No changes in triple network engagement following (combined) noradrenergic and glucocorticoid stimulation in healthy men.

Successful recovery from stress is integral for adaptive responding to the environment. At a cellular level, this involves (slow genomic) actions of cortisol, which alter or reverse rapid effects of noradrenaline and cortisol associated with acute stress. At the network scale, stress recovery is less well understood but assumed to involve changes within salience-, executive control-, and default mode networks. To date, few studies have investigated this phase and directly tested these assumptions. Here, we present results from a double-blind, placebo-controlled, between-group paradigm (N = 165 healthy males) administering 10 mg oral yohimbine and/or 10 mg oral hydrocortisone two hours prior to resting state scanning. We found no changes in within-network connectivity of the three networks, both after single and combined drug administration. We further report the results of Bayesian parameter inference to provide evidence for the null hypothesis. Our results contrast with previous findings, which may be attributable to systematic differences between paradigms, highlighting the need to isolate paradigm-specific effects from those related to stress.

Phase-separation: a possible new layer for transcriptional regulation by glucocorticoid receptor.

Glucocorticoids (GCs) are hormones involved in circadian adaptation and stress response, and it is also noteworthy that these steroidal molecules present potent anti-inflammatory action through GC receptors (GR). Upon ligand-mediated activation, GR translocates to the nucleus, and regulates gene expression related to metabolism, acute-phase response and innate immune response. GR field of research has evolved considerably in the last decades, providing varied mechanisms that contributed to the understanding of transcriptional regulation and also impacted drug design for treating inflammatory diseases. Liquid-liquid phase separation (LLPS) in cellular processes represents a recent topic in biology that conceptualizes membraneless organelles and microenvironments that promote, or inhibit, chemical reactions and interactions of protein or nucleic acids. The formation of these molecular condensates has been implicated in gene expression control, and recent evidence shows that GR and other steroid receptors can nucleate phase separation (PS). Here we briefly review the varied mechanisms of transcriptional control by GR, which are largely studied in the context of inflammation, and further present how PS can be involved in the control of gene expression. Lastly, we consider how the reported advances on LLPS during transcription control, specially for steroid hormone receptors, could impact the different modalities of GR action on gene expression, adding a new plausible molecular event in glucocorticoid signal transduction.

The Role of the Paraventricular-Coerulear Network on the Programming of Hypertension by Prenatal Undernutrition.

A crucial etiological component in fetal programming is early nutrition. Indeed, early undernutrition may cause a chronic increase in blood pressure and cardiovascular diseases, including stroke and heart failure. In this regard, current evidence has sustained several pathological mechanisms involving changes in central and peripheral targets. In the present review, we summarize the neuroendocrine and neuroplastic modifications that underlie maladaptive mechanisms related to chronic hypertension programming after early undernutrition. First, we analyzed the role of glucocorticoids on the mechanism of long-term programming of hypertension. Secondly, we discussed the pathological plastic changes at the paraventricular nucleus of the hypothalamus that contribute to the development of chronic hypertension in animal models of prenatal undernutrition, dissecting the neural network that reciprocally communicates this nucleus with the locus coeruleus. Finally, we propose an integrated and updated view of the main neuroendocrine and central circuital alterations that support the occurrence of chronic increases of blood pressure in prenatally undernourished animals.

Simulating physiological flexibility in the acute glucocorticoid response to stressors reveals limitations of current empirical approaches.

