scholarly journals Steroid Receptor Coactivator-1-Deficient Mice Exhibit Altered Hypothalamic-Pituitary-Adrenal Axis Function

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1322-1332 ◽  
Author(s):  
Jonathon N. Winnay ◽  
Jianming Xu ◽  
Bert W. O’Malley ◽  
Gary D. Hammer
Keyword(s):  
Chronic Stress ◽  
Hpa Axis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Feedback Inhibition ◽  
Steroid Receptor ◽  
Serum Glucose ◽  
Compensatory Mechanism ◽  
Hypothalamic Pituitary Adrenal ◽  
Steroid Receptor Coactivator ◽  
Acute And Chronic Stress

Steroidogenic factor-1 (SF-1), has emerged as a critical nuclear receptor regulating development and differentiation at several levels of the hypothalamic-pituitary-steroidogenic axis. Although many coregulatory factors have been shown to physically and functionally interact with SF-1, the relative importance of these interactions in SF-1 target tissues has not been thoroughly established. In this study we assessed roles of steroid receptor coactivator-1 (SRC-1) in hypothalamic-pituitary-adrenal (HPA) axis function using SRC-1-deficient (SRC-1−/−) mice in the absence or presence of SF-1 haploinsufficiency. Surprisingly, SRC-1 deficiency did not alter baseline HPA axis function or the acute rise in corticosterone after ACTH administration and failed to exacerbate adrenocortical dysfunction in SF-1+/− mice. However, after exposure to paradigms of acute and chronic stress, SRC-1−/− mice exhibited an elevation in serum corticosterone despite normal (nonsuppressed) ACTH, suggesting an increase in adrenal sensitivity as well as a concomitant defect in glucocorticoid-mediated feedback inhibition of the HPA axis. An examination of potential compensatory mechanism(s) revealed an increase in adrenal weight, selective elevation of melanocortin 2 receptor mRNA, and a coincident increase in SRC-2 and SRC-3 expression in SRC-1−/− adrenals. A reduction in blood glucose was observed in SRC-1−/− mice after chronic stress, consistent with a generalized state of glucocorticoid resistance. Dexamethasone suppression tests confirmed a weakened ability of glucocorticoids to 1) elevate serum glucose levels and induce hepatic phosphoenolpyruvate carboxykinase transcription and 2) suppress pituitary proopiomelanocortin transcript levels in SRC-1−/− animals. Collectively, these data are consistent with an indispensable role for SRC-1 in mediating actions of glucocorticoids in pituitary and liver.

The HPA and immune axes in stress: the involvement of the serotonergic system

2005 ◽  
Vol 20 (S3) ◽  
pp. S302-S306 ◽  
Author(s):  
B.E. Leonard
Keyword(s):  
Stress Response ◽  
Chronic Stress ◽  
Hpa Axis ◽  
Feedback Inhibition ◽  
Critical Role ◽  
Serotonergic System ◽  
Anxiety And Depression ◽  
Acute And Chronic Stress ◽  
The Impact ◽  
The Brain

AbstractThe impact of acute and chronic stress on the hypothalamic-pituitary-adrenal (HPA) axis is reviewed and evidence presented that corticotrophin releasing factor (CRF) is the stress neurotransmitter which plays an important role in the activation of the central sympathetic and serotonergic systems. The activity of CRF is expressed through specific receptors (CRF 1 and 2) that are antagonistic in their actions and widely distributed in the limbic regions of the brain, as well as in the hypothalamus, and on immune cells.The mechanism whereby chronic stress, via the CRF induced activation of the dorsal raphe nucleus, can induce a change in the serotonergic system, involves an increase in the 5HT2A and a decrease in the 5HT1A receptor mediated function. Such changes contribute to the onset of anxiety and depression. In addition, the hypersecretion of glucocorticoids that is associated with chronic stress and depression desensitises the central glucocorticoid receptors to the negative feedback inhibition of the HPA axis. This indirectly results in the further activation of the HPA axis.The rise in pro-inflammatory cytokines that usually accompanies the chronic stress response results in a further stimulation of the HPA axis thereby adding to the stress response. While CRF would appear to play a pivotal role, evidence is provided that simultaneous changes in the serotonergic and noradrenergic systems, combined with the activation of peripheral and central macrophages that increase the pro-inflammatory cytokine concentrations in the brain and blood, also play a critical role in predisposing to anxiety and depression. Neurodegenerative changes in the brain that frequently occur in the elderly patient with major depression, could result from the activation of indoleaminedioxygenase (IDO), a widely distributed enzyme that converts tryptophan via the kynenine pathway to for the neurotoxic end product quinolinic acid.

