Glucocorticoid Hormones Research Articles

Unraveling the phenotypic and genomic background of behavioral plasticity and temperament in North American Angus cattle

BackgroundLongitudinal records of temperament can be used for assessing behavioral plasticity, such as aptness to learn, memorize, or change behavioral responses based on affective state. In this study, we evaluated the phenotypic and genomic background of North American Angus cow temperament measured throughout their lifetime around the weaning season, including the development of a new indicator trait termed docility-based learning and behavioral plasticity. The analyses included 273,695 and 153,898 records for yearling (YT) and cow at weaning (CT) temperament, respectively, 723,248 animals in the pedigree, and 8784 genotyped animals. Both YT and CT were measured when the animal was loading into/exiting the chute. Moreover, CT was measured around the time in which the cow was separated from her calf. A random regression model fitting a first-order Legendre orthogonal polynomial was used to model the covariance structure of temperament and to assess the learning and behavioral plasticity (i.e., slope of the regression) of individual cows. This study provides, for the first time, a longitudinal perspective of the genetic and genomic mechanisms underlying temperament, learning, and behavioral plasticity in beef cattle.ResultsCT measured across years is heritable (0.38–0.53). Positive and strong genetic correlations (0.91–1.00) were observed among all CT age-group pairs and between CT and YT (0.84). Over 90% of the candidate genes identified overlapped among CT age-groups and the estimated effect of genomic markers located within important candidate genes changed over time. A small but significant genetic component was observed for learning and behavioral plasticity (heritability = 0.02 ± 0.002). Various candidate genes were identified, revealing the polygenic nature of the traits evaluated. The pathways and candidate genes identified are associated with steroid and glucocorticoid hormones, development delay, cognitive development, and behavioral changes in cattle and other species.ConclusionsCow temperament is highly heritable and repeatable. The changes in temperament can be genetically improved by selecting animals with favorable learning and behavioral plasticity (i.e., habituation). Furthermore, the environment explains a large part of the variation in learning and behavioral plasticity, leading to opportunities to also improve the overall temperament by refining management practices. Moreover, behavioral plasticity offers opportunities to improve the long-term animal and handler welfare through habituation.

Abstract IA022: Age-induced metabolic reprogramming: A bridge between the aging process and tumorigenesis

Abstract Lung cancer accounts for the largest number of cancer-associated deaths in the United States. While great strides have been made due to the introduction of immunotherapies and targeted therapies against oncogenic drivers, chemotherapies remain the standard of care for the majority of lung cancer patients. However, many patients do not respond to these treatments or relapse following an initial response. We postulate that part of the problem is the lack of consideration in preclinical research and clinical trials of the main driver of lung tumorigenesis, the aging process. Here, we show that the organismal metabolic reprogramming that occurs with aging endows cancer cells with pro-aggressive properties favoring progression into metastatic disease through, at least in part, the accumulation in the circulation of methylmalonic acid, a by-product of vitamin B12 deficiency. On the other hand, we also show that this age-induced organismal metabolic reprogramming makes lung tumors intrinsically more resistant to chemotherapies through the chronic upregulation of glucocorticoid hormones. Together, our work demonstrates a role for age-induced systemic metabolic reprogramming in shaping the tumorigenic process toward more aggressive, treatment-resistant disease and offers a rationale for using interventions that ameliorate the metabolic deregulation that occurs with age in the treatment of age-related cancers. Citation Format: Ana P. Gomes. Age-induced metabolic reprogramming: A bridge between the aging process and tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA022.

Does the Glucocorticoid Stress Response Make Toads More Toxic? An Experimental Study on the Regulation of Bufadienolide Toxin Synthesis.

