Hypothalamic-pituitary-adrenal Axis System Research Articles

Biological stress responses to multitasking and work interruptions: A randomized controlled trial

In the course of digitalization, new stressors are emerging. In modern working and living environments, two ubiquitous, technology-mediated stressors are multitasking demands and work interruptions. However, biological stress response patterns to multitasking and work interruptions have been sparsely investigated so far. We thus aimed to comprehensively assess biological stress response patterns to both stressors and, additionally, test whether responses differ between digital and partially non-digital settings. A controlled experimental set-up was established and humans’ biological markers of the Sympathetic Nervous System (SNS), the hypothalamic-pituitary adrenal (HPA) axis, and the immune system were assessed. N = 186 healthy participants (mean age: 23.2 ± 4.3 years, 74.7% female, body mass-index: 22.3 ± 3.1 kg/m2) took part in this pre-registered study. Each participant was randomly assigned to one of 6 experimental conditions (1 digital single-task, 3 dual-tasks [2 parallel tasks and 1 interruption], 1 multitasking, and 1 passive, control condition). Each one of the dual-tasking as well as the multitasking conditions included a non-digital sub-task, i.e., performing a task in presence of an examiner. All other conditions involved digital tasks only. Salivary alpha-amylase (sAA) levels as a marker for SNS reactivity significantly changed in work interruptions, parallel dual-tasking, and multitasking conditions. No changes were found for control conditions. Furthermore, no significant changes over time and no differences between the conditions were identified for three biological markers: cortisol as marker for HPA axis activity as well as for two immune system markers (secretory Immunoglobulin-A, C-reactive protein). A time course similar to sAA was found for perceived stress: with increases during task execution and decreases afterwards in multitasking and parallel dual-tasking. Yet, it did not change for the work interruption, passive control, and single-tasking condition. Overall, our findings show that dual- and multitasking are perceived as stressful and are associated with an activation of the SNS, but not with responses of HPA axis or immune system. This was consistent for digital as well as partially digital task demands. Our findings will also inform future research into the differential stress effects of digital and non-digital tasks to advance our understanding of biological stress response-patterns to multitasking and work interruptions. Therefore, our findings are highly relevant for understanding the long-term biological health effects of stress in modern (digitalized) environments.

Pregnancy-specific anxiety and gestational length: The mediating role of diurnal cortisol indices

BackgroundPreterm birth or shorter gestation is a common adverse pregnancy outcome. Pregnancy-specific anxiety is robustly associated with risk for shorter gestation. Hypothalamic-pituitary-adrenal (HPA) dysregulation, indicated by diurnal cortisol index variability [slope, area-under-the-curve (AUC) or cortisol awakening response (CAR)], could mediate associations between pregnancy-specific anxiety and shorter gestation. The purpose of this study was to explore whether diurnal cortisol index variability mediates associations between pregnancy-specific anxiety and gestational length. MethodsA sample of 149 women from the Healthy Babies Before Birth study reported pregnancy-specific anxiety in early pregnancy. Saliva samples were taken at three times during pregnancy, for two days each, at wake, 30 min post wake, noon, and evening. Diurnal cortisol indices were calculated using standard approaches. Pregnancy cortisol index variability was calculated across pregnancy timepoints. Gestational length was derived from medical charts. Covariates were sociodemographics, parity and obstetric risk. Mediation models were tested using SPSS PROCESS. ResultsThere was a significant indirect effect of pregnancy-specific anxiety on gestational length via CAR variability, b(SE)= −0.102(0.057), .95CI [− 0.227,− 0.008]. Higher pregnancy-specific anxiety was associated with lower CAR variability, b(SE)= −0.019(0.008), p = .022, and lower CAR variability was associated with shorter gestation, b(SE)= 5.29(2.64), p = .047. Neither AUC or slope variability mediated associations between pregnancy-specific anxiety and gestational length. ConclusionLower CAR variability during pregnancy mediated the association between higher pregnancy-specific anxiety and shorter gestational length. Pregnancy-specific anxiety could dysregulate HPA axis activity, as indicated by lower CAR variability, demonstrating the importance of the HPA axis system in regulating pregnancy outcomes.

Do categorically distinct stressors alter the attention to visual food cues?