scholarly journals Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress

2011 ◽  
Vol 58 (10) ◽  
pp. 889-904 ◽  
Author(s):  
Vladimir M. Markovic ◽  
Zeljko Cupic ◽  
Vladana Vukojevic ◽  
Ljiljana Kolar-Anic
Keyword(s):  
Chronic Stress ◽  
Hpa Axis ◽  
Predictive Modeling ◽  
Hypothalamic Pituitary Adrenal ◽  
Acute And Chronic Stress

scholarly journals Facilitation of the HPA Axis to a Novel Acute Stress Following Chronic Stress Exposure Modulates Histone Acetylation and the ERK/MAPK Pathway in the Dentate Gyrus of Male Rats

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2942-2952 ◽  
Author(s):  
Chantelle L. Ferland ◽  
Erin P. Harris ◽  
Mai Lam ◽  
Laura A. Schrader
Keyword(s):  
Dentate Gyrus ◽  
Histone Acetylation ◽  
Chronic Stress ◽  
Hpa Axis ◽  
Acute Stress ◽  
Male Rats ◽  
Stress Exposure ◽  
Erk Activation ◽  
Acute And Chronic Stress ◽  
Acute Stressor

Evidence suggests that when presented with novel acute stress, animals previously exposed to chronic homotypic or heterotypic stressors exhibit normal or enhanced hypothalamic-pituitary-adrenal (HPA) response compared with animals exposed solely to that acute stressor. The molecular mechanisms involved in this effect remain unknown. The extracellular signal-regulated kinase (ERK) is one of the key pathways regulated in the hippocampus in both acute and chronic stress. The aim of this study was to examine the interaction of prior chronic stress, using the chronic variable stress model (CVS), with exposure to a novel acute stressor (2,5-dihydro-2,4,5-trimethyl thiazoline; TMT) on ERK activation, expression of the downstream protein BCL-2, and the glucocorticoid receptor co-chaperone BAG-1 in control and chronically stressed male rats. TMT exposure after chronic stress resulted in a significant interaction of chronic and acute stress in all 3 hippocampus subregions on ERK activation and BCL-2 expression. Significantly, acute stress increased ERK activation, BCL-2 and BAG-1 protein expression in the dentate gyrus (DG) of CVS-treated rats compared with control, CVS-treated alone, and TMT-only animals. Furthermore, CVS significantly increased ERK activation in medial prefrontal cortex, but acute stress had no significant effect. Inhibition of corticosterone synthesis with metyrapone had no significant effect on ERK activation in the hippocampus; therefore, glucocorticoids alone do not mediate the molecular effects. Finally, because post-translational modifications of histones are believed to play an important role in the stress response, we examined changes in histone acetylation. We found that, in general, chronic stress decreased K12H4 acetylation, whereas acute stress increased acetylation. These results indicate a molecular mechanism by which chronic stress-induced HPA axis plasticity can lead to neurochemical alterations in the hippocampus that influence reactivity to subsequent stress exposure. This may represent an important site of dysfunction that contributes to stress-induced pathology such as depression, anxiety disorders, and posttraumatic stress disorder.

scholarly journals The Anteroventral Bed Nucleus of the Stria Terminalis Differentially Regulates Hypothalamic-Pituitary-Adrenocortical Axis Responses to Acute and Chronic Stress

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 818-826 ◽  
Author(s):  
Dennis C. Choi ◽  
Nathan K. Evanson ◽  
Amy R. Furay ◽  
Yvonne M. Ulrich-Lai ◽  
Michelle M. Ostrander ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Hpa Axis ◽  
Paraventricular Nucleus ◽  
Restraint Stress ◽  
Body Weight Gain ◽  
Stria Terminalis ◽  
Thymic Involution ◽  
Bed Nucleus ◽  
Acute And Chronic Stress

