Allostasis, Homeostasis, and the Costs of Physiological Adaptation

Sarah Coste reviews Allostasis, Homeostasis, and the Costs of Physiological Adaptation (edited by Jay Schulkin) for the Quarterly Review of Biology

The Effects of Social Stress on Voluntary Running Behavior in Female Mice

Regular physical activity (PA) positively impacts physical and mental health outcomes. However, there is a reciprocal relationship wherein stress significantly reduces healthy levels of routine PA. We showed previously that voluntary running behavior of male mice essentially ceases following exposure to a resident-intruder social stress. Here we examined female mice. Female mice were divided into four groups (n=8/group): sedentary/control, voluntary running/control, sedentary/stress, and voluntary running/stress. Running groups were given unlimited access to a running wheel in the home cage for 9 weeks with a nightly average of 6.86 ± 2.5 km. During the ninth week, stress groups were exposed to a single, 6-hour bout of a female-specific, resident-intruder social stress. Plasma corticosterone significantly increased following stress (34.56 ± 13 ng/ml basal to 330.5 ± 95 ng/ml immediately post-stress). Nightly running dropped significantly to 1.72 ± 0.9 km. Unlike male mice where running levels were slow to recover, voluntary running in these female mice returned to normal levels by the second night (5.01 ± 2.5 km). This study shows the sensitivity of habitual running behavior to stress exposure and suggests the utility of this mouse model in exploring the means by which stress negatively impacts routine PA

The Effects of Physical Activity on Stress-induced Cardiac Fibrosis

Purpose: This study examined whether routine physical activity limits stress-induced tissue remodeling processes that lead to cardiac fibrosis. The study also explored whether the cardiac urocortin 2/corticotropin releasing factor receptor 2β pathway was activated during physical activity and involved in reducing fibrotic processes. Methods: C67BL/6J male mice were divided into four groups (n=8/group): sedentary/control, voluntary running/control, sedentary/stress and voluntary running/stress. Voluntary running groups were given 24-hour access to a running wheel in the home cage for 9 weeks. During the 9th week, stress groups were exposed to a 5-day resident-intruder stress paradigm that models human post-traumatic stress outcomes. Ventricular cardiac tissue was collected for analysis. Results: Mice ran an average of 4.75 ± 1 km each night. Interestingly, running behavior essentially ceased following stress. Running distance dropped to 0.31 km following the 1st stress day. Some habituation to stress occurred, as running distance increased to 1.12 km by the 5th day of stress but remained significantly lower than pre-stress running distances and distances recorded in non-stressed mice. Quantitative RT-PCR showed small changes in ventricular urocortin 2 and CRF-R2β expression in the running groups. TGF-β, a signaling molecule known to induce fibrosis, had comparable expression levels across groups over controls. Conclusion: Further work is planned to fully characterize urocortin 2/ CRF-R2β and fibrotic processes. Our running data lead us in a new direction, as we have stumbled upon a paradigm that will be useful to study underlying mechanisms by which stress exposure impairs physical activity behavior

Cessation of Nightly Voluntary Wheel Running Activity Following Exposure to a Mouse Model of Posttraumatic Stress

Regular physical activity (PA) is well known to positively impact physical and mental health outcomes. In our work to examine cardiovascular benefits of PA in a mouse model of posttraumatic stress, we stumbled upon the reciprocal relationship between PA and stress exposure, wherein stress significantly reduced healthy levels of routine PA. The aim of the present studies was to define the parameters of our paradigm. C67BL/6J male mice were divided into four groups (n=8/group): sedentary/control, voluntary running/control, sedentary/stress, and voluntary running/stress. Voluntary running groups were given unlimited access to a running wheel for 9 weeks. Stress groups were then exposed to a 5-day resident-intruder social stress that models human posttraumatic stress. Running behavior essentially ceased following stress. Habituation to stress occurred, as running distance increased by the 5th day of stress but remained significantly low. A separate study examined a single exposure to resident-intruder social stress. Plasma corticosterone significantly increased while nightly running dropped significantly but returned to normal by the 3rd night post-stress. These studies show the sensitivity of habitual running behavior to stress exposure and suggest the utility of this mouse model in exploring the means by which stress negatively impacts routine PA

