Hypothalamic-pituitary-adrenocortical Axis Function Research Articles

The Interaction between Psychological Stress and Iron Status on Early-Life Neurodevelopmental Outcomes.

This review presents evidence from animal and human studies demonstrating the possible connection and significant impact of poor iron status and psychological distress on neurocognitive development during pregnancy and the neonatal period, with implications for long-term cognition. Stress and iron deficiency are independently prevalent and thus are frequently comorbid. While iron deficiency and early-life stress independently contribute to long-term neurodevelopmental alterations, their combined effects remain underexplored. Psychological stress responses may engage similar pathways as infectious stress, which alters fundamental iron metabolism processes and cause functional tissue-level iron deficiency. Psychological stress, analogous to but to a lesser degree than infectious stress, activates the hypothalamic-pituitary-adrenocortical (HPA) axis and increases proinflammatory cytokines. Chronic or severe stress is associated with dysregulated HPA axis functioning and a proinflammatory state. This dysregulation may disrupt iron absorption and utilization, likely mediated by the IL-6 activation of hepcidin, a molecule that impedes iron absorption and redistributes total body iron. This narrative review highlights suggestive studies investigating the relationship between psychological stress and iron status and outlines hypothesized mechanistic pathways connecting psychological stress exposure and iron metabolism. We examine findings regarding the overlapping impacts of early stress exposure to iron deficiency and children's neurocognitive development. We propose that studying the influence of psychological stress on iron metabolism is crucial for comprehending neurocognitive development in children exposed to prenatal and early postnatal stressors and for children at risk of early iron insufficiency. We recommend future directions for dual-exposure studies exploring iron as a potential mediating pathway between early stress and offspring neurodevelopment, offering opportunities for targeted interventions.

Assessment of the hypothalamic-pituitary-adrenocortical axis function using a vasopressin stimulation test in neonatal foals.

Bacterial sepsis is the leading cause of death in foals and is associated with hypothalamic-pituitary-adrenocortical axis (HPAA) dysfunction. HPAA function can be evaluated by an arginine-vasopressin (AVP) stimulation test. Administration of AVP will stimulate a dose-dependent rise in systemic adrenocorticotropin-releasing hormone (ACTH) and cortisol in neonatal foals. There will be no response seen in corticotropin-releasing hormone (CRH) and baseline AVP will be within reference interval. Twelve neonatal foals, <72 hours old. HPAA function was assessed in foals utilizing 3 doses of AVP (2.5, 5, and 7.5 IU), administered between 24 and 48 hours of age in this randomized cross-over study. Cortisol, ACTH, CRH and AVP were measured at 0 (baseline), 15, 30, 60 and 90 minutes after AVP administration with immunoassays. The fold increase in cortisol and ACTH was calculated at 15 and 30 minutes compared to baseline. All doses of AVP resulted in a significant increase in cortisol concentration over time, and a dose-dependent increase in ACTH concentration over time. ACTH and cortisol were significantly increased at 15 and 30 minutes, respectively after all 3 doses of AVP compared to baseline (P < .01). There was no change in endogenous CRH after stimulation with AVP. Administration of AVP is safe and results in a significant rise in ACTH and cortisol in neonatal foals. A stimulation test with AVP (5 IU) can be considered for HPAA assessment in septic foals.

The hypothalamic-pituitary-adrenal axis response to ovine corticotropin-releasing-hormone stimulation tests in healthy and hospitalized foals.