Stressor exposure affects food intake as well as the preference for high or low palatability foods, but little is known about how stressor types impact the visual attention to food images. We used eye tracking methodology in humans to determine if activation of the hypothalamus–pituitary-adrenal (HPA) axis and sympathetic nervous system is associated with changes in attention to food images as determined by measuring changes in oculomotor activity. Specifically, we tested two questions: 1) Do categorically distinct stressors alter aspects of visual attention to food images as determined by oculomotor activity (i.e., saccade latency, gaze duration, and saccade bouts)? 2) Do categorically distinct stressors differentially affect visual attention to food images of high or low palatability? A total of sixty participants were randomly divided into one of three test groups: controls, an anticipatory stressor group, or a reactive stressor group. We measured salivary cortisol and salivary alpha-amylase (sAA) before and after stressor exposure to confirm activation of the HPA axis and sympathetic nervous system, respectively. Following stressor exposure participants performed an eye-tracking test using a standardized food picture database (Food-pics). We analyzed saccade latency, gaze duration, and saccade bouts in balanced pairs of food and non-food images. Salivary cortisol was elevated by both stressors, although the elevation in salivary cortisol to the reactive stressor was driven by women only. sAA was elevated only by the anticipatory stressor. There were main effects of image type for all three eye-tracking variables, with initial saccades of shorter latency to food images and longer gaze duration and more saccade bouts with food images. Participants exposed to the reactive stressor reduced gaze duration on food images relative to controls, and this affect was not linked to palatability or salivary cortisol levels. We conclude that the reactive stressor decreased time spent looking at food, but not non-food, images. These data are partly consistent with the idea that reactive stressors reduce attention to non-critical visual signals.

Alterations of Stress-Related Glucocorticoids and Endocannabinoids in Hair of Chronic Cocaine Users.

BackgroundPrevious research in animals and humans has demonstrated a potential role of stress regulatory systems, such as the hypothalamic-pituitary-adrenal (HPA) axis and the endocannabinoid (eCB) system, in the development of substance use disorders. We thus investigated alterations of HPA and eCB markers in individuals with chronic cocaine use disorder by using an advanced hair analysis technique.MethodsWe compared hair concentrations of glucocorticoids (cortisone, cortisol) and the eCBs 2-arachidonylglycerol, anandamide (AEA), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA) between 48 recreational cocaine users (RCU), 25 dependent cocaine users (DCU), and 67 stimulant-naïve controls. Self-reported substance use and hair concentrations of substances were also assessed.ResultsSignificantly higher concentrations of hair cortisone were found in RCU and DCU compared with controls. Hair concentrations of OEA and PEA were significantly lower in DCU compared with RCU and controls. Additionally, within cocaine users, elevated cocaine hair concentration was a significant predictor for increased glucocorticoid and decreased OEA hair levels. Moreover, higher 3,4-methyl​enedioxymethamphetamine hair concentration was correlated with elevated cortisone and AEA, OEA, and PEA levels in hair within cocaine users, whereas more self-reported cannabis use was associated with lower eCBs levels in hair across the total sample.ConclusionOur findings support the hypothesis that the HPA axis and eCB system might be important regulators for substance use disorders. The mechanistic understanding of changes in glucocorticoid and eCB levels in future research might be a promising pharmacological target to reduce stress-induced craving and relapse specifically in cocaine use disorder.

Coordination between frontolimbic resting state connectivity and hypothalamic–pituitary–adrenal axis functioning in adolescents with and without depression

Depression is associated with abnormalities in Hypothalamic–Pituitary–Adrenal (HPA) axis functioning and neural circuitry that underlie the stress response. Resting-state functional connectivity (RSFC) between frontolimbic brain regions captures intrinsic connections that may set the stage for the rallying and regulating of the HPA axis system. This study examined the association between cortisol stress response and frontolimbic (amygdala and ventral and dorsal medial prefrontal cortex [vmPFC and dmPFC respectively]) RSFC in 88 (Age: M = 15.95, SD = 2.04; 71.60% female) adolescents with (N = 55) and without (N = 33) major depressive disorder (MDD). We collected salivary cortisol in the context of a modified Trier Social Stress Test (TSST) paradigm. Key findings were that adolescents with depression and healthy controls showed different patterns of association between amygdala and vmPFC RSFC and HPA functioning: while healthy controls showed a positive relationship between frontolimbic connectivity and cortisol levels that may indicate coordination across neural and neuroendocrine systems, adolescents with depression showed a minimal or inverse relationship, suggesting poor coordination of these systems. Results were similar when examining non-suicidal self-injury subgroups within the MDD sample. These findings suggest that the intrinsic quality of this frontolimbic connection may be related to HPA axis functioning. In MDD, inverse associations may represent a compensatory response in one system in response to dysfunction in the other. Longitudinal multilevel research, however, is needed to disentangle how stress system coordination develops in normal and pathological contexts and how these systems recover with treatment.