Chemical defense is a crucial component of fitness in many organisms, yet the physiological regulation of defensive toxin synthesis is poorly understood, especially in vertebrates. Bufadienolides, the main defensive compounds of toads, are toxic to many predators and other natural enemies, and their synthesis can be upregulated by stressors, including predation risk, high conspecific density, and pollutants. Thus, higher toxin content may be the consequence of a general endocrine stress response in toads. Therefore, we hypothesized that bufadienolide synthesis may be stimulated by elevated levels of corticosterone (CORT), the main glucocorticoid hormone of amphibians, or by upstream regulators that stimulate CORT production. To test these alternatives, we treated common toad tadpoles with exogenous CORT (exoCORT) or metyrapone (MTP, a CORT-synthesis inhibitor that stimulates upstream regulators of CORT by negative feedback) in the presence or absence of predation cues for 2 or 6 days, and subsequently measured their CORT release rates and bufadienolide content. We found that CORT release rates were elevated by exoCORT, and to a lesser extent also by MTP, regardless of treatment length. Bufadienolide content was significantly decreased by treatment with exoCORT for 6 days but was unaffected by exposure to exoCORT for 2 days or to MTP for either 6 or 2 days. The presence or absence of predation cues affected neither CORT release rate nor bufadienolide content. Our results suggest that changes in bufadienolide synthesis in response to environmental challenges are not driven by CORT but may rather be regulated by upstream hormones of the stress response.

The course of gout in a patient with Cushing’s disease after successful surgical treatment

Endogenous hypercortisolism is a severe endocrine disease characterized by prolonged exposure to excessive amounts of glucocorticoid hormones, accompanied by a wide range of symptoms and complications, including immunosuppression. Timely surgical treatment in most cases allows to save the patient’s life, significantly improve its quality. However, restoration of the normal concentration of glucocorticoid hormones can become a trigger factor in the development or exacerbation of autoimmune and auto-inflammatory diseases. We present a clinical case of atypical gout in a patient with hypercortisolism and a progressive increase in symptoms of the disease after successful surgical treatment for Cushing’s disease and achieving stable remission. The issues of diagnosis and treatment of this group of autoinflammatory diseases are highlighted, the leading clinical and radiological symptoms are considered, the differential diagnosis of microcrystalline (metabolic) arthritis is presented. Despite the widespread, the diagnosis and treatment of this group of diseases still cause difficulties for specialists. A competent choice of drug therapy allows to fully control diseases considered in the article, including when they are combined, and thereby improve the quality of life of the patient.

The cortisol switch between vulnerability and resilience.

In concert with neuropeptides and transmitters, the end products of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone (CORT), promote resilience: i.e., the ability to cope with threats, adversity, and trauma. To exert this protective action, CORT activates mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that operate in a complementary manner -as an on/off switch- to coordinate circadian events, stress-coping, and adaptation. The evolutionary older limbic MR facilitates contextual memory retrieval and supports an on-switch in the selection of stress-coping styles at a low cost. The rise in circulating CORT concentration after stress subsequently activates a GR-mediated off-switch underlying recovery of homeostasis by providing the energy for restraining the primary stress reactions and promoting cognitive control over emotional reactivity. GR activation facilitates contextual memory storage of the experience to enable future stress-coping. Such complementary MR-GR-mediated actions involve rapid non-genomic and slower gene-mediated mechanisms; they are time-dependent, conditional, and sexually dimorphic, and depend on genetic background and prior experience. If coping fails, GR activation impairs cognitive control and promotes emotional arousal which eventually may compromise resilience. Such breakdown of resilience involves a transition to a chronic stress construct, where information processing is crashed; it leads to an imbalanced MR-GR switch and hence increased vulnerability. Novel MR-GR modulators are becoming available that may reset a dysregulated stress response system to reinstate the cognitive flexibility required for resilience.

Assay validation of saliva glucocorticoids in Columbia spotted frogs and effects of handling and marking.

