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Feedback control systems are fundamental for physiological mechanisms. Disruption of feedback control almost inevitably leads to a pathological state. The consequence of a failure in negative feedback is exemplified by the adrenogenital syndrome. Failure in positive feedback is exemplified by disruption of the estrogen positive feedback on the hypo...
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... EE increases GR expression in the hippocampus (Olsson et al., 1994;Zhang et al., 2013b) and can increase CORT sensitivity by suppressing the release of corticotropin-releasing factor (CRF) through the negative feedback loop extending from the dorsal hippocampus to the hypothalamus (Antoni, 1986;Fink, 1997). Hence, increasing extra-synaptic GRs in the context of stress may enhance trafficking of GRs to the synapse, resulting in faster decreases in CORT and an increase in cytosolic GR (Reichardt et al., 2000). ...
Environmental enrichment (EE) housing paradigms have long been shown beneficial for brain function involving neural growth and activity, learning and memory capacity, and for developing stress resiliency. The expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA2, which is important for synaptic plasticity and memory, is increased with corticosterone (CORT), undermining synaptic plasticity and memory. Thus, we determined the effect of EE and stress on modulating GluA2 expression in Sprague-Dawley male rats. Several markers were evaluated which include: plasma CORT, the glucocorticoid receptor (GR), GluA2, and the atypical protein kinase M zeta (PKMζ). For 1 week standard-(ST) or EE-housed animals were treated with one of the following four conditions: (1) no stress; (2) acute stress (forced swim test, FST; on day 7); (3) chronic restraint stress (6 h/day for 7 days); and (4) chronic + acute stress (restraint stress 6 h/day for 7 days + FST on day 7). Hippocampi were collected on day 7. Our results show that EE animals had reduced time immobile on the FST across all conditions. After chronic + acute stress EE animals showed increased GR levels with no change in synaptic GluA2/PKMζ. ST-housed animals showed the reverse pattern with decreased GR levels and a significant increase in synaptic GluA2/PKMζ. These results suggest that EE produces an adaptive response to chronic stress allowing for increased GR levels, which lowers neuronal excitability reducing GluA2/PKMζ trafficking. We discuss this EE adaptive response to stress as a potential underlying mechanism that is protective for retaining synaptic plasticity and memory function.
... The twofold increase in the ACTH signal between the nadir and the peak of the circadian rhythm in the rat results in a nine-fold increase in corticosterone due to an increase in the responsiveness of the adrenal cortex. 3 In the unstressed state the HPA system operates in an approximately linear domain, with all the loop variables ( Fig. 3.3) showing circadian periodicity. 7 ACTH and cortisol are also released in pulsatile fashion, with circadian and ultradian rhythms governing secretion of these hormones. ...
This chapter focuses on the principles of negative feedback control using the hypothalamic pituitary adrenal (HPA) system as an example. Feedback control systems are fundamental for the normal physiological functioning of the body. Glucocorticoid feedback inhibition of ACTH release protects the organism against the deleterious effects of hypercortisolemia. The HPA system, together with the sympathetic-medullary system, plays a pivotal role in the neuroendocrine response to stress. Thyroid negative feedback control is more complex than originally thought. It seems that most of thyroid negative feedback is actioned by an effect on TRH at the level of the paraventricular nucleus. There are several types of inherited enzymatic defects in cortisol synthesis known to result in congenital adrenal hyperplasia (CAH), also known as the adrenogenital syndrome. Disruption of the HPA negative feedback system has serious deleterious effects, a point illustrated by the congenital adrenogenital syndrome and hypercortisolemia associated with serious mental illnesses.
... The twofold increase in the ACTH signal between the nadir and the peak of the circadian rhythm in the rat results in a nine-fold increase in corticosterone due to an increase in the responsiveness of the adrenal cortex. 3 In the unstressed state the HPA system operates in an approximately linear domain, with all the loop variables ( Fig. 3.3) showing circadian periodicity. 7 ACTH and cortisol are also released in pulsatile fashion, with circadian and ultradian rhythms governing secretion of these hormones. ...
