Hypothalamic-Pituitary-Adrenal Axis Activity of Newborn Mice Rapidly Desensitizes to Repeated Maternal Absence but Becomes Highly Responsive to Novelty

In CD1 mice we investigated the hypothalamic-pituitary-adrenal (HPA) axis response to maternal separation for 8 h daily from postnatal d 3 to 5. At d 3 a slow separation-induced corticosterone response developed that peaked after 8 h, and the pups became responsive to stressors. On the second and third day, the response to 8 h separation rapidly attenuated, whereas the response to novelty did not, a pattern reflected by the hypothalamic c-fos mRNA response. If maternal separation and exposure to novelty were combined, then after the third such daily exposure, the sensitivity to the stressor was further enhanced. Meanwhile, basal corticosterone and ACTH levels were persistently suppressed 16 h after pups were reunited with their mothers. To explain the HPA axis desensitization after repeated separation, we found that circulating ghrelin levels increased and glucose levels decreased after all periods of maternal separation, ruling out a role of altered metabolism. Glucocorticoid feedback was not involved either because a glucocorticoid receptor antagonist amplified the corticosterone response after the first but became ineffective after the third separation. In contrast, a mineralocorticoid receptor antagonist decreased and increased corticosterone levels after the first and third period of separation, respectively. In conclusion, the newborn’s HPA axis readily desensitizes to repeated daily maternal separation, but continues to respond to novelty in a manner influenced by a central mineralocorticoid receptor- rather than glucocorticoid receptor-mediated mechanism.

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Corticosteroids mediate fast feedback of the rat hypothalamic-pituitary-adrenal axis via the mineralocorticoid receptor

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00721.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. E1011-E1022 ◽

Cited By ~ 45

Author(s):

Helen C. Atkinson ◽

Susan A. Wood ◽

Emma S. Castrique ◽

Yvonne M. Kershaw ◽

Crispin C. R. Wiles ◽

...

Keyword(s):

Receptor Antagonist ◽

Hpa Axis ◽

Mineralocorticoid Receptor ◽

Feedback Inhibition ◽

Inhibitory Effect ◽

Plasma Corticosterone ◽

Time Of Day ◽

Sampling System ◽

Mineralocorticoid Receptor Antagonist ◽

Hypothalamic Pituitary Adrenal

The aim of this study was to investigate fast corticosteroid feedback of the hypothalamic-pituitary-adrenal (HPA) axis under basal conditions, in particular the role of the mineralocorticoid receptor. Blood samples were collected every 5 min from conscious rats at the diurnal peak, using an automated blood sampling system, and assayed for corticosterone. Feedback inhibition by rapidly increasing concentrations of ligand was achieved with an intravenous bolus of exogenous corticosteroid. This resulted in a significant reduction in plasma corticosterone concentrations within 23 min of the aldosterone bolus and 28 min of methylprednisolone. Evaluation of the pulsatile secretion of corticosterone revealed that the secretory event in progress at the time of administration of exogenous steroid was unaffected, whereas the next secretory event was inhibited by both aldosterone and methylprednisolone. The inhibitory effect of aldosterone was limited in duration (1 secretory event only), whereas that of methylprednisolone persisted for 4–5 h. Intravenous administration of canrenoate (a mineralocorticoid receptor antagonist) also had rapid effects on the HPA axis, with an elevation of ACTH within 10 min and corticosterone within 20 min. The inhibitory effect of aldosterone was unaffected by pretreatment with the glucocorticoid receptor antagonist RU-38486 but blocked by the canrenoate. These data imply an important role for the mineralocorticoid receptor in fast feedback of basal HPA activity and suggest that mineralocorticoids can dynamically regulate basal corticosterone concentrations during the diurnal peak, a time of day when there is already a high level of occupancy of the cytoplasmic mineralocorticoid receptor.

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Assessment of the hypothalamic–pituitary–adrenal axis activity: glucocorticoid receptor and mineralocorticoid receptor function in depression with early life stress – a systematic review

Acta Neuropsychiatrica ◽

10.1111/j.1601-5215.2011.00610.x ◽

2012 ◽

Vol 24 (1) ◽

pp. 4-15 ◽

Cited By ~ 26

Author(s):

Cristiane Von Werne Baes ◽

Sandra M. de Carvalho Tofoli ◽

Camila Maria S. Martins ◽

Mario F. Juruena

Keyword(s):

Systematic Review ◽

Glucocorticoid Receptor ◽

Hpa Axis ◽

Life Stress ◽

Early Life ◽

Mineralocorticoid Receptor ◽

Early Life Stress ◽

Hypothalamic Pituitary Adrenal ◽

Depressed Patients ◽

Suppression Test

Objective:The mechanisms involved in the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, especially in the functioning of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in depressed patients, are not well elucidated. The objective of this study was to conduct a systematic review of articles that assess the HPA axis activity from GR and MR in depressed patients and healthy controls with or without early life stress.Methods:We conducted a systematic review of articles in PubMed, SCOPUS and SciELO published between 2000 and 2011, using the following search terms:child abuse,depression,HPA axis,dexamethasone,prednisolone,fludrocortisoneandspironolactone. Thirty-four papers were selected for this review.Results:Most studies identified in this review used the dexamethasone/corticotropin-releasing hormone test and dexamethasone suppression test. In these studies, hypercortisolaemia was associated with depression. We identified three studies with the Prednisolone suppression test, only one study with the use of fludrocortisone and one with spironolactone. This review found nine studies that evaluated the HPA axis in individuals with early life stress.Conclusions:The majority of the studies assessed in this review show that early life stress leads to permanent changes in the HPA axis and may lead to development of depression in adults. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolaemia and reduced inhibitory feedback. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between GR and MR. Evidences have consistently showed that GR function is impaired in major depression, but few studies have assessed the activity of MR in depression and early life stress.

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