Non-invasive methods are important to the field of conservation physiology to reduce negative effects on organisms being studied. Glucocorticoid (GC) hormones are often used to assess health of individuals, but collection methods can be invasive. Many amphibians are imperiled worldwide, and saliva is a non- or semi-invasive matrix to measure GCs that has been partially validated for only four amphibian species. Validation ensures that assays are reliable and can detect changes in saliva corticosterone (sCORT) after exposure to stressors, but it is also necessary to ensure sCORT concentrations are correlated with plasma concentrations. To help validate the use of saliva in assessing CORT responses in amphibians, we captured uniquely marked Columbia spotted frogs (Rana luteiventris) on sequential days and collected baseline and stress-induced (after handling) samples. For a subset of individuals, we collected and quantified CORT in both saliva and blood samples, which have not been compared for amphibians. We tested several aspects of CORT responses and, by collecting across separate days, measured repeatability of CORT responses across days. We also evaluated whether methods common to amphibian conservation, such as handling alone or handling, clipping a toe and tagging elevated sCORT. Similar to previous studies, we show that sCORT is reliable concerning parallelism, recovery, precision and sensitivity. sCORT was weakly correlated with plasma CORT (R2 = 0.21), and we detected elevations in sCORT after handling, demonstrating biological validation. Toe clipping and tagging did not increase sCORT over handling alone, but repeated handling elevated sCORT for ~72hours. However, sCORT responses were highly variable and repeatability was low within individuals and among capture sessions, contrary to previous studies with urinary and waterborne CORT. sCORT is a semi-invasive and rapid technique that could be useful to assess effects of anthropogenic change and conservation efforts, but will require careful study design and future validation.

Exploring water-borne corticosterone collection as a non-invasive tool in amphibian conservation physiology: benefits, limitations and future perspectives.

Global change exposes wildlife to a variety of environmental stressors and is affecting biodiversity worldwide, with amphibian population declines being at the forefront of the global biodiversity crisis. The use of non-invasive methods to determine the physiological state in response to environmental stressors is therefore an important advance in the field of conservation physiology. The glucocorticoid hormone corticosterone (CORT) is one useful biomarker to assess physiological stress in amphibians, and sampling water-borne (WB) CORT is a novel, non-invasive collection technique. Here, we tested whether WB CORT can serve as a valid proxy of organismal levels of CORT in larvae of the common frog (Rana temporaria). We evaluated the association between tissue and WB CORT levels sampled from the same individuals across ontogenetic stages, ranging from newly hatched larvae to froglets at 10 days after metamorphosis. We also investigated how both tissue and WB CORT change throughout ontogeny. We found that WB CORT is a valid method in pro-metamorphic larvae as values for both methods were highly correlated. In contrast, there was no correlation between tissue and WB CORT in newly hatched, pre-metamorphic larvae, metamorphs or post-metamorphic froglets probably due to ontogenetic changes in respiratory and skin morphology and physiology affecting the transdermal CORT release. Both collection methods consistently revealed a non-linear pattern of ontogenetic change in CORT with a peak at metamorphic climax. Thus, our results indicate that WB CORT sampling is a promising, non-invasive conservation tool for studies on late-stage amphibian larvae. However, we suggest considering that different contexts might affect the reliability of WB CORT and consequently urge future studies to validate this method whenever it is used in new approaches. We conclude proposing some recommendations and perspectives on the use of WB CORT that will aid in broadening its application as a non-invasive tool in amphibian conservation physiology.

Evaluation of Serum Cortisol Levels in Patients with Hypothyroidism at a Tertiary Care Hospital, Telangana, India: A Case-control Study

