Access To Wheel Research Articles

Selective breeding of mice for high voluntary exercise alters adaptive plasticity of metabolic phenotypes in skeletal muscle

The response to selection on behavior necessarily entails associated changes in lower‐level (subordinate) traits. We studied mice from 4 replicate lines that had been selectively bred for high levels of voluntary exercise (High Runner or HR) that run ~3‐fold more wheel revolutions/day than those from 4 non‐selected control (C) lines, and have evolved higher baseline endurance and VO2max. We examined hindlimb skeletal muscle metabolic capacity in mice housed with or without wheel access for 8 weeks. Triceps surae muscles were assayed at 37C for Vmax of hexokinase (HK), citrate synthase (CS), carnitine palmitoyl‐transferase (CPT), and β‐hydroxyacyl‐CoA dehydrogenase (HAD). Wheel access increased heart ventricle mass in both HR and C lines, but only HR showed increased enzyme activities as well as higher phosphorylation of 5ˈ‐AMP‐activated protein kinase. Analysis of wheel‐access groups indicated the greater training effect in HR could be explained statistically by their greater wheel running for ventricle mass, CS, and HAD, but for HK and CPT, HR mice had greater adaptive plasticity of the response to voluntary exercise. Thus, HR do not have inherent baseline differences in metabolic capacity, but they have evolved greater adaptive plasticity for some traits. Supported by NSF IOB‐0543429 and IOS‐1121273 to TG.

Changes in semicircular canal morphology in response to selective breeding for high voluntary wheel running

Variation in semicircular canal (SCC) radius of curvature (R) and shape show correlations with locomotor agility among species of mammals. We used laboratory mice from 4 replicate lines bred for high voluntary wheel running (HR) and 4 non‐selected control lines (C) to examine responses in the SCC to 8 weeks of access to wheels and 21 generations of selection. Mouse crania were μCT scanned at 21 μm resolution and linear measurements, 3D landmarks, and centroid sizes of the SCC were taken. Linear measures were used to calculate R for all three canals and their mean, whereas landmarks were used to generate multivariate descriptors of 3D canal shape.HR mice weighed less than C and wheel access reduced body mass for both groups. ANCOVA showed that body mass was a significant positive predictor of R. However, when controlling for body mass we found no differences in R between HR and C, no effect of wheel access, and no interaction.SCC shape was also significantly correlated with body mass; controlling for body mass or centroid size, there were significant differences in SCC shape between HR and C mice. These results demonstrate that semicircular canal morphology is responsive to selection for locomotor activity and that canal shape may be more sensitive than canal size.Funding for this project provided by a U.C. Riverside Chancellor's Postdoctoral Fellowship to HS, Canadian Foundation for Innovation to BH and IOS‐1121273 to TG.

Cross sectional anatomy of the femoral diaphysis in mice bred for high levels of voluntary wheel running

Artificial selection for increased levels of voluntary activity in mice has resulted in differences in whole bone morphology. To study evolutionary adaptation and phenotypic plasticity of bone in response to increased levels of activity, we compared cross‐sectional geometry of the femoral mid‐shaft in 59 male and female mice from three lines: randomly bred controls, high‐runner mice (HR), and HR mice expressing the Mini‐Muscle (MM) phenotype. Half of each group was either allowed or denied wheel access for ten weeks. From histological sections, we measured several relevant biomechanical traits. Male and female mice generally followed similar trends, although female mice differed significantly in cross‐sectional area among lines while males did not. HR mice in both sexes had the thinnest cortical bone, the largest medullary diameters, and, consequently, the greatest resistance to torsional loads. MM male and female mice exhibited more elliptical femoral mid‐shafts (with males differing significantly), with greater resistances to torsion. We conclude that bone micro‐structure responds both evolutionarily and plastically to increased loading. Future studies will evaluate rates of bone growth resulting in the observed differences. Supported by NSF IOB‐0543429 to TG and NIH 1F32AR053008‐01 to KMM.