The anteroventral region of the bed nucleus of the stria terminalis (BST) stimulates hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress. However, the role of the anterior BST nuclei in chronic drive of the HPA axis has yet to be established. Therefore, this study tests the role of the anteroventral BST in physiological responses to chronic drive, using a chronic variable stress (CVS) model. Male Sprague-Dawley rats received either bilateral ibotenate lesions, targeting the anteroventral BST, or vehicle injection into the same region. Half of the lesion and control rats were exposed to a 14-d CVS paradigm consisting of twice-daily exposure to unpredictable, alternating stressors. The remaining rats were nonhandled control animals that remained in home cages. On the morning after the end of CVS exposure, all rats were exposed to a novel restraint stress challenge. CVS induced attenuated body weight gain, adrenal hypertrophy, thymic involution, and enhanced CRH mRNA in hypophysiotrophic neurons of the hypothalamic paraventricular nucleus, none of which were affected by anteroventral BST lesions. In the absence of CVS, lesions attenuated the plasma corticosterone and paraventricular nucleus c-fos mRNA responses to the acute restraint stress. In contrast, lesions of the anteroventral BST elevated plasma ACTH and corticosterone responses to novel restraint in the rats previously exposed to CVS. These data suggest that the anterior BST plays very different roles in integrating acute stimulation and chronic drive of the HPA axis, perhaps mediated by chronic stress-induced recruitment of distinct BST cell groups or functional reorganization of stress-integrative circuits.

scholarly journals Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (8) ◽  
pp. 2843-2853 ◽  
Author(s):  
Matia B. Solomon ◽  
Matthew Loftspring ◽  
Annette D. de Kloet ◽  
Sriparna Ghosal ◽  
Ryan Jankord ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Hpa Axis ◽  
Glucocorticoid Receptors ◽  
Acute Stress ◽  
Feedback Inhibition ◽  
Forced Swim Test ◽  
Feedback Regulation ◽  
Signaling Mechanism ◽  
Cell Groups ◽  
Neuroendocrine Responses

Abstract Glucocorticoids act rapidly at the paraventricular nucleus (PVN) to inhibit stress-excitatory neurons and limit excessive glucocorticoid secretion. The signaling mechanism underlying rapid feedback inhibition remains to be determined. The present study was designed to test the hypothesis that the canonical glucocorticoid receptors (GRs) is required for appropriate hypothalamic-pituitary-adrenal (HPA) axis regulation. Local PVN GR knockdown (KD) was achieved by breeding homozygous floxed GR mice with Sim1-cre recombinase transgenic mice. This genetic approach created mice with a KD of GR primarily confined to hypothalamic cell groups, including the PVN, sparing GR expression in other HPA axis limbic regulatory regions, and the pituitary. There were no differences in circadian nadir and peak corticosterone concentrations between male PVN GR KD mice and male littermate controls. However, reduction of PVN GR increased ACTH and corticosterone responses to acute, but not chronic stress, indicating that PVN GR is critical for limiting neuroendocrine responses to acute stress in males. Loss of PVN GR induced an opposite neuroendocrine phenotype in females, characterized by increased circadian nadir corticosterone levels and suppressed ACTH responses to acute restraint stress, without a concomitant change in corticosterone responses under acute or chronic stress conditions. PVN GR deletion had no effect on depression-like behavior in either sex in the forced swim test. Overall, these findings reveal pronounced sex differences in the PVN GR dependence of acute stress feedback regulation of HPA axis function. In addition, these data further indicate that glucocorticoid control of HPA axis responses after chronic stress operates via a PVN-independent mechanism.

scholarly journals Role of hypothalamic-pituitary adrenal-axis, toll-like receptors, and macrophage polarization in pre-atherosclerotic changes induced by social isolation stress in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Arvin Haj-Mirzaian ◽  
Kiana Ramezanzadeh ◽  
Siavash Shariatzadeh ◽  
Michael Tajik ◽  
Farima Khalafi ◽  
...  
Keyword(s):  
Social Isolation ◽  
Chronic Stress ◽  
Hpa Axis ◽  
Macrophage Polarization ◽  
Toll Like Receptors ◽  
Isolation Stress ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Atherosclerotic Changes ◽  
Pituitary Adrenal Axis

