Hypothalamic-pituitary-adrenal Function Research Articles

The Effects of Stress on Cognitive Aging, Physiology and Emotion (ESCAPE) Project.

BackgroundDespite evidence that psychological stress is an important risk factor for age-related cognitive loss, little research has directly evaluated psychological and physiological mediators of the relationship between stressful experiences and cognitive function. A key objective of the ESCAPE (Effects of Stress on Cognitive Aging, Physiology, and Emotion) project is to evaluate whether engaging in stress-related unconstructive repetitive thought (URT) is a pathway through which stressful experiences negatively affect cognitive health over the short- and long-term. Over the short-term, we hypothesize that engaging in URT will deplete attentional resources and result in worse cognitive performance in daily life. Over the long-term, we expect that the effects of chronic stress, from repeated exposure to stressors and regular engagement in URT, will be apparent in dysregulated hypothalamic-pituitary-adrenal (HPA) axis function and inflammation. Over time, stress-related physiological dysregulation will result in accelerated cognitive decline.Methods/DesignThis study utilizes a prospective longitudinal measurement-burst design. A systematic probability sample of participants aged 25 to 65 is recruited from residents of the Bronx, NY. Consenting participants complete a baseline assessment and follow-up waves at 9, 18, and 27 months post-baseline. At each wave, participants complete a 14 day measurement burst of brief surveys and cognitive assessments delivered via study smartphones during daily life. Participants provide saliva samples four times each day for five days during the measurement burst and fasting blood samples at the end of each burst from which cortisol and dehydroepiandrosterone sulfate (DHEAS), circulating inflammatory markers, and stimulated inflammatory responses to lipopolysaccharide in whole blood are determined.DiscussionThis study takes a multi-pronged approach to assessing stress (i.e., early adversity, chronic strains, major events, daily hassles), psychological mediators (e.g., URT), biological mechanisms (i.e., HPA function, inflammation) and outcomes across different time-scales (i.e., momentary cognitive performance, cognitive decline across years). The systematic probability sample is locally representative and can be compared with national norms on key markers of health and well-being. The findings will improve our understanding of how environmental, psychological, and physiological stress-related influences accumulate to affect cognitive health and identify potential targets (e.g., URT, inflammation) for prevention and intervention promoting cognitive health.

Stress induced by the socially evaluated cold-pressor test cause equivalent deficiencies of sensory gating in male subjects with schizophrenia and healthy controls

It is known that patients with schizophrenia show a deficiency in the prepulse inhibition reflex (PPI). These patients display abnormalities in autonomic nervous system and hypothalamic–pituitary–adrenal function and may have an altered sensitivity to stress. To date, no studies have been carried out to determine the effect of acute stress on the PPI. We investigated whether there was a differential response in reactivity to acute stress caused by the socially evaluated cold-pressor test (SECPT) in a sample of 58 chronic male patients with schizophrenia and 28 healthy control subjects. PPI, salivary cortisol and heart rate (HR) were measured. The patients were evaluated in two sessions (with and without the SECPT) 72h apart and basal measurements were carried out and 30min post-startle probe. We found an increase in salivary cortisol levels and the HR with SECPT condition in both groups and a significantly lower PPI% in patients with schizophrenia. The most relevant findings of this study are that the impairment of the PPI is increased by stress. Stress-induced increase in cortisol in both groups, mainly in healthy control group which allows us to hypothesize that at least such deterioration may be due to the hypercortisolemia caused by the SECPT.

Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

BackgroundDepressed patients who do not respond to second-line antidepressant drugs are characterised as suffering from treatment-refractory depression (TRD). Chronic psychosocial stress hypothalamic–pituitary–adrenal (HPA) axis dysfunction is associated with attenuated responses to antidepressants. Corticosteroid co-administration reduces the increase in forebrain 5-hydroxytryptamine with selective serotonin reuptake inhibitors, whereas antiglucocorticoids have the opposite effect. A Cochrane review suggesting that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD included a pilot study of the cortisol synthesis inhibitor, metyrapone. TheAntiglucocorticoid augmentation of antiDepressants inDepression (ADD Study) was a multicentre randomised placebo-controlled trial of metyrapone augmentation of serotonergic antidepressants in patients with TRD.ObjectiveTo determine the efficacy and safety of augmentation of standard serotonergic antidepressants with metyrapone 500 mg twice a day for 3 weeks in patients with TRD.MethodsA total of 165 patients with moderate to severe TRD aged 18–65 years were randomised to metyrapone 500 mg twice daily or placebo for 3 weeks, in addition to ongoing serotonergic antidepressants. The primary outcome was improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation estimated using analysis of covariance. Secondary outcomes included the degree of persistence of treatment effect for up to 6 months, and also safety and tolerability of metyrapone. ADD included substudies investigating the potential mechanism of action of metyrapone, and utilised a comparator group of healthy participants.ResultsThe estimated mean difference for each of our study outcomes between randomised groups, 5 weeks post randomisation (allowing for variation between centres and whether or not patients originate from primary or secondary care) was MADRS –0.51 [95% confidence interval (CI) –3.48 to 2.46]; Beck Depression Inventory (BDI) –2.65 (95% CI –6.41 to 1.10); Clinical Anxiety Scale 0.46 (95% CI –1.20 to 2.12); State–Trait Anxiety Inventory 1.2 (95% CI –0.6 to 3.0); European Quality of Life-5 Dimensions 0.015 (95% CI –0.069 to 0.099); EuroQol visual analogue scale 5.6 (95% CI –0.7 to 12.0); and Young Mania Rating Scale –0.04 (95% CI –0.52 to 0.45). The differences were not statistically significant and were small in relation to the change from baseline in both groups that was observed immediately after completion of therapy. Endocrinological data required for compliance assessment are not yet available. HPA function, similar in patients and control subjects, was not associated with differing clinical responses. Neuropsychological impairments were found, along with changes in brain structure and function, but no effect of metyrapone was seen on these measures.DiscussionThe inclusion criteria led to the sample being broadly representative of patients with TRD, within the UK NHS, with high anxiety and BDI scores. Metyrapone augmentation of antidepressants is not efficacious for outpatients with TRD who are moderately depressed. There was no obvious benefit associated with the use of metyrapone, either on the primary outcome or over the period of follow-up, and this negative result extended to other secondary outcomes. Metyrapone was well tolerated. There were no serious adverse events attributable to it and adverse events were as common with the placebo. HPA axis function was not associated with differing clinical or neuropsychological outcomes.ConclusionsThe results of the study suggest that although metyrapone augmentation was well tolerated, it is ineffective in the treatment of refractory depression. This finding is contrary to a previous proof of principle study in more acutely unwell patients. Future research should consider whether or not antiglucocorticoid treatments, such as metyrapone, should be targeted at patients with confirmed hypercortisolaemia.Trial registrationCurrent Controlled Trials ISRCTN45338259.Funding detailsThis study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

Early rearing experience is associated with vasopressin immunoreactivity but not reactivity to an acute non-social stressor in the prairie vole

The early life experiences of an organism have the potential to alter its developmental trajectories. Perhaps one of the most powerful influences during this period is the parent–offspring relationship. Previous work in several mammalian species has demonstrated that parental care in early life and specifically maternal behavior can influence several adult outcomes in offspring, including affiliative and aggressive behavior, parental behavior, hypothalamic–pituitary–adrenal (HPA) functioning and risk of psychopathology. We have previously demonstrated that naturally occurring variation in the type and amount of care given to offspring in a biparental species, the prairie vole (Microtus ochrogaster), is related to social, anxiety-like, aggressive behaviors as well as HPA response to chronic and acute social stressors. Here we aim to determine the effects of early biparental care on HPA functioning and the interaction between early care and later reactivity to a forced swim test, an acute non-social stressor. Behavior during the swim test as well as several indicators of HPA activity, including plasma corticosterone (CORT), corticotropin releasing hormone immunoreactivity (CRH-ir), and vasopressin immunoreactivity (AVP-ir) were measured. Results here indicate an effect of early experience on AVP-ir but not CRH-ir or plasma CORT. There were no differences in CORT levels between high-contact (HC) and low-contact (LC) males or females for either control animals or after a swim stressor. CRH-ir was higher in the central amygdala following a swim test but was not influenced by early care. However, AVP-ir was not influenced by exposure to a swim stressor but was affected by early parental care in a sex-dependent manner. Female HC offspring had increased AVP-ir in the SON while HC male offspring had decreased AVP-ir in the PVN compared to their LC counterparts. The differential response of CRH and AVP to early experience and later stress, and the lack of an interaction between early care rearing and later adult stress, suggest an independence in response of some components of the HPA system. In addition, these findings expand our understanding of the relationship between naturally occurring variation in early biparental care and sexual dimorphisms in adult outcomes.