Wild animals often experience unpredictable challenges that demand rapid and flexible responses. The glucocorticoid mediated stress response is one of the major systems that allows vertebrates to rapidly adjust their physiology and behavior. Given its role in responding to challenges, evolutionary physiologists have focused on the consequences of between-individual and, more recently, within-individual variation in the acute glucocorticoid response. However, empirical studies of physiological flexibility are severely limited by the logistical challenges of measuring the same animal multiple times. Data simulation is a powerful approach when empirical data are limited, but has not been adopted to date in studies of physiological flexibility. In this article, I develop a simulation that can generate realistic acute glucocorticoid response data with user specified characteristics. Simulated animals can be sampled continuously through an acute response and across as many separate responses as desired, while varying key parameters. Using the simulation, I develop several scenarios that address key questions in physiological flexibility. These scenarios demonstrate the conditions under which a single glucocorticoid trait can be accurately assessed with typical experimental designs, the consequences of covariation between different components of the acute stress response, and the way that context specific differences in variability of acute responses can influence the power to detect relationships between the strength of the acute stress response and fitness. I also describe how to use the simulation tools to aid in the design and evaluation of empirical studies of physiological flexibility.

The neuroendocrinology of stress: Glucocorticoid signaling mechanisms.

Glucocorticoid signaling plays major roles in energy homeostasis and adaptation to adversity, and dysregulation of this process is linked to systemic and psychological pathology. Over the last several decades, new work has challenged many of the long-standing assumptions regarding regulation of glucocorticoid secretion and glucocorticoid signaling mechanisms, revealing an exquisite complexity that accompanies the important and perhaps global role of these hormones in physiological and psychological regulation. New findings have included discovery of membrane signaling, direct neural control of the adrenal, a role for pulsatile glucocorticoid release in glucocorticoid receptor signaling, marked sex differences in brain glucocorticoid biology, and salutary as well as deleterious roles for glucocorticoids in long- and short-term adaptations to stress. This review covers some of the major lessons learned in the area of mechanisms of glucocorticoid signaling, and discusses how these may inform the field moving forward.

Glucocorticoid Receptor Signaling in Diabetes.

Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs-known to target GR mRNA-has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation.

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models.

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is, therefore, critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11ß-hydroxysteroid dehydrogenases 1 and 2 (HSD11B1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive HSD11B1 activity and amplification of local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and ageing-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated mechanisms by which glucocorticoids exert their metabolic effects and have guided us towards more targeted future treatments for metabolic diseases.

Endogenous Glucocorticoid Metabolism in Bone: Friend or Foe.

The role of tissue specific metabolism of endogenous glucocorticoids (GCs) in the pathogenesis of human disease has been a field of intense interest over the last 20 years, fuelling clinical trials of metabolism inhibitors in the treatment of an array of metabolic diseases. Localised pre-receptor metabolism of endogenous and therapeutic GCs by the 11ß-hydroxysteroid dehydrogenase (11ß-HSD) enzymes (which interconvert endogenous GCs between their inactive and active forms) are increasingly recognised as being critical in mediating both their positive and negative actions on bone homeostasis. In this review we explore the roles of endogenous and therapeutic GC metabolism by the 11ß-HSD enzymes in the context of bone metabolism and bone cell function, and consider future strategies aimed at modulating this system in order to manage and treat various bone diseases.

Stress-Associated Molecular and Cellular Hippocampal Mechanisms Common for Epilepsy and Comorbid Depressive Disorders.

The review discusses molecular and cellular mechanisms common to the temporal lobe epileptogenesis/epilepsy and depressive disorders. Comorbid temporal lobe epilepsy and depression are associated with dysfunction of the hypothalamic-pituitary-adrenocortical axis. Excessive glucocorticoids disrupt the function and impair the structure of the hippocampus, a brain region key to learning, memory, and emotions. Selective vulnerability of the hippocampus to stress, mediated by the reception of glucocorticoid hormones secreted during stress, is the price of the high functional plasticity and pleiotropy of this limbic structure. Common molecular and cellular mechanisms include the dysfunction of glucocorticoid receptors, neurotransmitters, and neurotrophic factors, development of neuroinflammation, leading to neurodegeneration and loss of hippocampal neurons, as well as disturbances in neurogenesis in the subgranular neurogenic niche and formation of aberrant neural networks. These glucocorticoid-dependent processes underlie altered stress response and the development of chronic stress-induced comorbid pathologies, in particular, temporal lobe epilepsy and depressive disorders.

Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders.

Stress is defined as a state of threatened or perceived as threatened homeostasis. The well-tuned coordination of the stress response system is necessary for an organism to respond to external or internal stressors and re-establish homeostasis. Glucocorticoid hormones are the main effectors of stress response and aberrant glucocorticoid signaling has been associated with an increased risk for psychiatric and mood disorders, including schizophrenia, post-traumatic stress disorder and depression. Emerging evidence suggests that life-stress experiences can alter the epigenetic landscape and impact the function of genes involved in the regulation of stress response. More importantly, epigenetic changes induced by stressors persist over time, leading to increased susceptibility for a number of stress-related disorders. In this review, we discuss the role of glucocorticoids in the regulation of stress response, the mechanism through which stressful experiences can become biologically embedded through epigenetic alterations, and we underline potential associations between epigenetic changes and the development of stress-related disorders.

Metabolic Disease Programming: From Mitochondria to Epigenetics, Glucocorticoid Signalling and Beyond.

Embryonic and foetal development are critical periods of development in which several environmental cues determine health and disease in adulthood. Maternal conditions and an unfavourable intrauterine environment impact foetal development and may programme the offspring for increased predisposition to metabolic diseases and other chronic pathologic conditions throughout adult life. Previously, non-communicable chronic diseases were only associated with genetics and lifestyle. Now the origins of non-communicable chronic diseases are associated with early-life adaptations that produce long-term dysfunction. Early-life environment sets the long-term health and disease risk and can span through multiple generations. Recent research in developmental programming aims at identifying the molecular mechanisms responsible for developmental programming outcomes that impact cellular physiology and trigger adulthood disease. The identification of new therapeutic targets can improve offspring's health management and prevent or overcome adverse consequences of foetal programming. This review summarizes recent biomedical discoveries in the Developmental Origins of Health and Disease (DOHaD) hypothesis and highlight possible developmental programming mechanisms, including prenatal structural defects, metabolic (mitochondrial dysfunction, oxidative stress, protein modification), epigenetic and glucocorticoid signalling-related mechanisms suggesting molecular clues for the causes and consequences of programming of increased susceptibility of offspring to metabolic disease after birth. Identifying mechanisms involved in DOHaD can contribute to early interventions in pregnancy or early childhood, to re-set the metabolic homeostasis and break the chain of subsequent events that could lead to the development of disease.

Glucocorticoid-Mediated Changes in Male Green Treefrog Vocalizations Alter Attractiveness to Females.

Adrenal glucocorticoids (GCs) are increasingly recognized as important modulators of male courtship signals, suggesting that circulating levels of these steroids can play a central role in sexual selection. However, few studies have examined whether GC-mediated effects on male sexual signals actually impact mate choice by females. Here, we examine how corticosterone (CORT)-mediated changes in the vocalizations of male green treefrogs, Dryophytes cinereus, influence attractiveness to females. In this species, agonistic acoustic signaling between rival males competing for mates increases circulating CORT levels in contest losers. Acute elevations in CORT, in turn, decrease the duration of male advertisement calls and increase the latency between successive calls, resulting in a net reduction in vocal effort (the amount of signaling per unit time) that occurs independently of changes in circulating androgens. Based on known preferences for acoustic features in D. cinereus, and other anuran species, the direction of CORT-mediated effects on temporal call characteristics is expected to compromise attractiveness to females, but whether they are of sufficient magnitude to impact female mate choice decisions is unclear. To examine whether CORT-mediated effects on male advertisement calls reduce attractiveness to females, we broadcast vocalizations in dual speaker playback experiments approximating the mean and 1 SD above and below the mean call duration and vocal effort values (the two primary vocal features impacted by elevated CORT) of males with low and high CORT levels. Results revealed strong preferences by females for the calls characteristic of males with low CORT in tests using the approximate mean and 1 SD above the mean call duration and vocal effort values, but females did not show a preference for calls of males with low CORT in trials using call values approximating 1 SD below the mean. Overall, females preferred males with signal traits predictive of low CORT, however this effect was nonlinear with attenuated preferences when signal alternatives differed only marginally indicating a possible thresholding effect. Specifically, females appeared to discriminate between males with low versus high CORT based primarily on differences in call rates associated with CORT-mediated changes in call duration and vocal effort. Our results highlight that changes in circulating CORT during male-male vocal interactions can decrease attractiveness to females, suggesting that circulating levels of CORT can play a critical role in both intra- and intersexual selection.

