Nicole E. Cyr

The Reactive Scope Model - a new model integrating homeostasis, allostasis, and stress.

Allostasis, the concept of maintaining stability through change, has been proposed as a term and a model to replace the ambiguous term of stress, the concept of adequately or inadequately coping with threatening or unpredictable environmental stimuli. However, both the term allostasis and its underlying model have generated criticism. Here we propose the Reactive Scope Model, an alternate graphical model that builds on the strengths of allostasis and traditional concepts of stress yet addresses many of the criticisms. The basic model proposes divergent effects in four ranges for the concentrations or levels of various physiological mediators involved in responding to stress. (1) Predictive Homeostasis is the range encompassing circadian and seasonal variation - the concentrations/levels needed to respond to predictable environmental changes. (2) Reactive Homeostasis is the range of the mediator needed to respond to unpredictable or threatening environmental changes. Together, Predictive and Reactive Homeostasis comprise the normal reactive scope of the mediator for that individual. Concentrations/levels above the Reactive Homeostasis range is (3) Homeostatic Overload, and concentrations/levels below the Predictive Homeostasis range is (4) Homeostatic Failure. These two ranges represent concentrations/levels with pathological effects and are not compatible with long-term (Homeostatic Overload) or short-term (Homeostatic Failure) health. Wear and tear is the concept that there is a cost to maintaining physiological systems in the Reactive Homeostasis range, so that over time these systems gradually lose their ability to counteract threatening and unpredictable stimuli. Wear and tear can be modeled by a decrease in the threshold between Reactive Homeostasis and Homeostatic Overload, i.e. a decrease in reactive scope. This basic model can then be modified by altering the threshold between Reactive Homeostasis and Homeostatic Overload to help understand how an individuals response to environmental stressors can differ depending upon factors such as prior stressors, dominance status, and early life experience. We illustrate the benefits of the Reactive Scope Model and contrast it with the traditional model and with allostasis in the context of chronic malnutrition, changes in social status, and changes in stress responses due to early life experiences. The Reactive Scope Model, as an extension of allostasis, should be useful to both biomedical researchers studying laboratory animals and humans, as well as ecologists studying stress in free-living animals.

Identifying hormonal habituation in field studies of stress

Habituation is a term commonly used to explain a decrement in response intensity to a repeated stimulus or set of stimuli. In the stress literature, hormonal habituation is often used to describe a situation where an individual has learned to perceive a repeated stressor as innocuous, and thus the intensity of the release of hormonal stress mediators reduces over time. Consequently, a habituated individual is not considered stressed. There are, however, situations where an individual may be chronically stressed despite a reduction in the response intensity of hormonal stress mediators to a repeated stimulus. These alternative explanations are rarely considered in field studies even though a false conclusion that an individual has habituated (i.e., is not stressed) may lead to false conclusions regarding the animals overall physiology and health. The present paper provides four alternative explanations for an observed attenuation in the response of hormonal stress mediators to a repeated stimulus or set of stimuli which lead to six criteria that define habituation in a field context. Furthermore, we propose four diagnostic tests to help distinguish hormonal habituation from these alternative explanations in field studies. These tests will help identify hormonal habituation in free-living animals and prevent potential problems of falsely describing an individual or population of individuals as habituated.

Increased Energy Expenditure but Decreased Stress Responsiveness during Molt

Baseline and stress‐induced corticosterone (CORT), heart rate (fH), and energy expenditure were measured in eight captive European starlings Sturnus vulgaris during and following a prebasic molt. The fH and oxygen consumption (V̇o2) were measured simultaneously across a range of heart rates, and energy expenditure (kJ/d) was then calculated from data. Energy expenditure and fH were strongly and positively correlated in each individual. Baseline fH and energy expenditure were significantly higher during molt. Molting starlings expended 32% more energy over 24 h than nonmolting birds, with the most significant increase (60%) occurring at night, indicating a substantial energetic cost to molt. Furthermore, the cardiac and metabolic responses to stress during molt were different than during nonmolt. Birds were subjected to four different 30‐min acute stressors. The fH and CORT responses to these stressors were generally lower during molt. Although restraint caused a 64% increase in daily energy expenditure during nonmolt, no other stressor caused a significant increase in energy expenditure. Overall, our data suggest that molt is not only energetically expensive but that it also alters multiple stress response pathways. Furthermore, most acute stressors do not appear to require a significant increase in energy expenditure.

