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      Regulation of Proopiomelanocortin Gene Transcription during Single and Repeated Immobilization Stress

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          Abstract

          We have previously reported that repeated immobilization produces persistent activation of the hypothalamic-pituitary-adrenocortical axis in rats. In an attempt to assess whether any adaptational responses occur at the pituitary level, we examined the detailed time courses of proopiomelanocortin (POMC) gene transcription in the anterior pituitary (AP) in comparison with those of corticotropin-releasing hormone (CRH) gene transcription in the hypothalamic paraventricular nucleus (PVN) during single and repeated immobilization using both intronic and exonic probes. During single immobilization, there was a robust and rapid increase in both CRH heteronuclear RNA (hnRNA) in the PVN and POMC hnRNA in the AP, together with a slower increase in CRH mRNA, but no significant increase in POMC mRNA. Single immobilization also caused significant increases in the plasma concentrations of both ACTH and corticosterone. Daily immobilization for 6 days increased the basal levels of CRH hnRNA and CRH mRNA in the PVN and POMC mRNA in the AP. Both CRH hnRNA and POMC hnRNA responded rapidly to a final episode of acute immobilization on day 7, whereas the peak values of CRH hnRNA and POMC hnRNA after 15 min of the final stress were smaller than those during single immobilization. In contrast to single stress, CRH mRNA did not change significantly, whereas POMC mRNA robustly increased after the final immobilization on day 7. Plasma ACTH increased to a similar degree to single stress, but its initial increase at 5 min was significantly higher than that during single immobilization. The increase in the plasma corticosterone concentration was higher during final immobilization than during single stress. These results suggest that, in response to the hypothalamic drive during repeated immobilization stress, pituitary corticotrophs are capable of upregulating the basal and stress-induced POMC mRNA levels via increased efficiency of the posttranscriptional processing of the hnRNA and/or increased mRNA stability.

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          Most cited references 40

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          Regulation of pituitary ACTH secretion during chronic stress.

          Maintenance of adequate levels of response of the hypothalamic-pituitary-adrenal axis during chronic stress is important for survival. Three basic patterns of response can be identified depending on the type of stress: (a) desensitization of ACTH responses to the sustained stimulus, but hyperresponsiveness to a novel stress despite elevated plasma glucocorticoid levels, as occurs in physical-psychological paradigms; (b) no desensitization of ACTH response to the repeated stimulus and hyperresponsiveness to a novel stress, as occurs during repeated painful stress and insulin hypoglycemia; and (c) small and transient increases in ACTH, but sustained elevations of plasma corticosterone and diminished ACTH responses. The level of response of the pituitary corticotroph is determined by differential regulation of the hypothalamic regulators, corticotropin-releasing hormone (CRH) and vasopressin (VP), and the sensitivity of the negative glucocorticoid feedback. While osmotic stimulation increases VP expression in magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei of the hypothalamus, chronic stress paradigms with high pituitary responsiveness are associated with activation of CRH and CRH/VP parvicellular neurons of the PVN, predominantly of the VP-containing population. While moderate increase of CRH output is important for stimulation of POMC transcription, the increase of the VP:CRH secretion ratio appears to be important in maintaining the secretory capacity of the pituitary corticotroph during chronic stimulation. Decreased sensitivity of the glucocorticoid feedback, probably due to interaction of glucocorticoid receptors with transcription factors induced by CRH and VP, is critical for the maintenance of ACTH responses in the presence of elevated plasma glucocorticoid levels during chronic stress. Although both CRH and VP receptors are activated and undergo regulatory variations during chronic stress, only the changes in VP receptor levels are parallel to the changes in pituitary ACTH responsiveness. The inhibitory effect of chronic osmotic stimulation on ACTH secretion in spite of high circulating levels of VP is probably the result of diminished activity of parvicellular PVN neurons and downregulation of pituitary VP receptors. Although the exact interaction between regulatory factors and the molecular mechanisms controlling the sensitivity of the corticotroph during adaptation to chronic stress remain to be determined, it is clear that regulation of the proportional secretion of CRH and VP in the PVN, modulation of pituitary VP receptors, and the sensitivity to feedback inhibition play a critical role.
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            Regulatory Changes in Neuroendocrine Stress-Integrative Circuitry Produced by a Variable Stress Paradigm

            Stress represents a complex stimulus to neuroendocrine systems regulating homeostasis. By and large, stress effects are mediated by stress-integrative corticotropin-releasing hormone (CRH) neurons present in the medial parvocellular division of the hypothalamic paraventricular nucleus (PVN). These neurons summate a large variety of neuronal and hormonal signals to eventually yield a physiologically meaningful level of circulating glucocorticoids. In the present experiments, we examined the effects of a chronic variable-stressor paradigm on indices of adrenocorticotropic hormone (ACTH) secretagogue biosynthesis in the PVN and adrenocorticosteroid receptor mRNA expression in the hippocampal formation, PVN and cortex. The variable-stressor paradigm produces a syndrome consistent with chronic stress, including baseline hypersecretion of corticosterone, ACTH and prolactin, and adrenal hypertrophy. CRH mRNA levels in the PVN are increased some 61 %, consistent with the observed hypothalamo-pituitary-adrenal (HPA) up-regulation. There was a small but significant increase in arginine vasopressin (AVP) mRNA expression in individual parvocellular PVN neurons (16%), and no demonstrable increase in the number of AVP mRNA-containing neurons. No change in AVP expression was seen in the magnocellular PVN, supraoptic or suprachiasmatic nuclei. In all, these data highlight the importance of CRH in maintaining HPA up-regulation in the face of prolonged challenge. To investigate effects of chronic stress on the regulation of glucocorticoid receptivity, mineralocorticoid receptor (MR) and glucocorticoid receptor mRNA expression was assessed in the hippocampus, frontoparietal cortex and PVN. Chronic stress significantly down-regulated MR mRNA expression in subfields CA1, CA3 and the dentate gyrus (DG), and GR mRNA expression in subfields CA1, the DG and frontoparietal cortex. The reduction in receptor biosynthesis suggests the capacity for stress to modulate the impact of glucocorticoid on hippocampal cell physiology at the genomic level, potentially influencing processes ranging from cognition to feedback regulation of the HPA axis. At the level of the parvocellular PVN, GR mRNA expression was decreased to 60% of control values. GR mRNA expression was negatively correlated with PVN CRH mRNA expression, suggesting a relationship between elevated CRH gene expression and down-regulation of GR at the level of the PVN.
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              Regulation of the hypothalamic corticotropin-releasing hormone neurosecretory system.

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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2006
                December 2006
                11 December 2006
                : 84
                : 1
                : 21-30
                Affiliations
                Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Nankoku, Japan
                Article
                96824 Neuroendocrinology 2006;84:21–30
                10.1159/000096824
                17085933
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, References: 45, Pages: 10
                Categories
                Original Paper

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