Corticosterone Stress Response Research Articles

Physiological and behavioral variation by urbanization and climate in an urban-tolerant toad

The distribution of a species is best understood by examining the organism-environment interaction. Climate and anthropogenic habitat degradation, including urbanization, are salient features of the environment that can limit species distributions, especially for ectotherms. Comparative studies of the capacity of individuals to cope with rapid environmental change can help us understand the future success or failure of local populations or even the species. Studies of the glucocorticoid stress response are commonly used to understand how species cope with environmental stressors. Glucocorticoids modulate many aspects of physiological homeostasis including changes in energetic allocation and behavior. In a time of global amphibian decline the Gulf Coast Toad (Incilius nebulifer) is increasing its distribution and abundance. To understand how this species deals with thermal and urban stressors, we studied glucocorticoid regulation, hop performance, and lipid storage in I. nebulifer juveniles across nine populations that differed in average annual temperature and level of imperviousness (as an indication of urbanization). We measured corticosterone release rates at baseline, during agitation stress, and during recovery; then measured locomotor performance and whole-body lipids. We tested if I. nebulifer in hotter temperatures and more urbanized habitats exhibits elevated baseline corticosterone levels and either a reduced corticosterone stress response (“stress resistance” hypothesis) or quick post-stress recovery by negative feedback (“on again, off again” hypothesis). We also tested whether they exhibit reduced fat stores and decreased locomotor performance as costs of dealing with thermal and urban stressors. We found that I. nebulifer showed elevated baseline and agitation (stressed-induced) corticosterone release rates, and higher lipid storage with increasing urbanization. Climate had quadratic effects on these traits, such that populations living at the lowest and highest temperatures had the lowest corticosterone release rates and lipid stores, and the highest hop performance was observed in the least urbanized site at the warmest climate. Additionally, the rate of glucocorticoid recovery after agitation (negative feedback) decreased with increasing temperature and increased with increasing urbanization. These results indicate that I. nebulifer follows the “on again, off again” hypothesis in an adaptive pattern, which may help them cope with environmental change in terms of urbanization and climatic differences.

THU118 Prefrontal-Medullary Circuit Is Necessary For Chronic Stress-Induced Neuroendocrine And Behavioral Outcomes

Abstract Disclosure: S.A. Pace: None. E. Lukinic: None. P. Barrette: None. T. Wallace: None. B. Myers: None. Chronic stress exposure is a major risk factor for psychiatric and cardiometabolic diseases. Although the pathologies associated with chronic stress are well-documented, the biological mechanisms underlying these physiological changes remain unknown. Human imaging studies indicate the prefrontal cortex is a key site for processing stress-related information. Within the rat prefrontal cortex, the infralimbic area (IL) is critical for regulating physiological stress reactivity in a sex-specific fashion. Here we examined the necessity of an IL downstream circuit for neurogenic regulation of neuroendocrine susceptibility after chronic stress. We focused on an IL to rostral ventrolateral medulla (RVLM) circuit due to the ability of the RVLM to initiate the sympatho-adrenomedullary stress responses and influence HPA axis activity. Critically, the IL-RVLM circuit is structurally positioned to underlie a crucial link between stress appraisal and sympathetic reactivity. To determine the role of the IL-RVLM circuit during chronic stress, an intersectional viral strategy was used to express a light-chain variant of Tetanus Toxin (TeLC) in RVLM-projecting IL neurons, thereby disrupting IL-RVLM signaling. TeLC-expressing IL neurons had less synaptobrevin-2 protein located on terminals and fewer synaptic appositions in the RVLM. This chronic circuit disruption approach was evaluated in the context of a 2-week chronic variable stress (CVS) paradigm in male and female rats. In males, CVS-exposed TeLC rats displayed decreased corticosterone levels in response to a novel stressor compared to control rats. CVS-naïve males showed no significant changes. In females, we similarly observed no differences in unstressed rats. However, CVS TeLC female rats had increased glycemic and corticosterone stress responses compared to CVS control animals. Additionally, female CVS TeLC rats had increased behavioral avoidance indicated by less time spent in the center of an open field arena compared to CVS control rats. This behavioral effect was not present in males. These results suggest that the IL-RVLM circuit is essential for preventing chronic stress outcomes in female rats, but not males. Further, this circuit regulation is necessary only after chronic stress exposure. Future studies will be aimed at determining sex differences in chronic stress effects on IL-RVLM signaling. Presentation: Thursday, June 15, 2023