Fecal glucocorticoid metabolites of experimentally stressed captive and free-living starlings: implications for conservation research.

Fecal glucocorticoid metabolite (FGM) analysis has received considerable attention in conservation biology because it has potential to be used as a noninvasive measure of stress in animals. There has been a recent and extensive literature describing the importance of technical, physiological, and biological validations of this technique, yet surprisingly little is known about how FGM concentrations change during chronic stress. Therefore, we experimentally induced chronic stress in both captive and free-living European starlings (Sturnus vulgaris). Chronic stress was elicited using a rotation of four different 30 min acute stressors for 16 days in the laboratory and 8 days in the field. Exogenous ACTH, the primary glucocorticoid secretagog, significantly increased FGM concentrations in approximately 2 h, and our assay detected endogenous diel glucocorticoid rhythms similar to those of other birds. Thus, our assay was both physiologically and biologically validated. However, experimentally induced chronic stress did not alter daytime or nighttime FGM concentrations in captive starlings. In contrast, chronically stressed adult female starlings had higher FGM concentrations than unstressed female starlings in the field. Our field data support the general assumption that higher FGM concentrations indicate chronic stress, but our captive data do not. Overall, our results suggest that more research is need before FGM analysis can be used as a reliable measure of stress in animals, especially those kept in captivity.

Heart Rate and Heart‐Rate Variability Responses to Acute and Chronic Stress in a Wild‐Caught Passerine Bird

The cardiovascular‐stress response has been studied extensively in laboratory animals but has been poorly studied in naturally selected species. We determined the relative roles of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS) in regulating stress‐induced changes in heart rate (HR) in wild‐caught European starlings (Sturnus vulgaris). In both heart‐rate variability (HRV) analysis and receptor blockade (atropine and propranolol) experiments, baseline HR was controlled predominantly by the PNS, whereas the increase in HR resulting from acute restraint stress was controlled predominantly by the SNS. These results indicate similar cardiac control of baseline and acute‐stress‐induced HR in wild‐caught starlings and mammals. We further investigated HR responses during chronic stress. Driven primarily by changes in PNS regulation, baseline HR increased during the day but decreased at night. In addition, elevated HRs during acute restraint stress were attenuated throughout chronic stress and were accompanied by decreased HRV. This suggested that increased SNS drive elevated HR, but the attenuated HR response combined with resistance to the SNS blocker propranolol suggested that the sympathetic signal was less effective during chronic stress. Overall, chronic stress in wild‐caught starlings elicited profound changes in cardiac function that were primarily regulated by changes in the PNS.

Effects of predictable and unpredictable food restriction on the stress response in molting and non-molting European starlings (Sturnus vulgaris).

This study tested whether an ethologically relevant stressor, a three-week period of food restriction where food was unavailable for four hours a day, caused chronic stress in molting and non-molting captive European starlings. Although all birds increased weight during the Food Restriction period, only non-molting birds increased food intake. Morning baseline heart rates increased during the Food Restriction period and all birds showed a decrease in heart rate when food was absent from the cage. In non-molting birds, there were no differences in either baseline or stress-induced corticosterone (CORT) concentrations, whereas molting birds showed attenuated baseline CORT, stress-induced CORT, and fecal glucocorticoid metabolite levels over the Food Restriction period. Although several parameters, such as increased morning heart rate, are consistent with chronic stress, the majority of these data suggest that restricting food availability is not chronically stressful. Furthermore, making the timing of food removal less predictable by randomizing when food was removed during the day did not enhance any of the above responses, but did alter the frequency of maintenance and feeding behaviors. In conclusion, starlings appear resistant to developing symptoms of chronic stress from repeated food restriction.