Introduction: Serum Cortisol is a glucocorticoid hormone released from the zona fasciculata layer of the adrenal cortex, which plays an important role in regulation of blood pressure and metabolism. Hypothyroidism causes elevated cortisol levels due to both decreased clearance and negative feedback of cortisol on the hypothalamic pituitary-adrenal axis. Aim: To investigate the correlation of serum cortisol and with Triiodothyronine (T3), Thyroxine (T4), Thyroid Stimulating Hormone (TSH) and serum cortisol levels in patients with hypothyroidism. Materials and Methods: Present case-control study was carried out in the Department of Biochemistry, Gandhi Medical College and Hospital, Secunderabad, Telanagana, India, July 2022 to August 2022. A total of 60 patients with hypothyroidism (cases) aged between 35-60 years, and 60 controls were selected from Gandhi Medical College and Hospital. Samples were analysed in Siemens Advia centaur XPT. T3, T4, TSH and cortisol levels were estimated by “CLIA” method. Data were statistically analysed using Karl Pearson’s correlation test. Results: In present study, there were five males and 55 females in control group, 23 males and 37 females were in case group. The mean age in cases was 39.39±6.44 years and in control group was 39.38±10.97 years. The mean T3 in subjects cases was 10.74±5.34 ng/mL, as compared to 8.93±2.78 ng/mL, in controls. The mean TSH level in cases was 13.38±20.43 mIU/L, as compared to 3.47±4.20 mIU/L, in controls. The mean cortisol level in cases was 64.88.44±16.25 µg/dL, as compared to 9.55±5.59 µg/dL, in controls. There was significant positive correlation between serum cortisol level and T3 (r=0.12, p-value 0.02), T4 (r=0.12, p-value 0.02), and TSH Levels ( r= 0.31, p-value 0.01) in case group. Conclusion: The results of present study showed that serum levels of cortisol were significantly increased in hypothyroidism patients as compared to normal healthy controls.

A review on hypothalamo-pituitary- adrenal axis

The effector hormones of the hypothalamic-pituitary-adrenal axis neuroendocrine system are the glucocorticoid hormones cortisol and corticosterone.The level of corticosterone, a systemic intercellular signal, changes dynamically with environmental and psychological stressors and predictably varies with time of day. A wide range of physiological and mental health issues are linked to irregularities in the typical HPA axis activity profiles. Despite several investigations that have uncovered molecular, cellular, and systems-level glucocorticoid actions to date, more glucocorticoid actions, and connections with clinical state, need to be discovered. Hypothalamic-pituitary-adrenal (HPA) axis feedback regulation may be compromised due to reduced mineralocorticoid receptor (MR)-mediated feedback in the brain. Medicinal herbs and their compounds have been shown to have a preventative impact against depression through a variety of ways. Medicinal plants can provide fresh ideas for antidepressant medication research.

Gut Bacterial Communities Vary across Habitats and Their Diversity Increases with Increasing Glucocorticoids in Toad Tadpoles

The gut microbiome is important for host health and can be influenced by environmental and hormonal changes. We studied the interactions between anthropogenic land use, glucocorticoid hormones, and gut bacterial communities in common toads (Bufo bufo). We sampled tadpoles from ponds of three habitat types (natural, agricultural, and urban ponds), examined gut microbiome composition using amplicon sequencing of the 16S rRNA gene, and measured the associated stress physiology using water-borne hormones. Tadpoles from different habitat types significantly differed in bacterial composition. However, bacterial richness, Shannon diversity, and Firmicutes to Bacteroidota ratio did not vary with habitat type. In contrast with other studies, we found a positive correlation between baseline corticosterone release rate and bacterial diversity. Stress response and negative feedback were not significantly correlated with bacterial diversity. These results suggest that, despite alterations in the composition of intestinal bacterial communities due to land-use change, common toad tadpoles in anthropogenic habitats may maintain their physiological health in terms of the “gut-brain axis”.

Body temperature and activity patterns modulate glucocorticoid levels across lizard species: A macrophysiological approach