The hypothalamic-pituitary-adrenocortical axis (HPAA) response to sepsis can be impaired in critical illness. Corticotropin-releasing hormone (CRH) stimulation test might assess HPAA function in foals. To evaluate plasma cortisol, ACTH, arginine vasopressin (AVP), and endogenous CRH (eCRH) response to different doses of ovine CRH (oCRH). Healthy (n=14) and hospitalized (n=15) foals <7 days of age. In this prospective randomized study, oCRH (0.1, 0.3, and 1μg/kg) was administered intravenously and blood samples were collected before, 15, 30, 60, and 90 minutes after administration of oCRH to determine plasma hormone concentrations. The hormonal response was evaluated as the difference (Delta; μg/dL or pg/mL) or percent change between baseline hormone concentration and each time point after oCRH stimulation. Cortisol concentrations increased from baseline at 15 minutes with 0.1 and 0.3μg/kg and at 30 and 60 minutes from baseline with 1μg/kg oCRH (P < .05) in healthy and hospitalized foals. ACTH concentrations increased from baseline at 15 minutes with 0.1μg/kg and at 30 minutes with 1μg/kg oCRH (P < .05) in hospitalized foals. Delta cortisol 0 - 30, ACTH 0 - 30, and eCRH 0 - 30 was higher for the 1μg/kg compared with 0.1μg/kg oCRH in healthy foals (P < .05). Delta ACTH 0 - 15 and eCRH 0 - 30 was higher for the 1μg/kg compared with the lower doses of oCRH in hospitalized foals (P < .05). Cortisol, ACTH, and eCRH concentrations increased in response to administration of all doses of oCRH. One microgram per kilogram of oCRH appears to be optimal for the assessment of HPAA in healthy and hospitalized foals.

Pre-pandemic Psychobiological Features Predict Impact of COVID-19 Confinement on Loneliness.

The coronavirus disease 2019 (COVID-19) pandemic led to various government-imposed limitations on social interaction and strict home confinement. Such involuntary social-distancing policies can exacerbate feelings of loneliness and alter emotional well-being. Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis is a potential mechanism for loneliness’ deleterious health effects. In this study, we explored whether pre-pandemic diurnal cortisol output (AUCG), a measure of HPA axis function, may predict the propensity to changes in loneliness during long-term COVID-19 home confinement and if extraversion would moderate this relationship. This association has been explored by analysing the impact of COVID-19 pandemic and strict home confinement on social and emotional loneliness in 45 Spanish young adults. Diurnal cortisol levels were measured from five saliva samples obtained across a day just before the pandemic, and data about participants’ perceived loneliness, empathic state, extraversion, and prospective volunteering were obtained both before and during the confinement. Participants’ social and family loneliness increased during long-term strict home confinement, while prospective volunteering tendencies and extraversion decreased. Importantly, after adjusting for relevant confounders, moderation analyses revealed that in young adults with high pre-pandemic extraversion, a higher AUCG predicted a larger increase in social loneliness during confinement, while in individuals with low extraversion, AUCG was negatively related to change in loneliness. Our findings highlight the utility of pre-pandemic diurnal cortisol output in predicting the social impact of COVID-19 home confinement, presenting this hormone as a potential biomarker for a priori identification of at-risk groups during public health crises.

The persistent associations between early institutional care and diurnal cortisol outcomes among children adopted internationally.

Young children in institutional care experience conditions that are incompatible with their needs for attachment relationships. As a result, early institutionalization is expected to have lasting effects on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. The current study tested whether early institutionalization has persistent consequences for diurnal HPA axis outcomes among 130 children who had been adopted internationally between the ages of 6 and 48months. Daily cortisol samples were collected from children at two time points: shortly after adoption (average of 5.3months after adoption) and approximately 3years later (average of 39.2months after adoption). Shortly after adoption, children who had experienced a long duration of institutional care had lower morning cortisol levels and more blunted declines in cortisol across the day than children who experienced minimal or no institutional care. Three years later, children who had experienced a long duration of institutionalization continued to exhibit low morning cortisol levels and also exhibited low bedtime cortisol levels. Altogether, these results support the idea that early adversity results in the downregulation of the HPA axis and suggest that the effects of institutionalization on HPA axis functioning may persist several years after children are adopted into highly enriched families.

