Hypothalamo-pituitary-adrenal Research Articles

Differential and temporal expression of corticotropin releasing hormone and its receptors in the nucleus of the hippocampal commissure and paraventricular nucleus during the stress response in chickens (Gallus gallus)

Recently, in addition to the paraventricular nucleus (PVN), the nucleus of the hippocampal commissure (NHpC) have been proposed to regulate stress in birds due to the discovery of corticotropin releasing hormone (CRH) neurons in the NHpC. Expression of CRH, CRHR1, CRHR2 and glucocorticoid receptors (GRs) were determined within the NHpC compared to the PVN. Additionally, two levels of the hypothalamo-pituitary-adrenal (HPA) axis: 1) anterior pituitary and 2) adrenal gland were examined following food deprivation (FD) stress including proopiomelanocortin (POMC) expression and plasma corticosterone (CORT), respectively. CRH expression in the NHpC increased rapidly, however it quickly returned to control levels, showing a negative feedback with CRHR1. In contrast, CRH expression in the PVN and its receptor CRHR1, steadily increased throughout the sampling period showing a positive feedback with CRH. Of interest, brain-derived neurotrophic factor (BDNF) mRNA was significantly elevated in the PVN, while no significant change in BDNF mRNA was observed in the NHpC. The rapid increase in BDNF expression that matched the pattern shown by CRHR1 in the PVN may play a role in the positive feedback of CRH and its receptor. GRs were downregulated in both the NHpC and PVN throughout the study. POMC hnRNA and mRNA were significantly elevated from 1 to 4 h of FD compared to controls. A significant increase in plasma CORT levels occurred at 2 h and persisted to the end of the experiment, suggesting that CRH neurons in the NHpC initiated, while PVN CRH neurons sustained the early response of the HPA axis to stress.

Prefrontal-Bed Nucleus Circuit Modulation of a Passive Coping Response Set.

One of the challenges facing neuroscience entails localization of circuits and mechanisms accounting for how multiple features of stress responses are organized to promote survival during adverse experiences. The rodent medial prefrontal cortex (mPFC) is generally regarded as a key site for cognitive and affective information processing, and the anteroventral bed nuclei of the stria terminalis (avBST) integrates homeostatic information from a variety of sources, including the mPFC. Thus, we proposed that the mPFC is capable of generating multiple features (endocrine, behavioral) of adaptive responses via its influence over the avBST. To address this possibility, we first optogenetically inhibited input to avBST from the rostral prelimbic cortical region of mPFC and observed concurrent increases in immobility and hypothalamo-pituitary-adrenal (HPA) output in male rats during tail suspension, whereas photostimulation of this pathway decreased immobility during the same challenge. Anatomical tracing experiments confirmed projections from the rostral prelimbic subfield to separate populations of avBST neurons, and from these to HPA effector neurons in the paraventricular hypothalamic nucleus, and to aspects of the midbrain periaqueductal gray that coordinate passive defensive behaviors. Finally, stimulation and inhibition of the prelimbic-avBST pathway, respectively, decreased and increased passive coping in the shock-probe defensive burying test, without having any direct effect on active coping (burying) behavior. These results define a new neural substrate in the coordination of a response set that involves the gating of passive, rather than active, coping behaviors while restraining neuroendocrine activation to optimize adaptation during threat exposure.SIGNIFICANCE STATEMENT The circuits and mechanisms accounting for how multiple features of responses are organized to promote adaptation have yet to be elucidated. Our report identifies a prefrontal-bed nucleus pathway that organizes a response set capable of gating passive coping behaviors while concurrently restraining neuroendocrine activation during exposure to inescapable stressors. These data provide insight into the central organization of how multiple features of responses are integrated to promote adaptation during adverse experiences, and how disruption in one neural pathway may underlie a broad array of maladaptive responses in stress-related psychiatric disorders.

Application of Single Prolonged Stress Induces Post-traumatic Stress Disorder-like Characteristics in Mice.

