Hypothalamic-pituitary-adrenal Activity Research Articles

Voluntary wheel running initially increases adrenal sensitivity to adrenocorticotrophic hormone, which is attenuated with long-term training

Although exercise is a common and potent activator of the hypothalamic-pituitary adrenal (HPA) axis, the effects of exercise on the acute stress response are not well understood. Here, we investigated the effects of short- (2 wk) and long-term (8 wk) voluntary wheel running on adrenal sensitivity to ACTH stimulation and the acute stress response to restraint in male rats. Diurnal glucocorticoid patterns were measured on days 7 (all groups) and 35 (8-wk groups). Rats were subjected to 20 min of restraint stress on either week 1 or on week 7 of treatment to assess HPA activation. One week later, exogenous ACTH (75 ng/kg) was administered to assess adrenal sensitivity to ACTH. Following this, adrenals were collected and analyzed for key proteins involved in corticosterone (CORT) synthesis. By the end of week 1, exercising (E) animals had twofold higher peak diurnal CORT levels compared with sedentary (S) animals (P < 0.01). CORT values were not different between groups at week 8. In response to restraint stress at week 2, CORT values in E were approximately threefold greater than in S (P < 0.05). No difference was found between E and S rats in the response to, or recovery from, restraint at week 8. During the ACTH challenge at week 2, E demonstrated a approximately 2.5-fold increase in adrenal sensitivity compared with S, while no difference was found between E and S at week 8. The expression of steroidogenic acute regulatory protein was found to be approximately 50% higher in the adrenals in E compared with S at week 2 (P < 0.05), but no difference existed between groups at week 8. These results show that volitional wheel running initially causes hyperactivation of the HPA axis, due to enhanced adrenal sensitivity to ACTH, but that these alterations in HPA activity are completely restored by 8 wk of training.

Repeated Ferret Odor Exposure Induces Different Temporal Patterns of Same-Stressor Habituation and Novel-Stressor Sensitization in Both Hypothalamic-Pituitary-Adrenal Axis Activity and Forebrain c-fos Expression in the Rat

Repeated exposure to a moderately intense stressor typically produces attenuation of the hypothalamic-pituitary-adrenal (HPA) axis response (habituation) on re-presentation of the same stressor; however, if a novel stressor is presented to the same animals, the HPA axis response may be augmented (sensitization). The extent to which this adaptation is also evident within neural activity patterns is unknown. This study tested whether repeated ferret odor (FO) exposure, a moderately intense psychological stressor for rats, leads to both same-stressor habituation and novel-stressor sensitization of the HPA axis response and neuronal activity as determined by immediate early gene induction (c-fos mRNA). Rats were presented with FO in their home cages for 30 min a day for up to 2 wk and subsequently challenged with FO or restraint. Rats displayed HPA axis activity habituation and widespread habituation of c-fos mRNA expression (in situ hybridization) throughout the brain in as few as three repeated presentations of FO. However, repeated FO exposure led to a more gradual development of sensitized HPA-axis and c-fos mRNA responses to restraint that were not fully evident until after 14 d of prior FO exposure. The sensitized response was evident in many of the same brain regions that displayed habituation, including primary sensory cortices and the prefrontal cortex. The shared spatial expression but distinct temporal development of habituation and sensitization neural response patterns suggests two independent processes with opposing influences across overlapping brain systems.