The 'Jekyll and Hyde' of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances.

The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA), and sympathetic nervous system activation. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance, and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, and the most prominent are early life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a "Jekyll and Hyde" role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.

Glucocorticoids: Dr. Jekyll and Mr. Hyde of Hippocampal Neuroinflammation.

Glucocorticoids (GCs) are an important component of adaptive response of an organism to stressogenic stimuli, a typical stress response being accompanied by elevation of GC levels in blood. Anti-inflammatory effects of GCs are widely used in clinical practice, while pro-inflammatory effects of GCs are believed to underlie neurodegeneration. This is particularly critical for the hippocampus, brain region controlling both cognitive function and emotions/affective behavior, and selectively vulnerable to neuroinflammation and neurodegeneration. The hippocampus is believed to be the main target of GCs since it has the highest density of GC receptors potentially underlying high sensitivity of hippocampal cells to severe stress. In this review, we analyzed the results of studies on pro- and anti-inflammatory effects of GCs in the hippocampus in different models of stress and stress-related pathologies. The available data form a sophisticated, though often quite phenomenological, picture of a modulatory role of GCs in hippocampal neuroinflammation. Understanding the dual nature of GC-mediated effects as well as causes and mechanisms of switching can provide us with effective approaches and tools to avert hippocampal neuroinflammatory events and as a result to prevent and treat brain diseases, both neurological and psychiatric. In the framework of a mechanistic view, we propose a new hypothesis describing how the anti-inflammatory effects of GCs may transform into the pro-inflammatory ones. According to it, long-term elevation of GC level or preliminary treatment with GC triggers accumulation of FKBP51 protein that suppresses activity of GC receptors and activates pro-inflammatory cascades, which, finally, leads to enhanced neuroinflammation.

Glucocorticoids do not promote prosociality in a wild group-living fish.

Individuals often respond to social disturbances by increasing prosociality, which can strengthen social bonds, buffer against stress, and promote overall group cohesion. Given their importance in mediating stress responses, glucocorticoids have received considerable attention as potential proximate regulators of prosocial behaviour during disturbances. However, previous investigations have largely focused on mammals and our understanding of the potential prosocial effects of glucocorticoids across vertebrates more broadly is still lacking. Here, we assessed whether experimentally elevated glucocorticoid levels (simulating endogenous cortisol responses mounted following disturbances) promote prosocial behaviours in wild groups of the cichlid fish, Neolamprologus pulcher. Using SCUBA in Lake Tanganyika, we observed how subordinate group members adjusted affiliation, helping, and submission (all forms of prosocial behaviour) following underwater injections of either cortisol or saline. Cortisol treatment reduced affiliative behaviours-but only in females-suggesting that glucocorticoids may reduce overall prosociality. Fish with elevated glucocorticoid levels did not increase performance of submission or helping behaviours. Taken together, our results do not support a role for glucocorticoids in promoting prosocial behaviour in this species and emphasize the complexity of the proximate mechanisms that underlie prosociality.

Loss of the glucocorticoid receptor causes accelerated ovarian ageing in zebrafish.