We tried to clarify the applicability of a single prolonged stress (SPS) protocol as post-traumatic stress disorder (PTSD) model in mice. To investigate PTSD pathophysiology, we conducted hypothalamo-pituitary-adrenal (HPA) negative feedback testing at 1, 4, 8 and 12 weeks after the SPS by administrating a dexamethasone (DEX) suppression test. The SPS induced over-suppression of the HPA system by DEX treatment at 8 and 12 weeks. To investigate PTSD-like behavioral characteristics, we subjected mice to testing in a light/dark box (to assess anxiety), a Y-maze (working memory), a cliff avoidance (visual cognition), and an open field (locomotor activity) at 1, 4, 8 and 12 weeks after the SPS. In the light/dark box test, the SPS-applied mice spent significantly less time in the light box at 8 or 12 weeks. In the cliff avoidance test, the SPS-applied mice spent significantly less time in the open area at 1 week. However, in both the Y-maze test and the open field test, SPS-applied mice tended toward slight decreases in a time-dependent manner until 12 weeks. Therefore, SPS-applied mice may thus be useful for assessing characteristics relevant to PTSD that coincide with changes in the HPA axis.

Peripheral DNA methylation of HPA axis-related genes in humans: Cross-tissue convergence, two-year stability and behavioural and neural correlates

Environmental factors can influence gene expression via epigenetic modifications such as DNA methylation. DNA methylation levels of regulatory regions in Hypothalamo-Pituitary-Adrenal (HPA) axis-related genes assessed from brain tissues as well as from surrogate, peripheral tissues have been associated with vulnerability to stress-related psychopathologies. Commonly used peripheral samples to assess DNA methylation in living humans are derived from blood, saliva or buccal cells. Although psychiatric epigenetic studies are increasingly relying on peripheral measures of DNA methylation, it is still unknown to what extent methylation patterns across peripheral tissues are associated with each other and with measures of brain processes and behavioural stress. In the present study, with a sample of 51 healthy adults, we assessed cross-tissue correlations of DNA methylation patterns in the glucocorticoid receptor (NR3C1) 1 F promoter and the FK506 Binding Protein 5 (FKBP5) gene intron 7 region using saliva and buccal cell samples, and assessed two-year stability in both tissues in a male subsample (N = 14). We also investigated associations between peripherally-derived DNA methylation and measures of neural function and perceived daily stress, and compared the extent of these associations across tissue samples. DNA methylation cross-tissue correlations were highly significant for FKBP5, but not significant for NR3C1. DNA methylation in both genes remained stable for two years. Tissue- and gene-specific associations were found for brain resting state connectivity and neural responses to sadness, thereby suggesting that saliva- and buccal cell-derived DNA methylation levels of NR3C1-1 F and FKBP5 gene regions might differently capture different measures of putatively related brain processes. It was also found that greater buccal cell- (but not saliva-) derived NR3C1-1 F methylation was associated with lower perceived daily life demands. Results of the present study may inform the design of future epigenetic studies on FKBP5-intron-7 and NR3C1-1 F-promoter methylation in relation to neuro-imaging and behavioural measures, and provide insight for the development of peripheral DNA methylation correlates of stress sensitivity and resilience.

A P2X7 receptor antagonist reverses behavioural alterations, microglial activation and neuroendocrine dysregulation in an unpredictable chronic mild stress (UCMS) model of depression in mice

A polymorphism in the P2RX7 gene that encodes for the P2X7 ionotropic ATP-gated receptor (P2X7R) protein has been shown to be associated with an increased risk for developing depressive illnesses. However, the role of P2X7R in depression is still unclear. To better understand the role of P2X7R and its subsequent impact on microglial activation, we compared the effect of the P2X7R antagonist Brilliant Blue G (BBG) with that of fluoxetine in an unpredictable chronic mild stress (UCMS) model of depression in mice. Our results indicate that BBG (50 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day) successfully reversed the degradation of coat states and nest-building scores induced by exposure to UCMS, similar to the conventional antidepressant fluoxetine (15 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day). BBG also reversed the UCMS-induced microglial activation in cortical and hippocampal regions and the basal nuclei of mouse brains and corrected the UCMS-induced hypothalamo-pituitary-adrenal (HPA) axis dysregulation. In contrast to fluoxetine, however, BBG treatment did not increase the density of doublecortin-positive cells in the dentate gyrus, indicating that BBG had no impact on hippocampal neurogenesis. These results suggest that P2X7R is involved in recovery from depressive-like states caused by exposure to UCMS in a mechanism that involves restoration of the HPA axis but not hippocampal neurogenesis. These results add to the evidence that P2X7R antagonist agents may have potential value in the pharmacological management of depression.

