Research reportQuantitative trait loci for novelty/stress-induced locomotor activation in recombinant inbred (RI) and recombinant congenic (RC) strains of mice
Introduction
Anxiety disorders are a highly prevalent and seriously debilitating group of disorders that produce an enormous impact on society in terms of comorbidity with medical disorders [17], [52], as well as lost productivity and mental health care costs [10]. Evidence from family, twin and linkage studies has shown that genes influence the development of anxiety-related disorders [3], [15], [16], [19], [23], [41], [44], [45]. Quantitative phenotypes have been recently defined in the human literature which describes the liability to “anxiety-proneness” in terms of early-onset, severe and comorbid anxiety disorders [43]. The mouse equivalents of anxiety-proneness include responses to novelty/stress in an open-field, elevated plus maze or light/dark box [6] as well as fear-potentiated startle [40]. When mice are introduced into a novel open-field (OF) environment, normal exploratory behavior is inhibited. Mice that are relatively inactive when exposed to a novel OF are regarded as highly anxious and show correlated responses on tests of timidity, fearfulness and avoidance [7]. The measurement of behavior in the OF has a number of advantages as a model system, including that fact that exploration it is a well-defined innate behavioral response with broad generalizability across species, and it has been shown to be heritable [13].
Trullas and Skolnick [46] ranked 16 inbred strains of mice on anxiety-related phenotypes; the A/J (A) and C57BL/6 J (B6) strains were found to be at opposite ends of the phenotypic spectrum. The A strain has been identified as one of the most anxiogenic-like or fearful strain across a number of paradigms [1], [6], [29], [50]. Mathis et al. [28] characterized the A and B6 progenitors as well as the AXB/BXA RIS derived from them for OF activity and transitions in a light/dark paradigm. The strongest linkages for OF activity were found for markers on chr 3 (Mpmv-9), chr 9 (Bgl) and chr 11 (Es-3).
Flint et al. [8] used an F2 intercross of DeFries High and Low lines of mice—originally selected for high versus low activity in an open field—to map significant quantitative trait loci (QTLs) for OF activity to chr 1 (D1Mit150, 100 cM), chr 4 (D4Mit81, 38 cM), chr 12 (D12Mit47, 45 cM), chr 15 (D15Mit63, 29.2 cM), chr 17 (D17Mit24, 20.43 cM) and chr 18 (D18Mit67, 4 cM). In follow-up studies, Turri et al. [47], [48] used this F2 cross and several behavioral paradigms to demonstrate that QTLs on chromosomes 1, 4 and 15 were common across multiple anxiety-related behavioral measures. The QTL on chr 4 was associated general activity levels, while the QTL on chr 1 influenced exploratory behavior and the QTL on chr 15 acted primarily on avoidance behavior. Most recently, Turri et al. [49] utilized a multivariate analysis of 23 anxiety-related traits to identify novel QTLs on chrs 3, 9, 13 and 17 in F2 mice.
Using an F2 intercross between A and B6 mice, Gershenfeld and Paul [12] mapped QTL for “fear-like” behaviors using the open-field (thigmotaxis) and light/dark (LD) transition paradigms. Significant QTL were mapped to chr 10 for LD behavior and chr 1 for thigmotaxis. Additional suggestive QTL for ambulation and rearing were mapped to chr 1 (D1Mit116, 100 cM), chr 10 (D10Mit237, 74.1 cM), chr 15 (D15Mit107, 41.5 cM) and chr 19 (D19Mit46, 24 cM) [12]. The loci on chr 1 (∼100 cM) and chr 15 (∼41 cM) independently replicated QTL found by Flint et al. [8] and Turri et al. [47] for activity in an open-field.
In a recent publication Henderson et al. [18] utilized an extensive test battery to identify anxiety-related QTLs in F2 mice derived from crosses of H1 and H2 strains (high activity) and L1 and L2 (low activity) strains. Phenotypic measures were derived from open-field, light-dark, mirror-chamber, elevated-plus maze and elevated square-maze paradigms. QTLs on chromosomes 1, 15 and 18 were associated anxiety-related behaviors.
In summary, a number of studies have mapped QTL for traits related to anxiety, emotionality and activity under novel conditions in an open field apparatus [e.g. [8], [11], [12]]. Despite a number of procedural differences between studies (e.g. behavioral paradigm, strain and gender of mice, age at testing) there were several QTLs, most notably on chromosomes 1 and 15, that have been consistently identified for anxiety. Some loci were less consistently identified across studies, suggesting that further confirmation is required using a variety of methods including RI strains, F2 intercrosses or congenic mice. Therefore, the objective of the present study was to compare QTLs for novelty/stress induced activation in two series of recombinant strains of mice—the AXB/BXA recombinant inbred strains (RIS) and the AcB/BcA recombinant congenic strains (RCS)—each independently derived from the A and B6 progenitors. The entire available series of RIS and RCS strains were tested for novelty/stress-induced activation using an OF paradigm in the same laboratory under identical conditions.
Section snippets
Progenitor and RI strains
Male and female C57BL/6 J, A/J, and breeder pairs of all available AXB/BXA recombinant inbred (RI) strains were purchased from Jackson Laboratory (Bar Harbor, Maine). Four breeder pairs of each AXB and BXA RI strain were established and maintained in an animal colony controlled for temperature and humidity on a 12-h day/12-h night cycle (lights on between 6.00 a.m. and 6.00 p.m.). Breeder pairs were kept for 8 months providing 4 to 6 litters. The mice were housed in standard shoe-box solid
AXB/BXA recombinant inbred strains
Mean novelty/stress-induced locomotor responses for the A/J, C57BL/6 J and AXB/BXA RI mice are presented separately for males and females in Fig. 1. Strain differences were confirmed in a two-way ANOVA (strain × gender) using total activity scores over the entire 15 min monitoring period. The analysis yielded a significant main effect for strain [F(24,1103) = 26.6, p < 0.0001], but no main effect for gender [F(1,1103) = 0.063, p = 0.80] or a strain by gender interaction [F(24,1103) = 1.14, p = 0.29).
Discussion
A wide, continuous range of novelty/stress-induced activation was displayed by the AXB/BXA RIS and AcB/BcA RCS, findings that are consistent with a quantitative trait involving additive effects of several genes. A large number of strains in both the RIS and RCS show significantly higher activational responses than either the A/J or B6 progenitors, suggesting potential gene interactions. In this context, it should be noted that correlations between novelty/stress-induced activation and the SDP
Acknowledgments
This research was supported by funds awarded to K. Gill from the Canadian Institutes of Health Research (CIHR). The authors which to thank G. Gauthier for her technical assistance in the testing of animals. In addition, the authors acknowledge Emerillon Therapeutics Inc. as well as Dr. E. Skamene, Director of the Research Institute of the McGill University Health Centre, for providing access to the AcB/BcA mice and genetic maps.
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