Hypothalamic-pituitary-adrenal Response Research Articles

0187 STRESSOR REACTIVITY IN SLEEP-DEPRIVED NORMAL SLEEPERS AND SLEEP-ONSET INSOMNIACS

Exposure to stressors increases physiological arousal through the hypothalamic-pituitary-adrenal (HPA) axis. Sleep deprivation has been reported to potentiate HPA axis stressor reactivity in healthy adults. Insomnia has been linked with hyperarousal and chronic HPA activation, which may also potentiate HPA axis stressor reactivity. In a highly standardized study protocol, we measured responses to psychosocial and physical stressors in normal sleepers and sleep-onset insomniacs while well-rested or exposed to acute total sleep deprivation (TSD). Twenty adults (9 sleep-onset insomniacs, 11 healthy normal sleepers; ages 22–39; 14 females) completed a 5-day (4-night) in-laboratory study. After an adaptation day and a baseline day (each 10h time in bed (TIB); 22:00-08:00), subjects were assigned to a 38h TSD condition (6 sleep-onset insomniacs, 6 healthy controls) or a matching control condition (10h TIB; 3 sleep-onset insomniacs, 5 healthy controls). After 36h TSD, subjects underwent the 10min Maastricht Acute Stress Test (MAST). This test involved 5 cold pressor trials, requiring subjects to submerge their non-dominant hand in cold water (0°C) for 60-90s. Between cold pressor trials, subjects performed a socially evaluated, difficult, mental arithmetic task. Salivary cortisol was measured just before and every 15 min after the MAST from 20:00 until 21:15, and at 21:45. Salivary cortisol was also collected at baseline 24 hours earlier. Cortisol levels, expressed relative to baseline, increased immediately following the MAST, peaked 30min later, and then gradually returned to pre-MAST levels (F=7.31, P<0.001). Relative to well-rested normal sleepers, the cortisol peak was dampened in the sleep-onset insomniacs and in the TSD condition, although this dampening did not reach statistical significance. The MAST psychosocial and physical stressors elicited an HPA axis response in both normal sleepers and sleep-onset insomniacs and in both TSD and control conditions. However, the results did not support the idea that sleep deprivation and/or insomnia potentiate HPA axis stressor reactivity. ONR grant N00014-13-C-0063.

Adolescent changes in hindbrain noradrenergic A2 neurons in male rats

During adolescence, the increased susceptibility to stress-related dysfunctions (e.g., anxiety, drug use, obesity) may be influenced by changes in the hormonal stress response mediated by the hypothalamic-pituitary-adrenal (HPA) axis. We have previously reported that restraint stress leads to significantly prolonged HPA responses in pre-adolescent compared to adult rats. Further, pre-adolescent animals exposed to restraint show greater levels of neural activation than adults in the paraventricular nucleus of the hypothalamus (PVN), a key nucleus integrating information from brain regions that coordinate HPA responses. Here, we examined the potential contribution of the noradrenergic A2 region of the nucleus of the solitary tract (NST) as a contributor to these age-dependent shifts in HPA reactivity. Specifically, we used double-labeled immunohistochemistry for FOS and dopamine-β-hydroxylase (DβH) to measure cellular activation and noradrenergic cells, respectively, before or after restraint stress in pre-adolescent (30days old) and adult (70days old) male rats. We also measured the density of DβH-immunoreactive fibers in the PVN as an index of noradrenergic inputs to this area. We found that pre-adolescent animals have a greater number of DβH-positive cells in the A2 region compared to adults, yet the number and percentage of double-labeled DβH/FOS cells were similar between these two ages. We found no differences between the ages in the staining intensity of DβH-immunoreactive fibers in the PVN. These data indicate there are adolescent-related changes in the number of noradrenergic cells in the A2 region, but no clear association between the increased stress reactivity prior to pubertal maturation and activation of A2 noradrenergic afferents to the PVN.

Neonatal overfeeding disrupts pituitary ghrelin signalling in female rats long-term; Implications for the stress response.