Sex differences in hippocampal mineralocorticoid and glucocorticoid receptor mRNA expression in response to acute mate pair separation in zebra finches (Taeniopygia guttata).

Mate separation has been shown to mediate changes in physiological and behavioral processes via activation of the hypothalamo-pituitary-adrenal (HPA) axis in both mammalian and avian species. To elucidate the neural mechanisms associated with changes in the HPA axis in response to social stress, we investigated the effects of mate pair separation on circulating corticosterone concentrations as well as gene expression levels of mineralocorticoid receptor (MR), glucocorticoid receptor (GR), and corticotropin releasing hormone (CRH) in the hypothalamus and hippocampus of both male and female zebra finches, a species that forms strong pair bonds. Zebra finches (Taeniopygia guttata) were housed three to a cage (a mated pair plus a stimulus female), and were assigned to one of three new housing treatment groups: (1) male or female removed from their respective mate and placed in a cage with a new opposite sex conspecific and stimulus female (2) male or female that remained with their mate, but a new stimulus female was introduced, or (3) the subjects were handled but not separated from their mate or the stimulus female. After 48 hr in the new housing condition, we observed significant increases in plasma corticosterone concentrations in response to both mate pair and stimulus female separation. No significant differences in MR, GR, or CRH mRNA expression in the hypothalamus were observed in response to any treatment for both males and females. Females exhibited a significant up regulation in hippocampal MR, but not GR mRNA, whereas males exhibited a significant down regulation of both hippocampal MR and GR mRNA in response to mate pair separation. Thus, the hippocampus appears to play a key role in regulating sex specific responses to social stressors.

Interactions of body temperature and nutritional status on hypothalamo-pituitary-adrenal axis activity in pre-thermoregulatory eastern bluebird chicks (Sialia sialis)

Early life experiences can affect the function of the hypothalamo-pituitary-adrenal (HPA) axis of vertebrates, with potential fitness consequences later in life. In altricial species, for example, variation in parental behavior, e.g. brooding or feeding, can modify the activity of the HPA axis of the young by altering their exposure to noxious stimuli as the young develop in the nest. We have shown that a drop in the body temperature of eastern bluebird (Sialia sialis) chicks, such as occurs when females are away from the nest, elevates their blood corticosterone levels. If repeated during the early days of their development, cooling bouts also reduce the chicks’ later corticosterone secretion in response to handling. Thus, variation in maternal behavior has the capacity to shape the function of the chicks’ HPA axis. To better understand how maternal absence from the nest activates the HPA axis of bluebird chicks, we experimentally mimicked the cooling that occurs when the female is away from the nest, and investigated a) the age at which the HPA axis becomes capable of responding to cooling by increasing corticosterone secretion, b) whether corticosterone secretion remains elevated throughout long periods of cooling, and c) whether fasting (also potentially associated with maternal absence) interacts with cooling to affect corticosterone secretion. Cooling for 18 min significantly elevated circulating corticosterone levels of chicks as young as 4 days post-hatch, indicating that their HPA axis is sensitive to cooling very early in life. Corticosterone levels remained elevated throughout longer bouts of cooling. However, a 1-hr period of fasting had no effect on corticosterone secretion, regardless of whether chicks were cooled or not. Collectively, these data demonstrate that variation in maternal brooding behavior can substantially modify the corticosterone profiles of chicks during early postnatal development, and that chick temperature is likely the main driver of this.

The Short Synacthen (Corticotropin) Test Can Be Used to Predict Recovery of Hypothalamo-Pituitary-Adrenal Axis Function.

