Browsing by Author "Mock, J."
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Item Catwalk analysis: a novel approach to profiling age differences in gait(2016-03-23) Wong, Jessica; Vann, Phillip; Forster, Michael; Sumien, Nathalie; Mock, J.The Catwalk is a validated video-based gait analysis tool for quantitative analysis of both static and dynamic differences in rodent gait and weight-bearing. The Catwalk has been used to analyze disease states such as stroke, sciatic nerve crush and osteoarthritis, however age-related changes in rodent gait are not well characterized. Motor impairments have been associated with dysregulated cellular redox state, namely levels of reduced to oxidized glutathione. Glutamate-cysteine ligase modifier (gclm) is a key enzyme sub-unit in the production of glutathione (GSH), and knocking it out reduces GSH levels by 85%. The gclm -/- mice are a potential model of accelerated aging and should develop impairments earlier than wild-type mice. Our hypothesis was that gait measures would decrease with advanced age and that impairments would occur sooner in gclm -/- mice. Wild-type (wt) and gclm-/- male and female mice were tested at 4, 10 or 17 months of age (n = 8-11/group). All testing was done in pitch black and a camera below the illuminated transparent platform captured each paw print as animals walked across the platform. Paw prints were automatically labeled according to left/right or front/hind then manually checked. A criterion for a good run was set as less than 60% speed variation within the run and less than 10% speed variation between runs. Two to five runs per animal were used for two-way analyses of variance of the dependent measures collected using Genotype and Age as in between factors. The dependent measures were gait speed (SP), front and hind base of support (BoSf, BoSh), front and hind stride length (SLf, SLh), front and hind stride speed (SSf, SSh), front and hind step cycle (SCf, SCh), and front and hind duty cycle (DCf, DCh). Gait speed decreased with age in both genotypes. BoS decreased in front legs and increased in hind legs in both genotypes. Stride length was decreased with age, and more prominently in the gclm-/-, while stride speed decreased with age and was higher in gclm-/-. Step cycles increased with age in the wt but not in the gclm-/-. Duty cycles increased with age, especially in the gclm-/-. These preliminary data suggest that age leads to measurable changes in mouse gait and that GSH dysregulation had only minor effects on gait. In conclusion, Catwalk analysis is sufficiently sensitive to measure subtle age-related changes in gait across several age-ranges, and can be added to the current battery of behavioral tests.Item Influence of exogenous oxidative stress on the resilience of aged glutathione-deficient mice(2018-03-14) Sumien, Nathalie; Mock, J.; Davis, DelaneyInfluence of exogenous oxidative stress on the resilience of aged glutathione-deficient mice Delaney L. Davis, J. Thomas Mock and Nathalie Sumien Introduction With age, individuals become less resilient against stressors, rendering them more susceptible to diseases and leading to exacerbated brain impairments. Aging also involves a shift in redox state that can be associated with the key molecule, glutathione. To determine the importance of glutathione in stress resilience, we sought to study the effect of an oxidative stressor (paraquat) in an animal model of chronic glutathione deficiency. Glutathione deficiency can be achieved by the genetic knockout of the modifier subunit of the enzyme, glutamate cysteine ligase (gclm). Our hypothesis was that chronic glutathione deficiency will render mice less resilient to the oxidative stress induced by paraquat and will cause further impairments in motor and cognitive function. Methods Old (18 months) male and female gclm+/+ and gclm-/- mice received one to two intraperitoneal injections of 10 mg/kg of paraquat (PQ) or saline for one week. Four days following the last injection, animals underwent behavioral tests measuring affective, cognitive and motor function (locomotor activity, elevated zero maze, bridge walking, wire suspension, fear conditioning, rotorod, and active avoidance). After the completion of behavioral testing, brain regions, skeletal muscle, liver, heart, and kidney tissues were harvested and will be used to examine biochemical changes in oxidative damage and redox signaling. The data were analyzed using 2 or 3-way ANOVAs followed by pairwise comparisons. Results Body weights in male and female mice dropped immediately after PQ injection, with the gclm-/-treatment group having a greater decrease in percentage of body weight than the gclm+/+. PQ injections appeared to decrease overall activity of both gclm+/+ and gclm -/-. PQ-treated mice seemed to spend less time in open arms, indicating increased anxiety levels. Overall, PQ-treated mice appeared to perform better on motor skills and worse on cognitive tests. Conclusions These preliminary data suggest a trend that paraquat may have differential effects depending on the task (cognitive vs. motor), and gclm -/- mice may be more susceptible to an oxidative stressor.Item Life on the Catwalk – Age and redox state effects on mouse gait(2018-03-14) Knight, Sherilynn; Vann, Phillip; Wong, Jessica; Davis, Delaney; Forster, Michael; Sumien, Nathalie; Mock, J.1. Purpose Human clinical research has determined that changes in gait speed can be predictive of other impairments and can help identify at-risk individuals for further declines. However, age-related gait changes are not well defined in rodents, even though they are used as the primary pre-clinical model for a multitudes of diseases and for aging research. The purpose of our study was to measure age-related differences in gait, using an automated system, the CatWalk™ XT. Furthermore, age-related functional declines have been associated with a decrease in the reduced to oxidized glutathione ratio leading to a pro-oxidizing cellular shift. Using a model of chronic glutathione deficiency, we sought to determine whether redox state was a key factor in age-related gait impairments. Our hypothesis was that gait declines observed with aging would be exacerbated in glutathione-depleted mice. 2. Methods Groups of wild-type (gclm+/+) and knock-out (gclm-/-) mice aged 4, 10 and 17 months were tested on the CatWalk and gait measurements were recorded. Resulting dependent measures including gait speed, front and hind base of support, front and hind stride length, front and hind stride speed, front and hind step cycle, and front and hind duty cycle were analyzed using two-way analyses of variance with Age and Genotype as between-groups factors, followed by pairwise comparisons. 