Body condition and corticosterone stress response, as markers to investigate effects of human activities on Adélie penguins (Pygoscelis adeliae)

IntroductionIn Antarctica, there is growing concern about the potential effect of anthropogenic activities (i.e., tourism, research) on wildlife, especially since human activities are developing at an unprecedented rate. Although guidelines exist to mitigate negative impacts, fundamental data are currently lacking to reliably assess impacts. Physiological tools, such as circulating corticosterone levels, appear promising to assess the potential impact of human disturbance on Antarctic vertebrates.MethodsIn this study, we compared the body condition, and the physiological sensitivity to stress (i.e., basal and stress-induced corticosterone level) of adult and chick Adélie penguins between a disturbed and an undisturbed area (i.e., 2 colonies located in the middle of a research station exposed to intense human activities and 2 colonies located on protected islands with minimal human disturbance).ResultsWe did not find any significant impact of human activities on body condition and corticosterone levels in adults (incubating adults, brooding adults). In chicks, there were significant inter-colony variations in stress-induced corticosterone levels. Specifically, the chicks from the disturbed colonies tended to have higher stress-induced corticosterone levels than the chicks from the protected areas although this difference between areas was not significant. In addition, and independently of human disturbance we also found significant differences in adult body condition, and chick corticosterone level between colonies.DiscussionOverall, our study suggests that this species is not dramatically impacted by human activities, at least when humans and penguins have cohabited for several decades. Our results support therefore the idea that this species is likely to be tolerant to human disturbance and this corroborates with the persistence of Adélie penguin colonies in the middle of the research station. However, our results also suggest that chicks might be more sensitive to human disturbance than adults and might therefore potentially suffer from human disturbance. Our study also suggests that specific individual and environmental variables outweigh the potential minor impact of human disturbance on these variables. Combining corticosterone with complementary stress-related physiological markers, such as heart rate, may strengthen further studies examining whether human disturbance may have subtle detrimental impacts on individuals.

Ontogeny and individual heterogeneity of the corticosterone stress response in a wild altricial seabird, the snow petrel (Pagodroma nivea)

In the current context of global change, there is evidence of a large inter-individual variability in the way animals physiologically respond to anthropogenic changes. In that context, the Hypothalamus-Pituitary-Adrenal (HPA) axis and the corticosterone stress response are of primary importance because they are thought to govern the ability of individuals to adjust to stress. Several studies have reported that this stress response is variable among adults and they have successfully linked this variability with abiotic and biotic factors. However, the inter-individual variability of the glucocorticoid stress response has rarely been examined during the developmental phase in wild vertebrates, and its potential ecological determinants remain unclear. In this study, we examined the ontogeny of the corticosterone stress response in an altricial seabird species (i.e., how corticosterone levels increase in response to a standardized stress protocol), the Snow petrel. We reported a strong heterogeneity of the corticosterone stress response at all ages in snow petrel chicks (11-, 20-, and 37-days old chicks). Although the magnitude of this corticosterone stress response decreases with the age of the chick, we also found that this corticosterone stress response was repeatable throughout the post-hatching developmental period (repeatability: r > 0.50 for stress-induced corticosterone levels after a 30-min restraint). Importantly, this glucocorticoid stress response was negatively associated with the body condition of the chicks (i.e., mass corrected for body size), and previous exposure to sampling was associated with a dampened corticosterone stress response. However, we did not find any link between parental traits (parental condition or parental corticosterone stress response), nest quality, hatching date, and the chick’s corticosterone stress response. Our study suggests that the corticosterone stress response is a consistent individual trait that is affected to some extent by post-natal conditions, and which differs among individuals very early in life.