Influence of early trauma on features of schizophrenia.

This proof-of-concept study examined if early trauma influences features of schizophrenia, consistent with hypothalamic-pituitary-adrenal (HPA) axis activation. Early trauma and current perceived stress were assessed in 28 treated schizophrenia cases, along with salivary cortisol, brain volumes, cognition and symptoms. Early trauma predicted more positive (r = .66, P = .005) and dysthymia symptoms (r -.65, P = .007), but less negative symptoms (r = -.56, P = .023), as well as reduced whole brain volumes (r = .50, P = .040) and increased amygdala to whole brain volume ratios (r = .56, P = .018). Larger volume reductions accompanied cortisol levels: evening values predicted smaller whole brain and hippocampal volumes whereas afternoon levels only significantly predicted smaller brain volumes in women. Sex differences were demonstrated between early trauma and cognition, with better cognition in traumatized women than other women and no male effects. Current perceived stress was related to dysthymia (especially in women) and diminished sense of purpose and social drive (especially in men). These results suggest that early trauma and current stress impact features of schizophrenia, consistent with stress sensitization and increased dopamine activity for treatment refractory positive symptoms, as well as the cascade of increased morning cortisol, reduced brain volumes, and depressive and deficit symptoms. Conversely, cognitive deficits and negative symptoms may arise from a distinct diathesis. The sex differences accord with the literature on human HPA function and stress responses. Early trauma may be a stressor in the aetiopathophysiology of schizophrenia, particularly for cases with treatment refractory positive symptoms, and may guide future treatment development.

Dysregulated hypothalamic-pituitary-adrenal axis function contributes to altered endocrine and neurobehavioral responses to acute stress.

Organisms react to environmental challenges by activating a coordinated set of brain–body responses known as the stress response. These physiological and behavioral countermeasures are, in large part, regulated by the neuroendocrine hypothalamic–pituitary–adrenal (HPA) axis. Normal functioning of the HPA axis ensures that an organism responds appropriately to altered environmental demands, representing an essential system to promote survival. Over the past several decades, increasing evidence supports the hypothesis that disruption of the HPA axis can lead to dysregulated stress response phenotypes, exacting a physiological cost on the organism commonly referred to as allostatic load. Furthermore, it has been recognized that high allostatic load can contribute to increased vulnerability of the organism to further challenges. This observation leads to the notion that disrupted HPA function and resulting inappropriate responses to stressors may underlie many neuropsychiatric disorders, including depression and anxiety. In the present set of studies, we investigate the role of both the normally functioning and disrupted HPA axis in the endocrine, neural, and behavioral responses to acute stress. Using a model of non-invasive chronic corticosterone treatment in mice, we show that dysregulating the normal function of the HPA leads to a mismatch between the hormonal and neural response to acute stress, resulting in abnormal behavioral coping strategies. We believe this model can be leveraged to tease apart the mechanisms by which altered HPA function contributes to neurobehavioral dysregulation in response to acute stress.

High fat feeding is associated with stimulation of the hypothalamic-pituitary-adrenal axis and reduced anxiety in the rat