Environmental and intrinsic factors interact to determine energy requirements in vertebrates. Glucocorticoid hormones (GCs) are key mediators of this interaction, as they fluctuate with energetic demands and regulate physiological and behavioral responses to environmental challenges. While a great body of research has focused on GC variation among individuals, the mechanisms driving GC variation across species and at broad spatial scales remain largely unexplored. Here, we adopted a macrophysiological approach to investigate the environmental factors and life-history traits driving variation in baseline GCs across lizard species. We tested three hypotheses: (1) If GCs increase with body temperature to meet higher metabolic demand, we expect an association between average baseline GCs and the mean species’ body temperature in the field (GC-temperature dependence hypothesis); (2) If GCs mediate behavioral responses to avoid thermal extremes, we expect that individuals frequently exposed to extreme conditions exhibit higher baseline GC levels (Behavioral thermoregulation hypothesis); (3) If GCs increase to support higher energy demands in active foragers during their period of activity, we expect that active foraging species have higher baseline GCs than sit-and-wait foragers, and that GC levels increase in relation to the duration of daily activity windows (Activity hypothesis). We used biophysical models to calculate operative temperatures and the activity patterns of lizards in sun-exposed and shaded microenvironments. Then, we tested the association between baseline GCs, body temperature, operative temperatures, foraging mode, and activity windows across 37 lizard species, using data from HormoneBase. Our comparative analyses showed that variation in baseline GCs was primarily related to the mean field body temperature and foraging mode, with higher baseline GCs in active foragers with higher body temperatures. Our results suggest that body temperature and foraging mode drive GC variation through their effects on energy requirements across lizard species.

Glucocorticoid effects on working memory impairment require l-type calcium channel activity within prefrontal cortex

Previous findings have indicated that glucocorticoid hormones impair working memory via an interaction with the β-adrenoceptor-cAMP signaling cascade to rapidly increase cAMP-dependent protein kinase (PKA) activity within the prefrontal cortex (PFC). However, it remains elusive how such activation of PKA can affect downstream cellular mechanisms in regulating PFC cognitive function. PKA is known to activate l-type voltage-gated Ca2+ channels (LTCCs) which regulate a broad range of cellular processes, including neuronal excitability and neurotransmitter release. The present experiments examined whether LTCC activity within the PFC is required in mediating glucocorticoid and PKA effects on spatial working memory. Male Sprague Dawley rats received bilateral administration of the LTCC inhibitor diltiazem together with either the glucocorticoid receptor agonist RU 28362 or PKA activator Sp-cAMPS into the PFC before testing on a delayed alternation task in a T-maze. Both RU 28362 and Sp-cAMPS impaired working memory, whereas the LTCC inhibitor diltiazem fully blocked the working memory impairment induced by either RU 28362 or Sp-cAMPS. Conversely, bilateral administration of the LTCC agonist Bay K8644 into the PFC was sufficient to impair working memory. Thus, these findings provide support for the view that glucocorticoids, via an interaction with the β-adrenergic signaling cascade and enhanced PKA activity levels, impair working memory by increasing LTCC activity in the PFC.

Sex-Dimorphic Glucocorticoid Receptor Regulation of Hypothalamic Primary Astrocyte Glycogen Metabolism: Interaction with Norepinephrine.

Astrocyte glycogen is a critical metabolic variable that impacts hypothalamic control of glucostasis. Glucocorticoid hormones regulate peripheral glycogen, but their effects on hypothalamic glycogen are not known. A hypothalamic astrocyte primary culture model was used to investigate the premise that glucocorticoids impose sex-dimorphic independent and interactive control of glycogen metabolic enzyme protein expression and glycogen accumulation. The glucocorticoid receptor (GR) agonist dexamethasone (DEX) down-regulated glycogen synthase (GS), glycogen phosphorylase (GP)-brain type (GPbb), and GP-muscle type (GPmm) proteins in glucose-supplied male astrocytes, but enhanced these profiles in female. The catecholamine neurotransmitter norepinephrine (NE) did not alter these proteins, but amplified DEX inhibition of GS and GPbb in male or abolished GR stimulation of GPmm in female. In both sexes, DEX and NE individually increased glycogen content, but DEX attenuated the magnitude of noradrenergic stimulation. Glucoprivation suppressed GS, GPbb, and GPmm in male, but not female astrocytes, and elevated or diminished glycogen in these sexes, respectively. Glucose-deprived astrocytes exhibit GR-dependent induced glycogen accumulation in both sexes, and corresponding loss (male) or attenuation (female) of noradrenergic-dependent glycogen build-up. Current evidence for GR augmentation of hypothalamic astrocyte glycogen content in each sex, yet divergent effects on glycogen enzyme proteins infers that glucocorticoids may elicit opposite adjustments in glycogen turnover in each sex. Results document GR modulation of NE stimulation of glycogen accumulation in the presence (male and female) or absence (female) of glucose. Outcomes provide novel proof that astrocyte energy status influences the magnitude of GR and NE signal effects on glycogen mass.