Sex differences in cortical‐hypothalamic circuitry mediating cardiovascular disease risk

Endocrine and autonomic stress responses adapt the body to real or perceived threats by engaging physiological pathways to maintain homeostasis. Unfortunately, the burden of prolonged stress contributes to maladaptive stress responding, increasing risk for pathologies including cardiometabolic disorders. However, the circuit mechanisms integrating endocrine and autonomic stress responses have yet to be defined. Our previous studies found that glutamate neurons of the infralimbic cortex (IL) have sex‐specific effects on endocrine and cardiovascular stress reactivity. While the IL is important for coordinating behavioral and physiological responses to stress, these cortical cells do not directly innervate the secretory or pre‐autonomic cells that initiate endocrine and autonomic stress responses. However, we previously found that the posterior hypothalamus (PH) receives dense stress‐activated inputs from the IL. Thus, the current study tests the hypothesis that IL glutamate release in the PH mediates sex‐specific effects on stress integration. To test this hypothesis, adult male and female Sprague‐Dawley rats received stereotaxic injections in the IL of a viral‐packaged construct expressing channelrhodopsin‐2 and bilateral fiber optics targeting the PH to stimulate IL synapses in the PH. After recovery and acclimatization to handling, rats were tested in the real‐time place preference paradigm to examine behavioral preference or aversion for circuit stimulation. These data indicate that IL‐PH signaling is preferred by males and that females have neither preference nor aversion for IL‐PH stimulation. Additionally, acute restraint was used to examine glucose and corticosterone responses to stress. Results found that IL synapses in the PH decrease stress‐induced glucose mobilization without affecting corticosterone in male rats. In contrast, IL‐PH stimulation in females increases corticosterone responses to restraint but does not affect glucose mobilization. Furthermore, non‐invasive assessment of hemodynamics indicate that IL‐PH stimulation increases heart rate in females but not males. Thus, the IL‐PH circuit increases place preference and reduces glucose responses to stress in males, while increasing corticosterone stress responses and heart rate in females. Taken together, these data suggest that the PH represents a key node for sex‐specific integration of descending cortical signals with endocrine and autonomic stress reactivity. Ultimately, sex‐specific delineation of stress‐regulatory neurocircuitry may provide insight into the differential impact of stress pathologies in men and women.

Stress-induced depressive-like behavior in male rats is associated with microglial activation and inflammation dysregulation in the hippocampus in adulthood

Neuroinflammation is increasingly recognized as playing a critical role in depression. Early-life stress exposure and constitutive differences in glucocorticoid responsiveness to stressors are two key risk factors for depression, but their impacts on the inflammatory status of the brain is still uncertain. Moreover, there is a need to identify specific molecules involved in these processes with the potential to be used as alternative therapeutic targets in inflammation-related depression. Here, we studied how peripubertal stress (PPS) combined with differential corticosterone (CORT)-stress responsiveness (CSR) influences depressive-like behaviors and brain inflammatory markers in male rats in adulthood, and how these alterations relate to microglia activation and miR-342 expression. We found that high-CORT stress-responsive (H-CSR) male rats that underwent PPS exhibited increased anhedonia and passive coping responses in adulthood. Also, animals exposed to PPS showed increased hippocampal TNF-α expression, which positively correlated with passive coping responses. In addition, PPS caused long-term effects on hippocampal microglia, particularly in H-CSR rats, with increased hippocampal IBA-1 expression and morphological alterations compatible with a higher degree of activation. H-CSR animals also showed upregulation of hippocampal miR-342, a mediator of TNF-α-driven microglial activation, and its expression was positively correlated with TNF-α expression, microglial activation and passive coping responses. Our findings indicate that individuals with constitutive H-CSR are particularly sensitive to developing protracted depression-like behaviors following PPS exposure. In addition, they show neuro-immunological alterations in adulthood, such as increased hippocampal TNF-α expression, microglial activation and miR-342 expression. Our work highlights miR-342 as a potential therapeutic target in inflammation-related depression.

Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response

The vagus nerve is one of the major signalling components between the gut microbiota and brain. However, the exact relationship between gut-brain signaling along the vagus and the effects of gut microbes on brain function and behaviour is unclear. In particular, the relationship between the vagus nerve and immune signaling, that also appears to play a critical role in microbiota-gut-brain communication, has not been delineated. The aim of the present study was to determine the effect of subdiaphragmatic vagotomy on peripheral and central immune changes associated with the anxiolytic actions of L.rhamnosus. Male mice underwent vagotomy or sham surgery, followed by administration of L.rhamnosus for 14 days. L.rhamnosus administration following sham surgery resulted in reduced anxiety-like behaviour, and an attenuation of the hypothalamic-pituitary-adrenal axis (HPA axis), as indicated by reduced plasma corticosterone after acute restraint stress. These effects were associated with an increase in splenic T regulatory cells and a decrease in activated microglia in the hippocampus. The anxiolytic effects, HPA modulation and increase in T regulatory cells were prevented by vagotomy, whereas vagotomy alone led to a significant increase in activated microglia in the hippocampus that was not altered with L.rhamnosus treatment. Thus, both microbe induced and constitutive vagal signaling influences critical immune components of the microbiota-gut-brain axis. These findings suggest that, rather than acting as a direct neural link to the central nervous system, the role of the vagus nerve in gut-microbe to brain signalling is as an integral component of a bi-directional neuroimmunoendocrine pathway.

Impact of chronic variable stress on neuroendocrine hypothalamus and pituitary in male and female C57BL/6J mice.

Chronic stress exerts multiple negative effects on the physiology and health of an individual. In the present study, we examined hypothalamic, pituitary and endocrine responses to 14days of chronic variable stress (CVS) in male and female C57BL/6J mice. In both sexes, CVS induced a significant decrease in body weight and enhanced the acute corticosterone stress response, which was accompanied by a reduction in thymus weight only in females. However, single-point blood measurements of basal prolactin, thyroid-stimulating hormone, luteinising hormone, growth hormone and corticosterone levels taken at the end of the CVS were not different from those of controls. Similarly, pituitary mRNA expression of Fshb, Lhb, Prl and Gh was unchanged by CVS, although Pomc and Tsh were significantly elevated. Within the adrenal medulla, mRNA for Th, Vip and Gal were elevated following CVS. Avp transcript levels within the paraventricular nucleus of the hypothalamus were increased by CVS; however, levels of Gnrh1, Crh, Oxt, Sst, Trh, Ghrh, Th and Kiss1 remained unchanged. Oestrous cycles were lengthened slightly by CVS and ovarian histology revealed a reduction in the number of preovulatory follicles and corpora lutea. Taken together, these observations indicate that 14days of CVS induces an up-regulation of the neuroendocrine stress axis and creates a mild disruption of female reproductive function. However, the lack of changes in other neuroendocrine axes controlling anterior and posterior pituitary secretion suggest that most neuroendocrine axes are relatively resilient to CVS.

Telomere shortening is associated with corticosterone stress response in adult barn swallows.

When vertebrates face stressful events, the hypothalamic–pituitary–adrenal (HPA) axis is activated, generating a rapid increase in circulating glucocorticoid (GC) stress hormones followed by a return to baseline levels. However, repeated activation of HPA axis may lead to increase in oxidative stress. One target of oxidative stress is telomeres, nucleoprotein complexes at the end of chromosomes that shorten at each cell division. The susceptibility of telomeres to oxidizing molecules has led to the hypothesis that increased GC levels boost telomere shortening, but studies on this link are scanty. We studied if, in barn swallows Hirundo rustica, changes in adult erythrocyte telomere length between 2 consecutive breeding seasons are related to corticosterone (CORT) (the main avian GC) stress response induced by a standard capture-restraint protocol. Within-individual telomere length did not significantly change between consecutive breeding seasons. Second-year individuals showed the highest increase in circulating CORT concentrations following restraint. Moreover, we found a decline in female stress response along the breeding season. In addition, telomere shortening covaried with the stress response: a delayed activation of the negative feedback loop terminating the stress response was associated with greater telomere attrition. Hence, among-individual variation in stress response may affect telomere dynamics.