Previous studies have shown that diet-induced obesity is associated with insulin resistance and impaired feedback control of the hypothalamic-pituitary-adrenal (HPA) axis. The objective of this study was to test the hypothesis that hyper-secretion of glucocorticoid, evoked by feeding rats a high fat (HF) diet for 12 weeks, also influences behavioural and neural responses to the elevated plus-maze (EPM) test of anxiety. HF-fed animals exhibited anxiolytic-like behaviour in the EPM but were also hyperactive in this test. Covariant analysis established that the anxiolytic-like behaviour was not secondary to the increase in activity. The HF diet significantly increased basal levels of plasma corticosterone. The groups exposed to the EPM also displayed increased plasma corticosterone levels compared to the relevant control group, although the increment was smaller in the HF-fed animals. Glucocorticoid receptor (GR) immunoreactivity in the cytoplasmic fraction of parietal cortex and hypothalamus and the particulate fraction of the parietal cortex were increased by HF feeding. The behavioural changes evoked by HF feeding did not correlate significantly with changes in GR immunoreactivity in each treatment group or 5-HT turnover in the brain areas studied. It is concluded that anxiolytic properties evoked in the EPM by high fat feeding are unlikely to be related to the changes in HPA function seen in animals fed this diet.

Children's cortisol and salivary alpha-amylase interact to predict attention bias to threatening stimuli

Physiological responses to threat occur through both the autonomic nervous system (ANS) and the hypothalamic pituitary adrenal (HPA) axis. Activity in these systems can be measured through salivary alpha-amylase (sAA) and salivary cortisol, respectively. Theoretical work and empirical studies have suggested the importance of examining the coordination of these systems in relation to cognitive functioning and behavior problems. Less is known, however, about whether these systems interactively predict more automatic aspects of attention processing such as attention toward emotionally salient threatening stimuli. We used a dot probe task to assess attention bias toward threatening stimuli in 347 kindergarten children. Cortisol and sAA were assayed from saliva samples collected prior to children's participation in assessments on a subsequent day. Using regression analyses, we examined relations of sAA and cortisol to attention bias. Results indicate that cortisol and sAA interact in predicting attention bias. Higher levels of cortisol predicted greater bias toward threat for children who had high levels of sAA, but predicted greater bias away from threat for children who had low levels of sAA. These results suggest that greater symmetry in HPA and ANS functioning is associated with greater reliance on automatic attention processes in the face of threat.

Relational victimization, friendship, and adolescents' hypothalamic-pituitary-adrenal axis responses to an in vivo social stressor-ERRATUM.

Adolescents' peer experiences may have significant associations with biological stress-response systems, adding to or reducing allostatic load. This study examined relational victimization as a unique contributor to reactive hypothalamic-pituitary-adrenal (HPA) axis responses as well as friendship quality and behavior as factors that may promote HPA recovery following a stressor. A total of 62 adolescents (ages 12-16; 73% female) presenting with a wide range of life stressors and adjustment difficulties completed survey measures of peer victimization and friendship quality. Cortisol samples were collected before and after a lab-based interpersonally themed social stressor task to provide measures of HPA baseline, reactivity, and recovery. Following the stressor task, adolescents discussed their performance with a close friend; observational coding yielded measures of friends' responsiveness. Adolescents also reported positive and negative friendship qualities. Results suggested that higher levels of adolescents' relational victimization were associated with blunted cortisol reactivity, even after controlling for physical forms of victimization and other known predictors of HPA functioning (i.e., life stress or depressive symptoms). Friendship qualities (i.e., low negative qualities) and specific friendship behaviors (i.e., high levels of responsiveness) contributed to greater HPA regulation; however, consistent with theories of rumination, high friend responsiveness in the context of high levels of positive friendship quality contributed to less cortisol recovery. Findings extend prior work on the importance of relational victimization and dyadic peer relations as unique and salient correlates of adaptation in adolescence.

Abstract 2971: Hypothalamic beta-endorphin neuron transplants modulate colonic proinflammatory cytokines and epithelial-mesenchymal transition factors and suppress preneoplastic and neoplastic lesions in 1,2-dimethylhydrazine-induced colon cancer