Habituation to repeated stress: Get used to it

Habituation, as described in the landmark paper by Thompson et al. [Thompson, R. F., & Spencer, W. A. (1966). Habituation: A model phenomenon for the study of neuronal substrates of behavior. Psychological Review, 73(1), 16–43], is a form of simple, nonassociative learning in which the magnitude of the response to a specific stimulus decreases with repeated exposure to that stimulus. A variety of neuronal and behavioral responses have been shown to be subject to habituation based on the criteria presented in that paper. It has been known for several decades that the magnitude of hypothalamic–pituitary–adrenal (HPA) activation occurring in response to a stressor declines with repeated exposure to that same stressor. For some time this decline has been referred to as “habituation” in the stress neurobiology literature. However, how this usage compares to the definition proposed by Thompson and Spencer has not been systematically addressed. For this special issue, we review the stress neurobiology literature and examine the support available for considering declines in HPA response to repeated stress to be response habituation in the sense defined by Thompson and Spencer. We conclude that habituation of HPA activity meets many, but not all, important criteria for response habituation, supporting the use of this term within the context of repeated stress. However, we also propose that response habituation can, at best, only partially explain the phenomenon of HPA habituation, which also involves well-known negative feedback mechanisms, activation of broad stress-related neural circuitry and potentially more complex associative learning mechanisms.

Differential effects of imipramine and phenelzine on corticosteroid receptor gene expression in mouse brain: Potential relevance to antidepressant response

Although glucocorticoid feedback sensitivity of the hypothalamic–pituitary–adrenal (HPA) axis is frequently impaired in depression, atypical depression may exhibit increased feedback sensitivity. Because monoamine oxidase inhibitors (MAOI) are often more effective than tricyclic antidepressants (TCA) for atypical depression, we hypothesized that to normalize HPA function in atypical depression, MAOI would differ from TCA in decreasing rather than increasing feedback sensitivity. Consistent with this hypothesis and prior evidence for opposing effects on HPA feedback in mice, we report contrasting effects of chronic MAOI (phenelzine) and TCA (imipramine) treatment on neural corticosteroid receptor gene expression in adrenalectomized male C57BL/6 mice with fixed glucocorticoid levels. Our findings corroborate prior reports of antidepressant-induced increases in hippocampal mineralocorticoid (MR) and glucocorticoid receptor (GR) expression. However, hippocampal effects were neither sustained nor representative of effects in other brain regions. Imipramine typically increased and phenelzine decreased GR expression in other feedback-related brain regions such as the paraventricular hypothalamus and prefrontal cortex. Imipramine effects were limited to feedback-related regions, whereas phenelzine had additional effects to decrease accumbens GR and central amygdala MR expression. Our results suggest an expansion of the corticosteroid receptor hypothesis of depression to include drug- and brain region-specific actions of antidepressants to decrease as well as increase corticosteroid receptor expression and feedback sensitivity. Our findings further suggest how antidepressants could improve glucocorticoid regulation of HPA activity without also facilitating the adverse effects of glucocorticoids on mood.

Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic‐pituitary‐adrenal axis and blood pressure adaptions to high‐fat diet

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GRβgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GRβgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin-aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GRβgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GRβgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.—Michailidou, Z., Carter, R. N., Marshall, E., Sutherland, H. G., Brownstein, D. G., Owen, E., Cockett, K., Kelly, V., Ramage, L., Al-Dujaili, E. A. S., Ross, M., Maraki, I., Newton, K., Holmes, M. C., Seckl, J. R., Morton, N. M., Kenyon, C. J., Chapman, K. E. Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet.

Effects of prenatal ethanol exposure on regulation of basal hypothalamic–pituitary–adrenal activity and hippocampal 5-HT 1A receptor mRNA levels in female rats across the estrous cycle

