Search for: All records

BackgroundHigh-Runner (HR) mice, selectively bred for increased voluntary wheel running behavior, exhibit heightened motivation to run. Exercise has been shown to influence hippocampal long-term potentiation (LTP) and memory, and is neuroprotective in several neurodegenerative diseases. ObjectiveThis study aimed to determine the impact of intense running in HR mice with wheel access on hippocampal LTP, compared to HR mice without wheels and non-selected control (C) mice with/without wheels. Additionally, we investigated the involvement of D1/D5 receptors and the dopamine transporter (DAT) in LTP modulation and examined levels of these proteins in HR and C mice. MethodsAdult female HR and C mice were individually housed with/without running wheels for at least two weeks. Hippocampal LTP of extracellular field excitatory postsynaptic potentials (fEPSPs) was measured in area CA1, and SKF-38393 (D1/D5 receptor agonist) and GBR 12909 (DAT inhibitor) were used to probe the role of D1/D5 receptors and DAT in LTP differences. Western blot analyses assessed D1/D5 receptor and DAT expression in the hippocampus, prefrontal cortex, and cerebellum. ResultsHR mice with wheel access showed significantly increased hippocampal LTP compared to those without wheels and to C mice with/without wheels. Treatment with SKF-38393 or GBR 12909 prevented the heightened LTP in HR mice with wheels, aligning it with levels in C mice. Hippocampal D1/D5 receptor levels were lower, and DAT levels were higher in HR mice compared to C mice. No significant changes were observed in other brain regions. ConclusionsThe increased hippocampal LTP seen in HR mice with wheel access may be related to alterations in dopaminergic synaptic transmission that underlie the neurophysiological basis of hyperactivity, motor disorders, and/or motivation. 

ABSTRACT The jaw muscles of the southern alligator lizard, Elgaria multicarinata, are used in prolonged mate-holding behavior, and also to catch fast prey. In both males and females, these muscles exhibit an unusual type of high endurance known as sustained force in which contractile force does not return to baseline between subsequent contractions. This phenomenon is assumed to facilitate the prolonged mate-holding observed in this species. Skeletal muscle is often subject to a speed–endurance trade-off. Here, we determined the isometric twitch, tetanic and isotonic force–velocity properties of the jaw muscles at ∼24°C as metrics of contractile speed and compared these properties with a more typical thigh locomotory muscle to determine whether endurance by sustained force allows for circumvention of the speed–endurance trade-off. The specialized jaw muscle was generally slower than the more typical thigh muscle: time to peak twitch force, twitch 90% relaxation time (P<0.01), and tetanic 90% and 50% relaxation times (P<0.001) were significantly longer, and force–velocity properties were significantly slower (P<0.001) in the jaw than the thigh muscle. However, there seemed to be greater effects on relaxation rates and shortening velocity than on force rise times: there was no effect of muscle on time to peak, or 50% of tetanic force. Hence, the jaw muscle of the southern alligator lizard does not seem to circumvent the speed–endurance trade-off. However, the maintenance of force rise times despite slow relaxation, potentially enabled by the presence of hybrid fibers, may allow this muscle to meet the functional demand of prey capture. 

Abstract Artificial selection yielded four replicate high runner (HR) lines of mice that reached apparent selection limits (~ threefold increase in wheel revolutions per day vs. four control lines), despite maintenance of additive genetic variance. After 68 generations, we used animal models to test for changes in additive-genetic variances and covariance of the two measured components (average speed and duration) of running distance. We also attempted to break the selection limit by crossing two HR lines, then continuing directional selection on this hybrid line and on the two parental lines for nine generations. The genetic correlation between speed and duration was positive in the base population, but evolved to be negative in the two parental HR lines. Although heritability for both speed and duration (but not distance) increased in the hybrid line, their genetic correlation remained negative. Hybrid F₁mice from generation 68 parents showed heterosis for running distance, which was lost in subsequent generations, and the hybrid line did not exceed the limit. Both male and female hybrids ran faster than parental lines for most generations, but running duration was intermediate or reduced, reflecting their negative genetic correlation. The evolved genetic trade-off between speed and duration may explain the inability for the hybrid line to break the selection limit for distance run, despite renewed additive genetic variance for at least one of its component traits. 

