The role of the hypothalamic pituitary adrenal axis in neuroendocrine responses to stress

@article{Smith2006TheRO,
  title={The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress},
  author={Sean M Smith and Wylie W. Vale},
  journal={Dialogues in Clinical Neuroscience},
  year={2006},
  volume={8},
  pages={383 - 395}
}

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The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress Translated title: Función del eje hipotálamo-hipofisis-suprarenal en las respuestas endocrinas al estrés Translated title: Rôle de l'axe hypothalamo-hypophyso-surrénalien dans les réponses neuro-endocriniennes au stress

Author[s]: , PhD Wylie W. Vale, PhD *

Publication date [Print]: December 2006

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Animals respond to stress by activating a wide array of behavioral and physiological responses that are collectively referred to as the stress response. Corticotropin-releasing factor [CRF] plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal [HPA] axis. In response to stress, CRF initiates a cascade of events that culminate in the release of glucocorticoids from the adrenal cortex. As a result of the great number of physiological and behavioral effects exerted by glucocorticoids, several mechanisms have evolved to control HPA axis activation and integrate the stress response. Glucocorticoid feedback inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid release. In addition to glucocorticoid feedback, the HPA axis is regulated at the level of the hypothalamus by a diverse group of afferent projections from limbic, mid-brain, and brain stem nuclei. The stress response is also mediated in part by brain stem noradrenergic neurons, sympathetic andrenornedullary circuits, and parasympathetic systems. In summary, the aim of this review is to discuss the role of the HPA axis in the integration of adaptive responses to stress. We also identify and briefly describe the major neuronal and endocrine systems that contribute to the regulation of the HPA axis and the maintenance of homeostasis in the face of aversive stimuli.

Los animales responden al estrés, activando una amplia gama de respuestas comportamentales y fisiológicas que se conocen, de forma genérica, como respuesta al estrés. El factor liberador de corticotro-pina [CRF] desempeña una misión cardinal en la respuesta al estrés, al regular e! eje hipotálamo-hipófisis-suprarrenal [HHS]. En respuesta al estrés, el CRF inicia una cascada de acontecimientos gue culminan con la liberación de glucocorticoides por la corteza suprarrenal. Como consecuencia del elevado número de efectos fisiológicos y conductuales inducidos por los glucocorticoides, han surgido varios mecanismos para controlar la activación del eje HHS e integrar la respuesta al estrés. La inhibición por retroaIimentación de los glucocorticoides contribuye decisivamente a regular la magnitud y la duración de su liberación. Además de esta reiroalimentación glucocorticoidea, el eje HHS está regulado en el hipotálamo por un grupo diverso de proyecciones aferente de los núcleos límbícos, mesencefálicos y del tronco cerebral. La respuesta al estrés está mediada también, en parte, por las neuronas noradrenérgicas del tronco cerebral, los circuitos adrenomedulares simpáticos y los sistemas parasimpáticos. En resumen, el objetivo de esta revisión es exponer la importancia del eje HHS en la integración de las respuestas adaptativas al estrés. Asimismo, se señalan y describen brevemente los principales sistemas neuronales y endocrinos que contribuyen a la regulación del eje HHS y al mantenimiento de la homeostasis frente a tos estímulos adversos.

Les animaux répondent au stress en activant un large panel de réponses comportementales et physiologiques, collectivement considérés comme constituant la réponse au stress. Le facteur de libération de corticotrophine [CRF] joue un rôle central dans la réponse au stress en régulant l'axe hypothalamo-hypophyso-surrénalien [HPA]. Dans la réponse au stress, le CRF déclenche une cascade d'événements qui aboutissent à la libération de glucocorticoïdes à partir du cortex surrénalien. Etant donné le grand nombre d'effets physiologiques et comportementaux produits par les glucocorticoïdes, plusieurs mécanismes se sont développés afin de contrôler l'activation de l'axe HPA et intégrer les réponses au stress. Le rétrocontrôle inhibiteur des glucocorticoïdes joue un rôle essentiel dans l'ampleur et la durée de leur libération. En plus de ce rétro-contrôle, l'axe HPA est régulé au niveau hypothalamique par différentes projections afférentes provenant du système limbique, du mésencéphale et des noyaux du tronc cérébral. La réponse au stress est également transmise en partie par les neurones noradrénergiques du tronc cérébral, les circuits sympathiques adrénomédullaires et le système parasympathique. En résumé, cet article a pour but d'examiner le rôle de l'axe HPA dans l'intégration des réponses adaptatives au stress. Nous avons aussi identifié et brièvement décrit les principaux systèmes neuronaux et endocriniens qui participent à la régulation de l'axe HPA et au maintien de l'homéostasie face à des agressions.

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Stress and the individual. Mechanisms leading to disease.

This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses. Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE. Independent extraction and cross-referencing by us. Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful. This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed.

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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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Endocrinology of the stress response.

The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal effectors of the stress system include corticotropin-releasing hormone [CRH]; arginine vasopressin; the proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin, the glucocorticoids; and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors.

Contributors

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, Calif, USA

Journal

Journal ID [nlm-ta]: Dialogues Clin Neurosci

Journal ID [pmc]: Dialogues Clin Neurosci

Title: Dialogues in Clinical Neuroscience

Publisher: Les Laboratoires Servier [France ]

ISSN [Print]: 1294-8322

ISSN [Electronic]: 1958-5969

Publication date [Print and electronic]: December 2006

Publication date [Print]: December 2006

Volume: 8

Issue: 4

Pages: 383-395

Affiliations

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, Calif, USA

Author notes Article

PMC ID: 3181830

PubMed ID: 17290797

SO-VID: b4907a8a-f669-4ea5-9271-362ff6bda55a

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License [ //creativecommons.org/licenses/by-nc-nd/3.0/], which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Comment on this article

What is the function of the HPA axis stress response?

The HPA axis is responsible for the neuroendocrine adaptation component of the stress response. This response is characterized by hypothalamic release of corticotropin-releasing factor [CRF]. CRF is also known as CRH or corticotropin-releasing hormone.

Does the HPA axis regulate stress?

Stress has long been suggested to be an important correlate of uncontrolled drinking and relapse. An important hormonal response system to stress—the hypothalamic–pituitary–adrenal [HPA] axis—may be involved in this process, particularly stress hormones known as glucocorticoids and primarily cortisol.

What is the significance of hypothalamic pituitary axis?

Specifically, the hypothalamic-pituitary axis directly affects the functions of the thyroid gland, the adrenal gland, and the gonads, as well as influencing growth, milk production, and water balance [table 1] [1-4].

What is the HPA axis and why is it relevant to health?

The HPA axis consists of a complex set of interactions between the hypothalamus, pituitary gland and adrenal cortex, which mediates the stress response through the actions of glucocorticoids. Main anatomical components of the HPA axis and glucocorticoid feedback loop are illustrated in Figure 1.