The hypothalamic-pituitary-adrenal (HPA) axis responses to psychological stress are exacerbated in adult female but not male rats made obese due to overfeeding in early life. Ghrelin, traditionally known for its role in energy homeostasis, has been recently recognised for its role in coordinating the HPA responses to stress, particularly by acting directly at the anterior pituitary where the growth hormone secretagogue receptor (GHSR), the receptor for acyl ghrelin, is abundantly expressed. We therefore hypothesised that neonatal overfeeding in female rats would compromise pituitary responsiveness to ghrelin, contributing to a hyperactive central stress responsiveness. Unlike in males where hypothalamic ghrelin signalling is compromised by neonatal overfeeding, there was no effect of early life diet on circulating ghrelin or hypothalamic ghrelin signalling in females, indicating hypothalamic feeding and metabolic ghrelin circuitry remains intact. However, neonatal overfeeding did lead to long-term alterations in the pituitary ghrelin system. The neonatally overfed females had increased neonatal and reduced adult expression of GHSR and ghrelin-O-acyl transferase (GOAT) in the pituitary as well as reduced pituitary responsiveness to exogenous acyl ghrelin-induced adrenocorticotropic hormone (ACTH) release in vitro. These data suggest that neonatal overfeeding dysregulates pituitary ghrelin signalling long-term in females, potentially accounting for the hyper-responsive HPA axis in these animals. These findings have implications for how females may respond to stress throughout life, suggesting the way ghrelin modifies the stress response at the level of the pituitary may be less efficient in the neonatally overfed.

HPA axis reactivity to pharmacologic and psychological stressors in euthymic women with histories of postpartum versus major depression

It is unclear whether women with a history of postpartum depression (PPD) have residual, abnormal hypothalamic-pituitary-adrenal (HPA) axis reactivity, as has been reported in major depression (MDD). Further unclear is whether the abnormalities in HPA axis reactivity associated with MDD represent a stable, underlying predisposition or a state-dependent phenomenon. This study sought the following: (1) to determine if euthymic postpartum women with a history of depression have an abnormal HPA axis reactivity to pharmacologic and psychological challenges and (2) to compare HPA reactivity in women with histories of PPD versus MDD. As a secondary objective, we wanted to determine the influence of trauma history on HPA axis function. Forty-five parous (12-24months postpartum), euthymic women with history of MDD (n = 15), PPD (n = 15), and controls (n = 15) completed pharmacologic (dexamethasone/corticotropin-releasing hormone (CRH) test [DEX/CRH]) and psychological (Trier social stress test [TSST]) challenges during the luteal phase. Outcome measures were cortisol and adrenocorticotropic hormone (ACTH) response after DEX/CRH, and blood pressure, heart rate, epinephrine, norepinephrine, and cortisol response during the TSST. All groups had robust cortisol and ACTH response to DEX/CRH and cortisol response to TSST. Groups did not differ significantly in cortisol or ACTH response to DEX/CRH or in blood pressure, heart rate, epinephrine, norepinephrine, or cortisol response to TSST. Cortisol/ACTH ratio did not differ significantly between groups. Trauma history was associated with decreased cortisol response to DEX/CRH in women with histories of MDD, which was not significant after correction (F 8,125, p = 0.02, Greenhouse-Geisser corrected p = 0.11). Currently euthymic women with histories of MDD or PPD did not demonstrate residual abnormal stress responsivity following administration of either a pharmacologic or psychological stressor.

Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity

ContextIncreased activities of the arginine-vasopressin (AVP) system and the hypothalamic-pituitary-adrenal (HPA) axis were shown to be associated with human obesity, but relationships between these systems in obesity remain unclear. ObjectivesTo assess HPA axis responsiveness and its relation to serum concentrations of the AVP-surrogate copeptin in subjects with obesity (OB) in comparison to non-obesity controls (NOC). MethodsIn a cross-sectional monocentric study, thirty-nine OB (f/m 25/14; age 36.5±10.0years; body mass index, BMI, 41.5±4.7kg/m2) were compared to twenty-two NOC (f/m 12/10; age 35.3±8.5years; BMI 23.1±2.4kg/m2), matched for age and sex. All individuals underwent the combined dexamethasone/CRH test. Main outcome measuresPlasma ACTH and cortisol curve indicators derived from the dex/CRH test (post-CRH concentrations 30min after 100μg CRH; maximum concentration, MAX; area-under-the-curve, AUC; ACTH/cortisol ratios). Copeptin was assessed in 1500h samples of the dex/CRH test (after 1.5mg of oral dexamethasone, prior to CRH administration). ResultsCopeptin serum concentrations were higher in OB (median [IQR]: OB 4.62 [2.60–5.88] vs. NOC 3.04 [2.52–4.29] pmol/l, P=0.04). Correspondingly, OB showed higher post-CRH cortisol concentrations (OB: 51.5 [25.9–159.3] vs. NOC: 28.6 [20.0–41.6] nmol/l, P=0.01) and a lower post-CRH ACTH/cortisol ratio (OB: 0.028 [0.016–0.053] vs. NOC: 0.048 [0.034–0.070] pmol/nmol, P<0.01). Serum copeptin was significantly associated with HPA responsiveness in OB (post-CRH ACTH: R=0.42, P<0.01), driven by OB men (post-CRH ACTH: R=0.76, P<0.01, post-CRH cortisol: R=0.64, P=0.02). All associations withstand adjustments for BMI and age. ConclusionsThe association between increased copeptin with ACTH and cortisol release suggests a potential mechanistic interaction of the AVP system with HPA activation in human obesity. The relation of copeptin and HPA responsiveness should be further validated in situations with pronounced HPA activation, such as depression or multiple sclerosis.