ABSTRACT Selection experiments play an increasingly important role in comparative and evolutionary physiology. However, selection experiments can be limited by relatively low statistical power, in part because replicate line is the experimental unit for analyses of direct or correlated responses (rather than number of individuals measured). One way to increase the ability to detect correlated responses is through a meta-analysis of studies for a given trait across multiple generations. To demonstrate this, we applied meta-analytic techniques to two traits (body mass and heart ventricle mass, with body mass as a covariate) from a long-term artificial selection experiment for high voluntary wheel-running behavior. In this experiment, all four replicate High Runner (HR) lines reached apparent selection limits around generations 17–27, running approximately 2.5- to 3-fold more revolutions per day than the four non-selected Control (C) lines. Although both traits would also be expected to change in HR lines (relative heart size expected to increase, expected direction for body mass is less clear), their statistical significance has varied, despite repeated measurements. We compiled information from 33 unique studies and calculated a measure of effect size (Pearson's R). Our results indicate that, despite a lack of statistical significance in most generations, HR mice have evolved larger hearts and smaller bodies relative to controls. Moreover, plateaus in effect sizes for both traits coincide with the generational range during which the selection limit for wheel-running behavior was reached. Finally, since reaching the selection limit, absolute effect sizes for body mass and heart ventricle mass have become smaller (i.e. closer to 0). 

Synopsis Trade-offs resulting from the high demand of offspring production are a central focus of many subdisciplines within the field of biology. Yet, despite the historical and current interest on this topic, large gaps in our understanding of whole-organism trade-offs that occur in reproducing individuals remain, particularly as it relates to the nuances associated with female reproduction. This volume of Integrative and Comparative Biology (ICB) contains a series of papers that focus on reviewing trade-offs from the female-centered perspective of biology (i.e., a perspective that places female reproductive biology at the center of the topic being investigated or discussed). These papers represent some of the work showcased during our symposium held at the 2024 meeting of the Society for Integrative and Comparative Biology (SICB) in Seattle, Washington. In this roundtable discussion, we use a question-and-answer format to capture the diverse perspectives and voices involved in our symposium. We hope that the dialogue featured in this discussion will be used to motivate researchers interested in understanding trade-offs in reproducing females and provide guidance on future research endeavors. 

Abstract Selective breeding has been utilized to study the genetic basis of exercise behavior, but research suggests that epigenetic mechanisms, such as DNA methylation, also contribute to this behavior. In a previous study, we demonstrated that the brains of mice from a genetically selected high runner (HR) line have sex‐specific changes in DNA methylation patterns in genes known to be genomically imprinted compared to those from a non‐selected control (C) line. Through cross‐fostering, we also found that maternal upbringing can modify the DNA methylation patterns of additional genes. Here, we identify an additional set of genes in which DNA methylation patterns and gene expression may be altered by selection for increased wheel‐running activity and maternal upbringing. We performed bisulfite sequencing and gene expression assays of 14 genes in the brain and found alterations in DNA methylation and gene expression forBdnf,Pde4dandGrin2b. Decreases inBdnfmethylation correlated with significant increases inBdnfgene expression in the hippocampus of HR compared to C mice. Cross‐fostering also influenced the DNA methylation patterns forPde4din the cortex andGrin2bin the hippocampus, with associated changes in gene expression. We also found that the DNA methylation patterns forAtrxandOxtrin the cortex andAtrxandBdnfin the hippocampus were further modified by sex. Together with our previous study, these results suggest that DNA methylation and the resulting change in gene expression may interact with early‐life influences to shape adult exercise behavior. 