Endocrine stress responsivity and social memory in 3xTg-AD female and male mice: A tale of two experiments

Stress confers risk for the development and progression of Alzheimer's disease (AD). Relative to men, women are disproportionately more likely to be diagnosed with this neurodegenerative disease. We hypothesized that sex differences in endocrine stress responsiveness may be a factor in this statistic. To test this hypothesis, we assessed basal and stress-induced corticosterone, social recognition, and coat state deterioration (surrogate for depression-like behavior) in male and female 3xTg-AD mice. Prior to reported amyloid plaque deposition, 3xTg females (4 months), but not 3xTg males, had heightened corticosterone responses to restraint exposure. Subsequently, only 3xTg females (6 months) displayed deficits in social memory concomitant with prominent β-amyloid (Aβ) immunostaining. These data suggest that elevated corticosterone stress responses may precede cognitive impairments in genetically vulnerable females. 3xTg mice of both sexes exhibited coat state deterioration relative to same-sex controls. Corticolimbic glucocorticoid receptor (GR) dysfunction is associated with glucocorticoid hypersecretion and cognitive impairment. Our findings indicate sex- and brain-region specific effects of genotype on hippocampal and amygdala GR protein expression. Because olfactory deficits may impede social recognition, in Experiment 2, we assessed olfaction and found no differences between genotypes. Notably, in this cohort, heightened corticosterone stress responses in 3xTg females was not accompanied by social memory deficits or coat state deterioration. However, coat state deterioration was consistent in 3xTg males. We report consistent heightened stress-induced corticosterone levels and Aβ pathology in female 3xTg-AD mice. However, the behavioral findings illuminate unknown inconsistencies in certain phenotypes in this AD mouse model.

Development of the corticosterone stress response differs among passerine species

Glucocorticoids are steroid hormones which increase dramatically in response to a physical or perceived stressor. However, developing young of altricial species typically have a damped glucocorticoid stress response. The developmental hypothesis posits that the physiological stress response should develop concurrently with an individual’s ability to respond to a challenge. The dampened response may benefit an organism, as chronic exposure to glucocorticoids can have short- and long-term detrimental effects, and altricial young are unable to escape most stressors. However, we do not know if or why species with similar ontogeny vary in their development of the physiological stress response. We assessed levels of baseline and stress-induced corticosterone (the main avian glucocorticoid) in six passerine species with varying life-history strategies, including a brood parasite, the brown-headed cowbird (Molothrus ater). Circulating baseline corticosterone levels increased with nestling age for all species. Stress-induced corticosterone levels sampled at 15-min post-capture significantly increased with nestling age at a similar rate and magnitude in brown-headed cowbirds, eastern phoebes (Sayornis phoebe), hooded warblers (Setophaga citrina), red-winged blackbirds (Agelaius phoeniceus), and song sparrows (Melospiza melodia). However, gray catbird (Dumetella carolinensis) nestlings showed an extremely dampened elevation in corticosterone in response to stress, even near fledge. Gray catbirds are unusual among songbirds, as they are open-ended song learners. Stress during development can profoundly influence avian song learning and performance abilities. However, further study is necessary to determine if there is a relationship between nestling adrenocortical activity and open- versus closed-ended song learning.

When do older birds better resist stress? A study of the corticosterone stress response in snow petrels.

Life-history theory predicts that, to optimize their fitness, individuals should increase their reproductive effort as their residual reproductive value decreases. Accordingly, several studies have shown that individuals downregulate their glucocorticoid stress response (a proxy of reproductive investment in vertebrates) as they age, and as the subsequent reproductive value decreases. However, and surprisingly, results appear inconsistent, suggesting that the environmental context or the individual state may affect the relationship between age and reproductive effort. Here, we tested for the first time this hypothesis, and more specifically, whether this attenuation of the corticosterone stress response with advancing age depends on the energetic status of individuals. We compared the influence of age on the corticosterone stress response between fasting and non-fasting breeding snow petrels (Pagodroma nivea), an extremely long-lived bird. As expected, we found that the corticosterone stress response was attenuated in old petrels, but only when they were not fasting. Interestingly, this pattern was not apparent in fasting petrels, suggesting that old birds downregulate their corticosterone stress response and increase their parental investment only when they are in good body condition. At the ultimate level, old individuals may maintain a strong corticosterone stress response when fasting because the survival costs of increased stress resistance and parental effort might then outweigh their reproductive benefits.