The 250-μg short Synacthen (corticotropin) test (SST) is the most commonly used tool to assess hypothalamo-pituitary-adrenal (HPA) axis function. There are many potentially reversible causes of adrenal insufficiency (AI), but no data to guide clinicians as to the frequency of repeat testing or likelihood of HPA axis recovery. To use the SST results to predict adrenal recovery. A retrospective analysis of 1912 SSTs data. Seven hundred seventy-six patients with reversible causes of AI were identified who had at least two SSTs performed. A subgroup analysis was performed on individuals previously treated with suppressive doses of glucocorticoids (n = 110). Recovery of HPA axis function. SST 30-minute cortisol levels above or below 350 nmol/L (12.7 μg/dL) best predicted HPA axis recovery [area under the curve (AUC) receiver operating curve (ROC) = 0.85; median recovery time: 334 vs 1368 days, P = 8.5 × 10-13]: 99% of patients with a 30-minute cortisol >350 nmol/L recovered adrenal function within 4 years, compared with 49% in those with cortisol levels <350 nmol/L. In the subgroup analysis, delta cortisol (30-minute-basal) best predicted the recovery (AUC ROC = 0.77; median recovery time: 262 vs 974 days, P = 7.0 × 10-6). No patient with a delta cortisol <100 nmol (3.6 μg/dL) and a subsequent 1-year random cortisol <200 nmol/L (7.3 μg/dL) recovered HPA axis function. Cortisol levels across an SST can be used to predict recovery of AI and may guide the frequency of repeat testing and inform both clinicians and patients as to the likelihood of restoration of HPA axis function.

Role of 11β-HSD type 1 in abnormal HPA axis activity during immune-mediated arthritis.

Patients with chronic immune-mediated arthritis exhibit abnormal hypothalamo-pituitary-adrenal (HPA) axis activity. The basis for this abnormality is not known. Immune-mediated arthritis is associated with increased extra-adrenal synthesis of active glucocorticoids by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. 11β-HSD1 is expressed in the central nervous system, including regions involved in HPA axis regulation. We examined whether altered 11β-HSD1 expression within these regions contributes to HPA axis dysregulation during arthritis. The expression of 11β-HSD1, and other components of glucocorticoid signaling, were examined in various brain regions and the pituitary gland of mice with experimentally induced arthritis. Two arthritis protocols were employed: The K/BxN spontaneous arthritis model for chronic arthritis and the K/BxN serum transfer arthritis model for acute arthritis. 11β-HSD1 mRNA (Hsd11b1) was expressed in the hippocampus, hypothalamus, cortex, cerebellum and pituitary gland. Hypothalamic Hsd11b1 expression did not change in response to arthritis in either model. Pituitary Hsd11b1 expression was however significantly increased in both chronic and acute arthritis models. Hippocampal Hsd11b1 was decreased in acute but not chronic arthritis. Chronic, but not acute, arthritis was associated with a reduction in hypothalamic corticotropin-releasing hormone and arginine vasopressin expression. In both models, serum adrenocorticotropic hormone and corticosterone levels were no different from non-inflammatory controls. These findings demonstrate inflammation-dependent regulation of Hsd11b1 expression in the pituitary gland and hippocampus. The upregulation of 11β-HSD1 expression in the pituitary during both chronic and acute arthritis, and thus, an increase in glucocorticoid negative feedback, could contribute to the abnormalities in HPA axis activity seen in immune-mediated arthritis.

Ameliorative effect of quercetin and rutin via modulation of hypothalamic–Pituitary–Adrenal axis and regulation of fasting glucose in chronic stress-induced prediabetes

Background: Quercetin (QUE) and Rutin (RUT) have nutritive and medicinal values. On the other hand, there are no reports of scientific assessment of its hypothalamo–pituitary–adrenal (HPA) axis modulation in the treatment of prediabetes (DM). Aim: The current study was designed to investigate the modulatory effects of QUE, RUT, and escitalopram (ESC) as antidepressants on HPA axis in chronic stress-induced pre-DM in rats. Materials and Methods: The experimental protocol was of 5 weeks. Chronic unpredictable mild stress (CUMS) was used as a model of depression to induce pre-DM in rats. The treatment was started at the end of 4 th week. After 5 th week, the plasma adrenocorticotropic hormone (ACTH), serum corticosterone (CORT), fasting blood glucose (FBG), and behavioral parameters were evaluated. Results: Oral administration of QUE (50 mg/kg), RUT (50 mg/kg), and ESC (2.5 mg/kg) to stressed control alleviated HPA axis-associated parameters (ACTH and CORT) and significantly decreased the FBG. Besides this, the depressive effects induced by CUMS were significantly improved as evident from results indicating a promising antidepressant activity. Moreover, submaximal dose of QUE (25 mg/kg) and RUT (25 mg/kg) enhanced the antidepressant activity of ESC (1 mg/kg, p.o.), which suggests that they may act through the HPA axis. Conclusion: Current results suggest that chronic stress in rats causes dysregulation of the HPA axis which leads to diabetic-like condition, i.e., “pre-DM.” It is possible that QUE, RUT, and ESC may be able to suppress the HPA axis response which could be beneficial for the treatment of stressed diabetic patients. Abbreviations used: QUE: Quercetin; RUT: Rutin; HPA: Hypothalamic–Pituitary–Adrenal Axis; CUMS: Chronic unpredictable mild stress; ACTH: Adrenocorticotropic hormone; CORT: Corticosterone; FBG: Fasting Blood Glucose; ESC: Escitalopram; FST: Fasting Blood Glucose.