Does exposure to parasites modify relationships between diurnal cortisol and leukocytes among Honduran women?

Altered hypothalamic-pituitary-adrenal (HPA) function and related changes in circulating glucocorticoids have been implicated in the pathogenesis of numerous diseases that involve dysregulated immune function. Glucocorticoid hormones have both direct and indirect modulatory effects on both pro- and anti-inflammatory aspects of the immune system, including granulocytic and lymphocytic leukocyte subsets. However, past findings are complicated by inconsistencies across studies in how glucocorticoids and immune markers interact and relate to disease risk. Some incongruencies are likely due to an overreliance on single-unit (e.g., HPA or one immune marker) measures, and a failure to consider ecological exposures that may shape the base levels or correspondence between these systems. Here, we test single-unit and diurnal measures of HPA axis and immune system interactions in a less-industrial ecological setting with relatively high parasite loads. In a sample of 114 Honduran women (mean age = 36 years), morning and evening blood samples were analyzed to quantify granulocytes, lymphocytes, and immunoglobulin-E (IgE). Saliva was collected over 2 days (8 samples per woman) to measure peak cortisol, cumulative cortisol, and slope of decline. These repeated measures of saliva and venous blood were used to investigate associations between single-point and diurnal salivary cortisol and leukocytes, under variable levels of past parasite exposure (proxied by IgE). Individuals with less of a decline in cortisol (i.e., "flatter" decline) show less of an increase in lymphocytes (2.27% increase in cells/μL/hr; 95% CI: 0.91-7.29; p = .01) across the day compared to those with steeper cortisol decline (7.5% increase in lymphocytes; 95% CI: 5.79-9.34; p < .001). IgE levels did not modify this association. Interestingly, IgE did moderate relationships between measures of cortisol and granulocytes: diurnal cortisol was positively associated with granulocytes, only in individuals with high previous exposure to parasites. There were no consistent relationships between single-unit measures of cortisol, lymphocytes or granulocytes, regardless of past parasite exposure. Results demonstrate that the relationship between HPA function and immune modulation cannot be fully understood without an understanding of local disease ecology. These results highlight the importance of research that seeks to identify etiologies of disease across environmental contexts.

Altered Expression of Glucocorticoid Receptor and Neuron-Specific Enolase mRNA in Peripheral Blood in First-Episode Schizophrenia and Chronic Schizophrenia.

IntroductionIt is well-known that altered hypothalamus–pituitary–adrenal (HPA) axis process has an important role in the neurodegenerative process in schizophrenia (SZ). However, this neurodegenerative mechanism has not been clarified in SZ. Therefore, the main purpose of this study was to determine HPA axis damage in the first-episode, unmedicated schizophrenia (FES) patients and chronic schizophrenia (CSZ) patients in comparison with healthy controls (HC) by means of quantitative analysis of the peripheral blood mRNA expression of glucocorticoid receptor (GR), GR transcripts containing exons 1B (GR-1B), and neuron specific enolase (NSE) genes and serum cortisol and NSE, a specific serum marker for neuronal damage.MethodsIn the present study, 43 FES patients, 39 CSZ, and 47 HC were included. The peripheral blood mRNA expressions for GR, GR-1B, and NSE genes were determined by real-time quantitative polymerase chain reaction (RT-qPCR). Serum cortisol and NSE were analyzed by electrochemiluminescence immunoassay technique.ResultsLevels of GR mRNA were significantly lower in FES and CSZ than that in HC. The expression of GR-1B mRNA was significantly decreased in CSZ when compared with that in FES. Levels of NSE mRNA were significantly lower in CSZ than that in FES patients or HC patients. CSZ patients showed significantly lower cortisol concentrations than FES and HC patients. FES patients showed significantly higher NSE concentrations than CSZ and HC.ConclusionOur findings support that there is disrupted HPA axis system in the SZ and suggest that CSZ patients suffer a greater HPA axis damage than FES patients. Our research implicated underlying GR mRNA dysregulation in SZ and the potential importance of the functional GR-1B transcription in CSZ.