Abstract In recent years, experimental studies suggest that impaired hypothalamic-pituitary-adrenal (HPA) axis modulates colonic motor function and pathologies. However, little is known about the functional role of beta-endorphin (BEP) neural populations, which control HPA function, on colonic function in response to inflammation or injury of colon. Based on our previous published work showing that transplantation of BEP neurons in the hypothalamus suppress tumor growth and development in numerous animal models including prostate, breast and liver cancer, we determined whether transplantation of BEP neurons into the hypothalamus suppress preneoplastic and neoplastic lesions and modulate colonic proinflammatory cytokines and epithelial-mesenchymal transition (EMT) by enhancing innate immune response. Colon cancer (injury) was induced in Sprague-Dawley male rats with BEP or control cell transplants by injecting 1,2-dimethylhydrazine (DMH) for 16 weeks. Our results reveled that control groups developed tumors at 100% incidence, while BEP transplanted animals developed tumor only at 30% rate. The mean volume of tumor in colon was smaller in BEP neurons transplanted rats than in control cells transplanted rats. Furthermore, histological results revealed that BEP neurons transplanted animals had lesser histopathological lesions such as aberrant crypt foci (ACF) and adenocarcinoma development in the colon than the control groups. In addition, immunohistochemical and western blot analyses of colon showed that DMH treatment increased expression of Ki-67, TNF-α and NF-κB more in cortical cells transplanted animals than in BEP cell-treated groups. Also, splenic NK cells cytolytic proteins such as perforin, granzyme B and IFN-γ levels in BEP neurons transplanted rats were higher when compared to control groups. Interestingly, BEP neurons transplantation repressed the expression of Snail and Twist, transcription factors linked to EMT, and concomitantly maintained E-cadherin, an epithelial cell marker expression. These data suggest that the antitumor action of BEP neuron transplants are due to the suppression of inflammatory milieu and EMT as well as the activation of NK cells mediated innate immune responses. These data also identify the potential use of BEP cell therapy to combat tumor growth and progression. (Supported by R37 AA08757) Citation Format: Dipak K. Sarkar, Sengottuvelan Murugan, Yatee Dave, Ankush Rakhit. Hypothalamic beta-endorphin neuron transplants modulate colonic proinflammatory cytokines and epithelial-mesenchymal transition factors and suppress preneoplastic and neoplastic lesions in 1,2-dimethylhydrazine-induced colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2971. doi:10.1158/1538-7445.AM2014-2971

Calorie restriction and corticosterone elevation during lactation can each modulate adult male fear and anxiety-like behaviour

Early life events, such as calorie restriction (CR) and elevated glucocorticoids, can calibrate the lifelong behavioural and physiological profile of an individual. Stress reactivity in adulthood is particularly sensitive to early life events; however, the consequence to fear and anxiety-like behaviour is less clear. Consequently, the current study sought to examine the effects of post-natal CR and glucocorticoid elevation, long considered powerful programming stimuli, on the subsequent fear and anxiety behaviour of the adult offspring. Rat dams received either corticosterone (200μg/ml) supplementation in drinking water (CORT) or a 25% CR from post-natal day (PND) 1 to 11. Responses to the elevated plus maze (EPM), open field and a predator odour (TMT; 2,5-dihydro-2,4,5-trimethylthiazoline) were characterised in the adult male offspring. Both treatment conditions resulted in enhanced fear responses to TMT, characterised by heightened risk assessment and increased avoidance of TMT. CORT nursed offspring further demonstrated an anxiogenic profile in the open field. Basal hypothalamic–pituitary–adrenal function was unchanged in CORT adult offspring, whilst corticosterone concentration was elevated by post-natal CR. CR and CORT treated dams both exhibited greater anxiety-like behaviour in the EPM. A modest and temporary enhancement of maternal care was observed in CR and CORT treated dams, with CR dams further exhibiting rapid pup retrieval latencies. The results indicate enhanced emotionality in the adult male progeny of dams exposed to CR and corticosterone supplementation during the post-natal period. The modest enhancement of maternal care observed by both treatments is unlikely to have influenced the behavioural profile of the offspring.

Relational victimization, friendship, and adolescents' hypothalamic-pituitary-adrenal axis responses to an in vivo social stressor.