Velocity, Distance and Shoulder Range of Motion in Two Throwing Programs

Success in baseball pitching is determined by throwing velocity and accuracy. Strength conditioning, as well as repetitive throwing programs, are used to improve the pitch. Recently, a weighted ball program has been developed and is believed to increase ball velocity with less potential injury. However, there is limited research examining the impact of this program on performance. The purpose of this study was to compare a traditional long toss program versus a weighted ball program. Baseline throwing velocity and distance as well as shoulder range of motion (ROM) were measured in collegiate baseball players. Participants were then randomized to either a six-week-long toss throwing program or weighted ball program. Following training, throwing velocity, distance, and shoulder ROM were measured again. Both training methods significantly improved throwing distance. However, throwing velocity did not change from pre-training measurements. All measurements of shoulder ROM (flexion, abduction, and external rotation) significantly improved in both groups, with abduction showing the greatest improvement in the long toss group. Our results suggest both training programs are beneficial for baseball performance

IL-1α and TNF-α Down-Regulate CRH Receptor-2 mRNA Expression in the Mouse Heart

Two receptors (CRH receptor type 1 and CRH receptor type 2) have been identified for the stress-induced neuropeptide, CRH and related peptides, urocortin, and urocortin II. We previously found marked down-regulation of cardiac CRH receptor type 2 expression following administration of bacterial endotoxin, lipopolysaccharide, a model of systemic immune activation, and inflammation. We postulated that inflammatory cytokines may regulate CRH receptor type 2. We show that systemic IL-1α administration significantly down-regulates CRH receptor type 2 mRNA in mouse heart. In addition, TNFα treatment also reduces CRH receptor type 2 mRNA expression, although the effect was not as marked as with IL-1α. However, CRH receptor type 2 mRNA expression is not altered in adult mouse ventricular cardiomyocytes stimulated in vitro with TNFα or IL-1α. Thus, cytokine regulation may be indirect. Exogenous administration of corticosterone in vivo or acute restraint stress also reduces cardiac CRH receptor type 2 mRNA expression, but like cytokines, in vitro corticosterone treatment does not modulate expression in cardiomyocytes. Interestingly, treatment with urocortin significantly decreases CRH receptor type 2 mRNA in cultured cardiomyocytes. We speculate that in vivo, inflammatory mediators such as lipopolysaccharide and/or cytokines may increase urocortin, which in turn down-regulates CRH receptor type 2 expression in the heart. Because CRH and urocortin increase cardiac contractility and coronary blood flow, impaired CRH receptor type 2 function during systemic inflammation may ultimately diminish the adaptive cardiac response to adverse conditions

Using ordinal logistic regression to evaluate the performance of laser-Doppler predictions of burn-healing time

Background Laser-Doppler imaging (LDI) of cutaneous blood flow is beginning to be used by burn surgeons to predict the healing time of burn wounds; predicted healing time is used to determine wound treatment as either dressings or surgery. In this paper, we do a statistical analysis of the performance of the technique. Methods We used data from a study carried out by five burn centers: LDI was done once between days 2 to 5 post burn, and healing was assessed at both 14 days and 21 days post burn. Random-effects ordinal logistic regression and other models such as the continuation ratio model were used to model healing-time as a function of the LDI data, and of demographic and wound history variables. Statistical methods were also used to study the false-color palette, which enables the laser-Doppler imager to be used by clinicians as a decision-support tool. Results Overall performance is that diagnoses are over 90% correct. Related questions addressed were what was the best blood flow summary statistic and whether, given the blood flow measurements, demographic and observational variables had any additional predictive power (age, sex, race, % total body surface area burned (%TBSA), site and cause of burn, day of LDI scan, burn center). It was found that mean laser-Doppler flux over a wound area was the best statistic, and that, given the same mean flux, women recover slightly more slowly than men. Further, the likely degradation in predictive performance on moving to a patient group with larger %TBSA than those in the data sample was studied, and shown to be small. Conclusion Modeling healing time is a complex statistical problem, with random effects due to multiple burn areas per individual, and censoring caused by patients missing hospital visits and undergoing surgery. This analysis applies state-of-the art statistical methods such as the bootstrap and permutation tests to a medical problem of topical interest. New medical findings are that age and %TBSA are not important predictors of healing time when the LDI results are known, whereas gender does influence recovery time, even when blood flow is controlled for. The conclusion regarding the palette is that an optimum three-color palette can be chosen 'automatically', but the optimum choice of a 5-color palette cannot be made solely by optimizing the percentage of correct diagnoses