The hypothalamic-pituitary-adrenocortical (HPA) system, together with the sympathetic-medullary system, plays a pivotal role in the neuroendocrine response to stress. Homeostasis within the hypothalamic HPA is maintained by a precise negative feedback system by which the adrenal glucocorticoids (the afferent feedback signal), cortisol or corticosterone, moderate adrenocorticotropin (ACTH) synthesis and release (the efferent output signal). Allostasis - that is, change in HPA activity to cope with increased stress load - is brought about by change in feedback set point. The major sites of negative feedback are the paraventricular nuclei of the brain, where glucocorticoids inhibit corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) synthesis and release, and the pituitary gland, where they block the ACTH response to CRH and inhibit ACTH synthesis. The limbic system of the brain, especially the hippocampus and amygdala, plays an important role in glucocorticoid negative feedback control of HPA output. Disruption of the HPA negative feedback system has serious deleterious effects.
... During inflammation, glucocorticoids are induced by proinflammatory cytokines and they can act on the adrenal pituitary axis to generate adrenocorticotrophic hormone and, subsequently, induce the production of cortisol. This provides a negative-feedback loop on inflammation , because corticosteroids inhibit gene expression of pro-inflammatory mediators and ensure restoration of homeostasis (Fink 1997). Here, we demonstrated that Ahsg gene transcription is up-regulated in primary mouse hepatocytes and mouse hepatoma cells after treatment with the glucocorticoid analogue, dexamethasone. ...
Alpha2HS-glycoprotein/fetuin-A (Ahsg) is a serum protein preventing soft tissue calcification. In trauma and inflammation, Ahsg is down-regulated and therefore considered a negative acute phase protein. Enhancement of Ahsg expression as a protective serum protein is desirable in several diseases including tissue remodelling after trauma and infection, kidney and heart failure, and cancer. Using reporter gene assays in hepatoma cells combined with electrophoretic mobility shift assays we determined that dexamethasone up-regulates hepatic Ahsg. A steroid response unit at position -146/-119 within the mouse Ahsg promoter mediates the glucocorticoid-induced increase of Ahsg mRNA. It binds the hepatocyte nuclear factor 3beta and CCAAT enhancer binding protein beta (C/EBP-beta). The up-regulation is mediated indirectly via glucocorticoid hormone-induced transcriptional up-regulation in C/EBP-beta protein. A high degree of sequence identity in mouse, rat and human Ahsg promoters suggests that the promoter is similarly up-regulated by dexamethasone in all three species. Therefore, our findings suggest that glucocorticoids may be used to enhance the level of Ahsg protein circulating in serum.
... There is surprisingly little previously published data that addresses whether a direct effect at the level of the pituitary is necessary to suppress hormone secretion. In support of this finding, the acute (< 2 h) effects of systemic glucocorticoid treatment on hypophyseal portal vein CRH levels have not been explored (37,38). However, there is one study that demonstrated rapid effects of glucocorticoids (< 1 h) on stress-induced changes in CRH bioactivity in rat hypothalamic tissue (3). ...
This study examined the effects of the glucocorticoid receptor (GR) agonist RU28362 on stress-induced gene expression in the pituitary of rats to investigate mechanisms of glucocorticoid negative feedback in vivo. In an initial experiment, acute restraint stress produced rapid (within 15 min) induction of c-fos mRNA, zif268 mRNA and pro-opiomelanocortin (POMC) hnRNA within the anterior and intermediate/posterior pituitary as determined by quantitative real-time polymerase chain reaction. Treatment with RU28362 (150 microg/kg, i.p.) 60 min before restraint inhibited adrenocorticotrophic hormone (ACTH) and corticosterone secretion and selectively suppressed the stress-induced increase in POMC hnRNA in the anterior pituitary gland. The failure of RU28362 to surpress the stress-induced rise in c-fos and expression of zif268 mRNA suggests that the central release of ACTH secretagogues was not affected at this time point by treatment with the GR agonist. Rather, the inhibition of ACTH release appeared to be due to a direct effect of RU28362 within the pituitary. A follow-up time-course study varied the interval (10, 60 or 180 min) between RU28362 pretreatment and the onset of restraint. The stress-induced increase in POMC hnRNA was completely blunted by RU28362 treatment within 10 min of treatment, although the stress induced hormone secretion, c-fos mRNA and zif268 mRNA were unaffected. The rapid inhibition of the stress-induced rise in POMC hnRNA in the anterior pituitary appears to reflect direct, GR-mediated suppression of POMC gene expression. RU28362 pretreatment 180 min before restraint onset was sufficient to suppress the stress-induced expression in the anterior pituitary gland of all three genes examined. Thus, the delayed negative feedback effects on hypothalamic-pituitary-adrenal axis activity that emerged after 180 min after glucocorticoid treatment were not evident at 60 min. Taken together, the data suggest that the inhibition of the stress-induced release of ACTH apparent within the first hour of glucocorticoid exposure is effected at the level of the pituitary gland. The delayed glucocorticoid effects evident 180 min after RU28362 treatment may include glucocorticoid actions in the brain and additional actions within the pituitary.