Changes in Glycemic Load Are Positively Associated with Small Changes in Primary Stress Markers of Allostatic Load in Puerto Rican Women

Puerto Ricans experience a high prevalence of type 2 diabetes. Dietary glycemic load (GL) and allostatic load (AL) have been linked with diabetes. AL, the wear and tear on the body from chronic stress, starts with secretion of primary stress markers from activation of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system (SNS), and immune system. GL can act as a physiological stressor, contributing to the primary AL response. We examined the relation between GL and a composite score of primary stress markers of AL in Puerto Rican adults. Data were from the Boston Puerto Rican Health Study, a cohort study of Puerto Ricans, aged 45-75 y, including 262 men and 697 women with complete data at baseline and 2-y follow-up. GL was calculated from dietary intake obtained with an FFQ. Sex-specific composite primary AL scores included markers of the HPA axis (cortisol and dehydroepiandrosterone sulfate), SNS (epinephrine and norepinephrine), and immune system (C-reactive protein). Linear regression models were stratified by sex and adjusted for covariates. Mean±SD baseline GL score was 155±28 for men and 135±34 for women. Mean primary stress AL score was 1.25±1.14 for men and 1.25±1.06 for women. GL was not associated with AL score in men. In women, increasing GL from baseline to 2 y was significantly associated with increasing AL, after adjusting for sociodemographics, physical activity, smoking, BMI, menopause, and baseline AL score (β=0.03; P=0.049). Results became marginally significant after further adjustment for chronic diseases (P=0.06) and intake of fats (P values: saturated fats=0.08; trans fats=0.06; unsaturated fats=0.07), but the magnitude of the association remained unchanged. Increasing GL over 2 y was positively associated with increasing composite score of primary markers of AL in Puerto Rican women. More studies are needed to confirm our findings.

Maternal Nutrition and Offspring Stress Response-Implications for Future Development of Non-Communicable Disease: A Perspective From India.

Psychological stress is recognized as a major modifiable risk factor for adult non-communicable disease (NCD) that includes depression, type 2 diabetes mellitus, and cardiovascular disease. Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity resulting in either exaggerated or blunted cortisol responses, and altered autonomic cardiovascular control have been thought to underlie this association. The developmental origins hypothesis proposes that impaired nutrition during fetal and early postnatal growth is associated with a higher NCD risk later in life. Maternal nutrients are vital for fetal growth and development, and both maternal undernutrition and over nutrition as in the case of gestational diabetes are associated with higher NCD risk markers in the offspring. Recent studies suggest that fetal exposure to maternal nutritional imbalances may permanently alter cortisol and cardio-sympathetic stress-responsiveness, which may link early life nutrition with adult disease risk. A few recent studies that examined the association between low birth weight as a marker of fetal undernutrition and stress response in humans showed that lower birth weight was associated with an altered HPA axis and cardiovascular sympathetic nervous system responses to stress in adults as well as in children. In addition, altered stress responses in relation to gestational diabetes have been noted. In this paper, we present available evidence from India for the association between maternal nutrition and offspring stress responsiveness against the backdrop of global evidence, and discuss its role in the escalating NCD rates in this population. We also discuss the scope for future studies in India and other transitioning countries.

Limbic response to stress linking life trauma and hypothalamus-pituitary-adrenal axis function