3. Results Age-related declines were observed in all aforementioned measures of gait, and chronic glutathione depletion was unexpectedly associated with delays in age-related declines for some of the measures. 4. Conclusions The CatWalk is a useful and sensitive tool to assess gait changes with age in rodents, and further studies will be required to identify the potential compensating mechanisms underlying the effects observed with the chronic glutathione depletion. Research Area Neuroscience Presentation Type Oral presentationItem Sexual Dimorphism in Mouse Age-Related Motor Impairments(2017-03-14) Wong, Jessica; Vann, Phillip; Davis, Delaney; Forster, Michael; Sumien, Nathalie; Mock, J.Purpose: Clinical measures such as frailty, disability, and strength loss are correlated with decreased survival and are more prevalent in women, yet men have a higher mortality risk at all ages. This contradictory sexual dimorphism in mortality versus morbidity is not fully understood. Furthermore, many pre-clinical studies using rodents have combined sexes or tested only males which limits the possible inferences regarding sex-dependent changes in function across the lifespan as well as inferences relating to interventions. Therefore, the purpose of this study was to examine murine sexual dimorphism in age-related motor function decline. Our hypothesis was that motor impairments would increase with age, and that these deficiencies would be exacerbated in females. Methods: Male and female C57BL/6J mice were tested at 5, 10, and 20 months of age. Animals underwent a battery of behavioral tests measuring difference aspects of motor function, including tests measuring coordinated running and motor learning (rotorod), strength (wire suspension), and balance (bridge walking). Resulting dependent measures were analyzed using two-way analyses of variance with Age and Sex as between-groups factors and two-way repeated measures analyses of variance with Session as the within group factor. Results: Rotorod performance (learning and maximum) declined with age in both sexes, however declines were smaller for females at 10 and 20 months compared to the males. Latency to fall from the wire was significantly shorter in adult and old males compared to their young counterpart, while there was no significant differences in the females. Bridge walking performance declined in both males and females, but there was a larger decline in the males. Furthermore, age-related decline in balance was observed in the females only on the most difficult bridge, while age-related declines were apparent on all the bridges for the males. Conclusions: These data support that age-related decline leads to measurable changes in mouse motor function. However these deficits occur primarily in the males whereas females displayed fewer and smaller declines in motor function. This suggests that combining sexes or testing only a single sex could lead to limited results. Interestingly, women are typically more sensitive to age-related functional decline, while female mice in our study were less affected by age-related decline. In conclusion, this study highlights the importance of including both sexes in rodent pre-clinical research.Item Tissue-specific effects of Exercise and Antioxidant Intake on Protein Damage in Young and Old Mice(2018-03-14) Scott, Amanda; Mock, J.; Wong, Jessica; Vann, Philip; Davis, Delaney; Sumien, Nathalie; Jafri, Saad1. Purpose: While oxidative stress is not the only factor involved in the aging process, it has been demonstrated that manipulating oxidative stress can affect function and delay age-related declines. Interventions such as moderate exercise and antioxidant supplementation have been shown to affect oxidative stress and improve function. With many individuals combining interventions, it is imperative to determine how they might interact. We hypothesized that exercise or antioxidants alone would decrease oxidative damage, and combining them would further decrease oxidative damage. 2. Methods: Cardiac and skeletal muscle tissues were homogenized and used to determine the levels of protein damage assessed by measuring carbonyl concentrations. The samples were collected from a prior study during which 4 and 20 month old C57BL/6 male mice were placed into one of four treatment groups: sedentary/ control diet, sedentary/ antioxidant diet, exercise/ control diet, and exercise/ antioxidant diet. The exercise consisted of a moderate aerobic treadmill forced exercise, and the antioxidant diet contained α-tocopherol (0.825mg/g diet) and ascorbate (1.65mg/g diet). The effects of age and treatment were analyzed by two-way ANOVAs, followed by pairwise comparisons. 3. Results: There was no main effect of age on protein oxidation in homogenates from cardiac or skeletal muscles. There was no effect of exercise, antioxidant or the combination on carbonyls in the skeletal muscles. However, in the cardiac muscles, all the treatments decreased protein oxidation especially in the old mice (only significantly in the old exercise group). There was no noticeable interaction between antioxidant and exercise treatments. 4. Conclusion: Overall, the effects of treatment were only observed in the cardiac muscle signifying a potential tissue-dependent response to exercise and antioxidants. Interestingly, there was no beneficial or antagonistic interaction between the two interventions. Other tissues will also be studied to strengthen this argument.