Peritoneal endometriosis induces time-related depressive- and anxiety-like alterations in female rats: involvement of hippocampal pro-oxidative and BDNF alterations.

Endometriosis is a gynecological condition affecting 10% of women in reproductive age. High rates of depression and anxiety are observed in these patients. The mechanisms underlying endometriosis-induced behavioral alterations are still elusive. Animal models provide a useful tool to study the temporal sequence and biological pathways involved in this disease and comorbid states. Here, we sought to characterize time-related behavioral alterations in rats submitted to endometriosis model (EM) induced by peritoneal auto-transplantation of uterine tissues weekly for three weeks. Corticosterone stress reactivity, oxidative stress markers - reduced glutathione (GSH), lipid peroxidation, activity of superoxide dismutase (SOD) and myeloperoxidase (MPO) - and brain-derived-neurotrophic factor (BDNF) levels in the hippocampus were also evaluated. We observed a progressive increase in anxiety-like behavior from 14th to 21st days post-EM. Despair-like behavior was observed from the 14th day post-EM on, while anhedonia and apathetic-like behaviors accompanied by increased corticosterone stress response were detected on 21days post-EM. Increased pain sensitivity was observed from the 7th day post-EM and was accompanied by increased endometrioma weight. The pro-oxidative alterations, decreased GSH and increased SOD activity were observed on 21days post-EM, except for lipid peroxidation that was altered from the 14th day. Decreased BDNF also occurred on the 21st day. Therefore, this study demonstrates that EM is related to several features of clinical depression and proposes the contribution of hippocampal oxidative state and neurotrophic support for the emergence of these changes. Our results support the use of this model as a useful tool to test new strategies for endometriosis-related neuropsychiatric symptoms.

Does urbanization cause stress in wild birds during development? Insights from feather corticosterone levels in juvenile house sparrows (Passer domesticus).

Urban landscapes are associated with abiotic and biotic environmental changes that may result in potential stressors for wild vertebrates. Urban exploiters have physiological, morphological, and behavioral adaptations to live in cities. However, there is increasing evidence that urban exploiters themselves can suffer from urban conditions, especially during specific life‐history stages. We looked for a link between the degree of urbanization and the level of developmental stress in an urban exploiter (the house sparrow, Passer domesticus), which has recently been declining in multiple European cities (e.g., London, UK). Specifically, we conducted a large‐scale study and sampled juvenile sparrows in 11 urban and rural sites to evaluate their feather corticosterone (CORT) levels. We found that juvenile feather CORT levels were positively correlated with the degree of urbanization, supporting the idea that developing house sparrows may suffer from urban environmental conditions. However, we did not find any correlation between juvenile feather CORT levels and body size, mass, or body condition. This suggests either that the growth and condition of urban sparrows are not impacted by elevated developmental CORT levels, or that urban sparrows may compensate for developmental constraints once they have left the nest. Although feather CORT levels were not correlated with baseline CORT levels, we found that feather CORT levels were slightly and positively correlated with the CORT stress response in juveniles. This suggests that urban developmental conditions may potentially have long‐lasting effects on stress physiology and stress sensitivity in this urban exploiter.

Deletion of Glucocorticoid Receptors in Forebrain GABAergic Neurons Alters Acute Stress Responding and Passive Avoidance Behavior in Female Mice.

The glucocorticoid receptor (GR) is critically involved in regulation of stress responses [inhibition of the hypothalamic-pituitary-adrenal (HPA) axis], emotional behavior and cognition via interactions with forebrain corticolimbic circuity. Work to date has largely focused on GR actions in forebrain excitatory neurons; however, recent studies suggest a potential role mediated by interneurons. Here, we targeted GR deletion in forebrain GABAergic neurons, including the cortical interneurons, using a Dlx5/6-Cre driver line to test the role of forebrain interneuronal GR in HPA axis regulation and behavior. Our data indicate that GR deletion in GABAergic neurons causes elevated corticosterone stress responsiveness and decreased cross-over latencies in a passive avoidance task in females, but not males. Dlx5/6-Cre driven gene deletion caused loss of GR in interneurons in the prefrontal cortex (PFC) and hippocampus, but also in select diencephalic GABAergic neurons (including the reticular thalamic nucleus and dorsomedial hypothalamus). Our data suggest that GR signaling in interneurons is differentially important in females, which may have implications for GR-directed therapies for stress-related affective disease states.