Prenatal ethanol exposure, like other early adverse experiences, is known to alter hypothalamic-pituitary-adrenal (HPA) activity in adulthood. The present study examined the modulatory effects of the gonadal hormones on basal HPA regulation and serotonin Type 1A receptor (5-HT(1A)) mRNA levels in adult female rats prenatally exposed to ethanol (E) compared to that in females from pair-fed (PF) and ad libitum-fed control (C) conditions. We demonstrate, for the first time, long-lasting consequences of prenatal ethanol exposure for basal corticosterone (CORT) regulation and basal levels of hippocampal mineralocorticoid (MR), glucocorticoid (GR) and serotonin Type 1A (5-HT(1A)) receptor mRNA, as a function of estrous cycle stage: (1) basal CORT levels were higher in E compared to C females in proestrus but lower in E and PF compared to C females in estrus; (2) there were no differences among groups in basal levels of adrenocorticotropin (ACTH), estradiol or progesterone; (3) hippocampal MR mRNA levels were decreased in E compared to PF and C females across the estrus cycle, with the greatest effects in proestrus, whereas E (but not PF or C) females had higher hippocampal GR mRNA levels in proestrus than in estrous and diestrus; (4) 5-HT(1A) mRNA levels were increased in E compared to PF and C females in diestrus. That alterations were revealed as a function of estrous cycle stage suggests a role for the ovarian steroids in mediating the adverse effects of ethanol. Furthermore, it appears that ethanol-induced nutritional effects may play a role in mediating at least some of the effects observed. The resetting of HPA activity by early environmental events could be one mechanism linking early life experiences with long-term health consequences. Thus, changes in basal CORT levels, a shift in the MR/GR balance and alterations in 5-HT(1A) receptor mRNA could have important clinical implications for understanding the secondary disabilities, such as an increased incidence of depression, in children with FASD.

Marked dissociation between hypothalamic–pituitary–adrenal activation and long-term behavioral effects in rats exposed to immobilization or cat odor

Exposure of rodents to cats or certain cat odors results in long-term behavioral effects reminiscent of enhanced anxiety that have been considered to model post-traumatic stress disorder. However, other severe stressors such as tail-shock or immobilization in wooden boards (IMO) appear to induce shorter lasting changes in anxiety. In addition, there are controversial results regarding the effects of urine/feces odors. In the present work, we studied in two experiments the relationship between the degree of stress experienced by the animals during exposure to IMO, urine odors or fur odors (as assessed by hypothalamic-pituitary-adrenal activation and plasma glucose) and the short- and long-term behavioral consequences. In the first experiment, rats were individually exposed for 15 min to a novel environment (white large cages) containing either clean cat litter (controls) or litter soiled by cats (urine odors). Half of the rats in each condition were left to freely explore the environment whereas the others were subjected to immobilization (IMO) within the cages. Although ACTH, corticosterone and glucose responses to IMO were much stronger than those to the white cages with clean litter or urine odors (which did not differ from each other), no effect of treatments on anxiety-like behavior in the elevated plus-maze (EPM) were found one week later. However, previous IMO exposure did cause sensitization of the ACTH response to the EPM. In the second experiment, the response to white large cages containing either no odor (controls), litter soiled by cats (urine odor) or a cloth impregnated with cat odor (fur odor) was compared. Urine and fur odors elicited similar ACTH and corticosterone responses that were higher than those of controls, but plasma glucose levels were slightly higher in rats exposed to fur odor. When compared to controls, activity was only diminished in the novel cages containing fur odor. Similarly, fur odor-exposed rats, but not those exposed to urine odor, showed signs of enhanced anxiety in the EPM seven days later, although the ACTH response to the EPM was similar in the three groups. The present data demonstrate: (a) a marked dissociation between the degree of ACTH, corticosterone and glucose responses to stressors and their long-term anxiety-like effects; (b) that the type of cat odor is critical in determining the short-term and long-term physiological and behavioral consequences of exposure; and (c) that plasma ACTH released during brief exposure to the EPM does not appear to reflect anxiety-like behavior.