Effects of leptin treatment and Western diet on wheel running in selectively bred high runner mice

The role of leptin in regulating physical activity is varied. The behavioral effects of leptin signaling depend on the type of activity and the animal's physiological state. We used mice from lines selectively bred for high voluntary wheel running to further study how leptin regulates volitional exercise. Mice from four replicate high runner (HR) lines typically run ~3-fold more revolutions per day than those from four non-selected control (C) lines. HR mice have altered dopamine function and differences from C in brain regions known to be important in leptin-mediated behavior. Furthermore, male HR mice have been found to dramatically increase running when administered Western diet, an effect possibly mediated through leptin signaling. Male mice from generation 61 (representing three HR lines and one C line) were allowed wheel access at 24days of age and given either Western diet (high in fat and with added sucrose) or standard chow. After four weeks, Western diet significantly increased circulating leptin, insulin, C-peptide, gastric inhibitory polypeptide, and inflammatory hormone resistin concentrations in HR mice (C mice not measured). Western diet increased running in HR mice, but did not significantly affect running in C mice. During the fifth week, all mice received two days of intra-peritoneal sham injections (physiological saline) followed by three days of murine recombinant leptin injections, and then another six days of sham injections. Leptin treatment significantly decreased caloric intake (adjusted for body mass) and body mass in all groups. Wheel running significantly increased with leptin injections in HR mice (fed Western or standard diet), but was unaffected in C mice. Whether Western diet and leptin treatment stimulate wheel running in HR mice through the same physiological pathways awaits future study. These results have implications for understanding the neural and endocrine systems that control locomotor activity, food consumption, and body weight, and how they may vary with genetic background.

Genetic variations and physical activity as determinants of limb bone morphology: An experimental approach using a mouse model

To gain insight into past human physical activity, anthropologists often infer functional loading history from the morphology of limb bone remains. It is assumed that, during life, loading had a positive, dose-dependent effect on bone structure that can be identified despite other effects. Here, we investigate the effects of genetic background and functional loading on limb bones using mice from an artificial selection experiment for high levels of voluntary wheel running. Growing males from four replicate high runner (HR) lines and four replicate nonselected control (C) lines were either allowed or denied wheel access for 2 months. Using μCT, femoral morphology was assessed at two cortical sites (mid-diaphysis, distal metaphysis) and one trabecular site (distal metaphysis). We found that genetic differences between the linetypes (HR vs. C), between the replicate lines within linetype, and between individuals with and without the so-called "mini-muscle" phenotype (caused by a Mendelian recessive gene that halves limb muscle mass) gave rise to significant variation in nearly all morphological indices examined. Wheel access also influenced femoral morphology, although the functional response did not generally result in enhanced structure. Exercise caused moderate periosteal enlargement, but relatively greater endocortical expansion, resulting in significantly thinner cortices and reduced bone area in the metaphysis. The magnitude of the response was independent of distance run. Mid-diaphyseal bone area and area moments, and trabecular morphology, were unaffected by exercise. These results underscore the strong influence of genetics on bone structure and the complexity by which mechanical stimuli may cause alterations in it.

Prior stress interferes with the anxiolytic effect of exercise in c57bl/6j mice.

Recent reports demonstrate that the beneficial effects of voluntary exercise may be sensitive to stress prior to and during the wheel access period. Here, a variate stress procedure is used with socially isolated mice for 7 days prior to the introduction of running wheels to assess the impact of prior and concurrent stress on the anxiolytic effect of exercise. Following stress exposure, functioning or nonfunctioning running wheels were introduced into stressed and unstressed group-housed control cages. Following 3 weeks of wheel access, the anxiolytic effect of exercise was assessed using acoustic startle, stress-induced hyperthermia, and a challenge with the anxiogenic drug metachlorophenylpiperazine (mCPP). Variate stress was demonstrated to interfere with normal weight gain. Further, exercise was not anxiolytic in stressed mice. Consistent with previous reports unstressed exercising mice demonstrated reduced acoustic startle, attenuated stress induced hyperthermia, and a blunted increase in startle following mCPP administration when compared with unstressed sedentary controls. Stressed exercising mice were indistinguishable from stressed sedentary and unstressed sedentary controls on each anxiety measure. Although running distance varied between individual mice, the distance run did not predict the level of anxiety on any measure. These findings suggest that prior and ongoing stress delays or prevents the anxiolytic effect of exercise without affecting exercise itself.

