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 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 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.

Disruption of mineralocorticoid receptor function increases corticosterone responding to a mild, but not moderate, psychological stressor

2005 ◽  
Vol 288 (6) ◽  
pp. E1082-E1088 ◽  
Author(s):  
Thaddeus W. W. Pace ◽  
Robert L. Spencer
Keyword(s):  
Hpa Axis ◽  
Negative Feedback ◽  
Glucocorticoid Receptors ◽  
Feedback Regulation ◽  
Sprague Dawley ◽  
Negative Feedback Regulation ◽  
Novel Environment ◽  
Sterile Saline ◽  
Sprague Dawley Rats ◽  
Psychological Stressor

Glucocorticoid negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis is mediated by corticosteroid receptors. It is widely thought that during stress, glucocorticoid receptors (GR) are essential for this negative feedback. In contrast, mineralocorticoid receptors (MR) are associated with HPA axis regulation in basal, nonstress conditions. Notions about the relative roles of MR and GR for HPA axis regulation during stressor challenge may not be complete. Recent work in our laboratory suggests that previous estimates of MR occupancy at resting plasma levels of corticosterone (CORT) may be overestimated. It is possible that a significant number of MR may be available to mediate negative feedback during stressor challenge. We hypothesized that this may be especially the case during mild stressor challenge when the plasma CORT response is weak. In the present studies, adult male Sprague-Dawley rats were first treated systemically or centrally with the selective MR antagonist RU28318 (50 mg/kg sc or 500 ng·10 μl−1·2 h−1 icv) or vehicle (300 μl propylene glycol sc or 10 μl/2 h sterile saline icv) and then challenged with 60-min novel environment or restraint. In vehicle controls, restraint resulted in a greater plasma CORT response than novel environment. Both systemic and central treatment with RU28318 significantly increased CORT responding to novel environment relative to vehicle controls. However, RU28318 treatment did not increase the CORT response to restraint. These data suggest that MR may be necessary for glucocorticoid regulation of HPA axis activity during mild stressors, but not during stressors that result in a more robust CORT response.

scholarly journals Fast Feedback Inhibition of the HPA Axis by Glucocorticoids Is Mediated by Endocannabinoid Signaling

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4811-4819 ◽  
Author(s):  
Nathan K. Evanson ◽  
Jeffrey G. Tasker ◽  
Matthew N. Hill ◽  
Cecilia J. Hillard ◽  
James P. Herman
Keyword(s):  
Hpa Axis ◽  
Negative Feedback ◽  
Stress Responses ◽  
Feedback Inhibition ◽  
Signaling Mechanism ◽  
Hypothalamic Tissue ◽  
Corticosterone Release ◽  
Arachidonoyl Glycerol ◽  
Local Release ◽  
Glucocorticoid Action

Glucocorticoid hormones are secreted in response to stimuli that activate the hypothalamo-pituitary-adrenocortical (HPA) axis and self-regulate through negative feedback. Negative feedback that occurs on a rapid time scale is thought to act through nongenomic mechanisms. In these studies, we investigated fast feedback inhibition of HPA axis stress responses by direct glucocorticoid action at the paraventricular nucleus of the hypothalamus (PVN). Local infusion of dexamethasone or a membrane-impermeant dexamethasone-BSA conjugate into the PVN rapidly inhibits restraint-induced ACTH and corticosterone release in a manner consistent with feedback actions at the cell membrane. The dexamethasone fast feedback response is blocked by the cannabinoid CB1 receptor antagonist AM-251, suggesting that fast feedback requires local release of endocannabinoids. Hypothalamic tissue content of the endocannabinoid 2-arachidonoyl glycerol is elevated by restraint stress, consistent with endocannabinoid action on feedback processes. These data support the hypothesis that glucocorticoid-induced fast feedback inhibition of the HPA axis is mediated by a nongenomic signaling mechanism that involves endocannabinoid signaling at the level of the PVN.

