Hypothalamo-pituitary-adrenal Axis Activity Research Articles

Investigation of effect peripheral kisspeptin treatment on hypothalamo-pituitary-gonadal axis and hypothalamo-pituitary-adrenal axis in male rats.

Kisspeptin is an endogenous peptide hormone that is the most potent stimulator of the hypothalamo-pituitary-gonadal (HPG) axis. The HPG axis can be suppressed by the activation of the hypothalamo-pituitary-adrenal (HPA) axis. The physiological role of kisspeptin in the interaction of the HPG axis and the HPA axis is not fully understood yet. The purpose of the current study was to investigate the possible effects of peripheral injection (intraperitoneally) of kisspeptin on HPG axis and HPA axis activity as well. Adult male Wistar rats were randomly divided into seven groups as sham (control), kisspeptin(10nmol), p234 (10nmol), kisspeptin + p234, kisspeptin + antalarmin (10mg/kg), kisspeptin + astressin2b (100μg/kg), and kisspeptin + atosiban (0.250mg/kg) (n = 10 each group). At the end of the experiment, the hypothalamus, pituitary gland, and serum samples of the rats were collected. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin and kisspeptin + astressin2b groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin, kisspeptin + antalarmin, kisspeptin + astressin2b, and kisspeptin + atosiban groups that compared to the control group. There was no a significant difference in corticotropic releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone and corticosterone concentrations among all groups. Moreover, no significant difference was found in the concentration of pituitary oxytocin. Our results suggest that peripheral kisspeptin injection induces an activation in the HPG axis, but not in the HPA axis in male rats.

Intracerebroventricular injection of kisspeptin in male rats activates hypothalamo-pituitary-gonadal axis, but not hypothalamo-pituitary-adrenal axis

Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 μg), kisspeptin + astressin 2B (1 μg), and kisspeptin + atosiban (300 ng/rat) (n = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.

Activities of the hypothalamo-pituitary-adrenal axis and autonomic nervous system following a strong earthquake.

This study aimed to investigate the effects of post-traumatic stress, caused by a strong earthquake, on the hypothalamo-pituitary-adrenal axis (HPA) and autonomous nervous system activity (ANS). Activities of the HPA (as salivary cortisol) and ANS (as heart-rate variability [HRV]) were measured following the 2020 Elazig (Türkiye) earthquake (6.8 Richter Scale, classified as strong). A total of 227 participants (103 men (45%) and 124 women (%55)) provided saliva samples twice, namely, 1week and 6weeks after the earthquake. Of these participants, HRV was measured in 51 participants by 5min continuous electrocardiogram (ECG) recording. Frequency- and time-domain parameters of the HRV were calculated to assess the activity of ANS and low/high frequency (LF/HF) ratio was used as surrogate for sympathovagal balance. Salivary cortisol levels decreased from week 1 towards week 6 (17.40±1.48 and 15.32±1.37ng/mL, respectively, p<0.05). There were no gender differences (17.99±2.63 and 16.90±1.60ng/mL, respectively for females and males, p>0.05) for salivary cortisol levels. There were no differences in time- and frequency domain parameters of the HRV including LF/HF ratio (2.95±0.38 ms2 and 3.60±0.70 ms2 , respectively for week 1 and 6, p>0.05). The data show that HPA axis activity, but not that of the ANS, remains higher 1week after the earthquake but decreases afterwards towards the sixth week, suggesting that the HPA axis might be responsible for the long-term effects of a traumatic event like a strong earthquake.

In early MS, the vasopressin peptide copeptin in serum is not a suitable surrogate for hypothalamo-pituitary-adrenal axis activity (P13-3.016)