Abstract The nutrient artery provides ~50%–70% of the total blood volume to long bones in mammals. Studying the functional characteristics of this artery in vivo can be difficult and expensive, so most researchers have measured the nutrient foramen, an opening on the outer surface of the bone that served as the entry point for the nutrient artery during development and bone ossification. Others have measured the nutrient canal (i.e., the passage which the nutrient artery once occupied), given that the external dimensions of the foramen do not necessarily remain uniform from the periosteal surface to the medullary cavity. The nutrient canal, as an indicator of blood flow to long bones, has been proposed to provide a link to studying organismal activity (e.g., locomotor behavior) from skeletal morphology. However, although external loading from movement and activity causes skeletal remodeling, it is unclear whether it affects the size or configuration of nutrient canals. To investigate whether nutrient canals can exhibit phenotypic plasticity in response to physical activity, we studied a mouse model in which four replicate high runner (HR) lines have been selectively bred for high voluntary wheel‐running behavior. The selection criterion is the average number of wheel revolutions on days 5 and 6 of a 6‐day period of wheel access as young adults (~6–8 weeks old). An additional four lines are bred without selection to serve as controls (C). For this study, 100 female mice (half HR, half C) from generation 57 were split into an active group housed with wheels and a sedentary group housed without wheels for 12 weeks starting at ~24 days of age. Femurs were collected, soft tissues were removed, and femora were micro‐computed tomography scanned at a resolution of 12 μm. We then imported these scans into AMIRA and created 3D models of femoral nutrient canals. We tested for evolved differences in various nutrient canal traits between HR and C mice, plastic changes resulting from chronic exercise, and the selection history‐by‐exercise interaction. We found few differences between the nutrient canals of HR versus C mice, or between the active and sedentary groups. We did find an interaction between selection history and voluntary exercise for the total number of nutrient canals per femur, in which wheel access increased the number of canals in C mice but decreased it in HR mice. Our results do not match those from an earlier study, conducted at generation 11, which was prior to the HR lines reaching selection limits for wheel running. The previous study found that mice from the HR lines had significantly larger total canal cross‐sectional areas compared to those from C lines. However, this discrepancy is consistent with studies of other skeletal traits, which have found differences between HR and C mice to be somewhat inconsistent across generations, including the loss of some apparent adaptations with continued selective breeding after reaching a selection limit for wheel‐running behavior. 

ABSTRACT In general, sustained high rates of physical activity require a high maximal aerobic capacity (V̇O2,max), which may also necessitate a high basal aerobic metabolism (BMR), given that the two metabolic states are linked via shared organ systems, cellular properties and metabolic pathways. We tested the hypotheses that (a) selective breeding for high voluntary exercise in mice would elevate both V̇O2,max and BMR, and (b) these increases are accompanied by increases in the size of some internal organs (ventricle, triceps surae muscle, liver, kidney, spleen, lung, brain). We measured 72 females from generations 88 and 96 of an ongoing artificial selection experiment comprising four replicate High Runner (HR) lines bred for voluntary daily wheel-running distance and four non-selected control lines. With body mass as a covariate, HR lines as a group had significantly higher V̇O2,max (+13.6%, P<0.0001), consistent with previous studies, but BMR did not significantly differ between HR and control lines (+6.5%, P=0.181). Additionally, HR mice did not statistically differ from control mice for whole-body lean or fat mass, or for the mass of any organ collected (with body mass as a covariate). Finally, mass-independent V̇O2,max and BMR were uncorrelated (r=0.073, P=0.552) and the only statistically significant correlation with an organ mass was for V̇O2,max and ventricle mass (r=0.285, P=0.015). Overall, our results indicate that selection for a behavioral trait can yield large changes in behavior without proportional modifications to underlying morphological or physiological traits. 

Abstract Replicate lines under uniform selection often evolve in different ways. Previously, analyses using whole-genome sequence data for individual mice (Mus musculus) from 4 replicate High Runner lines and 4 nonselected control lines demonstrated genomic regions that have responded consistently to selection for voluntary wheel-running behavior. Here, we ask whether the High Runner lines have evolved differently from each other, even though they reached selection limits at similar levels. We focus on 1 High Runner line (HR3) that became fixed for a mutation at a gene of major effect (Myh4Minimsc) that, in the homozygous condition, causes a 50% reduction in hindlimb muscle mass and many pleiotropic effects. We excluded HR3 from SNP analyses and identified 19 regions not consistently identified in analyses with all 4 lines. Repeating analyses while dropping each of the other High Runner lines identified 12, 8, and 6 such regions. (Of these 45 regions, 37 were unique.) These results suggest that each High Runner line indeed responded to selection somewhat uniquely, but also that HR3 is the most distinct. We then applied 2 additional analytical approaches when dropping HR3 only (based on haplotypes and nonstatistical tests involving fixation patterns). All 3 approaches identified 7 new regions (as compared with analyses using all 4 High Runner lines) that include genes associated with activity levels, dopamine signaling, hippocampus morphology, heart size, and body size, all of which differ between High Runner and control lines. Our results illustrate how multiple solutions and “private” alleles can obscure general signatures of selection involving “public” alleles.