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      The Importance of Biological Oscillators for Hypothalamic-Pituitary-Adrenal Activity and Tissue Glucocorticoid Response: Coordinating Stress and Neurobehavioural Adaptation

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          Abstract

          The hypothalamic-pituitary-adrenal (HPA) axis is critical for life. It has a circadian rhythm that anticipates the metabolic, immunoregulatory and cognitive needs of the active portion of the day, and retains an ability to react rapidly to perceived stressful stimuli. The circadian variation in glucocorticoids is very ‘noisy’ because it is made up from an underlying approximately hourly ultradian rhythm of glucocorticoid pulses, which increase in amplitude at the peak of circadian secretion. We have shown that these pulses emerge as a consequence of the feedforward–feedback relationship between the actions of corticotrophin hormone (ACTH) on the adrenal cortex and of endogenous glucocorticoids on pituitary corticotrophs. The adrenal gland itself has adapted to respond preferentially to a digital signal of ACTH and has its own feedforward–feedback system that effectively amplifies the pulsatile characteristics of the incoming signal. Glucocorticoid receptor signalling in the body is also adapted to respond in a tissue-specific manner to oscillating signals of glucocorticoids, and gene transcriptional and behavioural responses depend on the pattern (i.e. constant or pulsatile) of glucocorticoid presentation. During major stressful activation of the HPA, there is a marked remodelling of the pituitary–adrenal interaction. The link between ACTH and glucocorticoid pulses is maintained, although there is a massive increase in the adrenal responsiveness to the ACTH signals.

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          Most cited references 108

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          Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation.

          Two receptor systems for corticosterone (CORT) can be distinguished in rat brain: mineralocorticoid-like or CORT receptors (CR) and glucocorticoid receptors (GR). The microdistribution and extent of occupation of each receptor population by CORT were studied. The CR system is restricted predominantly to the lateral septum and hippocampus. Within the hippocampus, the highest density occurs in the subiculum +/- CA1 cell field (144 fmol/mg protein) and the dentate gyrus (104 fmol/mg protein). Affinity of CR for CORT was very high (Kd, approximately 0.5 nM). The GR system has a more widespread distribution in the brain. The highest density for GR is in the lateral septum (195 fmol/mg protein), the dentate gyrus (133 fmol/mg protein), the nucleus tractus solitarii and central amygdala. Substantial amounts of GR are present in the paraventricular nucleus and locus coeruleus and low amounts in the raphe area and the subiculum + CA1 cell field. The affinity of GR for CORT (Kd, approximately 2.5-5 nM) was 6- to 10-fold lower than that of CR. Occupation of CR by endogenous ligand was 89.5% during morning trough levels of pituitary-adrenal activity (plasma CORT, 1.4 micrograms/100 ml). Similar levels of occupation (88.7% and 97.6%) were observed at the diurnal peak (plasma CORT, 27 micrograms/100 ml) and after 1 h of restraint stress (plasma CORT, 25 micrograms/100 ml), respectively. Furthermore, a dose of 1 microgram CORT/100 g BW, sc, resulted in 80% CORT receptor occupation, whereas GR were not occupied. For 50% occupation of GR, doses needed to be increased to 50-100 micrograms/100 g BW, and for 95% occupation, a dose of 1 mg CORT was required. The plasma CORT level at the time of half-maximal GR occupation was about 25 micrograms/100 ml, which is in the range of levels attained after stress or during the diurnal peak of pituitary-adrenal activity. Thus, CR are extensively filled (greater than 90%) with endogenous CORT under most circumstances, while GR become occupied concurrent with increasing plasma CORT concentrations due to stress or diurnal rhythm. We conclude that CORT action via CR may be involved in a tonic (permissive) influence on brain function with the septohippocampal complex as a primary target. In view of the almost complete occupation of CR by endogenous hormones, the regulation of the CORT signal via CR will, most likely, be by alterations in the number of such receptors. In contrast, CORT action via GR is involved in its feedback action on stress-activated brain mechanisms, and GR occur widely in the brain.(ABSTRACT TRUNCATED AT 400 WORDS)
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            The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission.

            Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.
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              Glucocorticoid resistance in inflammatory diseases.

              Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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                Author and article information

                Journal
                J Neuroendocrinol
                J. Neuroendocrinol
                jne
                Journal of Neuroendocrinology
                Blackwell Publishing Ltd (Oxford, UK )
                0953-8194
                1365-2826
                June 2015
                26 May 2015
                : 27
                : 6
                : 378-388
                Affiliations
                Henry Wellcome Laboratories of Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol Bristol, UK
                Author notes
                Correspondence to: Dr Georgina M Russell, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK (e-mail: georgina.russell@ 123456bristol.ac.uk ).
                Article
                10.1111/jne.12247
                4539599
                25494867
                Copyright©2015 British Society for Neuroendocrinology

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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