It is Time to Carpe Diem with Porcine ACTH - A Comparison of Porcine Sequence Corticotropin to Tetracosactide Hexaacetate in Testing the Hypothalamic Pituitary Adrenal Axis in Healthy Individuals.

Context:Our literature search revealed that the use of porcine sequence corticotropin has not been validated against tetracosactide hexaacetate in a healthy population.Aims:To study the efficacy of using porcine sequence corticotropin in comparison with tetracosactide hexaacetate in the evaluation of hypothalamo pituitary adrenal (HPA) axis.Materials and Methods:Fifteen healthy volunteers were enrolled. Serum cortisol was measured at 0 minute in all subjects and at 30 and 60 minutes after tetracosactide hexaacetate 250 μg intravenously. Four weeks later, serum cortisol level was measured at 0 minute and at 30 and 60 minutes following 24 units of porcine sequence corticotropin given intramuscularly.Results:Mean serum cortisol values with tetracosactide were 30.3 (±7.83) μg/dl and 31.27 (±7.36) μg/dl at 30 and 60 minutes, respectively. The mean cortisol values with porcine sequence corticotropin were 26.33 (±5.47) μg/dl and 31.59 (±6.40) μg/dl at 30 and 60 minutes, respectively. All subjects had a response qualified as normal or adequate at 30 minutes itself. Mean peak serum cortisol response was 32.65 (±7.76) μg/dl in tetracosactide group and 31.59 (±6.4) μg/dl in porcine sequence corticotropin group, and the responses in two groups were comparable (P = 0.686). There were no immediate side effects in both groups, with a lower cost of procedure in the porcine corticotropin group.Conclusion:Our study established the efficacy of porcine sequence corticotropin in testing the adequacy of HPA axis in healthy individuals. Our study also revealed that, the intactness of the HPA axis could be confirmed as early as 30 minutes in healthy individuals.

An Ω-3 fatty acid-deficient diet during gestation induces depressive-like behavior in rats: the role of the hypothalamo-pituitary-adrenal (HPA) system.

Low intake of omega-3 (Ω-3) polyunsaturated fatty acids (PUFAs) especially docosahexaenoic acid (DHA) is associated with postpartum depression. DHA deficiency is accompanied by impaired attention and cognition, and will precipitate psychiatric symptoms. However, the effects of dietary DHA on postpartum depression remain unclear. We established a normal pregnancy model to evaluate whether an Ω-3 PUFA-deficient diet during gestation could induce depressive-like behavior and aggravate dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in rats. A between-group design was used to assess the effects of Ω-3 PUFA content (deficiency, control and supplementary) and reproductive status (virgin or parous). We assessed depressive-like behavior and measured the fatty acid composition in the liver. The protein expressions of glucocorticoid receptor (GR) and mineralocorticoid receptor (MCR) were also measured to evaluate the HPA activity. Exposure to the Ω-3 PUFA-deficient diet resulted in an increased immobility time in a forced swimming test (FST). Additionally, our results firstly showed the decreased expression of GR in the hippocampus of parous rats that were exposed to Ω-3 PUFA-deficient diets, which may partly facilitate the hyperactivity of the HPA axis and exert detrimental effects. Moreover, the reduction of GR was ameliorated by Ω-3 PUFA supplementation, providing new evidence for Ω-3 PUFAs in the progression of postpartum depression.