Adolescents' peer experiences may have significant associations with biological stress-response systems, adding to or reducing allostatic load. This study examined relational victimization as a unique contributor to reactive hypothalamic-pituitary-adrenal (HPA) axis responses as well as friendship quality and behavior as factors that may promote HPA recovery following a stressor. A total of 62 adolescents (ages 12-16; 73% female) presenting with a wide range of life stressors and adjustment difficulties completed survey measures of peer victimization and friendship quality. Cortisol samples were collected before and after a lab-based interpersonally themed social stressor task to provide measures of HPA baseline, reactivity, and recovery. Following the stressor task, adolescents discussed their performance with a close friend; observational coding yielded measures of friends' responsiveness. Adolescents also reported positive and negative friendship qualities. Results suggested that higher levels of adolescents' relational victimization were associated with blunted cortisol reactivity, even after controlling for physical forms of victimization and other known predictors of HPA functioning (i.e., life stress or depressive symptoms). Friendship qualities (i.e., low negative qualities) and specific friendship behaviors (i.e., high levels of responsiveness) contributed to greater HPA regulation; however, consistent with theories of rumination, high friend responsiveness in the context of high levels of positive friendship quality contributed to less cortisol recovery. Findings extend prior work on the importance of relational victimization and dyadic peer relations as unique and salient correlates of adaptation in adolescence.

Evaluating the stress response as a bioindicator of sub-lethal effects of crude oil exposure in wild house sparrows (Passer domesticus).

Petroleum can disrupt endocrine function in humans and wildlife, and interacts in particularly complex ways with the hypothalamus-pituitary-adrenal (HPA) axis, responsible for the release of the stress hormones corticosterone and cortisol (hereafter CORT). Ingested petroleum can act in an additive fashion with other stressors to cause increased mortality, but it is not clear exactly why—does petroleum disrupt feedback mechanisms, stress hormone production, or both? This laboratory study aimed to quantify the effects of ingested Gulf of Mexico crude oil on the physiological stress response of house sparrows (Passer domesticus). We examined baseline and stress-induced CORT, negative feedback, and adrenal sensitivity in house sparrows given a 1% oil or control diet (n = 12 in each group). We found that four weeks on a 1% oil diet did not alter baseline CORT titers or efficacy of negative feedback, but significantly reduced sparrows' ability to secrete CORT in response to a standardized stressor and adrenocorticotropin hormone injection, suggesting that oil damages the steroid-synthesizing cells of the adrenal. In another group of animals on the same 1% oil (n = 9) or control diets (n = 8), we examined concentrations of eight different blood chemistry parameters, and CORT in feathers grown before and during the feeding experiments as other potential biomarkers of oil exposure. None of the blood chemistry parameters differed between birds on the oil and control diets after two or four weeks of feeding, nor did feather CORT differ between the two groups. Overall, this study suggests that the response of CORT to stressors, but not baseline HPA function, may be a particularly sensitive bioindicator of sub-lethal chronic effects of crude oil exposure.

Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats

Exposure to stress during childhood and adolescence increases vulnerability to developing several psychopathologies in adulthood and alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis, the prototypical stress system. Rodent models of juvenile stress appear to support this hypothesis because juvenile stress can result in reduced activity/exploration and enhanced anxiety, although results are not always consistent. Moreover, an in-depth characterization of changes in the HPA axis is lacking. In the present study, the long-lasting effects of juvenile stress on adult behavior and HPA function were evaluated in male rats. The juvenile stress consisted of a combination of stressors (cat odor, forced swim and footshock) during postnatal days 23–28. Juvenile stress reduced the maximum amplitude of the adrenocorticotropic hormone (ACTH) levels (reduced peak at lights off), without affecting the circadian corticosterone rhythm, but other aspects of the HPA function (negative glucocorticoid feedback, responsiveness to further stressors and brain gene expression of corticotrophin-releasing hormone and corticosteroid receptors) remained unaltered. The behavioral effects of juvenile stress itself at adulthood were modest (decreased activity in the circular corridor) with no evidence of enhanced anxiety. Imposition of an acute severe stressor (immobilization on boards, IMO) did not increase anxiety in control animals, as evaluated one week later in the elevated-plus maze (EPM), but it potentiated the acoustic startle response (ASR). However, acute IMO did enhance anxiety in the EPM, in juvenile stressed rats, thereby suggesting that juvenile stress sensitizes rats to the effects of additional stressors.

