Showing papers on "Corticosterone published in 2021"

Microbiota regulate social behaviour via stress response neurons in the brain.

Abstract: Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut–brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus–pituitary–adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain. The gut microbiota in mice can modulate social behaviour by influencing activity in stress-related brain areas.

Chronic stress followed by social isolation promotes depressive-like behaviour, alters microglial and astrocyte biology and reduces hippocampal neurogenesis in male mice.

Abstract: Unpredictable chronic mild stress (UCMS) is one of the most commonly used, robust and translatable models for studying the neurobiological basis of major depression. Although the model currently has multiple advantages, it does not entirely follow the trajectory of the disorder, whereby depressive symptomology can often present months after exposure to stress. Furthermore, patients with depression are more likely to withdraw in response to their stressful experience, or as a symptom of their depression, and, in turn, this withdrawal/isolation can further exacerbate the stressful experience and the depressive symptomology. Therefore, we investigated the effect(s) of 6 weeks of UCMS followed by another 6 weeks of social isolation (referred to as UCMSI), on behaviour, corticosterone stress responsivity, immune system functioning, and hippocampal neurogenesis, in young adult male mice. We found that UCMSI induced several behavioural changes resembling depression but did not induce peripheral inflammation. However, UCMSI animals showed increased microglial activation in the ventral dentate gyrus (DG) of the hippocampus and astrocyte activation in both the dorsal and ventral DG, with increased GFAP-positive cell immunoreactivity, GFAP-positive cell hypertrophy and process extension, and increased s100β-positive cell density. Moreover, UCMSI animals had significantly reduced neurogenesis in the DG and reduced levels of peripheral vascular endothelial growth factor (VEGF) - a trophic factor produced by astrocytes and that stimulates neurogenesis. Finally, UCMSI mice also had normal baseline corticosterone levels but a smaller increase in corticosterone following acute stress, that is, the Porsolt Swim Test. Our work gives clinically relevant insights into the role that microglial and astrocyte functioning, and hippocampal neurogenesis may play in the context of stress, social isolation and depression, offering a potentially new avenue for therapeutic target.

Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence.

Abstract: Chronic, sustained exposure to stressors can profoundly affect tissue homeostasis, although the mechanisms by which these changes occur are largely unknown. Here we report that the stress hormone corticosterone—which is derived from the adrenal gland and is the rodent equivalent of cortisol in humans—regulates hair follicle stem cell (HFSC) quiescence and hair growth in mice. In the absence of systemic corticosterone, HFSCs enter substantially more rounds of the regeneration cycle throughout life. Conversely, under chronic stress, increased levels of corticosterone prolong HFSC quiescence and maintain hair follicles in an extended resting phase. Mechanistically, corticosterone acts on the dermal papillae to suppress the expression of Gas6, a gene that encodes the secreted factor growth arrest specific 6. Restoring Gas6 expression overcomes the stress-induced inhibition of HFSC activation and hair growth. Our work identifies corticosterone as a systemic inhibitor of HFSC activity through its effect on the niche, and demonstrates that the removal of such inhibition drives HFSCs into frequent regeneration cycles, with no observable defects in the long-term. Stress inhibits hair growth in mice through the release of the stress hormone corticosterone from the adrenal glands, which inhibits the activation of hair follicle stem cells by suppressing the expression of a secreted factor, GAS6, from the dermal niche.

Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15.

Abstract: An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic–pituitary–adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15−/− mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

Chronic stress and corticosterone exacerbate alcohol-induced tissue injury in the gut-liver-brain axis.

