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.

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 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 Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression

2021 ◽  
Vol 22 (22) ◽  
pp. 12240
Author(s):  
Yu-Lung Lin ◽  
Chin-Wen Wei ◽  
Thomas A. Lerdall ◽  
Jennifer Nhieu ◽  
Li-Na Wei
Keyword(s):  
Hpa Axis ◽  
Active Metabolite ◽  
Feedback Inhibition ◽  
Corticosterone Level ◽  
Stress Induction ◽  
Expression Studies ◽  
Pituitary Glands ◽  
Increased Sensitivity ◽  
Gene Expression Studies ◽  
First Time

Retinoic acid (RA), the principal active metabolite of vitamin A, is known to be involved in stress-related disorders. However, its mechanism of action in this regard remains unclear. This study reports that, in mice, endogenous cellular RA binding protein 1 (Crabp1) is highly expressed in the hypothalamus and pituitary glands. Crabp1 knockout (CKO) mice exhibit reduced anxiety-like behaviors accompanied by a lowered stress induced-corticosterone level. Furthermore, CRH/DEX tests show an increased sensitivity (hypersensitivity) of their feedback inhibition in the hypothalamic–pituitary–adrenal (HPA) axis. Gene expression studies show reduced FKBP5 expression in CKO mice; this would decrease the suppression of glucocorticoid receptor (GR) signaling thereby enhancing their feedback inhibition, consistent with their dampened corticosterone level and anxiety-like behaviors upon stress induction. In AtT20, a pituitary gland adenoma cell line elevating or reducing Crabp1 level correspondingly increases or decreases FKBP5 expression, and its endogenous Crabp1 level is elevated by GR agonist dexamethasone or RA treatment. This study shows, for the first time, that Crabp1 regulates feedback inhibition of the the HPA axis by modulating FKBP5 expression. Furthermore, RA and stress can increase Crabp1 level, which would up-regulate FKBP5 thereby de-sensitizing feedback inhibition of HPA axis (by decreasing GR signaling) and increasing the risk of stress-related disorders.

HPA-axis multilocus genetic variation moderates associations between environmental stress and depressive symptoms among adolescents

2018 ◽  
Vol 31 (04) ◽  
pp. 1339-1352 ◽  
Author(s):  
Lisa R. Starr ◽  
Meghan Huang
Keyword(s):  
Genetic Variation ◽  
Depressive Symptoms ◽  
Chronic Stress ◽  
Hpa Axis ◽  
Acute Stress ◽  
Childhood Adversity ◽  
Genetic Profile ◽  
Acute And Chronic Stress ◽  
Adolescent Depressive Symptoms ◽  
Gene Environment

AbstractResearch suggests that genetic variants linked to hypothalamic-pituitary-adrenal (HPA)-axis functioning moderate the association between environmental stressors and depression, but examining gene–environment interactions with single polymorphisms limits power. The current study used a multilocus genetic profile score (MGPS) approach to measuring HPA-axis–related genetic variation and examined interactions with acute stress, chronic stress, and childhood adversity (assessed using contextual threat interview methods) with depressive symptoms as outcomes in an adolescent sample (ages 14–17, N = 241; White subsample n = 192). Additive MGPSs were calculated using 10 single nucleotide polymorphisms within HPA-axis genes (CRHR1, NR3C2, NR3C1, FKBP5). Higher MGPS directly correlated with adolescent depressive symptoms. Moreover, MGPS predicted stronger associations between acute and chronic stress and adolescent depressive symptoms and also moderated the effect of interpersonal, but not noninterpersonal, childhood adversity. Gene–environment interactions individually accounted for 5%–8% of depressive symptom variation. All results were retained following multiple test correction and stratification by race. Results suggest that using MGPSs provides substantial power to examine gene–environmental interactions linked to affective outcomes among adolescents.

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.

scholarly journals SAT-451 Chronic Stress During Adolescence of Rats Shows Sex Dimorphism in the Thyroid Axis Response to Voluntary Exercise in Adulthood

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Marco Antonio Parra-Montes de Oca ◽  
Angélica Gutiérrez-Mata ◽  
Jean-Louis Charli ◽  
Patricia Joseph-Bravo
Keyword(s):  
Thyroid Hormones ◽  
Chronic Stress ◽  
Hpa Axis ◽  
Voluntary Exercise ◽  
Female Rats ◽  
Dependent Manner ◽  
Target Organs ◽  
Brown Adipose ◽  
Hpt Axis ◽  
Response To Exercise

