) For data in the Edmonton and Portland laboratories, the value for the wild-derived inbred strain PERA/Ei (number 15 in yellow circle) in Portland was considerably greater than in Edmonton, but other means were generally very similar for the two laboratories. (B) There were remarkable discrepancies for the strains BALB/cByJ (no. 3), C3H/HeJ (no. 5), and C57BL/6J (no. 6) in the Edmonton laboratory versus the study of Trullas and Skolnick (30). (C) Four of the same strains were tested in 1998 (1) and again in 2002 as part of the Mouse Phenome Project using the same apparatus and protocols as in 1998, but the actual laboratories had moved to new locations in each university, resulting in substantially different data, especially in Edmonton, where every strain was above 30% (blue line) in 1998. (D) Four inbred strains were tested recently in eight laboratories, indicated in the figure by the surname of the first author; complete references (–35) are provided in the text. The substrains were not identical across all laboratories shown in D. Dashed lines show that the profile of strain means was very similar for three studies [Ducottet and Belzung (32), Griebel et al. (33), and Khrapova et al. (34)], but remarkable differences between other laboratories are evident.