Reciprocal inhibitory effects of intravenous d-methamphetamine self-administration and wheel activity in rats

BackgroundSome epidemiological and cessation studies suggest physical exercise attenuates or prevents recreational drug use in humans. Preclinical studies indicate that wheel activity reduces cocaine self-administration in rats; this may, however, require the establishment of compulsive wheel activity. MethodsEffects of concurrent wheel activity on intravenous d-methamphetamine (METH) self-administration were examined in male Wistar and Sprague Dawley rats with negligible prior wheel experience. Wistar rats self-administered METH (0.05mg/kg/inf) under a fixed-ratio 1 (FR1) schedule with concurrent access to an activity wheel during sessions 1–14, 8–21 or 15–21. Control rats which did not self-administer METH had access to an activity wheel during sessions 1–14, 8–21 or 15–28. Sprague Dawley rats self-administered METH (0.1mg/kg/inf) under FR1 for 14 sessions with either concurrent access to a locked or an unlocked activity wheel. ResultsMETH self-administration was lower when the wheel was available concurrently from the start of self-administration training in both strains, even though Sprague Dawley rats self-administered twice as many METH infusions and ran one-sixth as much on the wheel compared to Wistar rats. Wheel access initiated after 7 or 14 days had no effect on METH self-administration in Wistar rats. Wheel activity was significantly reduced in these groups compared with the group with concurrent wheel and METH access for the first 14 sessions. ConclusionsThese data show that METH self-administration is reduced by exercise if initiated from the start of self-administration and that prior METH self-administration experience interferes with the value of exercise as a reinforcer.

Wheel running can accelerate or delay extinction of conditioned place preference for cocaine in male C57BL/6J mice, depending on timing of wheel access

Aerobic exercise may represent a useful intervention for drug abuse in predisposed individuals. Exercise increases plasticity in the brain that could be used to reverse learned drug associations. Previous studies have reported that exposing mice to a complex environment including running wheels after drug conditioning abolishes conditioned place preference (CPP) for cocaine, whereas running can enhance CPP when administered before conditioning. The purpose of the present study was to test the hypothesis that timing of exercise relative to conditioning has opposing effects on cocaine CPP. Male C57BL/6J mice experienced 30 days of running or sedentary treatments either before or after cocaine conditioning. Control animals always received saline and never cocaine, but otherwise underwent the same conditioning and exercise treatments. Animals were given bromodeoxyuridine injections at the onset of conditioning or exercise, and euthanized at the end of the study to quantify survival of new neurons in the hippocampus as a marker of plasticity. Wheel running accelerated extinction of CPP when running occurred entirely after drug conditioning, whereas running delayed extinction when administered before conditioning. A single conditioning day after running was sufficient to abolish the accelerated extinction observed when all conditioning preceded running. Running approximately doubled adult hippocampal neurogenesis, whereas cocaine had no effect. These results suggest that exercise-induced plasticity can facilitate learning that context is no longer associated with drug. However, if drug exposure occurs after exercise, running-induced plasticity may strengthen drug associations. The results provide insights into the interaction between exercise and drug conditioning that could have implications for drug abuse treatments.

Influences of activity wheel access on the body temperature response to MDMA and methamphetamine

Recreational ingestion of the drug 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) can result in pathologically elevated body temperature and even death in humans. Such incidents are relatively rare which makes it difficult to identify the relative contributions of specific environmental and situational factors. Although animal models have been used to explore several aspects of MDMA-induced hyperthermia and it is regularly hypothesized that prolonged physical activity (e.g., dancing) in the nightclub environment increases risk, this has never been tested directly. In this study the rectal temperature of male Wistar rats was monitored after challenge with doses of MDMA and methamphetamine (MA), another drug frequently ingested in the rave/nightclub environment, either with or without access to an activity wheel. Results showed that wheel activity did not modify the hyperthermia produced by 10.0mg/kg MDMA. However, individual correlations were observed in which wheel activity levels after a locomotor stimulant dose of MDMA were positively related to body temperature change and lethal outcome. A modest increase in the maximum body temperature observed after 5.6mg/kg MA was caused by wheel access but this was mostly attributable to a drop in temperature relative to vehicle treatment in the absence of wheel activity. These results suggest that nightclub dancing in the human Ecstasy consumer may not be a significant factor in medical emergencies.