A comparative study of adrenalin and fluocinolon induced oxidative stress in male wistar rats

Hormone secretion by the hypothalamic-pituitary-adrenocortical (HPA) axis is modulated by multiple factors which include the circadian rhythm, various types of stressors and glucocorticoids. Treatment with synthetic glucocorticoids as e.g. dexamethasone or dermocorticosteroids and repeated immobilization stress, decreases the total body weight gain of animals by disturbing the HPA axis function and accelerating the catabolism of the organism. Synthetic glucocorticoids are widely used as anti-inflammatory and anti-allergic drugs. Neverteheless, their administration may cause side effects in the normal functioning of several organs. Starting from the above findings and from the important physiological roles of the glucocorticoids in the metabolism, we investigated the reactions of the adrenal and thymus, the evolution of the body and organ weight and the level of the free radicals after adrenaline- and fluocinolon stress. In this study, we used electron paramagnetic resonance spectroscopy for the direct detection of free radical content in the organs o f stressed Wistar rats. We followed the changes of the blood glucose level, body weight,structural modification and whole redox state of the rats during adrenaline and Fluocinolon-acetonid N treatment, as endogenous and exogenous sources of elevated glucocoticoid levels. We found a relationship between changes of the redox state and modified homeostasis of the organism, as an effect of elevated glucocorticoid levels. The oxidative stress induced by adrenalin treatment seemed to be an inducer rather than the result of the tissue damage.

The association between maternal positive emotions and social support during pregnancy and mental disorders and their subclinical symptoms in children

Little is known about the associations between physical activity (PA) and hypothalamic–pituitary–adrenocortical axis (HPAA) activity in adolescents. This knowledge could offer insight into the links between PA and well-being in youth. We studied whether objectively-measured PA is associated with diurnal salivary cortisol responses and morning salivary cortisol responses after a low-dose overnight dexamethasone suppression test (DST) in adolescent girls and boys. We conducted a cross-sectional birth cohort study in Helsinki, Finland. At a mean age of 12.4 (SD = 0.5) years, 150 girls and 133 boys wore wrist-worn accelerometers over at least 4 days to measure PA. Their salivary cortisol was measured across 1 day and upon awakening after a low-dose overnight DST (3 μg/kg of weight). Girls with higher overall PA and vigorous PA (VPA), and less sedentary time had lower salivary cortisol upon awakening and/or after (decreases between |0.17| and |0.25| SDs per SD increase in overall PA, VPA and decrease in sedentary time; P-values < 0.039). Boys with higher overall PA, and less sedentary time had greater suppression of salivary cortisol following overnight DST (suppression between |0.24| and |0.27| SDs per SD increase in overall PA and decrease in sedentary time; P-values < 0.012). Overall PA, VPA and sedentary time did not associate with DST suppression in girls or with diurnal salivary cortisol in boys. These results show that PA is associated with altered HPAA function in early adolescents, and that the associations are sex specific.

Perceived discrimination and cardiovascular health disparities: a multisystem review and health neuroscience perspective.

There are distinct racial disparities in cardiovascular disease (CVD) risk, with Black individuals at much greater risk than White individuals. Although many factors contribute to these disparities, recent attention has focused on the role of discrimination as a stress-related factor that contributes to racial disparities in CVD. As such, it is important to understand the mechanisms by which discrimination might affect CVD. Recent studies have examined these mechanisms by focusing on neurobiological mediators of CVD risk. Given this increase in studies, a systematic review of perceived discrimination and neurobiological mediators of CVD risk is warranted. Our review uses a multisystem approach to review studies on the relationship between perceived discrimination and (1) cardiovascular responses to stress, (2) hypothalamic-pituitary-adrenocortical axis function, and (3) the immune system, as well as (4) the brain systems thought to regulate these parameters of peripheral physiology. In addition to summarizing existing evidence, our review integrates these findings into a conceptual model describing multidirectional pathways linking perceived discrimination with a CVD risk.

Attachment security buffers the HPA axis of toddlers growing up in poverty or near poverty: Assessment during pediatric well-child exams with inoculations