The lateral habenula interacts with the hypothalamo-pituitary adrenal axis response upon stressful cognitive demand in rats

The lateral habenula (LHb) is involved in emotional and cognitive behaviors. Recently, we have shown in rats that blockade of excitatory inputs to the LHb not only induced deficits of memory retrieval in the water maze, but also altered swim strategies (i.e., induced excessive thigmotaxis). The latter observation, although consistent with the occurrence of memory deficits, could also possibly be the consequence of an excessive level of stress, further suggesting a role for the LHb in the stress response in our behavioral paradigm. To test this hypothesis we performed in rats intra-LHb infusion of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 267 ng/side in 0.3 μL), or vehicle, and assessed the responsiveness of the hypothalamo-pituitary adrenal (HPA) axis to environmental stressful or non-stressful situations. We have measured plasma corticosterone (CORT) concentrations at different time points before and following intra-LHb infusion of CNQX – or of the same volume of vehicle – in three conditions: during the probe test of a water maze experiment; in an anxiety test, the elevated plus maze; and in a home cage condition. Whereas there were no differences in the home cage condition and in the elevated plus maze, in the water maze experiment we observed that CNQX-treated rats presented, along with memory deficits, a higher level of blood CORT than vehicle-treated rats. These results suggest that perturbations of the modulation of the HPA axis are consecutive to the alteration of LHb function, whether it is the result of a defective direct control of the LHb over the HPA axis, or the consequence of memory deficits.

Assessment of leukocyte activity in mice devoid of the glucocorticoid receptor in the noradrenergic system (GRDBHCre)

Disturbances in brain monoamines, overactivity of the hypothalamo-pituitary adrenal (HPA) axis and pro-inflammatory tendency in the immune system are the key features of depressive disorders. Recently, several murine lines with mutations in glucocorticoid receptors (GRs) have been generated and these animals may be utilized for study depressive-like disorders. In the present study, we have investigated whether selective ablation of GRs in noradrenergic neurons affects functional properties of leukocytes and redirects them towards pro-inflammatory activity.Transgenic mice selectively devoid of GRs on noradrenergic cells were constructed using the Cre/loxP approach. Peritoneal leukocytes were collected from mutant and wild type (WT) animals of both sexes and were cultured in vitro for 24h both in basal conditions and after application of selected pro- or anti-inflammatory stimuli. Metabolic activity and adherence were measured in basal conditions. Nitric oxide (NO) synthesis and arginase (ARG) activity were assessed as the markers of functional status of the cells. Because adult mutant mice lack adrenal medulla and thereby peripheral adrenaline, we modulated pro- and anti-inflammatory culture conditions by addition of noradrenaline (10–6M). Finally, effects of in vivo pro-inflammatory challenge (with intraperitoneal administration of lipopolysaccharide) on properties of leukocytes were assessed 24h (in both sexes) and 48h later (in males only).The experiments indicated that selective ablation of GR in noradrenergic neurons did not affect fundamental properties of peritoneal leukocytes and exerted effects only under conditions of selected pro- or anti-inflammatory stimuli in vitro. Stronger response to pro-inflammatory stimulation in terms of NO synthesis and ARG activity may suggest pro-inflammatory tendency in mutant mice. In vivo inflammatory challenge failed to show any effect of GR ablation on selected parameters of leukocyte activity. Both in vitro studies and in vivo challenge revealed mainly sex-related differences in leukocyte activity.

Neural and endocrine stress reactions in healthy women with and without severe early life trauma

Maladaptive responses to negative affective stimuli are pervasive, including clinically ill and healthy people, and men and women respond differently at neural and hormonal levels. Inspired by the Research Domain Criteria initiative, we used a transdiagnostic approach to investigate the impact of sex and dysphoric mood on neural-hormonal responses to negative affective stimuli.Participants included 99 individuals with major depressive disorder, psychosis and healthy controls. Functional magnetic resonance imaging (fMRI) was complemented with real-time acquisition of hypothalamo-pituitary-adrenal (HPA) and -gonadal (HPG) hormones. fMRI data were analyzed in SPM8 and task-related connectivity was assessed using generalized psychophysiological interaction.Across all participants, elevated cortisol response predicted lower brain activity in orbitofrontal cortex and hypothalamus-amygdala connectivity. In those with worse dysphoric mood, elevated cortisol response predicted lower activity in hypothalamus and hippocampus. In women, elevated cortisol response was associated with lower activity in medial prefrontal cortex and low hypothalamo-hippocampal connectivity. In women with high dysphoric mood, elevated cortisol response was associated with low hypothalamo–hippocampal connectivity. There were no interactions with diagnosis or medication.There was limited power to correct for multiple comparisons across total number of ROIs and connectivity targets; cortisol responses were relatively low.We conclude that the pathophysiology in neural-hormonal responses to negative affective stimuli is shared across healthy and clinical populations and varies as a function of sex and dysphoric mood. Our findings may contribute to the development of hormonal adjunctive therapeutics that are sex-dependent, underscoring the importance of one's sex to precision medicine.