Trauma alters neuroendocrine responses to stress and increases vulnerability to stress-related disorders. Yet, relationships among trauma, stress-induced neural changes and hypothalamic–pituitary–adrenal (HPA) axis activity have not been determined. The present study used functional magnetic resonance imaging to investigate the impact of life trauma on basal cortisol levels and neural responses to acute stress in 73 healthy individuals during brief stress and neutral-relaxing imagery using a well-established, individualized imagery method. We hypothesized that trauma experience would have a negative impact on brain function, resulting in altered basal cortisol levels via dysregulated neural control over the HPA axis system. Results showed that higher life trauma exposure was significantly associated with lower basal cortisol levels. Neuroimaging results indicated that both higher life trauma and low morning cortisol levels were associated with increased response to acute stress in limbic-medial temporal lobe (MTL) regions including the amygdala and hippocampus. A mediation analysis showed that increased limbic-MTL response to stress mediated the relationship between life trauma and low cortisol levels. Findings revealed a significant impact of lifetime trauma on neural responses to acute stress and HPA axis activity. Life trauma may sensitize limbic-MTL regions and its related peripheral systems, which could compromise stress regulation and HPA axis function, and increase risk for negative stress-related health outcomes.

Endocrine active metals, prenatal stress and enhanced neurobehavioral disruption

Metals, including lead (Pb), methylmercury (MeHg) and arsenic (As), are long-known developmental neurotoxicants. More recently, environmental context has been recognized to modulate metals toxicity, including nutritional state and stress exposure. Modulation of metal toxicity by stress exposure can occur through shared targeting of endocrine systems, such as the hypothalamic-pituitary-adrenal axis (HPA). Our previous rodent research has identified that prenatal stress (PS) modulates neurotoxicity of two endocrine active metals (EAMs), Pb and MeHg, by altering HPA and CNS systems disrupting behavior. Here, we review this research and further test the hypothesis that prenatal stress modulates metals neurotoxicity by expanding to test the effect of developmental As ± PS exposure. Serum corticosterone and behavior was assessed in offspring of dams exposed to As ± PS. PS increased female offspring serum corticosterone at birth, while developmental As exposure decreased adult serum corticosterone in both sexes. As + PS induced reductions in locomotor activity in females and reduced response rates on a Fixed Interval schedule of reinforcement in males, with the latter suggesting unique learning deficits only in the combined exposure. As-exposed males showed increased time in the open arms of an elevated plus maze and decreased novel object recognition whereas females did not. These data further confirm the hypothesis that combined exposure to chemical (EAMs) and non-chemical (PS) stressors results in enhanced neurobehavioral toxicity. Given that humans are exposed to multiple environmental risk factors that alter endocrine function in development, such models are critical for risk assessment and public health protection, particularly for children.

Diurnal Hypothalamic-Pituitary-Adrenal Axis Measures and Inflammatory Marker Correlates in Major Depressive Disorder.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory systems is a consistent finding in patients with Major Depressive Disorder (MDD). Cortisol is often assessed by measurement of the cortisol awakening response (CAR) and/or diurnal cortisol levels. Some methods of cortisol measurement overestimate cortisol concentration due to detection of other glucocorticoids including the relatively inert cortisone, therefore this study aimed to assess the presence of both cortisol and cortisone, and the cortisol-cortisone catalyzing enzyme 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1), in depressed patients and controls. Because the HPA axis is known to regulate the body’s immune system, relationships between measures of cytokines and cortisol were also assessed. Saliva samples were collected from 57 MDD patients and 40 healthy controls at five post-wakening time points (0, +30, +60, +720 and +750 min). Glucocorticoid concentrations were measured by liquid chromatography mass spectrometry. Whole blood mRNA expression of several inflammatory markers was measured by quantitative polymerase chain reaction. This study replicated the common finding of elevated morning cortisol and reduced CAR reactivity in MDD and found no differences in cortisone or 11β-HSD1 mRNA measures. There was a negative association between interleukin 1-β (IL-1β) mRNA and morning cortisol reactivity within the depressed group, indicating that dysregulation of the HPA axis and immune system may be interconnected.

IL-2 is involved in immune response of prenatally stressed rats exposed to postnatally stimulation

Environmental cues influence growth and development of mammals during prenatal and particularly early postnatal life and can exert long-lasting effects in adult life. High circulating concentration of glucocorticoids during pregnancy (prenatal stress) affects the activity of the hypothalamic-pituitary-adrenal axis (HPA) of offspring and has been linked to alter immune system responses. Early postnatal stimulation (handling) of prenatally stressed animals generates long-term beneficial effects on the reactiveness of the HPA axis and immune system function. The aim of this study was to further investigate the effect of handling on immune response inprenatally stressed male rats and to elucidate a possible relationship with the HPA axis activity. Control and prenatally stressed (PS) offspring by immobilization (IMO) were handled during the first week of life. Animals from both treatments were subjected to acute stress by IMO. Corticosterone (COR) plasma concentration was measured by RIA assay, T lymphocyte proliferation by [3H] thymidine assay and IL-2 levels by direct ELISA technique. Chronic IMO prenatal stress caused an increase in mother plasma COR basal levels. Furthermore, prenatally stressed rats subjected to an acute stress session had lower T cell proliferation and decreased IL-2 release. Inaddition, early postnatal stimulation reversed the negative effects of prenatal stress on proliferation of T lymphocytes and IL-2 release.