Abstract: Alcohol use disorders are associated with altered stress responses, but the impact of stress or stress hormones on alcohol-associated tissue injury remain unknown. We evaluated the effects of chronic restraint stress on alcohol-induced gut barrier dysfunction and liver damage in mice. To determine whether corticosterone is the stress hormone associated with the stress-induced effects, we evaluated the effect of chronic corticosterone treatment on alcoholic tissue injury at the Gut-Liver-Brain (GLB) axis. Chronic restraint stress synergized alcohol-induced epithelial tight junction disruption and mucosal barrier dysfunction in the mouse intestine. These effects of stress on the gut were reproduced by corticosterone treatment. Corticosterone synergized alcohol-induced expression of inflammatory cytokines and chemokines in the colonic mucosa, and it potentiated the alcohol-induced endotoxemia and systemic inflammation. Corticosterone also potentiated alcohol-induced liver damage and neuroinflammation. Metagenomic analyses of 16S RNA from fecal samples indicated that corticosterone modulates alcohol-induced changes in the diversity and abundance of gut microbiota. In Caco-2 cell monolayers, corticosterone dose-dependently potentiated ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. These data indicate that chronic stress and corticosterone exacerbate alcohol-induced mucosal barrier dysfunction, endotoxemia, and systemic alcohol responses. Corticosterone-mediated promotion of alcohol-induced intestinal epithelial barrier dysfunction and modulation of gut microbiota may play a crucial role in the mechanism of stress-induced promotion of alcohol-associated tissue injury at the GLB axis.

Adult-born neurons from the dorsal, intermediate, and ventral regions of the longitudinal axis of the hippocampus exhibit differential sensitivity to glucocorticoids.

Abstract: Hippocampal neurogenesis has been shown to play roles in learning, memory, and stress responses. These diverse roles may be related to a functional segregation of the hippocampus along its longitudinal axis. Indeed, the dorsal hippocampus (dHi) plays a predominant role in spatial learning and memory, while the ventral hippocampus (vHi) is predominantly involved in the regulation of anxiety, a behaviour impacted by stress. Recent studies suggest that the area between them, the intermediate hippocampus (iHi) may also be functionally independent. In parallel, it has been reported that chronic stress reduces neurogenesis preferentially in the vHi rather the dHi. We thus aimed to determine whether such stress-induced changes in neurogenesis could be related to differential intrinsic sensitivity of neural progenitor cells (NPCs) from the dHi, iHi, or vHi to the stress hormone, corticosterone, or the glucocorticoid receptor (GR) agonist, dexamethasone. Long-term exposure of rat NPCs to corticosterone or dexamethasone decreased neuronal differentiation in the vHi but not the dHi, while iHi cultures showed an intermediate response. A similar gradient-like response on neuronal differentiation and maturation was observed with dexamethasone treatment. This gradient-like effect was also observed on GR nuclear translocation in response to corticosterone or dexamethasone. Long-term exposure to corticosterone or dexamethasone treatment also tended to induce a greater downregulation of GR-associated genes in vHi-derived neurons compared to those from the dHi and iHi. These data suggest that increased intrinsic sensitivity of vHi NPC-derived neurons to chronic glucocorticoid exposure may underlie the increased vulnerability of the vHi to chronic stress-induced reductions in neurogenesis.

Experimental Chronic Prostatitis/Chronic Pelvic Pain Syndrome Increases Anxiety-Like Behavior: The Role of Brain Oxidative Stress, Serum Corticosterone, and Hippocampal Parvalbumin-Positive Interneurons.

Abstract: Mechanisms of the brain-related comorbidities in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are still largely unknown, although CP/CPPS is one of the major urological problems in middle-aged men, while these neuropsychological incapacities considerably diminish life quality. The objectives of this study were to assess behavioral patterns in rats with CP/CPPS and to determine whether these patterns depend on alterations in the brain oxidative stress, corticosterone, and hippocampal parvalbumin-positive (PV+) interneurons. Adult male Wistar albino rats from CP/CPPS (intraprostatic injection of 3% λ-carrageenan, day 0) and sham (0.9% NaCl) groups were subjected to pain and anxiety-like behavior tests (days 2, 3, and 7). Afterwards, rats were sacrificed and biochemical and immunohistochemical analyses were performed. Scrotal allodynia and prostatitis were proven in CP/CPPS, but not in sham rats. Ethological tests (open field, elevated plus maze, and light/dark tests) revealed significantly increased anxiety-like behavior in rats with CP/CPPS comparing to their sham-operated mates starting from day 3, and there were significant intercorrelations among parameters of these tests. Increased oxidative stress in the hippocampus, thalamus, and cerebral cortex, as well as increased serum corticosterone levels and decreased number of hippocampal PV+ neurons, was shown in CP/CPPS rats, compared to sham rats. Increased anxiety-like behavior in CP/CPPS rats was significantly correlated with these brain biochemical and hippocampal immunohistochemical alterations. Therefore, the potential mechanisms of observed behavioral alterations in CP/CPPS rats could be the result of an interplay between increased brain oxidative stress, elevated serum corticosterone level, and loss of hippocampal PV+ interneurons.