Island tameness: An altered cardiovascular stress response in Galápagos marine iguanas

Island tameness is a widely documented phenomenon in which island species, particularly those that have evolved with no or few natural predators, show a greatly reduced behavioral response when faced with unfamiliar predators. This insufficient anti-predator response has led to widespread population declines among many island species exposed to novel predators, and has become a serious conservation problem. Despite its prevalence, the underlying physiology of island tameness is not known. Here we report that although Galápagos marine iguanas (Amblyrhynchus cristatus) initiated flight from an evolutionarily recent and unfamiliar potential predator (humans), they failed to show the cardiovascular stress response that facilitates successful escape, even after a prior capture experience. In contrast, when approached by a native predator (the Galápagos hawk; Buteo galapagoensis), marine iguanas show markedly increased heart rate independent of initiating escape movement. The secretion of catecholamines appears to be central to the initiation of escape behavior: naïve animals remotely injected with epinephrine immediately increased flight initiation distance, whereas those injected with corticosterone did not. Our results provide the first evidence that muted escape behavior in predator-naïve species is indicative of both a cognitive deficit in recognizing potential predators and a catecholamine deficit in response. Understanding how the response to predators differs in predator-naïve species could enable the design of maximally effective techniques for inducing an anti-predator response in these vulnerable species.

Nuclear thimet oligopeptidase is coexpressed with oestrogen receptor alpha in hypothalamic cells and regulated by oestradiol in female mice

Thimet oligopeptidase (EC 3.4.24.15; also called EP24.15 and TOP; referred to here as TOP) is a neuropeptidase involved in the regulation of several physiological functions including reproduction. Among its substrates is gonadotrophin‐releasing hormone (GnRH), an important hypothalamic hormone that regulates the synthesis and release of oestradiol and facilitates female sexual behaviour. Using immunohistochemistry, we found that TOP is expressed in the nucleus of cells throughout the female mouse brain, and in high levels in steroid‐sensitive regions of the hypothalamus, which is consistent with previous findings in male rats. Furthermore, dual‐label immunofluorescence revealed that TOP and oestrogen receptor α (ERα) coexpress in several reproductively‐relevant brain regions, including the medial preoptic area (mPOA), arcuate nucleus (ARC), ventrolateral portion of the ventromedial hypothalamic nucleus (VMNvl) and the midbrain central grey (MCG). Previous studies in rats have shown that oestradiol decreases hypothalamic TOP levels or activity, possibly potentiating the effects of GnRH. In the present study, analysis by immunohistochemistry revealed that oestradiol decreased TOP immunoreactivity in the VMNvl, whereas no differences were detected in the mPOA, ARC or median eminence. Overall, the present findings indicate that TOP is coexpressed with ERα, and oestradiol regulates TOP expression in a brain region‐specific manner in female mice, providing neuroanatomical evidence that TOP may function in reproductive physiology and/or behaviour.

Neuropeptidase activity is down-regulated by estradiol in steroid-sensitive regions of the hypothalamus in female mice

Thimet oligopeptidase (TOP) and prolyl endopeptidase (PEP) are neuropeptidases involved in the hydrolysis of gonadotropin-releasing hormone, a key component of the hypothalamic-pituitary-gonadal axis. GnRH is regulated in part by feedback from steroid hormones such as estradiol. Previously, we demonstrated that TOP levels are down-regulated by estradiol in reproductively-relevant regions of the female rodent brain. The present study supports these findings by showing that TOP enzyme activity, as well as protein levels, in the ventromedial hypothalamic nucleus of female mice is controlled by estradiol. We further demonstrate that PEP levels in this same brain region are down-regulated by estradiol in parallel with those of TOP. These findings provide evidence that these neuropeptidases are part of the fine control of hormone levels in the HPG axis.