Childhood trauma: A factor for increased risk of major depression in psoriatic patients

A history of childhood maltreatment (CM) is an important determinant for understanding the development of psychiatric and physical disorders. CM is associated with sensitization of central nervous system (CNS) that leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis [1]. Early life stress is a well-known contributor to major depression [2]. The dysregulation of HPA axis and sympathetic nervous system activity also impact skin. Epidermis shows a high vulnerability to such psychological stressors resulting to increase risk for psoriasis [3]. The current study investigates the association between childhood trauma and major depression, childhood trauma and psoriasis, and also severity of major depression in female and male patients with psoriasis. Sixty-four psoriatic patients (female = 34, mean age = 46.87) were evaluated with the Childhood Trauma Questionnaire (CTQ) for the history of CM and with the MINI International Neuropsychiatric Interview for the diagnosis of major depression. CM was associated with major depression, indexed by a higher CTQ in emotional (χ2(3) = 26.002, P &lt; .0005) and physical abuse scores (χ2(3) = 23.764, P &lt; .0005). CM limited to sexual abuse was associated with higher severity of psoriasis (χ2(3) = 9.81, P &lt; .02). There was no indication of a difference between men and women in severity of major depression (U = 444, P = .304). Our findings highlight the importance of recognizing psychiatric comorbidity, in particular major depression, among psoriatic patients. Depressive disorder with the presence of psoriasis may constitute a separate etiology with a greater contribution of early environment.Disclosure of interestThe author has not supplied his/her declaration of competing interest.

QTL mapping of stress related gene expression in a cross between domesticated chickens and ancestral red junglefowl

Domestication of animals is associated with numerous alterations in physiology, morphology, and behavior. Lower reactivity of the hypothalamic-pituitary-adrenal (HPA) axis and reduced fearfulness is seen in most studied domesticates, including chickens. Previously we have shown that the physiological stress response as well as expression levels of hundreds of genes in the hypothalamus and adrenal glands are different between domesticated White Leghorn and the progenitor of modern chickens, the Red Junglefowl. To map genetic loci associated with the transcription levels of genes involved in the physiological stress response, we conducted an eQTL analysis in the F12 generation of an inter-cross between White Leghorn and Red Junglefowl. We selected genes for further studies based on their known function in the regulation of the HPA axis or sympathoadrenal (SA) system, and measured their expression levels in the hypothalamus and the adrenal glands after a brief stress exposure (physical restraint). The expression values were treated as quantitative traits for the eQTL mapping. The plasma levels of corticosterone were also assessed. We analyzed the correlation between gene expression and corticosterone levels and mapped eQTL and their potential effects on corticosterone levels. The effects on gene transcription of a previously found QTL for corticosterone response were also investigated. The expression levels of the glucocorticoid receptor (GR) in the hypothalamus and several genes in the adrenal glands were correlated with the post-stress levels of corticosterone in plasma. We found several cis- and trans-acting eQTL for stress-related genes in both hypothalamus and adrenal. In the hypothalamus, one eQTL for c-FOS and one QTL for expression of GR were found. In the adrenal tissue, we identified eQTL for the genes NR0B1, RGS4, DBH, MAOA, GRIN1, GABRB2, GABRB3, and HSF1. None of the found eQTL were significant predictors of corticosterone levels. The previously found QTL for corticosterone was associated with GR expression in hypothalamus. Our data suggests that domestication related modification in the stress response is driven by changes in the transcription levels of several modulators of the HPA and SA systems in hypothalamus and adrenal glands and not by changes in the expression of the steroidogenic genes. The presence of eQTL for GR in hypothalamus combined with the negative correlation between GR expression and corticosterone response suggests GR as a candidate for further functional studies regarding modification of stress response during chicken domestication.