Endocrine-disrupting chemicals (EDCs), such as perfluorooctanoate, perfluorooctane sulfonate, 2,2-dichlorodiphenyldichloroethylene, hexachlorobenzene, and polychlorinated biphenyl 153 are persistent pollutants that are found in human follicular fluid (FF). These compounds may affect endocrine function, disrupt steroid secretion by granulosa cells, and play a role in granulosa cell tumor (GCT) development. GCTs demonstrate endocrine activity, expressing aromatase and secreting 17β-estradiol (E2). We aimed to determine the effects of a mixture of EDCs, similar to that found in human FF, on human granulosa tumor cell lines representing the juvenile (JGCT) and adult (AGCT) forms (COV434 and KGN cells, respectively). We found that all the individual compounds and mixtures tested altered granulosa tumor cell function by disrupting E2 secretion. In KGN cells, which possess significantly higher basal aromatase gene expression, and therefore secrete more E2 than JGCT cells, EDC mixtures activated estrogen receptors (ERs) and G protein-coupled receptor-30 signaling, thereby stimulating E2 secretion, without affecting aromatase expression. By contrast, in COV434 cells, which demonstrate higher CYP1A1 expression, a key mediator of estrogen metabolism, than KGN cells, EDC mixtures reduced E2 secretion in parallel with increases in the 2-hydroxyestrogen 1/E2 ratio and CYP1A1 expression, implying an upregulation of E2 metabolism. These results indicate that the EDC mixture present in FF disrupts E2 secretion in JGCT and AGCT cells according to the estrogen metabolic potential of the cell type, involving both classical and non-classical ER pathways.
The human pituitary gland weighs no more than 1 g, but nonetheless controls all the major endocrine systems and is indispensable for life. Located at the base of the brain, and closely surrounded by protective dense bone and fibrous membranes, the gland is comprised of the neurohypophysis or neural lobe and the adenohypophysis. Embryologically derived from a neural downgrowth, the neural lobe is a bag of axons which project from nerve cells in the hypothalamus and terminate on capillaries of the inferior hypophysial artery. This is the site at which the nonapeptides, vasopressin, and oxytocin are released into the systemic circulation. Synthesized in the supraoptic and paraventricular nuclei, vasopressin, also termed the antidiuretic hormone, controls the volume of body water whereas oxytocin is concerned mainly with stimulating milk ejection during lactation, and contraction of the uterus (womb) during parturition.
Neuroendocrinology is the study of how the nervous system controls hormonal secretion and how, in turn, hormones affect the nervous system. The brain-pituitary neuroendocrine system processes information from and enables endocrine responses to external factors, such as stress, day length, and changes in ambient temperature. Attention here is focused on the hypothalamic-pituitary-adrenal and related neuroendocrine systems involved in the neuroendocrine response to stress. Brain control of the synthesis and secretion of pituitary adrenocorticotropic hormone (ACTH) is mediated by neurohormones released from the hypothalamus at the base of the brain and transported by the hypophysial portal vessels to the anterior pituitary gland. The function of the hypothalamic-pituitary-ACTH module is regulated by negative feedback by glucocorticoids secreted by the adrenal glands in response to ACTH stimulation. Neuroendocrine systems and the ACTH precursor proopiomelanocortin, in particular, provided some of the first models for our understanding of gene transcription, translation and posttranslational processing in vertebrates. These and other principles related to neurotransmitter/neurohormone synthesis, release, mode of action, and control are highlighted.
Glucocorticoids and corticotropin releasing hormone (CRH) underlie the physiology of change and adaptation. Both the steroid and peptide are quite ancient. The genes that underlie the production of these information molecules stretch back millions of years. The regulatory mechanisms of glucocorticoids have both restraining and enhancing capabilities on CRH gene expression. While restraint of CRH by glucocorticoids is a fundamental physiological feature of limiting CRH expression from over-use and exhaustion, CRH is also enhanced by glucocorticoids at both the level of extra-hypothalamic CRH sites and at the level of the placenta and fetal programming in the brain. This latter function of glucocorticoids increasing CRH gene expression underlies the physiology of change that underlies diverse adaptive functions.