Hypothalamic–pituitary–adrenal (HPA) axis function in 3-month old infants with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure

Background Prenatal exposure to stress and selective serotonin reuptake inhibitors (SSRIs) alter hypothalamic–pituitary–adrenal (HPA) stress reactivity in offspring, however, the effects of combined exposure to HPA activity in human infants is unknown. Objective To examine HPA basal levels and stress responsiveness in 3-month olds with prenatal exposure to SSRIs. Methods Salivary cortisol levels in infants of SSRI treated mothers ( n = 31, mean exposure 230.2 ± 72.2 days) were compared with non-SSRI exposed ( n = 45) infants in response to a challenge (infant-controlled habituation task) and under basal conditions in the late afternoon/early evening. Mode of feeding, to account for possible postnatal drug exposure via breast milk, as well as measures of pre and postnatal maternal mood, were included as covariates. Results Lower post-stress cortisol levels were observed in non-SSRI exposed/non-breastfed infants compared with non-SSRI exposed infants who were breastfed at 3 months of age. Stress reactivity patterns among SSRI exposed infants did not differ with mode of feeding. The cortisol reactivity slope (CRS) was significantly lower among non-SSRI exposed non-breastfed infants compared with non-SSRI exposed breastfed infants. Early evening basal cortisol levels were lower in SSRI exposed infants than in non-SSRI exposed infants, controlling for maternal mood and mode of feeding. Postnatal SSRI exposure (infant SSRI drug levels) via breast milk was not associated with stress or basal cortisol levels. Total cortisol, reflected by the AUC measure, did not differ significantly between exposure groups. Conclusions Prenatal SSRI exposure altered HPA stress response patterns and reduced early evening basal cortisol levels. Stress challenge HPA response differences only became apparent when the moderating effect of method of feeding was accounted for. These findings suggest an early “programming” effect of antenatal maternal mood, prenatal SSRI exposure and postnatal maternal care giving on the HPA system.

Effects of Perceived Control and Cognitive Coping on Endocrine Stress Responses to Pharmacological Activation

The hypothalamic-pituitary-adrenal (HPA) axis may mediate negative health effects of stress. It is sensitive to cognitive/emotional factors like novelty, perceived control, and coping. Psychological intervention that reduces novelty and enhances cognitive coping and sense of control can reduce cortisol responses to pentagastrin, a pharmacological HPA activator. This study attempted to identify the core factors that modulate HPA axis activity in this model. Varying instructions were administered prior to drug exposure in a two-visit (placebo first) pentagastrin infusion paradigm. Healthy subjects (n = 40) were randomly assigned to one of four instruction groups: 1) standard instruction (SI); 2) full cognitive intervention (CI); 3) the CI control component alone; or 4) the CI novelty reduction/coping components alone. Blood samples were obtained via intravenous catheter before and after pentagastrin. Subjects receiving an intervention had smaller cortisol responses than subjects receiving standard instructions. Coping alone had as strong an impact as the more complex intervention that combined coping and control. Control alone also reduced cortisol but its HPA impact appeared less robust. Brief psychological manipulation can significantly reduce HPA activation in challenge paradigms. Cognitive preparation that focused on side effects, reduced potential surprise, and enhanced cognitive coping modulated HPA axis activity as effectively as a previously tested intervention that combined coping and control manipulations. A sense of control alone also reduced cortisol release. The results support development of control or coping techniques to combat negative health effects of stress that are mediated by HPA axis activation.

Effect of aging on 24-hour pattern of stress hormones and leptin in rats

This work analyzes the 24-hour changes of hypothalamic–pituitary–adrenal (HPA) axis activity and leptin release in aged rats. Three- and 22-month-old male Wistar rats were killed at 6 time intervals during a 24-hour cycle ( n = 8–10 rats/group). Aging augmented plasma ACTH while it decreased plasma and adrenal gland corticosterone levels. Plasma and adrenal corticosterone levels attained high levels during all the scotophase, concomitantly with the maxima in ACTH levels, whereas in aged rats only a brief plasma corticosterone peak at the early scotophase and no time of day variations of adrenal corticosterone were observed. Aging augmented circulating leptin, with a significant interaction “age × time” in the factorial ANOVA, i.e. only in young rats time of day changes were significant, with the lowest values of leptin at the middle of the light period and higher values at night. When plasma leptin was expressed on body weight basis, the age-related differences became not significant but the daily pattern of plasma leptin found in young rats persisted. Plasma and adrenal corticosterone levels correlated significantly with plasma ACTH only in young rats. Likewise, plasma leptin correlated with plasma corticosterone only in young rats. These changes can be attributed to a disrupting effect of aging on the homeostatic mechanisms modulating HPA activity and leptin release.

