Voluntary Wheel Running Partially Attenuates Early Life Stress-Induced Neuroimmune Measures in the Dura and Evoked Migraine-Like Behaviors in Female Mice

Migraine is a complex neurological disorder that affects three times more women than men and can be triggered by endogenous and exogenous factors. Stress is a common migraine trigger and exposure to early life stress increases the likelihood of developing chronic pain disorders later in life. Here, we used our neonatal maternal separation (NMS) model of early life stress to investigate whether female NMS mice have an increased susceptibility to evoked migraine-like behaviors and the potential therapeutic effect of voluntary wheel running. NMS was performed for 3 h/day during the first 3 weeks of life and initial observations were made at 12 weeks of age after voluntary wheel running (Exercise, -Ex) or sedentary behavior (-Sed) for 4 weeks. Mast cell degranulation rates were significantly higher in dura mater from NMS-Sed mice, compared to either naïve-Sed or NMS-Ex mice. Protease activated receptor 2 (PAR2) protein levels in the dura were significantly increased in NMS mice and a significant interaction of NMS and exercise was observed for transient receptor potential ankyrin 1 (TRPA1) protein levels in the dura. Behavioral assessments were performed on adult (>8 weeks of age) naïve and NMS mice that received free access to a running wheel beginning at 4 weeks of age. Facial grimace, paw mechanical withdrawal threshold, and light aversion were measured following direct application of inflammatory soup (IS) onto the dura or intraperitoneal (IP) nitroglycerin (NTG) injection. Dural IS resulted in a significant decrease in forepaw withdrawal threshold in all groups of mice, while exercise significantly increased grimace score across all groups. NTG significantly increased grimace score, particularly in exercised mice. A significant effect of NMS and a significant interaction effect of exercise and NMS were observed on hindpaw sensitivity following NTG injection. Significant light aversion was observed in NMS mice, regardless of exercise, following NTG. Finally, exercise significantly reduced calcitonin gene-related peptide (CGRP) protein level in the dura of NMS and naïve mice. Taken together, these findings suggest that while voluntary wheel running improved some measures in NMS mice that have been associated with increased migraine susceptibility, behavioral outcomes were not impacted or even worsened by exercise.

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Voluntary wheel running improves outcomes in an early life stress-induced model of urologic chronic pelvic pain syndrome in male mice

10.1101/2020.07.20.212480 ◽

2020 ◽

Author(s):

Isabella M. Fuentes ◽

Brittni M. Jones ◽

Aaron D. Brake ◽

Angela N. Pierce ◽

Olivia C. Eller ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Chronic Pelvic Pain ◽

Wheel Running ◽

Chronic Pelvic Pain Syndrome ◽

Early Life Stress ◽

Pain Syndrome ◽

Pelvic Pain Syndrome ◽

Voluntary Wheel Running ◽

Voluntary Wheel

AbstractPatients with a history of early life stress (ELS) exposure have an increased risk of developing chronic pain and mood disorders later in life. The severity of ELS in patients with urologic chronic pelvic pain syndrome (UCPPS) is directly correlated with symptom severity and increased comorbidity, and is inversely related to likelihood of improvement. Voluntary exercise improves chronic pain symptoms and our group and others have shown that voluntary wheel running can improve outcomes in stress-induced UCPPS models, suggesting that exercise may negate some of the outcomes associated with ELS. Here we provide further evidence that voluntary wheel running can attenuate increased perigenital mechanical sensitivity, bladder output, and mast cell degranulation in the bladder and prostate in male mice that underwent neonatal maternal separation (NMS). Sedentary male NMS mice had reduced serum corticosterone, which was not impacted by voluntary wheel running, although stress-related regulatory gene expression in the hypothalamus and hippocampus was significantly increased following exercise. Neurogenesis in the dentate gyrus of the hippocampus was diminished in sedentary NMS mice and significantly increased in both exercised naïve and NMS mice. Sucrose consumption increased in exercised naïve but not NMS mice, and anxiety behaviors measured on an elevated plus maze were increased following exercise. Together these data suggest that voluntary wheel running is sufficient to normalize many of the UCPPS-related outcomes resulting from NMS. Exercise also increased hippocampal neurogenesis and stress-related gene expression within the hypothalamic-pituitary-adrenal axis, further supporting exercise as a non-pharmacological intervention for attenuating outcomes related to ELS exposure.