Lithium-induced malaise does not interfere with adaptation of the hypothalamic-pituitary-adrenal axis to stress

We have recently demonstrated that adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to repeated exposure to a stressor does not follow the rules of habituation and can be fully expressed after a single experience with severe stressors. In the present work we tested the hypothesis that adaptation could be impaired if animals experience malaise during initial exposure to the stressor. To this end, animals were allowed to drink saccharin for 30min before being exposed for 3h to immobilization on boards (IMO), a severe stressor; then they were given either saline or lithium ip after the first hour of IMO. Stress-naïve rats followed exactly the same procedure except IMO. Exposure to IMO caused a strong activation of the HPA axis whereas the effect of lithium was modest. Both IMO and lithium administration resulted in conditioned taste aversion to saccharin when evaluated 4days later. When all animals were exposed to IMO 6days later, reduced HPA response and less impact on body weight was observed in the two groups previously exposed to IMO as compared with stress-naïve rats. Therefore, lithium administration during the first IMO exposure did not affect adaptation of the HPA axis and weight gain. These results indicate that malaise per se only weakly activated the HPA axis and argue against the hypothesis that signs of physical malaise during exposure to the stressor could impair HPA adaptation.

Depressive symptom composites associated with cortisol stress reactivity in adolescents

BackgroundAltered hypothalamic-pituitary-adrenal (HPA) function is common in youth with major depressive disorder (MDD) but variability in the strength and direction of HPA alterations has prompted a search for symptom-based subtypes with unique neuroendocrine signatures. This study investigated the extent to which depressive symptom composites were differentially associated with cortisol responses to psychosocial stress. MethodsThis study examined salivary cortisol responses to the Trier Social Stress Test (TSST) in 145 adolescents who varied in their risk for MDD: 38 had current MDD; 35 were healthy but at high risk for MDD based on having one or both parents with unipolar MDD; and 72 were healthy youth with no personal or family history of a psychiatric disorder. Multilevel models examined within-person change in cortisol levels during a 2-h resting phase prior to the TSST and both linear and quadratic changes in cortisol levels following the TSST. ResultsAnticipatory cortisol reactivity was lower in MDD youth compared to low-risk youth, and in youth with higher compared to lower depressive symptom severity. Whereas affective symptoms were associated with increased anticipatory cortisol reactivity and more rapid recovery to the TSST, neurovegetative symptoms were associated with decreased anticipatory cortisol reactivity and slower recovery. LimitationsThe cross-sectional design does not permit inferences regarding temporal relations between cortisol responses and depressive symptom composites. ConclusionsThe present findings suggest that heterogeneity among studies examining HPA reactivity in depressed youth may be driven, in part, by differences in depressive symptom composites across samples.

Stress system dysregulation in pediatric generalized anxiety disorder associated with comorbid depression.

Because chronic stress is an important risk factor for anxiety states and depressive disorders, we studied hypothalamus-pituitary-adrenal (HPA) axis and sympathetic system activity via changes in cortisol and alpha amylase activity levels in pediatric generalized anxiety disorder (GAD) patients (n=26) with comorbid depression and a healthy comparison group (n=26). Morning plasma cortisol and diurnal profiles of salivary cortisol and salivary alpha amylase (sAA) activity were assessed, also reactivity of HPA-axis, sAA activity, and heart rate following a psychosocial stressor (Trier Social Stress Test for children). GAD patients with comorbid depression showed increased morning plasma and salivary cortisol levels, ameliorating throughout in-patient treatment, and higher sAA activity in their diurnal profile. Both HPA and sympathetic activity positively correlated with the severity of anxiety and depression. We also demonstrated a blunted HPA and sympathetic response to acute stress in patients. This pattern of neuroendocrine and sympathetic changes seems to be distinct from the one previously reported in pediatric patients with only social anxiety or depressive disorders. We propose morning plasma and saliva cortisol levels as potential physiological indicators for supporting the evaluation of symptoms' severity and treatment progress in children with GAD and comorbid depressive disorder.