Exploring the Reciprocal Relationship between Stress and Physical Activity

Regular physical activity (PA) is well known to positively impact physical and mental health outcomes. In our work to examine cardiovascular benefits of PA in a mouse model of post-traumatic stress, we stumbled upon the reciprocal relationship between PA and stress exposure, wherein stress significantly reduced healthy levels of routine PA. Specifically, our previous study showed that nightly voluntary running (average 4.75 ± 1 km) essentially ceased to 0.31 km following the first day of a 5-day resident-intruder social stress, a model of human posttraumatic stress. The aim of the present study was to define the parameters of our paradigm as first steps for its future use in examining mechanisms that underlie stress-induced declines in PA. Five-week-old C57BL/6J male mice were divided into four groups (n=8/group): sedentary/control, voluntary running/control, sedentary/stress, and voluntary running/stress. Voluntary running groups were given 24-hour unlimited access to a running wheel in the home cage for 9 weeks. Mice were then exposed to a single 6-hour bout of resident-intruder social stress. We found that plasma corticosterone significantly increased (16.66 ± 4 ng/ml basal to 496 ± 155 ng/ml immediately post stress), while nightly running dropped significantly from an average nightly distance of 5.58 ± 1.7 km to 1.22 ± 1.1 km during the night following stress. Voluntary running returned to near normal levels (4.35 ± 1.7 km) by the third night post-stress. Food intake was moderately increased in the first 2 nights post-stress, but also returned to normal by the third night. These studies show the sensitivity of habitual running behavior to stress exposure and suggest the utility of this mouse model in exploring the means by which stress negatively impacts routine PA

The Effects of Physical Activity on Stress-Induced Cardiac Fibrosis

The aim of this project was to examine whether routine physical activity limits stress-induced tissue remodeling processes that lead to cardiac fibrosis. A secondary aim was to take the first steps to explore a potential and novel underlying mechanism, wherein a cardiac urocortin 2/corticotropin releasing factor receptor 2β pathway may be activated during physical activity and involved in reducing fibrotic processes. C67BL/6J male mice were divided into four groups (n=8/group); sedentary control, voluntary running control, sedentary/stress and voluntary running/stress. Mice in the voluntary running groups were given 24-hour unlimited access to a running wheel in the home cage for 9 weeks with wheel running activity recorded continuously. During the 9th week of running, mice in the stress groups were exposed to a 5 day resident-intruder social stress paradigm that is considered to model human post traumatic stress outcomes and has been shown to induce cardiovascular fibrosis. Ventricular cardiac tissue was collected for analysis at the end of the experiment. We found that mice in the voluntary running groups ran an average of 4.75 ± 1 km each day with the majority of running bouts occurring within the first 6 hours of the dark cycle. Interestingly, running behavior essentially ceased in mice exposed to stress. Running distance dropped to 0.31 km following the first day of stress. Some habituation to stress occurred, as running distance increased to 1.12 km by the 5th day of stress but was still significantly lower then pre-stress running distances and distances recorded in non-stressed mice. Quantitative RT-PCR showed a 2-fold increase in ventricular urocortin 2 gene expression in the sedentary/stress group, while levels were slightly lower in the voluntary running/stress group with a 1.78-fold increase over controls. CRF-R2β expression was not significantly altered. TGF-β, a signaling molecule known to induce fibrosis, showed slight elevation in expression in the stress group. Total protein was isolated from heart ventricles and we are in the process of performing Western blots to assess levels of specific proteins that are indicative of fibrosis. Complete findings will be presented at the Linfield College Student Symposium this spring

The Effects of Social Stress on Routine Voluntary Running in Female Mice

This project explores the reciprocal relationship between regular physical activity (PA) and psychological stress. It is known that physical activity can reduce the physiological and behavioral responses to stress that contribute to the development and progression of various disease states. However, stress exposure significantly reduces healthy levels of routine physical activity. We showed previously that voluntary running behavior of male mice essentially ceases following exposure to a resident-intruder social stress that models human post-traumatic stress outcomes. Here we sought to determine whether a similar type of stress would inhibit habitual voluntary running in female mice. Five-week-old, C67BL/6J female mice were divided into four groups (n=8/group): sedentary/control, voluntary running/control, sedentary/stress, and voluntary running/stress. Voluntary running groups were given 24-hour unlimited access to a running wheel in the home cage for 9 weeks. Mice ran a nightly average of 6.86 ± 2.5 km. During the ninth week, stress groups were exposed to a single, 6-hour bout of a female-specific, resident-intruder social stress. Plasma corticosterone significantly increased following stress (34.56 ± 13 ng/ml basal to 330.5 ± 95 ng/ml immediately post-stress), while nightly running dropped significantly to 1.72 ± 0.9 km. Unlike male mice where running levels were slow to recover, voluntary running in these female mice returned to near normal levels by the second night (5.01 ± 2.5 km). This study shows the sensitivity of habitual running behavior to stress exposure and suggests the utility of this mouse model in exploring the means by which stress negatively impacts routine PA