Social Enhancement of Adult Neurogenesis in Zebrafish is Not Regulated by Cortisol

In Mammals adult neurogenesis is influenced by environmental conditions, and the glucocorticoid hormones (GC) play a major role in this regulation. In contrast in fish, the study of the effects of cortisol on the regulation of environmental driven adult neurogenesis has produced conflicting results. While in some species elevated cortisol levels impair cell proliferation, in others, it promotes cell proliferation and differentiation. This lack of consistency may be explained by methodological differences across studies, namely in the stimuli and/or cortisol treatments used. Here, we tested the effects of the social environment on adult neurogenesis, considering a positive and a negative social context, and different durations of cortisol exposure. We hypothesise that there is an interaction between the valence of the social environment and cortisol, such that elevated acute cortisol experienced during social interactions only have a detrimental effect on neurogenesis in negative social contexts. Therefore, fish were exposed to a positive (conspecific shoal) or negative (predator) social experience, and the interaction between the valence of the social context and cortisol exposure (acute and chronic) was tested. Our results indicate that adult neurogenesis is modulated by the social environment, with the number of newly generated cells being dependent on the valence of the social information (positive > negative). These effects were independent of cortisol, either for acute or chronic exposure, highlighting the social environment as a key factor in the modulation of cell proliferation in the adult zebrafish brain, and rejecting a role for cortisol in this modulation.

Contributions of water-borne corticosterone as one non-invasive biomarker in assessing nitrate pollution stress in tadpoles of Rana temporaria

Among a multitude of stressors to which wildlife is exposed, environmental pollution is a pervasive one that poses a serious threat. The permeable skin of amphibians is likely to increase direct contact of the body with pollutants, making them a group worth studying to access environmental quality. Consequently, finding reliable and complementary biomarkers that will present detectable and predictable changes in response to pollutants is essential to identify pollution sublethal effects on amphibians and to investigate whether these are in part responsible for population declines. The glucocorticoid hormone corticosterone (CORT), involved in many metabolic functions, is often used to measure the physiological stress response to environmental stressors in amphibians. In this study, we evaluated whether water-borne CORT can serve as a non-invasive biomarker for nitrate pollution stress in the European common frog (Rana temporaria) by comparing the effect of nitrate exposure on hormone release rates and on other physiological downstream biomarkers, i.e., ultimate physiological effects of the stressor. Specifically, we investigated the effect of different nitrate concentrations (0, 10, 50, and 100 mg/L) on water-borne CORT release rates, age, size, and body condition. Exposure to nitrate pollution significantly increased age at metamorphosis and water-borne CORT release rates, and led to reduced mass and body condition, but only at higher nitrate concentrations (i.e., 50 and 100 mg/L). Considering this similar sensitivity to other acknowledged biomarkers, water-borne CORT was a reliable biomarker of physiological stress in R. temporaria exposed to nitrate pollution stress in a controlled single-stressor laboratory approach. Thus, water-borne CORT is a promising method to be included in more holistic approaches. We recommend that such approaches keep testing multiple biomarker combinations, as species are exposed to several stressors likely to interact and produce varied outcomes in different biomarkers in their natural habitats.