Abstract Exposure to chronic stress during adolescence causes long-term effects on the response of Hypothalamus-Pituitary-Adrenal (HPA) axis, affecting behavior and energy homeostasis. Voluntary exercise activates the HP-Thyroid (HPT) axis allowing efficient fluxes of substrates to active target organs. Chronic stress in adult rats blunts HPT axis response to voluntary exercise in a sex-dependent manner (Front Endocrinol 10(418):1-13, 2019). As adolescents show sex-dependent responses to stress, we sought to evaluate the effect of chronic stress at this period in the response of HPT axis to voluntary exercise in adulthood. Wistar male and female rats were divided in an undisturbed group (Control, C) and one group exposed to chronic variable stress (CVS) where the rats were daily subjected to different stressors during postnatal day (PND) 30 to 60 for females and PND 30 to 70 for males. At adulthood (PND 74 for females and PND 84 for males) rats were exposed to running wheel following published protocol (Endocrinology 155:2020-2030, 2014). As females are more susceptible to stress during adolescence than males, additional independent experiments were performed with female rats kept in group or individual housing, since PND 30 (2 per cage or isolated (Iso)). At PND 64, Iso rats were housed in pairs and exposed to CVS every 3 days until PND 80; later, rats were exercised 26 days. Hormones were quantified by ELISA or RIA; mRNA expression was determined by RT-PCR. Voluntary exercise reduced fat mass in C groups, dependent on the amount of exercise performed; stressed rats exercised did not lose fat, indicating that adolescent stress avoids an appropriate energy distribution during exercise. The expression of Crh and Avp in hypothalamic paraventricular nucleus (PVN) decreased in stressed groups mainly in females, as reported. Exercise decreased corticosterone levels only in C rats, suggesting that CVS during adolescence modifies the HPA axis response to exercise. CVS inhibited Pomc expression induced by exercise and increased Npy expression in arcuate nucleus, decreased Trh expression in PVN for both sexes and in dorsomedial hypothalamus in males. Thyroid hormones were not altered in CVS males and Iso females; however, T3 and T4 levels were high in CVS females, so different stress exposures may modify the HPT axis state in females. The response to exercise of the target organs of thyroid hormones reveals with more accuracy the activity of HPT axis, exercise stimulated the expression of Adrb3 and Dio2 in brown adipose tissue of C females, and the expression of Dio2 and Pgc1a in skeletal muscle (gastrocnemius) of both sexes, changes attenuated by CVS. These results indicate that chronic stress during adolescence blunts the response of HPT axis to voluntary exercise, strongly in females than males.

scholarly journals Lateral Hypothalamus Corticotropin Releasing Hormone Receptor-1 Inhibition Modulates Stress- Induced Anxiety Behavior

2021 ◽  
Author(s):  
Masoumeh Eghtesad ◽  
◽  
Mahmoud Elahdadi Salmani ◽  
Taghi Lashkarbolouki ◽  
Iran Goudarzi1 ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Acute Stress ◽  
Corticosterone Level ◽  
Plasma Corticosterone ◽  
Corticotropin Releasing Hormone ◽  
Hypothalamic Area ◽  
Releasing Hormone ◽  
Male Wistar Rats ◽  
Induced Changes ◽  
Crh Receptor Type 1

Stress is a reaction to unwanted events disturbing body homeostasis which influences its pathways and target areas. Stress affects the brain through the lateral hypothalamic area (LHA) orexinergic system that mediates the effect of corticotropin-releasing hormone (CRH) through CRH receptor type 1 (CRHr1). Therefore, this study explores the outcome of stress exposure on anxiety development and the involvement of the LHA through LHA-CRHr1. Male Wistar rats (220-250g) implanted with a cannula in either side of the LHA received acute or chronic stress. Subsequently, exploratory behavior and anxiety was examined using the open field (OF) and elevated plus maze (EPM), respectively. Prior to sacrifice, the cerebrospinal fluid (CSF) and the blood were sampled. Nissl stain was performed on fixed brain tissues. Acute stress resulted in a decrease of exploration in the OF and an increase of anxiety in the EPM. LHA-CRHr1 inhibition reversed the variables to increase the exploration and decrease the anxiety. In contrast, chronic stress did not show any effect on the anxiety-related behaviors. Chronic stress decreased the cell population in the LHA, which was prevented by the CRHr1 inhibition. However, the CRHr1 inhibition was unable to reverse the chronic stress increase of the CSF orexin level. Furthermore, both acute and chronic stresses increased the plasma corticosterone level and only the CRHr1 inhibition impeded the effect. Our results recognize LHA-CRHr1 as a capable candidate modulating acute stress-induced anxiety development and chronic stress-induced changes in the cellular population of the region.

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.

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