Validation of autonomic and endocrine reactivity to a laboratory stressor in young children

The validation of laboratory paradigms that reliably induce a stress response [including hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) activation], is critical for understanding how children’s stress-response systems support emotional and cognitive function. Early childhood research to date is markedly limited, given the difficulty in establishing paradigms that reliably induce a cortisol response. Furthermore, research to date has not included a control condition or examined concurrent ANS reactivity. We addressed these limitations by characterizing the extent to which a modified matching task stressor paradigm induces HPA and ANS activation, beyond a closely matched control condition. Modifications include an unfamiliar and unfriendly assessor to increase the stressful nature of the task.Results validate the matching task as a laboratory stressor, with significant differences in HPA and ANS responsivity between conditions. The Stressor group exhibited a cortisol increase post-stressor, while the Control group was stable over time. Children in both conditions exhibited reduced parasympathetic activity to the first-half of the task, but in the second-half, only children in the Stressor condition, who were experiencing exaggerated signals of failure, exhibited further parasympathetic decline. The Stressor condition induced higher sympathetic activity (versus Control) throughout the task, with exaggerated second-half differences. Within the Stressor condition, responsivity was convergent across systems, with greater cortisol reactivity correlated with the magnitude of parasympathetic withdrawal and sympathetic engagement. Future research employing the matching task will facilitate understanding the role of HPA and ANS function in development.

COMTval158met polymorphism is associated with behavioral response and physiologic reactivity to socio-emotional stress in 4-month-old infants

Individual variability exists in infants’ socio-emotional stress regulation, in terms of behavioral response (i.e., negative emotionality) as well as magnitude and direction (i.e., increase or decrease) of hypothalamic-pituitary-adrenal (HPA) axis reactivity (i.e., salivary cortisol post-stress concentration). The catechol-O-methyltransferase polymorphism at codon 158 (COMTval158met) associates with stress regulation, but no evidence exists for infants. This study aimed to assess the association between COMTval158met and both negative emotionality and salivary cortisol reactivity to socio-emotional stress in 4-month-old infants. Sixty-nine infants were exposed to the Face-to-Face Still-Face (FFSF) paradigm. During the FFSF paradigm, socio-emotional stress is elicited by experimental manipulation of maternal responsiveness (i.e., Still-Face episode). A double-exposure FFSF with two Still-Face episodes was used to evaluate both behavioral response and HPA axis reactivity. Negative emotionality was 1-s microanalytically coded. Magnitude (i.e., area under the curve, AUC) and Direction (increase vs. decrease) of salivary cortisol post-stress concentration were assessed. COMTval158met genotype was categorized as val-homozygotes and met-carriers. Compared to val-homozygotes, met-carriers showed higher negative emotionality during the second Still-Face episode. AUC was greater in increaser met-carriers compared to val-homozygous infants. In addition, in the presence of an increasing HPA response, the met allele emerged as a specific risk condition in the face of repeated stress exposures. The present findings further extend previous studies conducted with children and adults suggesting that the COMT met allele might be involved in stress regulation during early infancy, especially in response to repeated socio-emotional stress exposure.

Cortisol Reactions During Family Conflict Discussions: Influences of Wives' and Husbands' Exposure to Family-of-Origin Aggression.

Though family-of-origin aggression (FOA) is a known risk for later emotional and physical problems in adulthood, little is known about how early exposure to aggression influences physiological reactivity in the domain-specific context of family conflict experienced as an adult. This study investigates whether report of FOA influences spouses' hypothalamic-pituitary-adrenal (HPA) axis responses during conflict discussions with their family-of-procreation and also whether current hostilities, observed during a family discussion, moderate those responses. In a sample of 91 families, we measured parents' HPA responses through salivary cortisol total output and discussion-related increase surrounding 15-minute hot-topic discussions that trained observers coded for family members' hostility. Partners' also reported on eight items assessing parent-to-child and interparental FOA. In models testing within-partner and across-partner influences, wives' higher FOA was linked with increases in their own and their husbands' cortisol. Spouses' own FOA showed significant interactions with the partners' hostility to affect total cortisol output, although in an attenuated direction for wives and a heightened direction for husbands. The results suggest that HPA responsiveness can elucidate links between family-of-origin experiences and adult intimate relationships and may be a factor in risk and resilience over time.