Chronic ethanol exposure increases the non-dominant glucocorticoid, corticosterone, in the near-term pregnant guinea pig

Maternal-fetal signaling is critical for optimal fetal development and postnatal outcomes. Chronic ethanol exposure alters programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in a myriad of neurochemical and behavioral alterations in postnatal life. Based on a recent study which showed that human intra-partum fetal stress increased fetal secretion of corticosterone, the non-dominant glucocorticoid, this investigation tested the hypothesis that an established model of HPA axis programming, chronic maternal ethanol administration to the pregnant guinea pig, would result in preferential elevation of corticosterone, which is also the non-dominant glucocorticoid. Starting on gestational day (GD) 2, guinea pigs received oral administration of ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding. Each treatment was administered daily and continued until GD 45, 55, or 65 (approximately 3 days pre-term), when pregnant animals were euthanized and fetuses delivered by Caesarean section. Maternal and fetal plasma samples were collected. After sample preparation (protein precipitation and C-18 solid phase extraction), plasma cortisol and corticosterone concentrations were determined simultaneously by liquid chromatography coupled to tandem mass spectrometry. As predicted, chronic ethanol exposure increased both fetal and maternal plasma corticosterone concentration in late gestation. In contrast, plasma cortisol did not differ across maternal treatments in maternal or fetal samples. The plasma concentration of both maternal glucocorticoids increased with gestational age. Thus, corticosterone, the non-dominant glucocorticoid, but not cortisol, was elevated by chronic ethanol exposure, which may have effects on HPA function in later life.

Enhancing offspring hypothalamic-pituitary-adrenal (HPA) regulation via systematic novelty exposure: the influence of maternal HPA function.

In the rat, repeated brief exposures to novelty early in life can induce long-lasting enhancements in adult cognitive, social, emotional, and neuroendocrine function. Family-to-family variations in these intervention effects on adult offspring are predicted by the mother’s ability to mount a rapid corticosterone (CORT) response to the onset of an acute stressor. Here, in Long-Evans rats, we investigated whether neonatal and adulthood novelty exposure, each individually and in combination, can enhance offspring hypothalamic-pituitary-adrenal (HPA) regulation. Using a 2 × 2 within-litter design, one half of each litter were exposed to a relatively novel non-home environment for 3-min (Neo_Novel) daily during infancy (PND 1–21) and the other half of the litter remained in the home cage (Neo_Home); we further exposed half of these two groups to early adulthood (PND 54–63) novelty exposure in an open field and the remaining siblings stayed in their home cages. Two aspects of HPA regulation were assessed: the ability to maintain a low level of resting CORT (CORTB) and the ability to mount a large rapid CORT response (CORTE) to the onset of an acute stressor. Assessment of adult offspring’s ability to regulate HPA regulation began at 370 days of age. We further investigated whether the novelty exposure effects on offspring HPA regulation are sensitive to the context of maternal HPA regulation by assessing maternal HPA regulation similarly beginning 7 days after her pups were weaned. We found that at the population level, rats receiving neonatal, but not early adulthood exposure or both, showed a greater rapid CORTE than their home-staying siblings. At the individual family level, these novelty effects are positively associated with maternal CORTE. These results suggest that early experience of novelty can enhance the offspring’s ability to mount a rapid response to environmental challenge and the success of such early life intervention is critically dependent upon the context of maternal HPA regulation.

Preterm delivery as a predictor of diurnal cortisol profiles in adulthood: evidence from Cebu, Philippines.

Fetal exposure to elevated maternal cortisol can permanently modify hypothalamic-pituitary-adrenal (HPA) axis function, and thereby have long-term health impacts. Maternal cortisol steadily increases throughout normal pregnancy, but is abnormally high in preterm deliveries (<37 weeks). Prematurity remains a widespread public health problem, yet little is known about its potential long-term effects on adult HPA function. Here we test the hypothesis that diurnal cortisol profiles measured in young adulthood will vary based upon an individual's preterm status. Diurnal salivary cortisol profiles, a marker of HPA-axis function, were measured in 1,403 young adults (ages 21-23 years) participating in the Cebu Longitudinal Health and Nutrition Survey, located in Metropolitan Cebu City, Philippines. Males who had been born preterm exhibited lower morning cortisol and non-significantly elevated evening cortisol, resulting in a more adverse, flatter rate of decline across the day. In contrast, there were no significant differences by preterm status in cortisol measured at any time of day in females. These findings point to potential long-term effects of having been born preterm on adult HPA-axis function, and add to evidence from this and other populations for sex differences in the biological and health impacts of prenatal stress exposure.