Targeting the Brain Stress Systems for the Treatment of Tobacco/Nicotine Dependence: Translating Preclinical and Clinical Findings.

Tobacco use is the leading cause of preventable mortality in the United States, and Food and Drug Administration (FDA) approved medications fail to maintain long-term abstinence for the majority of smokers. One of the principal mechanisms associated with the initiation, maintenance of, and relapse to smoking is stress. Targeting the brain stress systems as a potential treatment strategy for tobacco dependence may be of therapeutic benefit. This review explores brain stress systems in tobacco use and dependence. The corticotropin-releasing factor (CRF) system, the hypothalamic-pituitary-adrenal (HPA) axis, and the noradrenergic system are discussed in relation to tobacco use. Preclinical and clinical investigations targeting these stress systems as treatment strategies for stress-induced tobacco use are also discussed. Overall, nicotine-induced activation of the CRF system, and subsequent activation of the HPA axis and noradrenergic system may be related to stress-induced nicotine-motivated behaviors. Pharmacological agents that decrease stress-induced hyperactivation of these brain stress systems may improve smoking-related outcomes.

Electroacupuncture regulate hypothalamic–pituitary–adrenal axis and enhance hippocampal serotonin system in a rat model of depression

Hypothalamic–pituitary–adrenal (HPA) axis has been implicated in the pathogenesis of depression. Dysfunction of the hippocampal serotonin (5-hydroxytryptamine, 5-HT) system has been shown to be a key factor in depression. There is growing evidence that electro-acupuncture (EA) has antidepressant-like effect. However, the effect of EA on HPA axis and hippocampal serotonin system remains unknown. In our study, we investigated the antidepressant-like effect and mechanism of EA for depression rat models. Depression in rats was induced by chronic unpredictable mild stress (CUMS). EA treatment was administered once daily to CUMS rats for 14 days. The acupoints (ST36, bilateral and CV4) were selected. Untreated CUMS rats and normal rats were used as controls. Behavioral tests including forced swim test and open-field test were performed to evaluate the antidepressant effects of EA treatment. Hypothalamic corticotropin-releasing hormone (CRH) mRNA, plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were estimated as indices of HPA axis activity. Enzyme linked immunosorbent assay (ELISA) was performed to determine the concentrations of 5-HT in the hippocampus. Real-time PCR(RT-PCR)and Western blot were respectively used to detect the mRNA and protein levels of 5-hydroxytryptamine 1A receptor (5-HT1AR) in the hippocampus. Our results showed that EA treatment reversed the behavioral deficiency induced by CUMS in rats. EA treatment decreased CRH mRNA expression in the hypothalamic, and ACTH and CORT level in plasma, and markedly increased 5-HT concentration, 5-HT1AR (mRNA and protein) expression in the hippocampus. These results indicated that EA treatment could act on depression by modulating HPA axis and enhancing hippocampal 5-HT/5-HT1AR in CUMS Rats.

Improvement of kidney yang syndrome by icariin through regulating hypothalamus-pituitary-adrenal axis.

To investigate whether Epimedium brevicornu Maxim (EB) and icariin could exert their protective effects on hydrocortisone induced (HCI) rats by regulating the hypothalamus-pituitary-adrenal (HPA) axis and endocrine system and the possible mechanism. Male 10-week-old Sprague Dawley (SD) rats were allotted to 6 groups (A-F) with 12 each, group A was injected normal saline (NS) 3 mL/kg day intraperitoneally, group A and B were given NS 6 mL/kg day by gastrogavage, group B-F were injected hydrocortisone 15 mg/kg intraperitoneally, group C and D were given EB 8 or 5 g/(kg day) by gastrogavage, group E and F were given icariin 25 or 50 mg/(kg day) by gastrogavage. Gene expressions of hypothalamus corticotropin releasing hormone (CRH) and pituitary proopiomelanocortin (POMC) were detected by reverse transcription-polymerase chain reaction (RT-PCR), and protein of pituitary POMC by Western-blot. The serum T4, testosterone, cortisol and POMC mRNA expression were increased after treatment with EB or icariin in HCI rats, the serum CRH and the hypothalamus CRH mRNA expression released from hypothalamus corticotropin decreased compared with group B (P<0.05).The treatment with only icariin increased serum adrenocorticotropic hormone (ACTH) compared with group B (P<0.05). EB and icariin might be therapeutically beneficial in the treatment of HCI rats through attuning the HPA axis and endocrine system which was involved in the release of CRH in hypothalamic, and the production of POMC-derived peptide ACTH in anterior pituitary, the secretion of corticosteroids in adrenal cortex.