Gender dimorphic effects of voluntary running in laboratory rats depends on maturational status

This study examined the effect of 24hr per day wheel access on running, body weight, and food intake for 30- or 50-day-old male and female rats under ad lib feeding conditions. Food intake and body weight were also monitored in a control group housed without access to running wheels. A dimorphic effect was observed after wheel introduction in 50-day-old but not 30-day-old rats: A temporary decline in food intake and a lasting decrease in body weight occurred for active male rats in comparison to their sedentary controls, and wheel access facilitated food intake and preserved body weight gain in female rats in comparison to their sedentary counterparts. Hyperphagia in adult females is interpreted in terms of the evolutionary acquired advantage linked to their reproductive function.

Voluntary exercise, spontaneous physical activity, and food consumption in High Runner lines of mice

To explore the effect voluntary exercise has on spontaneous physical activity (SPA, aka non-exercise activity thermogenesis), we housed 50 female mice from lines that had been artificially selected for high endurance running (HR lines) and 50 mice from non-selected control (C) lines in cages with or without wheels. Wheels were monitored each 1-min interval. All 100 cages had passive infrared sensors to monitor SPA during each 1-min interval. Data presented here are from week 8 of the 12-week experiment, at which point the mice had plateaued in body mass and weekly wheel-running distance. The total SPA of both HR and C mice was reduced (9.9 to 8.2 h and 8.5 to 7.6 h, respectively) when they had wheel access, and the reduction was a function of both duration and average intensity of SPA. However, total duration of activity (SPA + running) was still 1/3 greater when mice were housed with wheels, and food consumption was increased. Thus, wheel running was not fully compensated by the reduction in SPA. Both duration and intensity of wheel running and SPA were positive, significant predictors of food consumption. Wheel-running duration has a stronger effect than the average running speed, while for SPA, the intensity of activity has a stronger effect. To our knowledge, this sort of detailed analysis of the effects of different aspects of activity on food consumption has not previously been reported for a non-human animal. Funding by NSF DDIG #0925793 to LC and IOB-0543429 to TG. Grant Funding Source: NSF

Exercise ancestry decreases lipogenesis‐related gene expression in skeletal muscle of male offspring

The study objective was to examine the influence of exercise (EX) ancestry compared to sedentary (SED) ancestry on offspring skeletal muscle gene expression. C57/Bl6 mice (F0) were exposed to EX (wheel running, N=20) or a SED condition (no wheel access, N=20) for 12 weeks prior to breeding. EX males and EX females, and SED males and SED females were bred to produce F1 pups. F0 EX mice had continued access to the wheel during breeding, pregnancy, and weaning. F1 pups were sacrificed at 8 wk without direct exercise exposure. Microarray analysis of gene expression was performed on pooled gastrocnemius RNA from F1 males of each ancestry (5 animals per array; 4 total arrays). After processing the microarray data to minimize false positives, 109 transcripts were differentially expressed between F1 EX and F1 SED. Three targets identified as upregulated in F1 SED offspring have been previously associated with lipogenesis and were selected for real‐time PCR validation (Adipoq, Scd1, and Cidec). Adipoq and Scd1 were verified as significantly upregulated in F1 SED offspring (p < 0.05) and Cidec tended to be upregulated in F1 SED offspring (p = 0.06). These preliminary findings indicate that exercise ancestry (i.e., parental exercise stimulus) can affect lipogenesis‐related skeletal muscle gene expression in male mouse offspring.Supported by the UMD School of Public Health Research Seed Money Program and NIH AG000268.

P.1.020 Influence of melatonin on blood flow in cerebral cortex under conditions of global transient ischemia

The biological regulating factors of physical activity in animals are not well understood. This study investigated differences in the central mRNA expression of seven dopamine genes (Drd1, Drd2, Drd3, Drd4, Drd5, TH, and DAT) between high active C57/LJ (n = 17) male mice and low active C3H/HeJ (n = 20) male mice, and between mice with access to a running wheel and without running wheel access within strain. Mice were housed with running wheels interfaced with a computer for 21 days with distance and duration recorded every 24 h. On day 21, the striatum and nucleus accumbens were removed during the active period (∼9 pm) for dopaminergic analysis. On average, the C57L/J mice with wheels ran significantly farther (10.25 ± 1.37 km/day vs. 0.01 ± 0.09 km/day, p < 0.001), longer (329.73 ± 30.52 min/day vs. 7.81 ± 6.32 min/day, p < 0.001), and faster (31.27 ± 3.13 m/min vs. 11.81 ± 1.08 m/min, p < 0.001) than the C3H/HeJ mice with wheels over the 21 day period. No differences in gene expression were found between mice in either strain with wheels and those without wheels suggesting that access to running wheels did not alter dopaminergic expression. In contrast, relative expression for two dopamine genes was significantly lower in the C57L/J mice compared to the C3H/HeJ mice. These results indicate that decreased dopaminergic functioning is correlated with increased activity levels in C57L/J mice and suggests that D1-like receptors as well as tyrosine hydroxylase (an indicator of dopamine production), but not D2-like receptors may be associated with the regulation of physical activity in inbred mice.