Corticosterone in ovo Injection Effects on the Development of Iraqi Native Chicken Embryos

Background: Corticosterone is a major glucocorticoid hormone in the plasma of birds. It is produced in the adrenal gland and transferred to the eggs after 1-2 days of circulation in females by distributing within the yolk. So, this study aimed to evaluate Iraqi native chicken hatching eggs with different levels of corticosterone hormone on embryonic development. Methods: Three hundred Iraqi native hatching eggs from 30 weeks old breeds were utilized in this research. Eggs were divided into five treatments and three replicates (20 eggs for each). Eggs were injected with different levels of corticosterone hormone as follows: Control group without injection, Sesame oil group: Injected with 5 µl of sterile sesame oil only, Group 1: Injected with 0.25, Group 2: Injected with 0.5 and Group 3: Injected with one ng of corticosterone hormone dissolved with sterile sesame oil. The embryonic test was checked after 72 hours, 7 days, 14 days and 18 days of egg incubation. After hatching, hatchability from fertile eggs, early, intermediate and late embryonic mortality, life and dead pipped eggs as a percentage of fertile eggs were measured. Result: Results showed a significant increase (P≤0.05) in embryo length for Group 1 and a significant decrease (P≤0.05) in amniotic fluid and amniotic weight percentage for Group 2, a significant decrease (P≤0.05) in amniotic fluid, amniotic sac membrane percentage, hatchability early embryonic mortality percentage for Group 3 compared with a control group. In conclusion, a high concentration of corticosterone hormone in Iraqi native chicken hatching eggs causes an increase in embryo length, amniotic fluid and amniotic weight percentage. Also, it causes a decrease in amniotic fluid, amniotic sac membrane percentage, hatchability and early embryonic mortality percentage.

Great tits differ in glucocorticoid plasticity in response to spring temperature.

Fluctuations in environmental temperature affect energy metabolism and stimulate the expression of reversible phenotypic plasticity in vertebrate behavioural and physiological traits. Changes in circulating concentrations of glucocorticoid hormones often underpin environmentally induced phenotypic plasticity. Ongoing climate change is predicted to increase fluctuations in environmental temperature globally, making it imperative to determine the standing phenotypic variation in glucocorticoid responses of free-living populations to evaluate their potential for coping via plastic or evolutionary changes. Using a reaction norm approach, we repeatedly sampled wild great tit (<i>Parus major</i>) individuals for circulating glucocorticoid concentrations during reproduction across five years to quantify individual variation in glucocorticoid plasticity along an environmental temperature gradient. As expected, baseline and stress-induced glucocorticoid concentrations increased with lower environmental temperatures at the population and within-individual level. Moreover, we provide unique evidence that individuals differ significantly in their plastic responses to the temperature gradient for both glucocorticoid traits, with some displaying greater plasticity than others. Average concentrations and degree of plasticity covaried for baseline glucocorticoids, indicating that these two reaction norm components are linked. Hence, individual variation in glucocorticoid plasticity in response to a key environmental factor exists in a wild vertebrate population, representing a crucial step to assess their potential to endure temperature fluctuations.

OR26-6 | LBMON298 The Role Of Nuclear Receptor Coregulator Grip1 In Homeostatic Programming Of Macrophages