Poverty is associated with poor physical and emotional development. Activation of the hypothalamic-pituitary-adrenocortical (HPA) axis is argued to be one of the pathways through which poverty acts on these outcomes. While studies of school-aged children have found some evidence for this, there is little evidence for this hypothesis early in development. This may be, in part, because for very young children, the security of their attachment relationships with parents moderates the impact of poverty on HPA axis functioning. The current study investigated the relations between family income as a percentage of the federal poverty limit (FPL), salivary cortisol and attachment (Attachment Q-sort) during well-child checkups with inoculations in 177 toddlers between 12- and 22-months of age. Approximately half of the toddlers were in families living below 150% FPL, with 47% of these classified as securely attached, compared to 72% of toddlers in families living above 150% FPL. Cortisol levels increased in response to the inoculation and this did not differ by poverty or attachment security. Overall, however, beginning at clinic arrival toddlers in families living below 150% FPL who had an insecure attachment had significantly higher cortisol compared to toddlers living in poverty or near poverty with secure attachments. This finding held when we removed toddlers with high levels of negative life events in their families and primary caregivers who exceeded the screening cutoff for depressive symptoms. Thus, attachment was a significant moderator of the association between poverty and HPA axis activity, with significant implications for screening and referral of caregiving dyads at risk.

Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo.

Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight (BW), and HPA axis functioning. Little is known about the biological mechanisms by which prenatal stress affects postnatal functioning. This study addresses this gap by examining the effect of chronic stress and traumatic war-related stress on epigenetic changes in four key genes regulating the HPA axis in neonatal cord blood, placenta, and maternal blood: CRH, CRHBP, NR3C1, and FKBP5. Participants were 24 mother-newborn dyads in the conflict-ridden region of the eastern Democratic Republic of Congo. BW data were collected at delivery and maternal interviews were conducted to assess culturally relevant chronic and war-related stressors. Chronic stress and war trauma had widespread effects on HPA axis gene methylation, with significant effects observed at transcription factor binding (TFB) sites in all target genes tested. Some changes in methylation were unique to chronic or war stress, whereas others were observed across both stressor types. Moreover, stress exposures impacted maternal and fetal tissues differently, supporting theoretical models that stress impacts vary according to life phase. Methylation in several NR3C1 and CRH CpG sites, all located at TFB sites, was associated with BW. These findings suggest that prenatal stress exposure impacts development via epigenetic changes in HPA axis genes.

Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3β signaling.

Interactions between genetic and environmental factors, like exposure to stress, have an important role in the pathogenesis of mood-related psychiatric disorders, such as major depressive disorder. The polyspecific organic cation transporters (OCTs) were shown previously to be sensitive to the stress hormone corticosterone in vitro, suggesting that these transporters might have a physiologic role in the response to stress. Here, we report that OCT2 is expressed in several stress-related circuits in the brain and along the hypothalamic-pituitary-adrenocortical (HPA) axis. Genetic deletion of OCT2 in mice enhanced hormonal response to acute stress and impaired HPA function without altering adrenal sensitivity to adrenocorticotropic hormone (ACTH). As a consequence, OCT2(-/-) mice were potently more sensitive to the action of unpredictable chronic mild stress (UCMS) on depression-related behaviors involving self-care, spatial memory, social interaction and stress-sensitive spontaneous behavior. The functional state of the glycogen synthase kinase-3β (GSK3β) signaling pathway, highly responsive to acute stress, was altered in the hippocampus of OCT2(-/-) mice. In vivo pharmacology and western blot experiments argue for increased serotonin tonus as a main mechanism for impaired GSK3β signaling in OCT2(-/-) mice brain during acute response to stress. Our findings identify OCT2 as an important determinant of the response to stress in the brain, suggesting that in humans OCT2 mutations or blockade by certain therapeutic drugs could interfere with HPA axis function and enhance vulnerability to repeated adverse events leading to stress-related disorders.

Diurnal salivary cortisol measurement in the neurosurgical-surgical intensive care unit in critically ill acute trauma patients

Acute trauma patients represent a specific subgroup of the critically ill population due to sudden and dramatic changes in homeostasis and consequently extreme demands on the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. Salivary cortisol is an accepted surrogate for serum free cortisol in the assessment of HPA axis function. The purpose of this study was (1) to establish the feasibility of salivary cortisol measurement in acute trauma patients in the neurosurgical–surgical intensive care unit (NSICU), and (2) to determine the diurnal pattern of salivary cortisol in the acute phase after injury. Saliva from 50 acute trauma patients was prospectively collected twice a day at 6AM and 4PM during the first week after injury in the NSICU. Mean PM cortisol concentrations were significantly higher in subjects versus controls (p<0.001). Subjects failed to develop the expected PM versus AM decrease in cortisol concentration seen in controls (p=0.005). Salivary cortisol did not vary significantly with baseline Glasgow Coma Scale (GCS), Injury Severity Score, sex, injury type, ethnicity, or age. When comparing mean AM and PM salivary cortisol by GCS severity category (GCS ⩽8 and GCS >8) the AM salivary cortisol was significantly higher in patients with GCS ⩽8 (p=0.002). The results show a loss of diurnal cortisol variation in acute trauma patient in the NSICU during the first week of hospitalization. Patients with severe brain injury had higher morning cortisol levels than those with mild/moderate brain injury.