Cipadesin A, a bioactive ingredient of Xylocarpus granatum, produces antidepressant-like effects in adult mice

BackgroundXylocarpus granatum Koenig, widely used in folk medicine in southeast countries, has been reported to exert neuropharmacological activities as well as mood regulation. The neuroprotective activities of limonoids, riches in X. granatum, are poorly understood. Hypothesis/PurposeTo investigate the potential antidepressant-like effects and the underlying mechanisms of cipadesin A, one limonoid component, extracted from X. granatum, in acute stress-induced depression mouse models. Study designAntidepressant-like effects of cipadesin A were investigated through behavioral tests, and potential mechanism was assessed by neuroendocrine system. MethodsAntidepressant-like effects of cipadesin A (5, 15, 50mg/kg/day for 7days, intragastrically) were estimated through forced-swimming test (FST), tail suspension test (TST) and open field test (OFT). Effects of cipadesin A on hypothalamus-pituitary- adrenal (HPA) axis were evaluated by analysis of serum corticosterone (CORT) and adrenocorticotropic hormone (ACTH) using enzyme-linked immunosorbent assay (ELISA). ResultsCipadesin A administration significantly reduced the floating time in the FST and immobility time in the TST (15–50mg/kg). Cipadesin A dose-dependently increased the time in the central zone in the OFT (5–50mg/kg), without altering the locomotor activity. Moreover, repeated cipadesin A treatment significantly inhibited the increase levels of serum CORT (5–50mg/kg), ACTH (15–50mg/kg) following the forced swimming, but not in the absence of stress. ConclusionsCipadesin A has antidepressant-like activities in acute stressed mice model of depression, which likely occurs by inhibiting the HPA axis activity response to stress. These data support further exploration for developing cipadesin A as a potential agent to treat depression and anxiety disorders.

Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice

BackgroundAdverse childhood experiences (ACEs) are one of the greatest predictors of affective disorders for women. Periods of dynamic hormonal flux, including pregnancy, exacerbate the risk for affective disturbance and promote hypothalamic-pituitary-adrenal (HPA) axis dysregulation, a key feature of affective disorders. Little is understood as to how stress experienced in late childhood, defined as preadolescence, alters the programming unique to this period of brain maturation and its interaction with the hormonal changes of pregnancy and postpartum. MethodsPreadolescent female mice were exposed to chronic stress and examined for changes in their HPA axis during pregnancy and postpartum, including assessment of maternal-specific stress responsiveness and transcriptomics of the paraventricular nucleus of the hypothalamus. Translationally, pregnant women with low or high ACEs were examined for their maternal stress responsiveness. ResultsAs predicted, preadolescent stress in mice resulted in a significant blunting of the corticosterone response during pregnancy. Transcriptomic analysis of the paraventricular nucleus revealed widespread changes in expression of immediate early genes and their targets, supporting the likely involvement of an upstream epigenetic mechanism. Critically, in our human studies, the high ACE women showed a significant blunting of the HPA response. ConclusionsThis unique mouse model recapitulates a clinical outcome of a hyporesponsive HPA stress axis, an important feature of affective disorders, during a dynamic hormonal period, and suggests involvement of transcriptional regulation in the hypothalamus. These studies identify a novel mouse model of female ACEs that can be used to examine how additional life adversity may provoke disease risk or resilience.

Critical features of acute stress-induced cross-sensitization identified through the hypothalamic-pituitary-adrenal axis output.

Stress-induced sensitization represents a process whereby prior exposure to severe stressors leaves animals or humans in a hyper-responsive state to further stressors. Indeed, this phenomenon is assumed to be the basis of certain stress-associated pathologies, including post-traumatic stress disorder and psychosis. One biological system particularly prone to sensitization is the hypothalamic-pituitary-adrenal (HPA) axis, the prototypic stress system. It is well established that under certain conditions, prior exposure of animals to acute and chronic (triggering) stressors enhances HPA responses to novel (heterotypic) stressors on subsequent days (e.g. raised plasma ACTH and corticosterone levels). However, such changes remain somewhat controversial and thus, the present study aimed to identify the critical characteristics of the triggering and challenging stressors that affect acute stress-induced HPA cross-sensitization in adult rats. We found that HPA cross-sensitization is markedly influenced by the intensity of the triggering stressor, whereas the length of exposure mainly affects its persistence. Importantly, HPA sensitization is more evident with mild than strong challenging stressors, and it may remain unnoticed if exposure to the challenging stressor is prolonged beyond 15 min. We speculate that heterotypic HPA sensitization might have developed to optimize biologically adaptive responses to further brief stressors.