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 Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABA-ergic Parvalbumin Interneurons Attenuates Chronic Stress Adaptions in Male Mice

2019 ◽  
Author(s):  
Nawshaba Nawreen ◽  
Rachel Morano ◽  
Parinaz Mahbod ◽  
Evelin M. Cotella ◽  
Khushali Dalal ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Chronic Stress ◽  
Stress Responses ◽  
Acute Stress ◽  
Forced Swim Test ◽  
Designer Drugs ◽  
Gabaergic Interneurons ◽  
Coping Behaviors ◽  
Passive Coping ◽  
Parvalbumin Interneurons

ABSTRACTHypofunction of the prefrontal cortex (PFC) contributes to stress-related neuropsychiatric illnesses. Mechanisms leading to prefrontal hypoactivity remain to be determined. Prior evidence suggests that enhanced activity of parvalbumin (PV) expressing GABAergic interneurons (INs) play a role in chronic stress related pathologies. In this study, the role of PFC PV INs in stress related phenotypes were explored using Cre inducible inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). Mice were first tested in the tail suspension test (TST) to determine the effects of PV IN inhibition during acute stress. Following this, the long term impact of PV IN inhibition during chronic variable stress (CVS) was tested in the forced swim test (FST). Acute PV IN inhibition reduced active (struggling) and increased passive coping behaviors (immobility) in the TST. In contrast, inhibition of PV INs during CVS increased active and reduced passive coping behaviors in the FST. Moreover, chronic inhibition of PV INs attenuated CVS-induced changes in Fos expression in the prelimbic cortex, basolateral amygdala and ventrolateral periaqueductal gray and also prevented adrenal hypertrophy and body weight loss associated with chronic stress. Our results suggest differential roles of PV INs to acute vs chronic stress, indicative of distinct biological mechanisms underlying acute vs. chronic stress responses. Our results also indicate a role for PV INs in driving chronic stress adaptation and support literature evidence suggesting cortical GABAergic interneurons as a therapeutic target in stress related diseases.SIGNIFICANCEStress related diseases are associated with prefrontal hypoactivity, the mechanism of which is currently not known. In this study we showed that by inhibiting prefrontal GABA-ergic Parvalbumin interneurons (PV INs) using DREADDs, we can attenuate some of chronic stress related phenotypes. Additionally, we showed that modulation of PV IN activity during acute vs chronic stress had opposing effects on stress coping strategies, suggesting different underlying mechanisms behind acute vs chronic stress paradigms. Our findings indicate that GABA-ergic PV INs may be involved in driving stress related phenotypes and thereby an important target for treatment of stress-related illnesses. Our data suggest that reducing PV IN activity to promote prefrontal output may be an effective treatment strategy for stress related disorders.

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 Physiological and behavioral responses of house sparrows to repeated stressors

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4961 ◽  
Author(s):  
Brenna M.G. Gormally ◽  
Jessica Wright-Lichter ◽  
J. Michael Reed ◽  
L. Michael Romero
Keyword(s):  
Uric Acid ◽  
Stress Response ◽  
Chronic Stress ◽  
Hpa Axis ◽  
Repeated Measures ◽  
Acute Stress ◽  
Behavioral Responses ◽  
Uric Acid Concentration ◽  
House Sparrows ◽  
Bacterial Killing

Despite decades of research, we still lack a complete understanding of what factors influence the transition of the necessary and adaptive acute stress response to what has become known as chronic stress. This gap in knowledge has illuminated the necessity for studies that examine the thresholds between these two sides of the stress response. Here, we determine how repeated exposure to acute stressors influences physiological and behavioral responses. In this repeated measures study, house sparrows (Passer domesticus) were exposed to a chronic stress protocol. We took physiological and behavioral measurements before, during, and after the protocol. Blood samples were used to assess four aspects of hypothalamic-pituitary-adrenal (HPA) axis function: baseline corticosterone, stress-induced corticosterone, negative feedback, and the maximal capacity to secrete corticosterone. We also assessed bacterial killing capacity and changes in uric acid concentration. Neophobia trials were used to assess behavioral changes throughout the protocol. We found no significant changes in HPA axis regulation in any of the four aspects we tested. However, we found that uric acid concentrations and neophobia significantly decreased after only four days of the chronic stress protocol, while bacterial killing capacity did not decrease until after eight days of exposure. These results indicate that different components of the stress response can be impacted by chronic stress on different timescales. Our results further indicate the importance of assessing multiple aspects of both physiology and behavior in order to understand how exposure to chronic stress may influence ability to cope with future challenges.

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