Physical activity and hypothalamic–pituitary–adrenocortical axis function in adolescents

Little is known about the associations between physical activity (PA) and hypothalamic-pituitary-adrenocortical axis (HPAA) activity in adolescents. This knowledge could offer insight into the links between PA and well-being in youth. We studied whether objectively-measured PA is associated with diurnal salivary cortisol responses and morning salivary cortisol responses after a low-dose overnight dexamethasone suppression test (DST) in adolescent girls and boys. We conducted a cross-sectional birth cohort study in Helsinki, Finland. At a mean age of 12.4 (SD=0.5) years, 150 girls and 133 boys wore wrist-worn accelerometers over at least 4 days to measure PA. Their salivary cortisol was measured across 1 day and upon awakening after a low-dose overnight DST (3 μg/kg of weight). Girls with higher overall PA and vigorous PA (VPA), and less sedentary time had lower salivary cortisol upon awakening and/or after (decreases between |0.17| and |0.25| SDs per SD increase in overall PA, VPA and decrease in sedentary time; P-values<0.039). Boys with higher overall PA, and less sedentary time had greater suppression of salivary cortisol following overnight DST (suppression between |0.24| and |0.27| SDs per SD increase in overall PA and decrease in sedentary time; P-values<0.012). Overall PA, VPA and sedentary time did not associate with DST suppression in girls or with diurnal salivary cortisol in boys. These results show that PA is associated with altered HPAA function in early adolescents, and that the associations are sex specific.

Effects of a high-fat–high-fructose diet, stress and cinnamon on central expression of genes related to immune system, hypothalamic–pituitary–adrenocortical axis function and cerebral plasticity in rats – CORRIGENDUM

Effects of a high-fat–high-fructose diet, stress and cinnamon on central expression of genes related to immune system, hypothalamic–pituitary–adrenocortical axis function and cerebral plasticity in rats – CORRIGENDUM

Effects of Antenatal Corticosteroids on the Hypothalamic-Pituitary-Adrenocortical Axis of the Fetus and Newborn

The hypothalamic-pituitary-adrenocortical (HPA) axis is a major neuroendocrine pathway that modulates the stress response. The glucocorticoid, cortisol, is the principal end product of the HPA axis in humans and plays a fundamental role in maintaining homeostasis and in fetal maturation and development. Antenatal administration of synthetic glucocorticoids (GCs) accelerates fetal lung maturation and has significantly decreased neonatal mortality and morbidity in infants born before 34 weeks of gestation. Exposure to excess levels of endogenous GCs and exogenous GCs (betamethasone and dexamethasone) has been shown to alter the normal development trajectory. The development and regulation of the fetal HPA axis is discussed and the experimental animal evidence presented suggests long-term adverse consequences of altered HPA function. The clinical data in infants exposed to GCs also suggest altered HPA axis function over the short term. The longer-term consequences of antenatal GC exposure on HPA axis function and subtler neurodevelopmental outcomes including adaptation to stress, cognition, behavior, and the cardiovascular and immune responses are poorly understood. Emerging clinical strategies and interventions may help in the selection of mothers at risk for preterm delivery who would benefit from existing or future formulations of antenatal GCs with a reduction in the associated risk to the fetus and newborn. Detailed longitudinal long-term follow-up of those infants exposed to synthetic GCs are needed.