The Role of ACTH and Corticosteroids for Sepsis and Septic Shock: An Update.

Sepsis is a common disorder associated with high morbidity and mortality. It is now defined as an abnormal host response to infection, resulting in life-threatening dysfunction of organs. There is evidence from in vitro and in vivo experiments in various animal models and in patients that endotoxin or sepsis may directly and indirectly alter the hypothalamic–pituitary–adrenal response to severe infection. These alterations may include necrosis or hemorrhage or inflammatory mediator-mediated decreased ACTH synthesis, steroidogenesis, cortisol delivery to tissues, clearance from plasma, and decreased sensitivity of tissues to cortisol. Disruption of the hypothalamic–pituitary–adrenal axis may translate in patients with sepsis into cardiovascular and other organ dysfunction, and eventually an increase in the risk of death. Exogenous administration of corticosteroids at moderate dose, i.e., <400 mg of hydrocortisone or equivalent for >96 h, may help reversing sepsis-associated shock and organ dysfunction. Corticosteroids may also shorten the duration of stay in the ICU. Except for increased blood glucose and sodium levels, treatment with corticosteroids was rather well tolerated in the context of clinical trials. The benefit of treatment on survival remains controversial. Based on available randomized controlled trials, the likelihood of survival benefit is greater in septic shock versus sepsis patients, in sepsis with acute respiratory distress syndrome or with community-acquired pneumonia versus patients without these conditions, and in patients with a blunted cortisol response to 250 μg of ACTH test versus those with normal response.

HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis.

The onset of psychosis is thought to involve interactions between environmental stressors and the brain, with cortisol as a putative mediator. We examined the relationship between the cortisol stress response and brain structure in subjects at ultra-high risk (UHR) for psychosis. Waking salivary cortisol was measured in 22 individuals at UHR for psychosis and 17 healthy controls. Grey matter volume was assessed using magnetic resonance imaging at 3 T. The relationship between the stress response and grey matter volume was investigated using voxel-based analyses. Our predictions of the topography of cortisol action as a structural brain modulator were informed by measures of brain glucocorticoid and mineralcorticoid receptor distribution obtained from the multimodal neuroanatomical and genetic Allen Brain Atlas. Across all subjects, reduced responsivity of the hypothalamus–pituitary–adrenal (HPA) axis was correlated with smaller grey matter volumes in the frontal, parietal and temporal cortex and in the hippocampus. This relationship was particularly marked in the UHR subjects in the right prefrontal, left parahippocampal/fusiform and parietal cortices. The subgroup that subsequently developed psychosis showed a significant blunting of HPA stress response, observed at trend level also in the whole UHR sample. Altered responses to stress in people at high risk of psychosis are related to reductions in grey matter volume in areas implicated in the vulnerability to psychotic disorders. These areas may represent the neural components of a stress vulnerability model.

Depression and anxiety predict sex-specific cortisol responses to interpersonal stress

Clinical theories posit interpersonal stress as an important factor in the emergence and exacerbation of depression and anxiety, while neuroendocrine research confirms the association of these syndromes with dysregulation in a major stress response system, the hypothalamic-pituitary-adrenal (HPA) axis. However, the proposal that depression and anxiety symptoms and diagnoses are associated with problematic HPA responses to close relationship stress has not been directly tested. We examined 196 heterosexual dating couples’ depression and anxiety symptoms and diagnoses, assessed with questionnaires and diagnostic interviews, in relation to cortisol responses to discussion of an unresolved relationship conflict. Participants provided seven salivary samples in anticipation of and directly following the discussion, and throughout an hour-long recovery period, which were assayed for cortisol. Multilevel models of the HPA response predicted by symptoms or diagnoses showed that women’s depressive symptoms predicted attenuated cortisol levels, with a flatter response curve. In contrast, men’s depression symptoms and women’s anxiety symptoms and diagnoses predicted higher cortisol levels. These findings highlight the importance of examining sex differences in responses to interpersonal stressors for understanding HPA dysregulation in internalizing psychopathology.