Do corticosterone levels predict female depressive‐like behavior in rodents?

Abstract: Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is often linked to the neurobiology of depression, though the presence and type of this dysregulation is not a consistent finding. Meanwhile, significant sex differences exist regarding depression and the HPA axis. Animal models of depression simulate certain aspects of the human disease and aim to advance our knowledge regarding its neurobiology and discover new antidepressant treatments. Most animal models of depression induce a depressive-like phenotype taking advantage of stressful experimental conditions, that also increase corticosterone, the main stress hormone in rodents. In this review we present inconsistent results in male and female rodents regarding the interaction between the depressive-like behavioral phenotype and corticosterone. In commonly used models, the female depressive-like phenotype in rodents seems significantly less dependent on the stress hormone corticosterone, whereas the male behavioral response is more evident and associates with variations of corticosterone. Further research and clarification of this sex-dependent interaction will have significant ramifications on the improvement of the validity of animal models of depression.

Hippocampal glucocorticoid target genes associated with enhancement of memory consolidation

Abstract: Glucocorticoids enhance memory consolidation of emotionally arousing events via largely unknown molecular mechanisms. This glucocorticoid effect on the consolidation process also requires central noradrenergic neurotransmission. The intracellular pathways of these two stress mediators converge on two transcription factors: the glucocorticoid receptor (GR) and phosphorylated cAMP response element-binding protein (pCREB). We therefore investigated, in male rats, whether glucocorticoid effects on memory are associated with genomic interactions between the GR and pCREB in the hippocampus. In a two-by-two design, object exploration training or no training was combined with post-training administration of a memory-enhancing dose of corticosterone or vehicle. Genomic effects were studied by chromatin immunoprecipitation followed by sequencing (ChIP-seq) of GR and pCREB 45 min after training and transcriptome analysis after 3 hr. Corticosterone administration induced differential GR DNA-binding and regulation of target genes within the hippocampus, largely independent of training. Training alone did not result in long-term memory nor did it affect GR or pCREB DNA-binding and gene expression. No strong evidence was found for an interaction between GR and pCREB. Combination of the GR DNA-binding and transcriptome data identified a set of novel, likely direct, GR target genes that are candidate mediators of corticosterone effects on memory consolidation. Cell-specific expression of the identified target genes using single-cell expression data suggests that the effects of corticosterone reflect in part non-neuronal cells. Together, our data identified new GR targets associated with memory consolidation that reflect effects in both neuronal and non-neuronal cells.

Knockout of the circadian gene, Per2, disrupts corticosterone secretion and results in depressive-like behaviors and deficits in startle responses.