Effect of a high-fat–high-fructose diet, stress and cinnamon on central expression of genes related to immune system, hypothalamic–pituitary–adrenocortical axis function and cerebral plasticity in rats

The intake of a high-fat/high-fructose (HF/HFr) diet is described to be deleterious to cognitive performances, possibly via the induction of inflammatory factors. An excess of glucocorticoids is also known to exert negative effects on cerebral plasticity. In the present study, we assessed the effects of an unbalanced diet on circulating and central markers of inflammation and glucocorticoid activity, as well as their reversal by dietary cinnamon (CN) supplementation. A group of male Wistar rats were subjected to an immune challenge with acute lipopolysaccharide under a HF/HFr or a standard diet. Another group of Wistar rats were fed either a HF/HFr or a control diet for 12 weeks, with or without CN supplementation, and with or without restraint stress (Str) application before being killed. We evaluated the effects of such regimens on inflammation parameters in the periphery and brain and on the expression of actors of brain plasticity. To assess hypothalamic-pituitary-adrenocortical axis activity, we measured the plasma concentrations of corticosterone and the expression of central corticotrophin-releasing hormone, mineralocorticoid receptor, glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase. We found that the HF/HFr diet induced the expression of cytokines in the brain, but only after an immune challenge. Furthermore, we observed the negative effects of Str on the plasma concentrations of corticosterone and neuroplasticity markers in rats fed the control diet but not in those fed the HF/HFr diet. Additionally, we found that CN supplementation exerted beneficial effects under the control diet, but that its effects were blunted or even reversed under the HF/HFr diet. CN supplementation could be beneficial under a standard diet. [corrected].

Non-pain-related CRF1 activation in the amygdala facilitates synaptic transmission and pain responses.

BackgroundCorticotropin-releasing factor (CRF) plays an important role in affective states and disorders. CRF is not only a “stress hormone” but also a neuromodulator outside the hypothalamic-pituitary-adrenocortical (HPA) axis. The amygdala, a brain center for emotions, is a major site of extrahypothalamic expression of CRF and its G-protein-coupled receptors. Our previous studies showed that endogenous activation of CRF1 receptors in an arthritis pain model contributes to amygdala hyperactivity and pain-related behaviors. Here we examined the synaptic and behavioral effects of CRF in the amygdala of normal animals in the absence of tissue injury or disease.ResultsWhole-cell patch-clamp recordings of neurons in the latero-capsular division of the central nucleus of the amygdala (CeLC) in brain slices from normal rats showed that CRF (0.1-10 nM) increased excitatory postsynaptic currents (EPSCs) at the “nociceptive” parabrachio-amygdaloid (PB-CeLC) synapse and also increased neuronal output. Synaptic facilitation involved a postsynaptic action and was blocked by an antagonist for CRF1 (NBI27914, 1 μM) but not CRF2 (astressin-2B, 1 μM) and by an inhibitor of PKA (KT5720, 1 μM) but not PKC (GF109203X, 1 μM). CRF increased a latent NMDA receptor-mediated EPSC, and this effect also required CRF1 and PKA but not CRF2 and PKC. Stereotaxic administration of CRF (10 μM, concentration in microdialysis probe) into the CeLC by microdialysis in awake rats increased audible and ultrasonic vocalizations and decreased hindlimb withdrawal thresholds. Behavioral effects of CRF were blocked by a NBI27914 (100 μM) and KT5720 (100 μM) but not GF109203x (100 μM). CRF effects persisted when HPA axis function was suppressed by pretreatment with dexamethasone (50 μg/kg, subcutaneously).ConclusionsNon-pain-related activation of CRF1 receptors in the amygdala can trigger pain-responses in normal animals through a mechanism that involves PKA-dependent synaptic facilitation in CeLC neurons independent of HPA axis function. The results suggest that conditions of increased amygdala CRF levels can contribute to pain in the absence of tissue pathology or disease state.