Antidepressant-like effect of Butea superba in mice exposed to chronic mild stress and its possible mechanism of action

Ethnopharmacological relevanceButea superba (BS) is a Thai medicinal plant that has been used as a folk medicine to improve physical and mental conditions and to prevent impaired sexual performance in middle-aged or elderly males. We have previously reported that this plant extract could improve cognitive deficits and depression-like behavior in olfactory bulbectomized mice, an animal model of dementia and depression. Aim of the studyIn this study we examined the effect of BS on depression-like behavior in mice subjected to unpredictable chronic mild stress (UCMS) to clarify the antidepressant-like activity of BS and the molecular mechanism underlying this effect. Materials and methodsUCMS mice were administered BS daily (300mg of dried herb weight/kg, p.o.) or a reference drug, imipramine (IMP, 10mg/kg, i.p.), 1 week after starting the UCMS procedure. We employed the sucrose preference test and the tail suspension test to analyze anhedonia and depression-like behavior of mice, respectively. Serum and brain tissues of mice were used for neurochemical and immunohistochemical studies. The UCMS procedure induced anhedonia and depression-like behavior, and BS treatment, as well as IMP treatment, attenuated these symptoms. UCMS caused an elevation of serum corticosterone level, an index of hyper-activation of the hypothalamic–pituitary–adrenal (HPA) axis, in a manner attenuated by BS and IMP treatment. BS treatment also attenuated UCMS-induced decrease in the expression levels of brain-derived neurotrophic factor (BDNF) mRNA, cyclic AMP-responsive element binding protein (CREB) and a phosphorylated form of N-methyl-d-aspartate receptor subunit NR1, synaptic plasticity-related signaling proteins. Moreover, the UCMS procedure reduced doublecortin-positive cells in the dentate gyrus region of the hippocampus. BS administration reversed these UCMS-induced neurochemical and histological abnormalities. ConclusionThese results suggest that BS can ameliorate chronic stress-induced depression-like symptoms and that the effects of BS are mediated by restoring dysfunctions of the HPA axis and synaptic plasticity-related signaling systems and neurogenesis in the hippocampus.

Neonatal amygdala lesions lead to increased activity of brain CRF systems and hypothalamic-pituitary-adrenal axis of juvenile rhesus monkeys.

The current study examined the long-term effects of neonatal amygdala (Neo-A) lesions on brain corticotropin-releasing factor (CRF) systems and hypothalamic-pituitary-adrenal (HPA) axis function of male and female prepubertal rhesus monkeys. At 12-months-old, CSF levels of CRF were measured and HPA axis activity was characterized by examining diurnal cortisol rhythm and response to pharmacological challenges. Compared with controls, Neo-A animals showed higher cortisol secretion throughout the day, and Neo-A females also showed higher CRF levels. Hypersecretion of basal cortisol, in conjunction with blunted pituitary-adrenal responses to CRF challenge, suggest HPA axis hyperactivity caused by increased CRF hypothalamic drive leading to downregulation of pituitary CRF receptors in Neo-A animals. This interpretation is supported by the increased CRF CSF levels, suggesting that Neo-A damage resulted in central CRF systems overactivity. Neo-A animals also exhibited enhanced glucocorticoid negative feedback, as reflected by an exaggerated cortisol suppression following dexamethasone administration, indicating an additional effect on glucocorticoid receptor (GR) function. Together these data demonstrate that early amygdala damage alters the typical development of the primate HPA axis resulting in increased rather than decreased activity, presumably via alterations in central CRF and GR systems in neural structures that control its activity. Thus, in contrast to evidence that the amygdala stimulates both CRF and HPA axis systems in the adult, our data suggest an opposite, inhibitory role of the amygdala on the HPA axis during early development, which fits with emerging literature on "developmental switches" in amygdala function and connectivity with other brain areas.