Gender‐ and Age‐Related Differences in the Association Between Social Relationship Quality and Trait Levels of Salivary Cortisol

The majority of studies linking individual differences in the quality of social relationships and activity of the hypothalamic‐pituitary‐adrenal (HPA) axis have focused on the early development of attachment between infants and their caregivers. Later in development, during middle childhood and adolescence, the parallel HPA links to age‐appropriate social relationships with peers, parents, and siblings remain largely unspecified. This study addressed this knowledge gap. Early morning saliva samples were obtained from 367 children in middle childhood (ages 6–10) and 357 adolescents (M age=11–16 years) on two successive days 1 year apart and assayed for cortisol. Latent state–trait modeling was employed to separate variance in cortisol levels attributable to “stable trait‐like” versus “state or situational specific” sources to minimize the high moment‐to‐moment variation in basal adrenocortical activity. During adolescence but not middle childhood, and for girls but not boys, lower levels of “trait cortisol” were associated with poor quality social relationships. The pattern was robust, extending to the quality of relationships with parents, siblings, and peers. Importantly, the relationship was independent of the rates of internalizing or externalizing problem behavior. We found that isolating the variance in cortisol levels attributable to stable intrinsic sources revealed an interpretable pattern that linked individual differences in basal HPA activity to social relationships during adolescence. Studies are needed to reveal the biosocial mechanisms involved in the establishment of this gender‐ and age‐specific phenomenon and to decipher whether or not individual differences in this hormone‐behavior link are adaptive.

Effect of Cardiorespiratory Fitness on Cortisol and Cardiorespiratory Responses to Concurrent Mental and Physical Stress

Aerobic fitness is associated with increased sensitivity to mental challenge, evidenced by a relative elevation in heart rate (HR) response, and enhanced efficiency, demonstrated by a relative attenuation in absolute HR. However, the impact of aerobic fitness on cardiorespiratory and hypothalamic pituitary adrenal (HPA) activation in responses to mental challenge during exercise has not been investigated. PURPOSE: This study compared cortisol (CORT) and cardiorespiratory responses between individuals with below average fitness (VO2max = 34.29 ± 0.99 ml/kg/min-1) and individuals with above average fitness (VO2max = 48.04 ± 1.60 ml/kg/min-1). METHODS: Forty-eight apparently healthy individuals (24 high fit [HF] and 24 low fit [LF]) participated in two counter-balanced experimental conditions. In one condition, the participant was mentally challenged while exercising on a cycle ergometer at 60% of VO2max (dual-stress condition; DSC) and the other in which the participant exercised at the same intensity without the mental challenge (exercise-alone condition; EAC). State anxiety measures and the NASA Task Load Index (NTLX) were used to assess perceived mental and physical workload during each condition. RESULTS: State anxiety and NTLX scores were elevated in the DSC. The DSC also elicited greater elevations in HR, respiration rate, ventilation, ventilatory efficiency and CORT values. Additionally, HF individuals demonstrated significantly lower CORT levels (HF = 11.59 ± 0.83 nmol/L; LF = 15.17 ± 0.55 nmol/L; p = .01) in the DSC following the conclusion of the mental challenge. CONCLUSIONS: These results suggest that a mental challenge during a physical challenge impacts the cardiorespiratory system and activates the HPA axis, and that increased fitness levels may attenuate these effects.

Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11β-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure

To determine the expression of glucocorticoid metabolizing and action genes in the hippocampus of fetal, neonatal, and adult sheep. Pregnant ewes (or their fetuses) received intramuscular injections of saline or betamethasone (BETA, 0-5 mg/kg) at 104, 111, 118, and/or 125 days of gestation (dG). Hippocampal tissue was collected prior to (75, 84, and 101 dG), during (109 and 116 dG), or after (121, 132, and 146 dG; 6 and 12 postnatal weeks; 3.5 years of age) saline or BETA injections. Hippocampal glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and 11beta-hydroxysteroid dehydrogenase (11betaHSD)1 and 11betaHSD2 mRNA levels were determined using qRT-PCR. Control animals late in gestation demonstrated a decrease in mRNA encoding GR and 11betaHSD1, whereas 11betaHSD2 was undetectable, consistent with a damping of the negative feedback influence of circulating or locally produced cortisol on the hypothalamic-pituitary-adrenal (HPA) axis. BETA-administration had transient effects on fetal GR and MR, and early in postnatal life (12 weeks of age) 11betaHSD1 mRNA was increased. Hippocampal MR mRNA was elevated in adult offspring exposed to either one or four doses of maternal BETA (P<0.001). Four courses of maternal BETA increased 11betaHSD2 (P<0.05) but not 11betaHSD1 mRNA levels. Late in gestation a reduction in hippocampal GR and 11betaHSD1 mRNA suggests lessening of glucocorticoid negative feedback, facilitating increased preterm HPA activity and parturition. Adult offspring of BETA-treated mothers demonstrated increased MR and 11betaHSD2 mRNA, therefore it appears that exposure of fetus to high levels of synthetic glucocorticoids may have long-lasting effects on the hippocampal expression of HPA-related genes into adulthood.

Stress and the Hypothalamic Pituitary Adrenal Axis in the Developmental Course of Schizophrenia

Diathesis-stress models of schizophrenia and other psychotic disorders have dominated theorizing about etiology for over three decades. More recently, with advances in our understanding of the biological processes mediating the effects of stress, these models have incorporated mechanisms to account for the adverse impact of stress on brain function. This review examines recent scientific findings on the role of the hypothalamic-pituitary-adrenal (HPA) axis, one of the primary neural systems triggered by stress exposure, in the expression of vulnerability for schizophrenia. The results indicate that psychotic disorders are associated with elevated baseline and challenge-induced HPA activity, that antipsychotic medications reduce HPA activation, and that agents that augment stress hormone (cortisol) release exacerbate psychotic symptoms. The cumulative findings are discussed in light of a neural diathesis-stress model that postulates that cortisol has the potential to increase activity of dopamine pathways that have been implicated in schizophrenia and other psychotic disorders.

Struggling behavior during restraint is regulated by stress experience

Restraint elicits a number of physiological stress responses that can be increased or decreased in magnitude based on prior stress history. For instance, repeated exposure to restraint leads to habituation of hypothalamic-pituitary-adrenal (HPA) activation to restraint. In contrast, acute restraint after a different repeated stressor leads to facilitation of HPA activity to the novel stress. Acute restraint also elicits a variety of behaviors, including struggling, but the effect of prior stress in regulating behavioral responses to restraint is not clear. The goal of the present studies was to assess struggling during restraint with or without a prior history of repeated stress. Using automated behavioral analysis software (EthoVision), we quantified struggling during restraint. We found that acutely restrained rats exhibited vigorous struggling behavior that declined during a single restraint period. Repeated restraint lead to habituated struggling behavior, whereas acute restraint after repeated swim elicited facilitated struggling behavior. These effects on struggling were found alongside expected differences in HPA activity. Removing stress-induced increases in corticosterone via adrenalectomy did not significantly affect struggling responses to restraint. Overall, restraint-induced struggling appears to be regulated in a manner similar to HPA responses to restraint, but is not dictated by adrenal hormones.

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

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.