Dynamic evaluation of the hypothalamic–pituitary–adrenal and growth hormone axes and metabolic consequences in chronic insomnia; a case–control study

The stimulability and supressibility of hypothalamo-pituitary–adrenal (HPA) axis and stimulability of growth hormone (GH) axis is not known in chronic insomnia (CI). We aimed to examine the effects of CI on HPA and GH axes by dynamic tests, and metabolic consequences. Eighteen CI patients and 14 controls, without any other accompanying sleep and metabolic disorders and drug usage were enrolled into the study. Serum leptin and ghrelin levels were measured at 08:00 a.m. in the fasting state. Salivary cortisol rhythm (06:00, 12:00, 18:00, 24:00) and oral glucose tolerance test (OGTT) were performed on separate days. Low dose (1 µg) ACTH stimulation, glucagon stimulation test (GST), and dexamethasone suppression test (DST) were performed at 08:00 a.m. leaving 48 h in between. Salivary cortisol levels at 18:00 were found to be significantly higher in CI compared to controls (0.14 ± 0.11 vs 0.08 ± 0.06, respectively; p = 0.027). Basal, peak and area under curve of cortisol responses to dynamic stimulation tests were similar in two groups. Cortisol levels after overnight DST were also similar in two groups. GH responses to GST were not different between groups. Fasting glucose levels, HOMA-IR, OGTT and lipid levels were similar in both groups. The insomnia group had similar leptin and ghrelin levels compared to the control group. Our results indicate that, although CI is associated with elevated evening salivary cortisol levels, neither dynamic feedback regulation of the HPA and GH axis nor leptin and ghrelin levels are affected.

Corticotropin-Releasing Hormone As the Homeostatic Rheostat of Feto-Maternal Symbiosis and Developmental Programming In Utero and Neonatal Life

A balanced interaction between the homeostatic mechanisms of mother and the developing organism during pregnancy and in early neonatal life is essential in order to ensure optimal fetal development, ability to respond to various external and internal challenges, protection from adverse programming, and safeguard maternal care availability after parturition. In the majority of pregnancies, this relationship is highly effective resulting in successful outcomes. However, in a number of pathological settings, perturbations of the maternal homeostasis disrupt this symbiosis and initiate adaptive responses with unpredictable outcomes for the fetus or even the neonate. This may lead to development of pathological phenotypes arising from developmental reprogramming involving interaction of genetic, epigenetic, and environmental-driven pathways, sometimes with acute consequences (e.g., growth impairment) and sometimes delayed (e.g., enhanced susceptibility to disease) that last well into adulthood. Most of these adaptive mechanisms are activated and controlled by hormones of the hypothalamo-pituitary adrenal axis under the influence of placental steroid and peptide hormones. In particular, the hypothalamic peptide corticotropin-releasing hormone (CRH) plays a key role in feto-maternal communication by orchestrating and integrating a series of neuroendocrine, immune, metabolic, and behavioral responses. CRH also regulates neural networks involved in maternal behavior and this determines efficiency of maternal care and neonate interactions. This review will summarize our current understanding of CRH actions during the perinatal period, focusing on the physiological roles for both mother and offspring and also how external challenges can alter CRH actions and potentially impact on fetus/neonate health.

