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Review
. 2006;8(4):383-95.
doi: 10.31887/DCNS.2006.8.4/ssmith.

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

Affiliations
Review

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

Sean M Smith et al. Dialogues Clin Neurosci. 2006.

Abstract

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, midbrain, and brain stem nuclei. The stress response is also mediated in part by brain stem noradrenergic neurons, sympathetic andrenomedullary 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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Figures

Figure 1.
Figure 1.. Schematic representation of the hypothalamic-pituitary-adrenal (HPA) axis. Hypophysiotropic neurons localized in the paraventricular nucleus (PVN) of the hypothalamus synthesize corticotropin-releasing factor (CRF) and vasopressin (AVP). In response to stress, CRF is released into hypophysial portal vessels that access the anterior pituitary gland. Binding of CRF to the CRF type 1 receptor (CRFR1) on pituitary corticotropes activates cyclic adenosine monophosphate (cAMP) pathway events that induce the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. In the presence of CRF, AVP elicits synergistic effects on ACTH release that are mediated through the vasopressin V1b receptor. Circulating ACTH binds to the melanocortin type 2 receptor (MC2-R) in the adrenal cortex where it stimulates glucocorticoid synthesis and secretion into the systemic circulation. Glucocorticoids regulate physiological events and inhibit further HPA axis activation (red lines) through intracellular receptors that are widely distributed throughout the brain and peripheral tissues. IP3, inositol triphosphate; DAG, diacylglycerol
Figure 2.
Figure 2.. Depiction of the major brain regions and neurotransmitter groups that supply afferent innervation to the medial parvocellular zone of the paraventricular nucleus (PVN). Cell groups of the nucleus of the solitary tract (NTS) and ventral medulla (C1) relay visceral information to the PVN though noradrenergic (NE), adrenergic (Epi), and glucagon-like peptide 1(GLP-1) containing neurons. Hypothalamic nuclei (HYPO) encode information from endocrine systems and send mainly γ-aminobutyric acid (GABA)-ergic (GABA) projections to the PVN. Cell groups of the lamina terminalis relay information concerning the osmotic composition of blood to the PVN through glutamatergic (Glu) and angiotensinergic (Ang) neurons. Limbic structures including the hippocampus, prefrontal cortex, and the amygdala contribute to the regulation of PVN neurons through intermediary neurons of the bed nucleus of the stria terminalis (BNST). PIT, pituitary. Adapted from reference 20: Sawchenko PE, Imaki T, Potter E, Kovacs K, Imaki J, Vale W. The functional neuroanatomy of corticotropin-releasing factor. Gba Found Symp. 1993;172:5-21; discussion 21-29. Copyright © John Wiley and Sons 1993.

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