AbstractIt has been well documented that chronic stress can induce atherosclerotic changes, however, the underlying mechanisms is yet to be established. In this regard, this study aimed to elucidate the relation between hypothalamic-pituitary adrenal-axis (HPA-axis), toll-like receptors (TLRs), as well as M1/M2 macrophage ratio and pre-atherosclerotic changes in social isolation stress (SIS) in mice. We used small interfering RNA against the glucocorticoid receptor (GR) to evaluate the relation between HPA-axis and TLRs. C57BL/6J mice were subjected to SIS and RT-PCR, ELISA, flow cytometry, and immunohistochemistry were used to assess the relations between pre-atherosclerotic changes and TLRs, macrophage polarization, pro-inflammatory cytokines, and cell adhesion molecules in aortic tissue. We used TAK-242 (0.3 mg/kg, intraperitoneally), a selective antagonist of TLR4, as a possible prophylactic treatment for atherosclerotic changes induced by SIS. We observed that isolated animals had higher serum concentration of corticosterone and higher body weight in comparison to normal animals. In isolated animals, results of in vitro study showed that knocking-down of the GR in bone marrow–derived monocytes significantly decreased the expression of TLR4. In vivo study suggested higher expression of TLR4 on circulating monocytes and higher M1/M2 ratio in aortic samples. Pathological study showed a mild pre-atherosclerotic change in isolated animals. Finally, we observed that treating animals with TAK-242 could significantly inhibit the pre-atherosclerotic changes. SIS can possibly increase the risk of atherosclerosis through inducing abnormal HPA-axis activity and subsequently lead to TLR4 up-regulation, vascular inflammation, high M1/M2 ratio in intima. Thus, TLR4 inhibitors might be a novel treatment to decrease the risk of atherosclerosis induced by chronic stress.

scholarly journals The Stress Axis in Obesity and Diabetes Mellitus: An Update

Endocrines ◽  
2021 ◽  
Vol 2 (3) ◽  
pp. 334-347
Author(s):  
Laura Gianotti ◽  
Sara Belcastro ◽  
Salvatore D’Agnano ◽  
Francesco Tassone
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Chronic Stress ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Acute And Chronic Stress ◽  
Pituitary Adrenal Axis

The hypothalamic–pituitary–adrenal axis is a tightly regulated system that represents one of the body’s mechanisms for responding to acute and chronic stress. Prolonged stress and/or inadequate regulation of the stress system can lead to a condition of chronic hypercortisolism or, in some cases, a blunted cortisol response to stress, contributing to insulin resistance, increased adiposity and type 2 diabetes mellitus. Moreover, acute and chronic stress can exacerbate or worsen metabolic conditions by supporting an inflammatory state and a tight relationship between stress, inflammation and adipose tissue has been reported and has been a growing subject of interest in recent years. We reviewed and summarized the evidence supporting hypothalamic–pituitary–adrenal axis dysregulation as an important biological link between stress, obesity, inflammation and type 2 diabetes mellitus. Furthermore, we emphasized the possible role of infectious-related stress such as SarsCov2 infection in adrenal axis dysregulation, insulin resistance and diabetes in a bidirectional link. Understanding and better defining the links between stress and obesity or diabetes could contribute to further definition of the pathogenesis and the management of stress-related complications, in which the HPA axis dysregulation has a primary role.

scholarly journals Differential Adaptive Responses to Chronic Stress of Maternally Stressed Male Mice Offspring

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 3202-3210 ◽  
Author(s):  
Sooyoung Chung ◽  
Gi Hoon Son ◽  
Sung Ho Park ◽  
Eonyoung Park ◽  
Kun Ho Lee ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Hpa Axis ◽  
Acute Stress ◽  
Feedback Inhibition ◽  
Corticosterone Level ◽  
Dependent Manner ◽  
Male Mice ◽  
Adaptive Responses ◽  
Repeated Restraint Stress ◽  
Postnatal Stress

Abstract It is well established that stress in early life can alter the activity of the hypothalamus-pituitary-adrenal (HPA) axis, but most studies to date have focused on HPA reactivity in response to a single acute stress. The present study addressed whether stress in pregnant mice could influence the adaptive responses of their offspring to chronic stress. Male offspring were exclusively used in this study. Elevated plus maze tests revealed that 14 d of repeated restraint stress (6 h per day; from postnatal d 50–63) significantly increased anxiety-like behavior in maternally stressed mice. NBI 27914, a CRH receptor antagonist, completely eliminated anxiety-related behaviors in a dose-dependent manner, indicating an involvement of a hyperactive CRH system. In accordance with increased anxiety, CRH contents in the hypothalamus and amygdala were significantly higher in these mice. Despite an increased basal activity of the CRH-ACTH system, the combination of chronic prenatal and postnatal stress resulted in a significant reduction of basal plasma corticosterone level, presumably because of a defect in adrenal function. Along with alterations in hypothalamic and hippocampal corticosteroid receptors, it was also demonstrated that a dysfunction in negative feedback inhibition of the HPA axis could be deteriorated by chronic stress in maternally stressed male mice. Taken together, these results indicate that exposure to maternal stress in the womb can affect an animal’s coping capacity to chronic postnatal stress.

Sign in / Sign up

Export Citation Format

Share Document