The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression

Background and aimsDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in irritable bowel syndrome (IBS). Enhanced HPA axis response has been associated with reduced glucocorticoid receptor (GR) mediated negative feedback inhibition. We aimed to study the effects of IBS status, sex, or presence of early adverse life events (EAL) on the cortisol response to corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and on GR mRNA expression in peripheral blood mononuclear cells (PBMCs). MethodsRome III+ IBS patients and healthy controls underwent CRF (1μg/kg ovine) and ACTH (250μg) stimulation tests with serial plasma ACTH and cortisol levels measured (n=116). GR mRNA levels were measured using quantitative PCR (n=143). Area under the curve (AUC) and linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups. ResultsThere were divergent effects of IBS on the cortisol response to ACTH by sex. In men, IBS was associated with an increased AUC (p=0.009), but in women AUC was blunted in IBS (p=0.006). Men also had reduced GR mRNA expression (p=0.007). Cumulative exposure to EALs was associated with an increased HPA response. Lower GR mRNA was associated with increased pituitary HPA response and increased severity of overall symptoms and abdominal pain in IBS. ConclusionThis study highlights the importance of considering sex in studies of IBS and the stress response in general. Our findings also provide support for PBMC GR mRNA expression as a peripheral marker of central HPA response.

Stress-induced oxytocin release and oxytocin cell number and size in prepubertal and adult male and female rats

Studies indicate that adolescent exposure to stress is a potent environmental factor that contributes to psychological and physiological disorders, though the mechanisms that mediate these dysfunctions are not well understood. Periadolescent animals display greater stress-induced hypothalamic–pituitary–adrenal (HPA) axis responses than adults, which may contribute to these vulnerabilities. In addition to the HPA axis, the hypothalamo-neurohypophyseal tract (HNT) is also activated in response to stress. In adults, stress activates this system resulting in secretion of oxytocin from neurons in the supraoptic (SON) and paraventricular (PVN) nuclei. However, it is currently unknown whether a similar or different response occurs in prepubertal animals. Given the influence of these hormones on a variety of emotional behaviors and physiological systems known to change as an animal transitions into adulthood, we investigated stress-induced HPA and HNT hormonal responses before and after stress, as well as the number and size of oxytocin-containing cells in the SON and PVN of prepubertal (30d) and adult (70d) male and female rats. Though we found the well-established protracted adrenocorticotropic hormone and corticosterone response in prepubertal males and females, only adult males and prepubertal females showed a significant stress-induced increase in plasma oxytocin levels. Moreover, though we found no pubertal changes in the number of oxytocin cells, we did find a pubertal-related increase in oxytocin somal size in both the SON and PVN of males and females. Taken together, these data indicate that neuroendocrine systems can show different patterns of stress reactivity before and after adolescent development and that these responses can be further modified by sex. Given the impact of these hormones on a variety of systems, it will be imperative to further explore these changes in hormonal stress reactivity and their role in adolescent health.

Parachute Jumping Induces More Sympathetic Activation Than Cortisol Secretion in First-Time Parachutists.

Background:The word “stress” describes the status of the body affected by external or internal forces, or “stressors”, threatening to alter its dynamic balance or homeostasis. The adaptive changes which occur in reply to stressors are either behavioral or physical. Once a given threshold is surpassed, a systemic reaction takes place involving the “stress system” in the brain together with its peripheral components, the hypothalamic-pituitary-adrenal axis and autonomic sympathetic.Objectives:Stress induces an activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. The purpose of this study was to investigate whether the SNS and the HPA axis would show parallel or divergent stress response patterns in a session of first parachute jump.Patients and Methods:Activation of the SNS was evaluated by dosage of salivary alpha-amylase, galvanic skin responses, and heart rate in seven male novice parachutists. Activation of HPA axis was tested by dosage of cortisol. These variables were measured before and 1 minute and 90 minute after the jump.Results:All variables reached a peak at 1 minute post-jump. Salivary alpha-amylase, galvanic skin responses and heart rate did not return to basal value at 90 minutes post-jump, while cortisol returned to basal value at 90 minutes post-jump.Conclusions:This evidence indicates that parachute jumping is accompanied by a dissociation of SNS and HPA response patterns in novice parachutists, showing a slower recovery in sympathetic activity than in cortisol secretion.