Child abuse, disruptive behavior disorders, depression, and salivary cortisol levels among institutionalized and community-residing boys in Mongolia.

Hypothalamic-pituitary-adrenal (HPA) axis activity is related to childhood disruptive behavior disorders and to exposure to abuse and neglect. This study explores the relationship of diurnal salivary cortisol levels with oppositional defiant disorder (ODD) and caregiver attitudes toward physical punishment among boys in Mongolia. Salivary cortisol was collected in the home or institution 4 times daily for 4 days from 46 boys, aged 4-10 years, in Ulaanbaatar, Mongolia. Caregivers rated child disruptive behavior symptoms, attitudes toward physical punishment, and community violence exposures. Mixed effects models were used to estimate the association of psychopathology and caregiver attitudes with salivary cortisol levels. Boys meeting criteria for ODD displayed consistently lower diurnal salivary cortisol levels compared to boys without ODD diagnoses. Controlling for ODD diagnosis, boys with depression showed higher cortisol levels throughout the day. No other diagnosis was associated with cortisol levels. Psychiatric diagnosis accounted for 17% of between individual variations in cortisol levels unexplained by the covariates. In a separate model, caregivers' beliefs regarding physical punishment accounted for 11% of between individual differences: boys with caregivers who stated physical punishment was necessary for discipline displayed hypocortisolism. Institutionalization did not associate with cortisol levels. Salivary cortisol data from a non-Western naturalistic setting support an association of reduced basal HPA activity with disruptive behavior disorders and caregiver attitudes toward discipline. These findings suggest HPA functioning may be a reflection of or mediate disruptive behavior disorders in children across ethnic and cultural settings.

Population variation in neuroendocrine activity is associated with behavioral inhibition and hemispheric brain structure in young rhesus monkeys.

Population variation in hypothalamic-pituitary-adrenal (HPA) activity and reactivity was assessed in a healthy sample of 48 juvenile rhesus monkeys. Cluster analysis of the HPA profiles revealed four distinct neuroendocrine phenotypes based on six indices of HPA functioning. Behavioral reactivity was also evaluated in response to novel stimuli, and revealed marked differences between animals in the highest- and lowest-cortisol clusters. Specifically, animals in the high-cortisol cluster showed larger stress-induced cortisol responses and blunted feedback sensitivity to dexamethasone. They were also emotionally reactive, displayed more aggressive behaviors, and were less likely to approach novel objects. In contrast, monkeys in the low-cortisol cluster were more likely to approach and explore novel objects. Representative animals with high or low cortisol profiles were scanned with Magnetic Resonance Imaging to evaluate structural differences in global and regional gray matter (GM) and white matter (WM) volumes. Monkeys with higher cortisol reactivity evinced less hemispheric brain asymmetry, due to decreased GM in the right hemisphere. Stress reactivity was inversely related to global GM and positively related to total cerebrospinal fluid volume. This inverse relationship was also observed in several stress-sensitive regions, including prefrontal and frontal cortices. Our study demonstrates that population variation in pituitary-adrenal activity is related to behavioral disposition and cerebral structure in this nonhuman primate species.

Peer pressures: Social instability stress in adolescence and social deficits in adulthood in a rodent model

Studies in animal models generate and test hypotheses regarding developmental stage-specific vulnerability that might inform research questions about human development. In both rats and humans, peer relationships are qualitatively different in adolescence than at other stages of development, and social experiences in adolescence are considered important determinants of adult social function. This review describes our adolescent rat social instability stress model and the long-lasting effects social instability has on social behaviour in adulthood as well as the possible neural underpinnings. Effects of other adolescent social stress experiences in rats on social behaviours in adulthood also are reviewed. We discuss the role of hypothalamic–pituitary–adrenal (HPA) function and glucocorticoid release in conferring differential susceptibility to social experiences in adolescents compared to adults. We propose that although differential perception of social experiences rather than immature HPA function may underlie the heightened vulnerability of adolescents to social instability, the changes in the trajectory of brain development and resultant social deficits likely are mediated by the heightened glucocorticoid release in response to repeated social stressors in adolescence compared to in adulthood.