Restricted wheel access following a light cycle inversion slows re-entrainment without internal desynchrony as measured in Per2 Luc mice

Circadian rhythms are physiological and behavioral oscillations that have period lengths of approximately 24 h. In mammals, circadian rhythms are driven by a master pacemaker in the hypothalamic suprachiasmatic nucleus (SCN). These rhythms can be entrained to light:dark cycles through photic and non-photic cues. Current research suggests that the SCN re-entrains rapidly to new light:dark (LD) cycles with the first photic cues, whereas peripheral tissues re-entrain more slowly, leading to a transient state of internal disorder while the organism adjusts to the new timing of photic input. To assess internal temporal order during the readjustment we used dim light to slow the rate of re-entrainment following a 12-h inversion of the LD cycle. We also used a wheel-restriction paradigm, which can block behavioral evidence of re-entrainment. Per2 Luc mice were entrained to a 12:12 dim LD cycle with wheel access ad libitum. Following a 12-h shift in the LD cycle, some animals were subjected to wheel restriction; wheels were locked during the new dark period and available during the new light period. Other mice had wheels available ad lib throughout the experiment. Behavioral actograms of general locomotor activity as measured with motion sensors indicated that mice with ad lib access to wheels were able to re-entrain at a rate significantly faster than mice with restricted wheel access. Up to 2 weeks following the LD inversion many wheel-restricted animals were still active predominantly in the new light period. Phase of the PER2::LUC bioluminescence rhythms in SCN and four peripheral tissues (lung, esophagus, thymus, and spleen), measured ex vivo on days 2, 9, and 16 following the inversion, indicated that within each condition the SCN and peripheral tissues shifted at the same rate, whereas the rate of re-entrainment for the tissues differed between conditions. Ex vivo data showed that the PER2::LUC peaks in SCN and peripheral tissues were closely linked to time of activity onset in both groups. Thus, this wheel restriction protocol is capable of reducing and in some cases apparently hindering photic re-entrainment of the circadian system, verifying this protocol as a mechanism for study of photic/non-photic entrainment interactions. Our results suggest that LD inversion under dim light and a wheel-restriction protocol does not induce internal desynchrony, indicating that slowing the rate of shift by limiting both entrainment inputs may induce less “jet lag”.

The effect of pre-exposure and recovery type on activity-based anorexia in rats

Activity-based anorexia (ABA) occurs when there is limited access to food and an opportunity to engage in high levels of physical activity. While the ABA effect is well established, the distinct functions of exercise and food restriction in maintaining ABA have not been determined. The current study examined the effect of pre-exposure to a restricted feeding schedule and pre-exposure to a running wheel on the incidence of ABA in 36 rats. Access to food and the running wheel was also varied in the recovery phase of the study in order to establish the effect of these variables on recovery from ABA. Three adaptation conditions (pre-exposed to food restriction, pre-exposed to wheel access and non-exposed) and two recovery conditions (wheel access and food restriction recovery) defined the six groups in the current study. Pre-exposure to food restriction was found to ameliorate the ABA effect during the anorexia phase while pre-exposure to wheel access exacerbated ABA. It was also found that subjects in the wheel access recovery condition gained more weight than the subjects in the food restriction recovery. In food restriction recovery, there was an interaction between the adaptation and recovery condition, with subjects that were pre-exposed to food restriction gaining the most weight. The results of the current study aid in understanding the distinct functions of food restriction and exercise in maintaining and recovering from ABA and have possible implications for the treatment of people diagnosed with some types of anorexia nervosa.