Abstract: The Period Circadian Regulator 2 (Per2) gene is important for the modulation of circadian rhythms that influence biological processes. Circadian control of the hypothalamus-pituitary-adrenal (HPA) axis is critical for regulation of hormones involved in the stress response. Dysregulation of the HPA axis is associated with neuropsychiatric disorders. Therefore, it is important to understand how disruption of the circadian rhythm alters the HPA axis. One way to address this question is to delete a gene involved in regulating a central circadian gene such as Per2 in an animal model and to determine how this deletion may affect the HPA axis and behaviors that are altered when the HPA axis is dysregulated. To study this, corticosterone (CORT) levels were measured through the transition from light (inactive phase) to dark (active phase). Additionally, CORT levels as well as pituitary and adrenal mRNA expression were measured following a mild restraint stress. Mice were tested for depressive-like behaviors (forced swim test (FST)), acoustic startle response (ASR), and pre-pulse inhibition (PPI). The present results showed that Per2 knockout impacted CORT levels, mRNA expression, depressive-like behaviors, ASR and PPI. Unlike wild-type (WT) mice, Per2 knockout (Per2) mice showed no diurnal rise in CORT levels at the onset of the dark cycle. Per2−/− mice had enhanced CORT levels and adrenal melanocortin receptor 2 (Mc2R) mRNA expression following restraint. There were no changes in expression of any other pituitary or adrenal gene. In the FST, Per2−/− mice spent more time floating (less time struggling) than WT mice, suggesting increased depressive-like behaviors. Per2−/− mice had deficits in ASR and PPI startle responses compared to WT mice. In summary, these findings showed that disruption of the circadian system via Per2 gene deletion dysregulated the HPA stress axis and is subsequently correlated with increased depressive-like behaviors and deficits in startle response.

Jie-Yu-He-Huan Capsule Ameliorates Anxiety-Like Behaviours in Rats Exposed to Chronic Restraint Stress via the cAMP/PKA/CREB/BDNF Signalling Pathway.

Abstract: Chronic stress is a critical factor in the aetiology of anxiety disorders; however, in the clinic, enduring and preventive measures are not available, and therapeutic drugs are associated with inevitable side effects. Our study established an anxiety rat model using chronic restraint stress (CRS) and assessed these animals using the open-field test, elevated plus-maze test, and light-dark box test. Jie-Yu-He-Huan capsule (JYHH), a Chinese medicine formula, was used as a preventative drug. The HPA axis-mediated release of corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone from the hypothalamus was tested. In the hippocampus and prefrontal cortex, concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid, as well as monoamine oxidase A, glucocorticoid receptor, and 5-HT1A receptor expression levels, were measured. Furthermore, we examined protein and mRNA expression of cAMP-PKA-CREB-BDNF pathway components. The results showed that JYHH had a significant preventative effect on the anxiety-like behaviour induced by CRS and prevented abnormal changes in the HPA axis and 5-HT system. Furthermore, CRS inhibited the cAMP-PKA-CREB-BDNF pathway, which returned to normal levels following JYHH treatment. This might be the underlying molecular mechanism of the antianxiety effect of JYHH, which could provide a new clinical target for preventative anxiolytic drugs for chronic stress.

Low doses of ketamine and guanosine abrogate corticosterone-induced anxiety-related behavior, but not disturbances in the hippocampal NLRP3 inflammasome pathway

Abstract: Guanosine has been shown to potentiate ketamine’s antidepressant-like actions, although its ability to augment the anxiolytic effect of ketamine remains to be determined. This study investigated the anxiolytic-like effects of a single administration with low doses of ketamine and/or guanosine in mice subjected to chronic administration of corticosterone and the role of NLRP3-driven signaling. Corticosterone (20 mg/kg, p.o.) was administered for 21 days, followed by a single administration of ketamine (0.1 mg/kg, i.p.), guanosine (0.01 mg/kg, p.o.), or ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.). Anxiety-like behavior and NLRP3-related targets were analyzed 24 h following treatments. Corticosterone reduced the time spent in the open arms and the central zone in the elevated plus-maze test and open-field test, respectively. Corticosterone raised the number of unsupported rearings and the number and time of grooming, and decreased the latency to start grooming in the open-field test. Disturbances in regional distribution (increased rostral grooming) and grooming transitions (increased aborted and total incorrect transitions) were detected in corticosterone-treated mice. These behavioral alterations were accompanied by increased immunocontent of Iba-1, ASC, NLRP3, caspase-1, TXNIP, and IL-1β in the hippocampus, but not in the prefrontal cortex. The treatments with ketamine, guanosine, and ketamine plus guanosine were effective to counteract corticosterone-induced anxiety-like phenotype, but not disturbances in the hippocampal NLRP3 pathway. Our study provides novel evidence that low doses of ketamine and/or guanosine reverse corticosterone-induced anxiety-like behavior and shows that the NLRP3 inflammasome pathway is likely unrelated to this response.