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Voluntary wheel running improves outcomes in an early life stress-induced model of urologic chronic pelvic pain syndrome in male mice

Pain ◽

10.1097/j.pain.0000000000002178 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

Isabella M. Fuentes ◽

Brittni M. Jones ◽

Aaron D. Brake ◽

Angela N. Pierce ◽

Olivia C. Eller ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Chronic Pelvic Pain ◽

Wheel Running ◽

Chronic Pelvic Pain Syndrome ◽

Early Life Stress ◽

Pain Syndrome ◽

Pelvic Pain Syndrome ◽

Male Mice ◽

Voluntary Wheel

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Early life stress reduces voluntary exercise and its prevention of diet-induced obesity and metabolic dysfunction in mice

10.1101/2020.01.24.918805 ◽

2020 ◽

Author(s):

Olivia C. Eller-Smith ◽

E. Matthew Morris ◽

John P. Thyfault ◽

Julie A. Christianson

Keyword(s):

Hpa Axis ◽

Life Stress ◽

Early Life ◽

Wheel Running ◽

Control Diet ◽

Early Life Stress ◽

Voluntary Exercise ◽

Free Access ◽

Mrna Levels ◽

Diet Induced Obesity

AbstractThe development of obesity-related metabolic syndrome (MetS) involves a complex interaction of genetic and environmental factors. One environmental factor found to be significantly associated with MetS is early life stress (ELS). We have previously reported on our mouse model of ELS, induced by neonatal maternal separation (NMS), that displays altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis and increased sensitivity in the urogenital organs, which was attenuated by voluntary wheel running. Here, we are using our NMS model to determine if ELS-induced changes in the HPA axis also influence weight gain and MetS. Naïve (non-stressed) and NMS male mice were given free access to a running wheel and a low-fat control diet at 4-weeks of age. At 16-weeks of age, half of the mice were transitioned to a high fat/sucrose (HFS) diet to investigate if NMS influences the effectiveness of voluntary exercise to prevent diet-induced obesity and MetS. Overall, we observed a greater impact of voluntary exercise on prevention of HFS diet-induced outcomes in naïve mice, compared to NMS mice. Although body weight and fat mass were still significantly higher, exercise attenuated fasting insulin levels and mRNA levels of inflammatory markers in epididymal adipose tissue in HFS diet-fed naïve mice. Only moderate changes were observed in exercised NMS mice on a HFS diet, although this could partially be explained by reduced running distance within this group. Interestingly, sedentary NMS mice on a control diet displayed impaired glucose homeostasis and moderately increased pro-inflammatory mRNA levels in epididymal adipose, suggesting that early life stress alone impairs metabolic function and negatively impacts the therapeutic effect of voluntary exercise.

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Effects of a high-fat diet and voluntary wheel running on gluconeogenesis and lipolysis in rats

Journal of Applied Physiology ◽

10.1152/jappl.1999.86.4.1374 ◽

1999 ◽

Vol 86 (4) ◽

pp. 1374-1380 ◽

Cited By ~ 26

Author(s):

Deborah A. Podolin ◽

Yuren Wei ◽

Michael J. Pagliassotti

Keyword(s):

High Fat Diet ◽

Corn Oil ◽

Wheel Running ◽

Whole Body ◽

Free Access ◽

Fat Pad ◽

High Fat ◽

Voluntary Wheel Running ◽

Voluntary Wheel

The purpose of the present study was to determine the effects of diet composition and exercise on glycerol and glucose appearance rate (Ra) and on nonglycerol gluconeogenesis (Gneo) in vivo. Male Wistar rats were fed a high-starch diet (St, 68% of energy as cornstarch, 12% corn oil) for a 2-wk baseline period and then were randomly assigned to one of four experimental groups: St ( n = 7), high-fat (HF; 35% cornstarch, 45% corn oil; n = 8), St with free access to exercise wheels (StEx; n = 7), and HF with free access to exercise wheels (HFEx; n = 7). After 8 wk, glucose Rawhen using [3-3H]glucose, glycerol Rawhen using [2H5]glycerol (estimate of whole body lipolysis), and [3-13C]alanine incorporation into glucose (estimate of alanine Gneo) were determined. Body weight and fat pad mass were significantly ( P < 0.05) decreased in exercise vs. sedentary animals only. The average amount of exercise was not significantly different between StEx (3,212 ± 659 m/day) and HFEx (3,581 ± 765 m/day). The ratio of glucose to alanine enrichment and absolute glycerol Ra(μmol/min) were higher ( P < 0.05) in HF and HFEx compared with St and StEx rats. In separate experiments, the ratio of3H in C-2 to C-6 of glucose from3H2O (estimate of Gneo from pyruvate) was also higher ( P < 0.05) in HF ( n = 5) and HFEx ( n = 5), compared with St ( n = 5) and StEx ( n = 5) rats. Voluntary wheel running did not significantly increase estimated alanine or pyruvate Gneo or absolute glycerol Ra. Voluntary wheel running increased ( P< 0.05) glycerol Rawhen normalized to fat pad mass. These data suggest that a high-fat diet can increase in vivo Gneo from precursors that pass through pyruvate. They also suggest that changes in the absolute rate of glycerol Ramay contribute to the high-fat diet-induced increase in Gneo.

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