High‐resolution genetic mapping of mammalian motor activity levels in mice

Abstract

The generation of motor activity levels is under tight neural control to execute essential behaviors, such as movement toward food or for social interaction. To identify novel neurobiological mechanisms underlying motor activity levels, we studied a panel of chromosome substitution (CS) strains derived from mice with high (C57BL/6J strain) or low motor activity levels (A/J strain) using automated home cage behavioral registration. In this study, we genetically mapped the expression of baseline motor activity levels (horizontal distance moved) to mouse chromosome 1. Further genetic mapping of this trait revealed an 8.3‐Mb quantitative trait locus (QTL) interval. This locus is distinct from the QTL interval for open‐field anxiety‐related motor behavior on this chromosome. By data mining, an existing phenotypic and genotypic data set of 2445 genetically heterogeneous mice (http://gscan.well.ox.ac.uk/), we confirmed linkage to the peak marker at 79 970 253 bp and refined the QTL to a 312‐kb interval containing a single gene (A830043J08Rik). Sequence analysis showed a nucleotide deletion in the 3′ untranslated region of the Riken gene. Genome‐wide microarray gene expression profiling in brains of discordant F2 individuals from CS strain 1 showed a significant upregulation of Epha4 in low‐active F2 individuals. Inclusion of a genetic marker for Epha4 confirmed that this gene is located outside of the QTL interval. Both Epha4 and A830043J08Rik are expressed in brain motor circuits, and similar to Epha4 mutants, we found linkage between reduced motor neurons number and A/J chromosome 1. Our findings provide a novel QTL and a potential downstream target underlying motor circuitry development and the expression of physical activity levels.

Genetic architecture of voluntary exercise in an advanced intercross line of mice

“…Thus, on the basis of our present findings, we preliminarily conclude that fear, or lack thereof, of a novel object (e.g., a running wheel), or more general anxiety resulting from novel solitary housing conditions, may contribute to wheel running during initial exposure to wheels. Additionally, given the results of Kas et al (34), regions on MMU1 may play a role in the initial "learning" (broadly involving neural circuitry) process involved with wheel running. Follow-up investigations will be needed to elucidate a clearer picture of the regions on MMU1 identified here and their putative role in wheel-running behavior.…”

“…Regions on MMU1 have previously been implicated in both home-cage activity (34) and open-field behavior (27 (58,59). These regions have been shown to harbor genes involved in anxiety-like behavior in rodents, and human homologs have been associated with panic disorder (38).…”

“…8, 16, 57) and mice (e.g., Refs. 34,42,46,72). Like studies will continue to improve our understanding of the biological factors controlling individual variation in voluntary physical activity levels and, in conjunction with data reviewed by Bray et al (4), may aid clinicians in designing more effective physical activity-based therapies with targeted dosages and intensities (see Refs.…”

Parent-of-origin effects on voluntary exercise levels and body composition in mice

“…Although the predisposition to engage in voluntary physical activity is heritable, used as a common therapeutic intervention for health-related disease, and may be a primary factor in the prevention of chronic health conditions, the location or nature of underlying genetic variation is still an emerging field in humans (9,13,22,72) and rodents (49,51,56,71,79,88). Thus, our long-term goal was to create a mapping population to detect quantitative trait loci (QTL) underlying the predisposi-tion to engage in voluntary exercise.…”

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

“…Similarly, analysis of 26 RI strains identified a single QTL on mouse Chromosome 10 for a cone photoreceptor number that was then validated in the Chromosome 10 substitution strain derived from C57BL/6J and A/J (Whitney et al 2011). Kas et al (2009) used the CSSs to identify a single QTL on mouse Chromosome 1 for motor activity levels. Higher resolution mapping was then performed analyzing F2 offspring from the Chromosome 1 CSS strain as well as integrating existing mapping data from the HS mice.…”