Adoption as an intervention for institutionally reared children: HPA functioning and developmental status

Institutional care, particularly when experienced early in life, is associated with delays in social and emotional development that often persist years after adoption. It has been hypothesized that compromise of the hypothalamic–pituitary–adrenocortical (HPA) axis due to adverse condition in institutions is a mediator of later emotional and behavioral problems. The first goal of our project was to investigate whether improvements in the social and emotional environment are associated with changes in HPA axis function. The second goal was to explore whether HPA alterations related to early social adversity were associated with more compromised general development and social and emotional functioning post adoption. Children adopted from Eastern European orphanages (N=76, mean age was 17 months, SD=5) were followed as part of an ongoing longitudinal study. Data, including diurnal cortisol patterns, were collected at two time points: baseline (within one month of adoption) and follow-up (six months later). Cortisol values were averaged over two days of saliva sampling after wake-up and before bedtime. We found that morning cortisol values increased between the baseline assessment (M=0.27μg/dl, SD=0.13) and follow-up (M=0.33μg/dl, SD=0.20), t(76)=−2.1, p<0.05. HPA functioning was not associated with general developmental level at either the initial or six months post-adoption assessments. However, dysregulation of the HPA axis (i.e., flatter diurnal pattern) at follow-up was associated with more behavioral and emotional problems. Overall, these results suggest that investigating specific physiological mechanisms is important in identifying children at risk for persistent social and emotional problems and in understanding the long-term consequences of early adversity. Future work should investigate whether disturbance in the HPA system is a heightened risk for long-term negative developmental outcomes.

Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression-like behavior in males but not females

Dysfunction in central glucocorticoid signaling is implicated in hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation and major depression. In comparison with men, women are twice as likely to suffer from depression and have heightened HPA axis responses to stress. We hypothesized that this striking increase in stress vulnerability in females may be because of sex differences in central glucocorticoid signaling. The current study tests the role of the forebrain type II glucocorticoid receptor (GR) on HPA axis function in female mice and depression-like behavior in both female and male mice. This was accomplished by using mice with selective deletion of GR in forebrain cortico-limbic sites including the prefrontal cortex, hippocampus, and basolateral amygdala (forebrain glucocorticoid receptor knockout mouse (FBGRKO)). In order to examine HPA axis function in female FBGRKO, we measured nadir, peak circadian and restraint-induced corticosterone concentrations in female FBGRKO. The data indicate that unlike male FBGRKO, basal and stress-induced corticosterone concentrations are not increased in female FBGRKO. Given the pronounced effect of central glucocorticoid signaling on mood, we also examined the necessity of corticolimbic GR on depression-like behavior with the sucrose preference and forced swim tests (FST) in male and female FBGRKO mice. Consistent with previous studies, male FBGRKO displayed increased depression-like behavior as indicated by greater immobility in the FST and decreased sucrose preference compared with littermate controls, effects that were not observed in females. Overall the findings indicate a marked sex difference in the function of forebrain GR on HPA axis regulation and depression-like behaviors, and may have implications for therapeutic approaches using GR-modulating drugs.

Sex-specific associations between sleep problems and hypothalamic–pituitary–adrenocortical axis activity in children

Sleep problems are associated with reduced physical and mental health. Altered function of the hypothalamic-pituitary-adrenocortical axis (HPAA) may be one underlying mechanism. We studied the associations between sleep problems and HPAA activity in children. A cross-sectional epidemiological cohort study. Salivary cortisol was sampled throughout one day at home and during the Trier Social Stress Test for Children (TSST-C) in clinic. Sleep disorders were measured with a parent-rated Sleep Disturbance Scale for Children, and sleep duration measured by actigraphy for one week. 284 (51% girls) 8-year-old children. Boys with sleep problems (≥ 85 th percentile in any of the sleep-wake transition, arousal, excessive daytime somnolence or sleep hyperhydrosis subscales) had lower diurnal salivary cortisol levels and salivary cortisol responses to TSST-C stress in comparison to boys without sleep problems. Girls with sleep problems (≥ 85 th percentile in disorders of initiating and maintaining sleep) displayed a higher overall level of salivary cortisol during the TSST-C. Salivary cortisol responses to stress were lower in boys and higher in girls with more than one sleep problem. Sleep problems in children are associated with altered HPAA function, after controlling for actual sleep quantity measured by actigraphy. Boys with sleep problems had lower HPAA activity and girls with sleep problems had higher HPAA activity, compared to children without sleep problems.