Abstract Aberrant macrophage function is implicated in acute and chronic inflammatory settings, and central to diseases such as obesity, atherosclerosis and cancer. However, the transcriptional and epigenomic programs driving macrophage polarization toward distinct phenotypic states are not well understood. Macrophage phenotypes exist on a spectrum, with pro-inflammatory (M1-like) and homeostatic, tissue repair (M2-like) states viewed as polar opposites and relatively stable. The main driver of the M2-like program is a type-2 cytokine, IL4 which signals to STAT6 followed by the Krüppel-like factor 4 (KLF4), a master regulator for numerous M2-specific genes. Reportedly, glucocorticoid (GC) hormones also promote the M2-like state, although the extent to which the phenotypes elicited by such disparate signals overlap is unknown. Interestingly, we discovered that GRIP1, a well-known cofactor for nuclear receptors including GR, serves as a KLF4 coactivator, suggesting that GRIP1 could mediate transcriptional and phenotypic convergence of the IL4- and GC-driven pathways. Gene expression profiling on differentially polarized macrophages revealed a highly significant overlap between M2IL4 and M2GC transcriptomes which was mirrored by the H3K27ac de novo enhancer landscape. Notably, loss of GRIP1 blunted both up-regulation of M2- and downregulation of M1-associated genes irrespective of the signal driving M2 polarization. At the cellular level, polarization with either IL4 or GCs enhanced macrophage phagocytosis relative to non-polarized M0, and did so in a GRIP1-dependent manner. Finally, in the dextran sulphate sodium (DSS)-induced colitis model of intestinal inflammation and tissue damage, GRIP1-cKO mice lacking GRIP1 in myeloid cells, including macrophages, displayed more severe destruction of the colonic mucosa and greater immune cell infiltration into the mucosa and submucosa. Moreover, in total colon RNA, the abundance of many characteristic M2 transcripts was reduced in the cKO mice. Surprisingly, the expression of proinflammatory mediators such as TNF, IL1b and IL23 was unaffected by GRIP1 deletion, suggesting that the more severe disease in the cKO stems primarily from the failure of M2-like resolving macrophage to efficiently mitigate tissue destruction and repair the damage. Together, these findings point to GRIP1 as a crucial regulator of macrophage polarization to the homeostatic state in vitro and in vivo. Presentation: Monday, June 13, 2022 12:15 p.m. - 12:30 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Activity in a prefrontal-periaqueductal gray circuit overcomes behavioral and endocrine features of the passive coping stress response

The question of how the brain links behavioral and biological features of defensive responses has remained elusive. The importance of this problem is underscored by the observation that behavioral passivity in stress coping is associated with elevations in glucocorticoid hormones, and each may carry risks for susceptibility to a host of stress-related diseases. Past work implicates the medial prefrontal cortex (mPFC) in the top-down regulation of stress-related behaviors; however, it is unknown whether such changes have the capacity to buffer against the longer-lasting biological consequences associated with aversive experiences. Using the shock probe defensive burying test in rats to naturalistically measure behavioral and endocrine features of coping, we observed that the active behavioral component of stress coping is associated with increases in activity along a circuit involving the caudal mPFC and midbrain dorsolateral periaqueductal gray (PAG). Optogenetic manipulations of the caudal mPFC-to-dorsolateral PAG pathway bidirectionally modulated active (escape and defensive burying) behaviors, distinct from a rostral mPFC-ventrolateral PAG circuit that instead limited passive (immobility) behavior. Strikingly, under conditions that biased rats toward a passive coping response set, including exaggerated stress hormonal output and increased immobility, excitation of the caudal mPFC-dorsolateral PAG projection significantly attenuated each of these features. These results lend insight into how the brain coordinates response features to overcome passive coping and may be of importance for understanding how activated neural systems promote stress resilience.

Evaluation of stress response in black-tailed prairie dogs (Cynomys ludovicianus) in arid regions from colonies in Chihuahua Mexico

Among all the regulatory homeostatic networks in vertebrates, the activation of the hypothalamic–pituitaryadrenal axis during the stress response, has gained considerable attention, and the measurement of fecal glucocorticoids (FGC) has become an invaluable tool to assess adrenocortical activity related to stressful events in wild and captive animals. However, the use of FGC requires the validation of measurement techniques and the proper selection of the specific hormone according to the study species. The main objective of this study was to identify the dominant glucocorticoid (GC) hormone in the stress response of black-tailed prairie dogs (Cynomys ludovicianus) in an arid grassland of Chihuahua, Mexico. A capture stress challenge in the field was developed to determine if the levels of glucocorticoids (cortisol and corticosterone) both in serum and fecal samples could be attributed to stress in Cynomys ludovicianus. The samples were analysed with the technique of liquid phase radioimmunoassay , and this study showed that both cortisol and corticosterone are present at measurable levels in serum and fecal samples of black-tailed prairie dogs. We found that both GCs were present in similar concentrations in serum, however, corticosterone concentration in fecal samples was higher than cortisol. Likewise, biochemical validations performed in this study to test the assay reached acceptable levels of reliability. Therefore, we confirm that fecal analysis can be implemented as a method to measure stress responses in wild prairie dogs.