Corticosterone in feathers is a long‐term, integrated measure of avian stress physiology

1. Stress has pervasive consequences for the well-being of animals. Currently, understanding how individuals cope with stressors is typically accomplished via short-term quantification of blood glucocorticoids released after activation of the hypothalamic-pituitary-adrenal (HPA) axis. 2. We investigated whether the amount of corticosterone (CORT) deposited in growing feathers provides a long-term, integrated measure of HPA activity in birds using captive red-legged partridges Alectoris rufa as a model species. 3. We examined CORT levels in primary feathers induced to grow at the same time as stress series were performed with a capture and restraint protocol. Plasma CORT titres after stress-induced stimulation, but not baseline values, correlated with feather CORT. Feather levels showed the same pattern as plasma of decline across the breeding season, but more severely. 4. For females, CORT in naturally moulted flank feathers was highly and positively correlated with the number of eggs laid in the previous few months, but not clutch size of the following year. For males, the amount of black on a feather, known to be a social signal, was positively correlated with its CORT level. 5. The analysis of feather CORT is a novel methodology that allows for meaningful interpretations of how individuals respond to environmental perturbations and adjust to life-history stages. 6. The analysis of feather hormones has the unique advantages of allowing for experimentation and sampling at any time of the year with minimal investigator-induced impacts and artefacts, and shows the HPA activity of an individual with a flexible time frame from days to months depending on the length of time taken to grow the feather. As this technique can be applied to living or dead birds, or feathers picked up after moult, it provides the ultimate non-invasive physiological measure of considerable benefit in terms of animal welfare and sampling effort.

The psychobiology of trait shame in young women: Extending the social self preservation theory.

The social self preservation theory (SSPT) proposes that social evaluative threat evokes the emotion of shame, which then shapes a coordinated psychobiological response. While this is supported in acute stress studies, there is no data on chronic experiences of shame. We investigated the association of trait shame with activity of the hypothalamic-pituitary-adrenal (HPA) axis, of the sympathetic nervous system (SNS), and regulation of inflammation in n = 56 young women. Daily profiles of salivary cortisol and alpha-amylase were assessed as indices of HPA axis and SNS activity, respectively. Inflammatory regulation was assessed by lipopolysaccharide-stimulated production and glucocorticoid inhibition of interleukin-6 in vitro. Trait shame was associated with SNS (r = .49; p = .001), but not HPA activity (r = .14; ns). Shame was associated with inflammatory activity (r = .35; p = .006) and glucocorticoid sensitivity (r = -0.43; p = .001). Relationships were not mediated by HPA and SNS activity. Results support SSPT predictions with respect to chronic shame experience and inflammation. Results further suggest the importance of SNS activation related to shame, and the possibility that HPA activation may be limited acute experiences of shame.

Differential hypothalamic–pituitary–adrenal activation of the neuroactive steroids pregnenolone sulfate and deoxycorticosterone in healthy controls and alcohol-dependent subjects

Differential hypothalamic–pituitary–adrenal activation of the neuroactive steroids pregnenolone sulfate and deoxycorticosterone in healthy controls and alcohol-dependent subjects

Interleukin-6 and the Hypothalamic-Pituitary-Adrenal Activation in a Tumor Bearing Mouse

Tumor derived cytokines have been suggested to activate the hypothalamic-pituitary-adrenal (HPA) axis; that is, increase the hypothalamic releases of corticotropin-releasing hormone (CRH) and adrenocorticotrophic hormone. The authors previously reported that tumor mice bearing a human oral squamous cell carcinoma exhibit an anorectic phenotype with increased expression of CRH mRNA in their hypothalamic paraventricular nuclei. This study examined the plasma levels of tumor-derived cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in order to determine potential mediator(s) implicated in CRH expression in this tumor mouse model. Plasma corticosterone levels were assayed as well to confirm the HPA activation. In the results, plasma levels of IL-6, but not TNF-α, were increased significantly in the tumor mice compared with age-matching non-tumor controls. Plasma corticosterone levels were also increased in the tumor mice. These results together with the previous findings suggest IL-6 as a potential mediator in the control of hypothalamic CRH expression in the authors’ tumor mouse model.