Neural - hormonal responses to negative affective stimuli: Impact of dysphoric mood and sex

BackgroundMaladaptive responses to negative affective stimuli are pervasive, including clinically ill and healthy people, and men and women respond differently at neural and hormonal levels. Inspired by the Research Domain Criteria initiative, we used a transdiagnostic approach to investigate the impact of sex and dysphoric mood on neural-hormonal responses to negative affective stimuli. MethodsParticipants included 99 individuals with major depressive disorder, psychosis and healthy controls. Functional magnetic resonance imaging (fMRI) was complemented with real-time acquisition of hypothalamo-pituitary-adrenal (HPA) and -gonadal (HPG) hormones. fMRI data were analyzed in SPM8 and task-related connectivity was assessed using generalized psychophysiological interaction. ResultsAcross all participants, elevated cortisol response predicted lower brain activity in orbitofrontal cortex and hypothalamus-amygdala connectivity. In those with worse dysphoric mood, elevated cortisol response predicted lower activity in hypothalamus and hippocampus. In women, elevated cortisol response was associated with lower activity in medial prefrontal cortex and low hypothalamo-hippocampal connectivity. In women with high dysphoric mood, elevated cortisol response was associated with low hypothalamo–hippocampal connectivity. There were no interactions with diagnosis or medication. LimitationsThere was limited power to correct for multiple comparisons across total number of ROIs and connectivity targets; cortisol responses were relatively low. ConclusionsWe conclude that the pathophysiology in neural-hormonal responses to negative affective stimuli is shared across healthy and clinical populations and varies as a function of sex and dysphoric mood. Our findings may contribute to the development of hormonal adjunctive therapeutics that are sex-dependent, underscoring the importance of one's sex to precision medicine.

Panik bozukluğu ve yaygın anksiyete bozukluğu olan hastalarda hipotalamo-pituiter-adrenal eksen aktivitesinin deksametazon baskılama testi ile değerlendirilmesi

Objective: The aim of this study was to investigate the role of hypothalamo-pituitary-adrenal (HPA) axis activity on the pathophysiology of anxiety disorders by examining the HPA axis activity in patients with panic disorder (PD) and generalized anxiety disorder (GAD). Method: Baseline and post dexamethasone suppression test (DST) serum concentrations of cortisol and dehydroepiandrosterone-sulfate (DHEA-S) were measured in patients with PD (n=24), GAD (n=21) and in healthy controls (n=20). Results: The baseline cortisol levels in GAD group were found lower than those of the patients with PD and healthy controls. Cortisol suppression by dexamethasone in GAD group was found to be lower than PD patients and healthy controls. Baseline and post-DST DHEA-S levels in the patients with PD and GAD were similar to those of the healthy controls. Conclusion: Lower cortisol levels and inadequate cortisol suppression with DST in GAD patients may suggest a downregulation in both corticotropin releasing hormone and glucocorticoid receptors in the central nervous system.

Pro-inflammatory immune-to-brain signaling is involved in neuroendocrine responses to acute emotional stress

Activation of the hypothalamo-pituitary-adrenal (HPA) axis by inflammatory stressors (e.g., bacterial lipopolysaccharide) is thought to involve vascular transduction of circulating cytokines, with perivascular macrophages (PVMs) along with endothelia, effecting activation of HPA control circuitry via inducible (cyclooxygenase-2- or COX-2-dependent) prostaglandin synthesis. To test the stressor-specificity of this mechanism, we examined whether ablation of PVMs or pharmacologic blockade of COX activity affected HPA responses to a representative emotional stressor, restraint. Exposing rats to a single 30min acute restraint episode provoked increased plasma levels of at least one proinflammatory cytokine, IL-6, microglial activation and multiple indices of cerebrovascular activation, including COX-2 expression and increased brain prostaglandin E2 levels at 0–2h after stress. Pretreatment with the nonselective COX inhibitor, indomethacin, either icv (10μg in 5μl) or iv (1mg/kg) significantly reduced restraint-induced Fos expression in the paraventricular hypothalamic nucleus (PVH) by 45%, relative to vehicle-injected controls. A 75% reduction of the PVH activational response was seen in rats exposed to acute restraint 5–7days after ablation of brain PVMs by icv injection of liposomes encapsulating the bisphosphonate drug, clodronate. Basal plasma levels of ACTH and corticosterone were not altered in clodronate liposome-injected rats, but the peak magnitude of restraint-induced HPA secretory responses was substantially reduced, relative to animals pretreated with saline-filled liposomes. These findings support an unexpectedly prominent role for inducible prostaglandin synthesis by PVMs in HPA responses to acute restraint, a prototypic emotional stressor.