Reproductive decline in mid-adult females is an established phenotype of the ageing process. Stress and the rise in glucocorticoids (GCs) accelerate reproductive ageing, but little is known about the mechanisms involved. During stress, GCs activate the glucocorticoid receptor (GR), a ubiquitously expressed, ligand-bound transcription factor, to elicit physiological changes for restoring homeostasis. Here, we tested the hypothesis that GC-GR signalling is essential for accelerating reproductive ageing. To test this, we used a ubiquitous GR knockout (GRKO) zebrafish, which is inherently hypercortisolemic, to delineate the role of high cortisol and GR signalling on reproductive ageing. The loss of GR led to premature ovarian ageing, including high frequency of typical and atypical follicular atresia in vitellogenic oocytes, yolk liquefaction and large inflammatory infiltrates. The reduction in oocyte quality was also associated with a decline in ovarian tert expression in the adult GRKO fish compared to the early adult GRKO and adult wild-type zebrafish. Accelerated ovarian ageing also impacted the progeny, including lower breeding success, fecundity, egg fertilization rate and delayed somitogenesis and embryo survival in the adult GRKO fish. We adduce that GR signalling is essential for prolonging the reproductive lifespan and improving the egg quality and embryo viability in zebrafish.

Glucocorticoids Regulate Circadian Rhythm of Innate and Adaptive Immunity.

Animals have evolved circadian rhythms to adapt to the 24-h day-night cycle. Circadian rhythms are controlled by molecular clocks in the brain and periphery, which is driven by clock genes. The circadian rhythm is propagated from the brain to the periphery by nerves and hormones. Glucocorticoids (GCs) are a class of steroid hormones produced by the adrenal cortex under the control of the circadian rhythm and the stress. GCs have both positive and negative effects on the immune system. Indeed, they are well known for their strong anti-inflammatory and immunosuppressive effects. Endogenous GCs inhibit the expression of inflammatory cytokines and chemokines at the active phase of mice, regulating the circadian rhythm of tissue inflammation. In addition, GCs induce the rhythmic expression of IL-7R and CXCR4 on T cells, which supports T cell maintenance and homing to lymphoid tissues. Clock genes and adrenergic neural activity control the T cell migration and immune response. Taken together, circadian factors shape the diurnal oscillation of innate and adaptive immunity. Among them, GCs participate in the circadian rhythm of innate and adaptive immunity by positive and negative effects.

Familial Mediterranean fever: the molecular pathways from stress exposure to attacks.

FMF is an autoinflammatory disease characterized by recurrent attacks and increased IL-1 synthesis owing to activation of the pyrin inflammasome. Although knowledge of the mechanisms leading to the activation of pyrin inflammasome is increasing, it is still unknown why the disease is characterized by attack. The emergence of FMF attacks after emotional stress and the induction of attacks with metaraminol in previous decades suggested that stress-induced sympathoadrenal system activation might play a role in inflammasome activation and triggering attacks. In this review, we will review the possible molecular mechanism of stress mediators on the inflammation pathway and inflammasome activation. Studies on stress mediators and their impact on inflammation pathways will provide a better understanding of stress-related exacerbation mechanisms in both autoinflammatory and autoimmune diseases. This review provides a new perspective on this subject and will contribute to new studies.

Associations between brain activity and endogenous and exogenous cortisol - A systematic review.

To arrive at a coherent understanding of the relation between glucocorticoids and the human brain, we systematically reviewed the literature for studies examining the associations between endogenous or exogenous cortisol and human brain function. Higher levels of endogenous cortisol during psychological stress were related to increased activity in the middle temporal gyrus and perigenual anterior cingulate cortex (ACC), decreased activity in the ventromedial prefrontal cortex, and altered function (i.e., mixed findings, increased or decreased) in the amygdala, hippocampus and inferior frontal gyrus. Moreover, endogenous cortisol response to psychological stress was related to increased activity in the inferior temporal gyrus and altered function in the amygdala during emotional tasks that followed psychological stress. Exogenous cortisol administration was related to increased activity in the postcentral gyrus, superior frontal gyrus and ACC, and altered function in the amygdala and hippocampus during conditioning, emotional and reward-processing tasks after cortisol administration. These findings were in line with those from animal studies on amygdala activity during and after stress.