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

Abstract: 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 14 days 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 14 days 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.

Melatonin Ameliorates Corticosterone-Mediated Oxidative Stress-Induced Colitis in Sleep-Deprived Mice Involving Gut Microbiota

Abstract: Background Inflammatory bowel disease (IBD) is a result of a complex interplay, making development of a specific treatment a challenging task. Corticosterone was considered a risk factor of stress relative enteritis. Our previous studies found that melatonin exerts an improvement effect in sleep deprivation (SD)- induced corticosterone overproduction and colitis. A present study further explored the mechanism whereby melatonin prevented corticosterone-mediated SD-induced colitis. Methods A 72-hour SD mouse model with or without melatonin supplementation and fecal microbiota transplantation (FMT) to investigate the core role of corticosterone in melatonin-mediated gut microbiota improving SD-induced colitis. Further, corticosterone-treated mice were assessed to the effect of melatonin on corticosterone-mediated gut microbiota dysbiosis-induced colitis. Meanwhile, an in vitro test studied modulatory mechanism of metabolite melatonin. Results SD caused an excessive corticosterone, gut microbiota disorder and colitis phenotype. Similarly, corticosterone-supplemented mice also exhibited gut microbiota dysbiosis and colitis, and the FMT from SD-mice to normal mice could restore the SD-like colitis, but no change in the corticosterone level, which suggested that corticosterone-mediated intestinal microbiota imbalance plays a central role in SD-induced colitis. Further, we demonstrated melatonin-mediated MT2 weakened GR feedback, suppressed oxidative stress, restored the intestinal microbiota and its metabolites homeostasis, and inactivated the STAT3/AP-1/NF-κB pathway-induced inflammatory response in vivo and in vitro. Conclusions We revealed that excessive corticosterone is a core risk factor for SD-induced colitis and provided a better understanding of the effects of melatonin, expected to be a personalized targeted therapy drug, on corticosterone-mediated gut microbiota inducing colitis.

Repeated unpredictable stress and social isolation induce chronic HPA axis dysfunction and persistent abnormal fear memory

Abstract: The lack of progress in the psychopharmacological treatment of stress-related disorders such as PTSD is an ongoing crisis due to its negative socioeconomic implications. Current PTSD pharmacotherapy relies on a few FDA approved medications used primarily for depression which offer only symptomatic relief and show limited efficacy. As the population of PTSD patients is growing, the identification of effective etiology-based treatments for the condition is a high priority. This requires an in-depth understanding of the neurobiological and behavioral outcomes of stress in translationally relevant animal models. In this study, we use neuroendocrine, biochemical and behavioral measures to assess the HPA axis function and fear-memory deficits in a mouse model of chronic stress. The chronic stress procedures involved exposure to 21 days of repeated unpredictable stress (RUS), including predator stress, restraint and foot shock, followed by chronic social isolation. We show that mice exposed to our stress paradigm demonstrate exaggerated fear memory recall and blunted HPA axis functionality at one month after RUS. Our neuroendocrinal testing suggests that the attenuated stress response in our model may be related to an alteration in the adrenal MC2 receptor reactivity. While there was no noticeable change in pituitary negative feedback regulation mechanisms, CRH and phosphorylated Glucocorticoid receptors levels were altered in the hypothalamus. We also show that chronic supplementation with a peripheral glucocorticoid receptor agonist (low-dose dexamethasone) after RUS partially restores a number of stress-related behavioral deficits in the RUS model. This suggests a direct relationship between HPA axis function and behavior in our model. Our findings emphasize the importance of the adrenal receptors as a target for HPA axis dysfunction in stress and fear-related disorders.