Regular handling reduces corticosterone stress responses to handling but not condition of semi-precocial mottled petrel (Pterodroma inexpectata) chicks

Handling of avian study species is common in ecological research, yet few studies account for the impact of handling in nestlings where exposure to stress may result in negative lifetime fitness consequences. As a result, our understanding of stress reactivity in free-living avian young is limited. In this study we examined the cumulative impact of three levels of research-relevant handling (control, daily and every three days) on the development of the stress response, growth and condition of semi-precocial seabird chicks from near-hatching to near-fledging. By measuring corticosterone concentrations in plasma, we found that mottled petrel (Pterodroma inexpectata) chicks were capable of mounting a stress response comparable to adults from near-hatching. There were no differences in plasma corticosterone concentrations in initial samples (<4 min) between groups at six weeks of age, though by 12 weeks of age plasma corticosterone concentrations in initial samples collected from chicks handled daily were lower than chicks that were handled once every three days, and from control chicks. Corticosterone responses to handling were lower in chicks handled daily at six and 12 weeks of age when compared to other handling groups. Handling chicks daily or every three days had no negative effect on the growth or condition of chicks when compared to control chicks. These findings indicate that daily handling results in chicks became accustomed to handling, with no evidence that regular handling was detrimental to mottled petrel chicks. However, given the unique life-history characteristics of mottled petrels relative to closely related species, we caution that this finding may be species-specific, and wider testing is recommended.

Low vagal tone in two rat models of psychopathology involving high or low corticosterone stress responses

The two stress-responsive physiological systems, autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis exert complementary and interrelated actions in the organism. Individuals that suffer stress-related psychopathologies frequently present simultaneous alterations –i.e., either low or high- responsiveness– in both systems. However, there is scarce evidence establishing whether a priori alterations in these systems –i.e., independent of previous stress exposure– may predispose to the development of psychopathologies possibly due to the lack of animal models simultaneously involving aberrant HPA and SNS responses. In this study, we describe two animal models selectively bred according to their differential (either high, ‘High’, or low, ‘Low’) glucocorticoid responsiveness to stress, in comparison to a third line of rats that displays intermediate (‘Inter’) glucocorticoid responses. The two extreme lines may be considered distinct models of psychopathology; the High line representing a model of constitutive mood alterations while the Low line a model of vulnerability to develop stress-induced psychopathologies. We recorded the electrocardiogram in rats from the three lines and quantified heart rate variability and vagal tone indexes during rest and stress challenges. Rats from both High and Low lines displayed higher heart rate and lower basal vagal tone than the Inter group, both at resting and following stress exposure. Specific pharmacological manipulations probing the relative contribution of sympathetic and parasympathetic components on HR modulation confirmed a relative lower vagal tone in High and Low lines and discarded differences in the sympathetic regulation of heart rate between the lines. Therefore, the two genetically-selected High and Low glucocorticoid rat lines emerge as two valuable preclinical models of psychopathology involving two key risk factors for psychiatric and cardiovascular disorders, namely dysregulations in the HPA axis and cardiac vagal functioning.

Maternal regulation of the infant's hypothalamic-pituitary-adrenal axis stress response: Seymour 'Gig' Levine's legacy to neuroendocrinology.