The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives.

Mammals expend energy in many ways, including basic cellular maintenance and repair, digestion, thermoregulation, locomotion, growth and reproduction. These processes can vary tremendously among species and individuals, potentially leading to large variation in daily energy expenditure (DEE). Locomotor energy costs can be substantial for large-bodied species and those with high-activity lifestyles. For humans in industrialized societies, locomotion necessary for daily activities is often relatively low, so it has been presumed that activity energy expenditure and DEE are lower than in our ancestors. Whether this is true and has contributed to a rise in obesity is controversial. In humans, much attention has centered on spontaneous physical activity (SPA) or non-exercise activity thermogenesis (NEAT), the latter sometimes defined so broadly as to include all energy expended due to activity, exclusive of volitional exercise. Given that most people in Western societies engage in little voluntary exercise, increasing NEAT may be an effective way to maintain DEE and combat overweight and obesity. One way to promote NEAT is to decrease the amount of time spent on sedentary behaviours (e.g. watching television). The effects of voluntary exercise on other components of physical activity are highly variable in humans, partly as a function of age, and have rarely been studied in rodents. However, most rodent studies indicate that food consumption increases in the presence of wheels; therefore, other aspects of physical activity are not reduced enough to compensate for the energetic cost of wheel running. Most rodent studies also show negative effects of wheel access on body fat, especially in males. Sedentary behaviours per se have not been studied in rodents in relation to obesity. Several lines of evidence demonstrate the important role of dopamine, in addition to other neural signaling networks (e.g. the endocannabinoid system), in the control of voluntary exercise. A largely separate literature points to a key role for orexins in SPA and NEAT. Brain reward centers are involved in both types of physical activities and eating behaviours, likely leading to complex interactions. Moreover, voluntary exercise and, possibly, eating can be addictive. A growing body of research considers the relationships between personality traits and physical activity, appetite, obesity and other aspects of physical and mental health. Future studies should explore the neurobiology, endocrinology and genetics of physical activity and sedentary behaviour by examining key brain areas, neurotransmitters and hormones involved in motivation, reward and/or the regulation of energy balance.

Monosodium iodoacetate-induced osteoarthritis produces pain-depressed wheel running in rats: Implications for preclinical behavioral assessment of chronic pain

Pain stimulates some behaviors (e.g., withdrawal responses) and depresses other behaviors (e.g., feeding and locomotion). We are developing methods for testing candidate analgesics using measurements of pain-depressed behaviors. Such assays may model important aspects of clinical pain and complement traditional procedures that measure pain-stimulated behaviors. The present study characterized the effects of a chronic pain manipulation (monosodium iodoacetate (MIA)-induced osteoarthritis) on wheel running in rats. Rats had 24h voluntary access to running wheels. Duration of running wheel acquisition was manipulated such that rats had either 21 or 7days of running wheel access prior to MIA administration. Wheel running was monitored for an additional 21days following MIA administration. MIA produced concentration- and acquisition length-dependent decreases in wheel running. Parallel experiments demonstrated that MIA produced concentration-dependent tactile allodynia and shifts in hind limb weight bearing. MIA was differentially potent across assays with a potency rank: weight-bearing≥von Frey>running wheel. MIA produced greater depression of wheel running in rats with relatively high baseline running rates compared to rats with relatively low baseline running rates. The differential potency of MIA across assays and apparent rate-dependent effects in running wheels may impact our traditional interpretations of preclinical nociceptive and antinociceptive testing.

Voluntary Running Prevents Progressive Memory Decline and Increases Adult Hippocampal Neurogenesis and Growth Factor Expression after Whole-Brain Irradiation

Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention.

Transgenerational Effects of Physical Activity Ancestry on Mouse Body Composition, Glucose Metabolism, and Gene Expression