Dysfunction in Sertoli cells participates in glucocorticoid-induced impairment of spermatogenesis.

Abstract: The effect of stress on male fertility is a widespread public health issue, but less is known about the related signaling pathway. To investigate this, we established a hypercortisolism mouse model by supplementing the drinking water with corticosterone for four weeks. In the hypercortisolism mice, the serum corticosterone was much higher than in the control, and serum testosterone was significantly decreased. Moreover, corticosterone treatment induced decrease of sperm counts and increase of teratozoospermia. Increased numbers of multinucleated giant cells and apoptotic germ cells as well as downregulated meiotic markers suggested that corticosterone induced impaired spermatogenesis. Further, upregulation of macrophage-specific marker antigen F4/80 as well as inflammation-related genes suggested that corticosterone induced inflammation in the testis. Lactate content was found to be decreased in the testis and Sertoli cells after corticosterone treatment, and lactate metabolism-related genes were downregulated. In vitro phagocytosis assays showed that the phagocytic activity in corticosterone-treated Sertoli cells was downregulated and accompanied by decreased mitochondrial membrane potential, while pyruvate dehydrogenase kinase-4 inhibitor supplementation restored this process. Taken together, our results demonstrated that dysfunctional phagocytosis capacity and lactate metabolism in Sertoli cells participates in corticosterone-induced impairment of spermatogenesis.

A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function.

Abstract: Objective: Brown adipose tissue (BAT) displays a strong circadian rhythm in metabolic activity, but it is unclear how this rhythm is regulated. As circulating levels of corticosterone coincide with the rhythm of triglyceride-derived fatty acid (FA) uptake by BAT, we investigated whether corticosterone regulates BAT circadian rhythm.Methods: Corticosterone levels were flattened by implanting mice with subcutaneous corticosterone-releasing pellets, resulting in constant circulating corticosterone levels.Results: Flattened corticosterone rhythm caused a complete loss of circadian rhythm in triglyceride-derived fatty acid uptake by BAT. This effect was independent of glucocorticoid receptor expression in (brown) adipocytes and was not caused by deregulation of clock gene expression or overexposure to glucocorticoids, but rather seemed mediated by reduced sympathetic innervation of BAT. In a mouse model of hyperlipidemia and metabolic syndrome, long-term experimental flattening of corticosterone -and thus rhythm in BAT function -resulted in adiposity.Conclusions: This study highlights that a physiological rhythm in glucocorticoids is an important regulator of BAT function and essential for the maintenance of metabolic health.(c) 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

The Gut Microbiota Affects Corticosterone Production in the Murine Small Intestine.

Abstract: Glucocorticoids (GCs) are hormones that are released in response to stressors and exhibit many activities, including immunomodulatory and anti-inflammatory activities. They are primarily synthesized in the adrenal gland but are also produced in peripheral tissues via regeneration of adrenal 11-oxo metabolites or by de novo synthesis from cholesterol. The present study investigated the influence of the microbiota on de novo steroidogenesis and regeneration of corticosterone in the intestine of germ-free (GF) and specific pathogen-free mice challenged with a physical stressor (anti-CD3 antibody i.p. injection). In the small intestine, acute immune stress resulted in increased mRNA levels of the proinflammatory cytokines IL1β, IL6 and Tnfα and genes involved in de novo steroidogenesis (Stard3 and Cyp11a1), as well as in regeneration of active GCs from their 11-oxo metabolites (Hsd11b1). GF mice showed a generally reduced transcriptional response to immune stress, which was accompanied by decreased intestinal corticosterone production and reduced expression of the GC-sensitive marker Fkbp5. In contrast, the interaction between stress and the microbiota was not detected at the level of plasma corticosterone or the transcriptional response of adrenal steroidogenic enzymes. The results indicate a differential immune stress-induced intestinal response to proinflammatory stimuli and local corticosterone production driven by the gut microbiota.

Plasma steroid profiling in patients with adrenal incidentaloma.