Thirty years ago, Seymour 'Gig' Levine published a serendipitous, yet, seminal finding with respect to the regulatory role of maternal presence on the corticosterone stress response of neonatal rats during the developmental period known as the stress hyporesponsive period. At the same time, his group of students also investigated the stress response of infant monkeys with respect to maternal separation, as a means of understanding the stress to the primary caregiver resulting from disruptions of attachment. Gig and his group of students and collaborators, mainly in the USA and the Netherlands, investigated how initial social relationships buffer the stress response of nonhuman primates and rodent infants. His work in rodents involved determining how prolonged deprivation of maternal care disinhibits the stress response of neonates and how maternal behaviours regulate specific aspects of the hypothalamic-pituitary-adrenal axis. Maternal deprivation for 24hours was useful for determining the importance of nutrition in suppressing the corticosterone stress response, whereas anogenital licking and grooming inhibited stress-induced adrenocortoctrophic hormone release, with the combination of both behaviours preventing the effects of maternal deprivation on the central hypothalamic stress response. Levine's group also studied the consequences of maternal deprivation on basal and stress-induced activity of the hypothalamic-pituitary-adrenal axis in juveniles and the persistent effects of the replacement of maternal behaviours on these parameters. Gig's legacy allowed many groups around the world to use the 24-hour maternal deprivation paradigm as an animal model of vulnerability and resilience to stress-related psychiatric disorders, as well as in studies of the neurobiological underpinnings of disruption of the mother-infant relationship and loss of parental care, a highly prevalent condition in humans. This review pays homage to a great scientist and mentor, whose discoveries paved the way for the understanding of how early social relationsships build resilience or lead to susceptibility to emotional disorders later in life.

Reproduction impairments in metal-polluted environments and parental hormones: No evidence for a causal association in an experimental study in breeding feral pigeons exposed to lead and zinc

Humans are responsible for land-cover changes resulting in the emission of hazardous chemical elements including metallic trace elements i.e. MTEs. As a consequence, urban wildlife is exposed to high concentrations of MTEs, which exposure is linked to reproductive impairments. MTE effects on reproduction outputs might result from MTE exposure disrupting the endocrine pathways involved in reproductive behaviours. In birds, there is strong evidence that prolactin, corticosterone and testosterone are all involved in the regulation of parental effort during incubation and chick rearing. Endocrine-disrupting chemicals might stimulate or inhibit the production of those hormones and consequently alter parental investment and reproductive success outcomes. We measured baseline corticosterone, prolactin and testosterone plasma levels, and the corticosterone stress response of breeding feral pigeons (Columba livia) experimentally exposed to ecologically relevant lead and/or zinc concentrations. Independently of lead and/or zinc exposure, male and female plasma levels of corticosterone and prolactin (but not testosterone) showed temporal variations along the reproduction stages (i.e. incubation, early rearing and late rearing). In addition, both hatching and fledging success were slightly correlated with corticosterone, prolactin and testosterone levels. However, our study did not find any influence of lead or zinc exposure on hormone levels, suggesting that MTE effects on reproductive outputs might not be explained by MTE-induced modifications of corticosterone, prolactin and testosterone-linked behaviours during incubation and rearing. Alternatively, MTE-induced reproductive impairments might result from MTE exposure having direct effects on offspring phenotypes or prenatal indirect effects on the embryo (e.g. maternal transfer of MTEs, hormones or immune compounds).

Sex- and breeding stage-specific hormonal stress response of seabird parents

Changes in corticosterone (CORT) and prolactin (PRL) levels are thought to provide complementary information on parental decisions in birds in the context of stressful situations. However, these endocrine mechanisms have yet to be fully elucidated, appearing to vary among avian species without any clear pattern. Here, we examined CORT and PRL stress responses in a small Arctic seabird, the little auk (Alle alle). We analysed the levels of these hormones (baseline, and stress response, i.e. the change in the baseline in response to stress) with respect to the breeding phase (mid incubation and mid chick rearing) and the sex of the birds. Baseline CORT concentrations were similar during both breeding phases but baseline PRL levels were higher during incubation than chick rearing. The CORT and PRL stress responses were stronger during incubation than chick rearing (although with respect to CORT the effect was only marginally significant). There were also some sex-specific baseline levels and stress responses for both hormones (during the incubation period males compared to females exhibited higher CORT stress response and lower baseline PRL; during the chick rearing period males exhibited higher PRL stress response). Our results suggest that in the case of the little auk, both the incubation and the chick rearing periods may represent similar levels of physiological stress. However, the birds may be more sensitive to stress during incubation than during chick rearing, possibly because of inter-phase differences in predation pressure. The sex differences suggest differential exposure of males and females to stressors.