Stress-Induced Sensitization of the Hypothalamic-Pituitary Adrenal Axis Is Associated with Alterations of Hypothalamic and Pituitary Gene Expression

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Abstract

We have previously reported that inescapable tail shock (IS) produces persistent changes in hypothalamic-pituitary-adrenal (HPA) axis function. These changes are manifest as an elevation in basal corticosterone (CORT) levels, a sensitization of adrenocorticotropin hormone (ACTH) and CORT responses to subsequent challenge, and a failure of dexamethasone to suppress both the ACTH and CORT responses to a subsequent challenge. The experiments presented here examine IS-induced alterations in the responsiveness of the HPA axis, particularly at the level of the anterior pituitary. The data presented show that adrenalectomy does not abolish the IS-induced sensitization of the HPA axis, suggesting that the sensitization is not solely caused by a defect in glucocorticoid negative feedback. Analysis of gene expression in the anterior pituitary revealed that IS exposure persistently elevated basal levels of proopiomelanocortin (POMC; the precursor to ACTH) mRNA and sensitized the POMC hnRNA and c-fos mRNA response to a subsequent challenge. Analysis of gene expression in the parvocellular division of the paraventricular nucleus of the hypothalamus (pPVN) after IS exposure revealed that basal levels of corticotropin-releasing hormone (CRH) mature mRNA are elevated and the c-fos mRNA response to a subsequent challenge is enhanced. Finally, a blunted in vitro ACTH response to CRH challenge is observed after IS exposure. These data suggest that the ultimate source of the IS-induced sensitization is not the anterior pituitary and implicate an increased drive on the anterior pituitary from the pPVN.

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Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress.

S Bhatnagar, M Dallman (1998)

Animals exposed to chronic stress exhibit normal or enhanced hypothalamic-pituitary adrenal responses to novel, acute stimuli despite the inhibitory endogenous corticosteroid response to the chronic stressor. Prior stress is thought to induce a central facilitatory trace that, upon exposure to a novel stimulus, balances or overcomes the inhibitory effects of corticosterone. The neuroanatomical basis for this facilitation of hypothalamic pituitary adrenal responses is unknown. In this study, we first show increased adrenocorticotropin and corticosterone responses to the novel stressor of restraint in rats exposed to intermittent cold for seven days. We then compared numbers of Fos-immunoreactive cells in 26 sites in control and chronically stressed rats at various times after onset of a 30 min restraint. At 60 min, density of Fos-stained cells was significantly higher in chronically stressed than in control rats in the parabrachial/Kölliker-Fuse area, posterior paraventricular thalamus, central, basolateral and basomedial nuclei of the amygdala and parvocellular paraventricular hypothalamus. The posterior paraventricular nucleus of the thalamus receives projections from the parabrachial nucleus and projects heavily to the differentially stained subnuclei of the amygdala, which in turn project to the parvocellular paraventricular nucleus of the hypothalamus. We propose that increased activity in the parabrachial-posterior paraventricular thalamus-amygdala-parvocellular paraventricular hypothalamus underlies facilitation of the hypothalamic pituitary-adrenal axis to novel stress in chronically stressed rats. We confirmed part of this proposal by showing that lesions of the posterior paraventricular nucleus of the thalamus increase adrenocorticotropin responses to restraint only in previously chronically stressed animals. This potential circuit provides a basis for further examination of the functional roles of these regions in stress-induced facilitation of hypothalamic pituitary-adrenal activity.

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Regulatory Changes in Neuroendocrine Stress-Integrative Circuitry Produced by a Variable Stress Paradigm

James P Herman, David Michael Adams, Chantal Prewitt (1995)

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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Anatomical specificity of noradrenergic inputs to the paraventricular and supraoptic nuclei of the rat hypothalamus.

Francesca Cunningham, P Sawchenko (1988)

The distribution of neural inputs to the paraventricular (PVH) and supraoptic (SO) nuclei from the regions of the A1, the A2, and the A6 (locus coeruleus) noradrenergic cell groups was investigated by using a plant lectin, Phaseolus vulgaris leucoagglutinin (PHA-L), as an anterogradely transported tracer. An immunofluorescence double-labeling procedure was used to determine the extent to which individual anterogradely labeled fibers and terminals in the PVH and the SO also displayed immunoreactive dopamine-beta-hydroxylase (DBH), a marker for catecholaminergic neurons. The results may be summarized as follows: (1) Projections from the A1 region were found primarily, and in some experiments almost exclusively, in those parts of the magnocellular division of the PVH and the SO known to contain vasopressinergic neurons. (2) Projections from the A2 region were distributed primarily throughout the parvicellular division of the PVH and were most dense in the dorsal medial part, a region known to contain a prominent population of corticotropin-releasing factor (CRF)-immunoreactive neurons. In addition, a less-dense projection to the magnocellular division of the PVH and to the SO was consistently found. (3) Fibers originating from the locus coeruleus were distributed almost exclusively to the parvicellular division of the PVH, with the most prominent input localized to the periventricular zone, a part of the PVH known to contain dopamine-, somatostatin-, and thyrotropin-releasing-hormone-containing neurons. We found no evidence for a projection from A6 to the SO. (4) The majority of fibers originating from the A1, the A2 or the A6 regions contained DBH immunoreactivity, although an appreciable number did not. These results suggest that each of the three brainstem noradrenergic cell groups that contribute to the innervation of the PVH and/or the SO is in a position to modulate the activity of anatomically and chemically distinct groups of neurosecretory neurons.

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Journal

Journal ID (publisher-id): NEN

Journal ID (nlm-ta): Neuroendocrinology

Journal ID (doi): 10.1159/issn.0028-3835

Title: Neuroendocrinology

Publisher: S. Karger AG

ISSN (Print): 0028-3835

ISSN (Electronic): 1423-0194

Publication date Subscription-year: 2004

Publication date (Print): January 2005

Publication date (Electronic): 25 January 2005

Volume: 80

Issue: 4

Pages: 252-263

Affiliations

Center for Neuroscience and Department of Psychology, University of Colorado at Boulder, Boulder, Colo., USA

Article

Publisher ID: 82876 Other ID: Neuroendocrinology 2004;80:252–263

DOI: 10.1159/000082876

PubMed ID: 15627803

SO-VID: 494c06a2-9288-4cf1-b556-4a8cd1f55e24

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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.

History

Date received : 04 May 2004

Date accepted : 21 October 2004

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Figures: 5, References: 56, Pages: 12

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Stress-Induced Sensitization of the Hypothalamic-Pituitary Adrenal Axis Is Associated with Alterations of Hypothalamic and Pituitary Gene Expression

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Most cited references 44

Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress.

Regulatory Changes in Neuroendocrine Stress-Integrative Circuitry Produced by a Variable Stress Paradigm

Anatomical specificity of noradrenergic inputs to the paraventricular and supraoptic nuclei of the rat hypothalamus.

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