Abstract: Context Most patients with adrenal incidentaloma have non-functional lesions that do not require treatment, while others have functional or malignant tumors that require intervention. The plasma steroid metabolome may be useful to assess therapeutic need. Objective Establish the utility of plasma steroid profiling combined with metanephrines and adrenal tumor size for differential diagnosis of patients with adrenal incidentaloma. Design Retrospective cross-sectional study. Setting European tertiary-care centers. Participants 577 patients with adrenal incidentaloma, including 19, 77, 65, 104 and 312 respective patients with adrenocortical carcinoma (ACC), pheochromocytoma, primary aldosteronism (PA), autonomous cortisol secretion (ACS) and non-functional adrenal incidentaloma (NFAI). Outcome measures Measures of diagnostic performance (with [95% confidence intervals]) for discriminating different subgroups of patients with adrenal incidentaloma. Results Patients with ACC were characterized by elevated plasma concentrations of 11-deoxycortisol, 11-deoxycorticosterone, 17-hydroxprogesterone, androstenedione and dehydroepiandrosterone-sulfate, whereas patients with PA had elevations of aldosterone, 18-oxocortisol and 18-hydroxycortisol. A selection of those 8 steroids, combined with 3 others (cortisol, corticosterone, and dehydroepiandrosterone) and plasma metanephrines, proved optimal for identifying patients with ACC, PA and pheochromocytoma at respective sensitivities of 83.3[66.1-100]%, 90.8[83.7-97.8]% and 94.8[89.8-99.8]% and specificities of 98.0[96-9-99.2]%, 92.0[89.6-94.3]% and 98.6[97.6-99.6]%. With addition of tumor size, discrimination improved further, particularly for ACC (100[100-100]% sensitivity, 99.5[98.9-100]% specificity). In contrast, discrimination of ACS and NFAI remained suboptimal (70-71% sensitivity, 89-90% specificity). Conclusions Among patients with adrenal incidentaloma, the combination of plasma steroid metabolomics with routinely available plasma free metanephrines and data from imaging studies may facilitate identification of almost all clinically relevant adrenal tumors.

Steroid profiling of glucocorticoids in microdissected mouse brain across development

Abstract: Corticosterone is produced by the adrenal glands and also produced locally by other organs, such as the brain. Local levels of corticosterone in specific brain regions during development are not known. Here, we microdissected brain tissue and developed a novel liquid chromatography tandem mass spectrometry method (LC-MS/MS) to measure a panel of seven steroids (including 11-deoxycorticosterone (DOC), corticosterone, and 11-dehydrocorticosterone (DHC) in the blood, hippocampus (HPC), cerebral cortex (CC), and hypothalamus (HYP) of mice at postnatal day (PND) 5, 21, and 90. In a second cohort of mice, we measured the expression of three genes that code for steroidogenic enzymes that regulate corticosterone levels (Cyp11b1, Hsd11b1, and Hsd11b2) in the HPC, CC, and HYP. There were region-specific patterns of steroid levels across development, including higher corticosterone levels in the HPC and HYP than in the blood at PND5. In contrast, corticosterone levels were higher in the blood than in all brain regions at PND21 and PND90. Brain corticosterone levels were not positively correlated with blood corticosterone levels, and correlations across brain regions increased with age. Local corticosterone levels were best predicted by local DOC levels at PND5, but by local DHC levels at PND21 and PND90. Transcripts for the three enzymes were detectable in all samples (with highest expression of Hsd11b1) and showed region-specific changes with age. These data demonstrate that individual brain regions fine-tune local levels of corticosterone during early development and that coupling of glucocorticoid levels across regions increases with age.

Serum Corticosterone and Insulin Resistance as Early Biomarkers in the hAPP23 Overexpressing Mouse Model of Alzheimer's Disease.

Abstract: Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer’s disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/−) AD mouse model. Memory and spatial learning of male hAPP23+/− and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/− brains, amyloid-beta (Aβ) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/− mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/− animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/− mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/− mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD.