SUMMARYIncreased brain size, relative to body mass, is a primary characteristic distinguishing the mammalian lineage. This greater encephalization has come with increased behavioral complexity and, accordingly, it has been suggested that selection on behavioral traits has been a significant factor leading to the evolution of larger whole-brain mass. In addition, brains may evolve in a mosaic fashion, with functional components having some freedom to evolve independently from other components, irrespective of, or in addition to, changes in size of the whole brain. We tested whether long-term selective breeding for high voluntary wheel running in laboratory house mice results in changes in brain size, and whether those changes have occurred in a concerted or mosaic fashion. We measured wet and dry brain mass via dissections and brain volume with ex vivo magnetic resonance imaging of brains that distinguished the caudate-putamen, hippocampus, midbrain, cerebellum and forebrain. Adjusting for body mass as a covariate, mice from the four replicate high-runner (HR) lines had statistically larger non-cerebellar wet and dry brain masses than those from four non-selected control lines, with no differences in cerebellum wet or dry mass or volume. Moreover, the midbrain volume in HR mice was ~13% larger (P<0.05), while volumes of the caudate-putamen, hippocampus, cerebellum and forebrain did not differ statistically between HR and control lines. We hypothesize that the enlarged midbrain of HR mice is related to altered neurophysiological function in their dopaminergic system. To our knowledge, this is the first example in which selection for a particular mammalian behavior has been shown to result in a change in size of a specific brain region.Key words: activity, allometry, cerebellum, dopamine, exercise behavior, locomotion, motor control. convergences within primates, spatio-sensory convergences within insectivores). Similar evidence for mosaic evolution in the avian brain has also been found and correlated to functional differences in the enlarged brain regions (Iwaniuk et al., 2006). Cellular changes have also been observed with increased brain size. As brain volume increases, axon diameters and the fraction of myelinated axons increase, thereby reducing the delay in neural signaling between more distant regions (Wang et al., 2008). Moreover, different cellular scaling rules apply across different mammalian orders (Herculano-Houzel, 2010). For example, in rodents, neuronal cell size increases with brain size, such that neuronal density is lower in larger-brained species (albeit with a greater absolute number of neurons) (Herculano-Houzel et al., 2006). Conversely, in primates, neuronal cell size is constant and neuron density is constant, such that total neuron number is much greater with increasing brain size (Herculano-Houzel et al., 2007). Therefore, an increase in the size of a brain region could be the product of a variety of cellular changes (e.g. neuron number, neuron density, glial density, gray-to-white matte...

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