Responses to Artificial Selection for Voluntary Activity in Mice

University Of California-Riverside, Riverside CA

Investigators

Abstract

Natural and sexual selection act on complex, highly integrated phenotypes, but theories of how evolutionary response will occur across multiple levels of biological organization are non-comprehensive, and existing empirical tests are both fragmentary and inconclusive. Previous NSF support allowed development of a novel model system to study multi-level evolutionary responses to selection for high locomotor activity. Selective breeding for high voluntary wheel running was implemented with outbred laboratory mice. By generation 16, mice in the 4 replicate selection (S) lines ran 170% more than in the 4 randombred control (C) lines (for females, " 15 vs. 5.5 km/day). This difference continued for generations 17-29, indicating a selection limit. Increased activity has occurred primarily by higher running speed. S mice run more at weaning and for at least 18 months. Proposed research will test the nature of the physiological limit to selection, elucidate the mechanisms of locomotor adaptation, and explore the neurobiology of increased activity. Research will emphasize training of graduate and undergraduate students, as well as a postdoctoral researcher. A lack of evolutionary plasticity in maximal aerobic speed is hypothesized to limit further increase in wheel running. Effects of both increased and decreased oxygen on wheel running and on maximal oxygen consumption will be studied. The energetic cost of locomotion will be measured during both wheel and treadmill running. Lung diffusing capacity will be estimated morphometrically. Components of the skeleton will be examined for differences in size, shape, symmetry, and amount of secondary remodeling. Myosin heavy-chain isoform expression will be quantified in hindlimb muscle, and the "mighty mini-muscles" that occur in two of the selected lines will be characterized biochemically and by electron microscopy. For many of the above-mentioned traits, both genetic and phenotypic plasticity, and potential interactions, will be examined by measuring S and C mice that have been housed chronically with or without wheel access. Immunocytochemistry with cFos as an indicator of neuronal activity will be used to compare key brain regions in S and C mice at rest and during peak wheel running (motivation, reward, & addiction; voluntary control of movement; spatial memory & learning). Results will lead to a comprehensive understanding of how increased activity levels evolve in a model mammalian system. Mice will be made available to other researchers and they will be an important model for studying effects of exercise on physical fitness, health, and aging.