PURPOSE: To examine the influence of a physical activity (PA) ancestry compared to a sedentary (SED) ancestry on body composition, glucose metabolism, and skeletal muscle gene expression in multiple generations of mouse offspring. METHODS: C57/Bl6 mice (F0) were exposed to PA (voluntary wheel running, N=20) or a SED condition (no wheel access, N=20) for 12 weeks prior to breeding. PA males were bred with PA females and SED males were bred with SED females to produce F1 pups. PA animals had continued access to the running wheel during breeding, pregnancy, and weaning. F1 pups were either sacrificed at 8 wk without exposure to PA (PA ancestry was the only distinguishing feature), or bred with F1 littermates to produce an F2 generation. Similarly, F2 offspring were sacrificed at 8 wk without any PA exposure. Body, muscle (quadriceps, gastrocnemius, plantaris, soleus, TA, EDL), and omental fat mass and glucose tolerance were measured in F1 and F2 offspring. mRNA expression of several metabolic genes (Ppargc1a, Pdk4, Ppara, Ppard, Alas1, Hk2, Cycs, Cs, and Mt-co1) was measured in gastrocnemius muscle of F1 and F2 offspring. RESULTS: Body (p<0.01) and omental fat (p<0.01) mass were lower in the F1 females with PA compared to SED ancestry. Average TA (p<0.01) and soleus (p=0.05) mass were lower in F1 females with a PA compared to SED ancestry. Average soleus (p=0.03) and quadriceps (p=0.04) mass were lower, while average EDL mass was greater (p=0.02) in F1 males with a PA compared to SED ancestry. No other body, fat, or muscle mass differences were observed. Glucose AUC was smaller (p=0.01) in PA F0 females compared to their SED counterparts. There were no differences in glucose AUC between ancestries in the F1 generation, but glucose AUC was smaller in F2 females with a SED compared to PA ancestry (p=0.01). No differences in mRNA level of Pdk4, Ppara, Alas1, or Cs were observed due to ancestry (PA vs. SED ancestry in the F1 or the F2 generation). mRNA levels were lower for Ppargc1a (p=0.03), Hk2 (p=0.03), Mt-co1(p=0.05), and Ppard (p<0.01) in F1 males with a PA compared to a SED ancestry. Cycs mRNA levels were greater (p=0.03) in F2 males with a PA compared to a SED ancestry. mRNA levels were higher for Ppargc1a (p=0.02) and tended to be higher for Ppard (p=0.06) in F2 females with a PA compared to a SED ancestry. CONCLUSIONS: These preliminary findings indicate that PA ancestry (independent of direct PA) can influence aspects of body composition, glucose metabolism, and skeletal muscle metabolic gene expression in multiple generations of mouse offspring. This work was supported by the School of Public Health Research Seed Money Program at UMD.

Physical Activity and Food Consumption in High- and Low-Active Inbred Mouse Strains

To determine the effect of innate activity level and running wheel access on food consumption in high-active (SWR/J) low-active (DBA/2J) mice. Two strains of inbred mice were used in this study owing to their high activity level (SWR/J) and low activity level (DBA/2J). Mice were housed in individual cages, and half of the mice in each strain had free access to running wheels in their cages, whereas the other half received no running wheel. All mice consumed standard chow and water ad libitum for 13 wk during the study period. Running wheel activity (daily), food consumption (biweekly), and body mass (weekly) were recorded. SWR/J runners consumed more food (6.0 ± 0.4 g·d)(-1) than SWR/J nonrunners (4.7 ± 0.2 g·d(-1), P = 0.03), DBA/2J runners (4.6 ± 0.2 g·d(-1), P = 0.02), and DBA/2J nonrunners (4.2 ± 0.2 g·d(-1), P = 0.006). SWR/J nonrunners consumed more food than DBA/2J nonrunners (P = 0.03). Average daily distance and duration were significantly greater for the SWR/J runners (6.4 ± 0.7 km·d(-1) and 333.6 ± 40.5 min·d(-1), respectively) compared with those for the DBA/2J runners (1.6 ± 0.4 km·d(-1) and 91.3 ± 23.0 min·d(-1), respectively). There was a significant correlation between food consumption and distance (r = 0.74, P < 0.001), duration (r = 0.68, P < 0.001), and speed (r = 0.58, P < 0.001), respectively, in all mice. However, when considering the individuals strains, the relationship between running wheel activity and food consumption was only statistically significant for the SWR/J mice. Higher running wheel activity in mice was associated with increased food consumption in the SWR/J mice but not in the DBA/2J mice. In DBA/2J mice, addition of a running wheel did not result in increased food consumption, suggesting that energy expenditure of nonwheel cage activity in the control DBA/2J mice was similar to the energy expenditure of the wheel activity because body mass was similar between the two groups.