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Daily patterns of animal behavior are potentially of vast functional importance. Fitness benefits have been identified in nature by the association between individual timing and survival or by the fate of individuals after experimental deletion of their circadian pacemaker. The recent advances in unraveling the molecular basis of circadian timing enable new approaches to natural selection on timing. The investigators report on the effect and fate of the mutant Per2 Brdm1 allele in 4 replicate populations of house mice in a seminatural outside environment over 2 years. This allele is known to compromise circadian organization and entrainment and to cause multiple physiological disturbances. Mice (N = 250) bred from Per2Brdm1 heterozygotes were implanted subcutaneously with transponders and released in approximately Mendelian ratios in four 400 m 2 pens. An electronic system stored the times of all visits to feeders of each individual. The study first demonstrates that mice are not explicitly nocturnal in this natural environment. Feeding activity was predominantly and sometimes exclusively diurnal and spread nearly equally over day and night under the protective snow cover in winter. The effect of Per2 Brdm1 on activity timing is negligible compared to seasonal changes in all genotypes. Second, the Per2 Brdm1 allele did not have persistent negative effects on fitness. In the first year, the allele gradually became less frequent by reducing survival. New cohorts captured had the same Per2Brdm1 frequency as the survivors from previous cohorts, consistent with an absence of an effect on reproduction. In the second year, the allele recovered to about its initial frequency (0.54). These changes in selective advantage were primarily due to female mice, as females lived longer and the sex ratio dropped to about 25% males in the population. While it is unknown which selective advantage led to the recovery, the results caution against inferences from laboratory experiments on fitness consequences in the natural environment. It also demonstrates that the activity of mice, while strictly nocturnalPublished in " " which should be cited to refer to this work.

Variations in the extent of adult neurogenesis and natural and experimental factors controlling it have been described in laboratory animals. The wide range of variation seen even within a species, the mouse, raises the question as to which rates of neurogenesis can be expected in natural populations. Answering this question is important to evaluate the functional significance of adult neurogenesis under natural conditions and to define the factors controlling it. To address this issue, we investigated four species of wild-living rodents and outbred laboratory mice using markers for proliferating cells, Ki-67, and developing neurons, doublecortin and NeuroD. We found about four times as many Ki-67-positive cells per mm3 granule cell layer in two wood mouse species (Muridae; Apodemus spp.) than in bank and pine voles (Arvicolidae; Clethrionomys glareolus and Microtus subterraneus). Laboratory mice show proliferation rates between wood mice and voles. Markers for developing neurons, NeuroD and doublecortin, reflect the findings of proliferation activity. Hippocampal cell proliferation decreases dramatically with age in wild-living species. The onset of the downregulation varies among species. It occurs late in the life span of the yellow-necked wood mouse. In aged animals, the number of proliferating cells per mm3 granule cell layer is reduced to 19% of the adult value. Downregulation occurs early in pine voles, in which cell proliferation in adult animals is reduced to 33% of juvenile values. Proliferation and age-dependent changes along the deep border of the alveus and angular bundle follow those of the dentate gyrus. We conclude that cell proliferation and neurogenesis in the dentate gyrus vary significantly among wild-living rodents, and that they are downregulated with age, but at species-specific time points.

Summary Deletion of the p66Shc gene results in lean and healthy mice, retards aging, and protects from aging-associated diseases, raising the question of why p66 Shc has been selected, and what is its physiological role. We have investigated survival and reproduction of p66 Shc ) ⁄ ) mice in a population living in a large outdoor enclosure for a year, subjected to food competition and exposed to winter temperatures. Under these conditions, deletion of p66Shc was strongly counterselected. Laboratory studies revealed that p66 Shc ) ⁄ ) mice have defects in fat accumulation, thermoregulation, and reproduction, suggesting that p66Shc has been evolutionarily selected because of its role in energy metabolism. These findings imply that the health impact of targeting aging genes might depend on the specific energetic niche and caution should be exercised against premature conclusions regarding gene functions that have only been observed in protected laboratory conditions.

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