<h3>Objective:</h3> To determine if a single measurement of copeptin, the C-terminal part of the AVP precursor (CT-proAVP), a stable and sensitive surrogate for AVP release, may serve as a more simply acquired substitute for the more cumbersome combined dexamethasone-corticotropin-releasing hormone test (DexCRH-test) to assess hypothalamo-pituitary-adrenal (HPA) axis activity in MS. <h3>Background:</h3> Activation of the HPA axis has been observed in MS by using the DexCRH-test, and may affect pathogenesis and clinical course. Vasopressin (AVP) costimulates ACTH secretion with CRH, but is not inhibited by dexamethasone. <h3>Design/Methods:</h3> Open, monocenter study, 44 HC, 55 patients with early relapsing-remitting MS (RRMS), 10 patients with clinically isolated syndrome (CIS). DexCRH-test (1.5 mg oral dexamethasone at 2300h the evening before; 100 μg i.v. synthetic hCRH at 1502h; serum ACTH and cortisol between 1500h and 1615h). Copeptin serum concentration before CRH application, and in a subset at 0900h before dexamethasone. Calculation of AUC for ACTH and cortisol output according to the trapezoidal rule. Independant samples t test, linear regression. <h3>Results:</h3> In HC (n=19) and MS (n=51), copeptin before and after dexamethasone correlated significantly, more stringently in HC (Pearson correlation, r²=0.627) than in MS (r²=0.301, both p&lt;0.001). No correlation was found between copeptin (before or after dexamethasone) and DexCRH test variables in either HC or MS (AUC of ACTH or cortisol secretion; p 0.13–0.35). Copeptin, AUC-ACTH and AUC-cortisol were not significantly different between HC and RRMS/CIS (p=0.35–0.42). <h3>Conclusions:</h3> In HC and MS, copeptin appears equally affected by dexamethasone. Our sample of early RRMS patients predominantly on DMT did not display significant activation of the HPA axis, and had a fairly homogeneous HPA axis activity. At least in this setting, a single measurement of copeptin did not appear suitable as a surrogate marker of HPA axis activity. A sample including more advanced stages and different courses of MS may be more informative. <b>Disclosure:</b> Maike Schlingmann has nothing to disclose. Muriel Stoppe has nothing to disclose. Klara Mayer has nothing to disclose. Christian Schinke has nothing to disclose. Ms. Haars has nothing to disclose. Elisa Schmidt has nothing to disclose. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Actelion. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genzyme. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Fresenius. The institution of Dr. Then Bergh has received research support from Actelion. The institution of Dr. Then Bergh has received research support from Novartis. The institution of Dr. Then Bergh has received research support from DFG (German Science Fund). Dr. Then Bergh has received personal compensation in the range of $10,000-$49,999 for serving as a Member of the Institutional Ethics Board with University of Leipzig, Medical Faculty.

Cortisol, chronotype, and coping styles as determinants of tolerance of nursing staff to rotating shift work

ABSTRACT Hypothalamo–pituitary–adrenal axis activity and cortisol patterns are likely to play a role in shift work tolerance, i.e., ability to adapt to shift work without suffering stress-related consequences. Yet, the evidence is scanty. Here, salivary cortisol output during night shifts and leisure days was assessed in fast-forward rotating shift work nursing staff (N = 30), and possible links with a series of variables – gender (30% male), age (M = 39.6, SEM = 1.57 y), years of service (M = 12.43, SEM = 1.48 y), BMI (M = 23.29, SEM = 0.66 Kg/m2), self-rated chronotype, sleep quality, and psycho-behavioral factors – were investigated. Main results show that cortisol output during night shifts: i) is larger in morning-oriented chronotypes, thus affected by the circadian misalignment between biological and working rhythms; ii) associates with dysfunctional coping styles at work; iii) positively correlates with diurnal cortisol secretion on leisure days, i.e., individuals with larger cortisol output during shifts display higher cortisol secretion on non-working days. Chronotype and psycho-behavioral factors explain most of the correlational weight linking cortisol output during the night shift and off-days. In conclusion, we confirm salivary cortisol testing as a suitable objective marker of occupational stress and propose it as a valuable index for monitoring shift work tolerance, in combination with chronotype. Moreover, we emphasize the importance of evaluating psycho-behavioral factors in professional settings, because these modifiable variables can be addressed with tailored psychological interventions to ameliorate poor job satisfaction, reduce work-related distress, and avoid chronic cortisol excess experienced by shift workers.

The nonhuman primate hypothalamo-pituitary-adrenal axis is an orchestrator of programming-aging interactions: role of nutrition.

Developmental programming alters life-course multi-organ function and significantly affects life-course health. Recently, interest has developed in how programming may influence the rate of aging. This review describes interactions of nutrition and programming-aging interactions in hypothalamo-pituitary-adrenal (HPA) development and function from fetal development to old age. A full picture of these interactions requires data on levels of HPA activity relating to the hypothalamic, adrenal cortical, circulating blood, and peripheral cortisol metabolism. Data are provided from studies on our baboon, nonhuman primate model both across the normal life course and in offspring of maternal baboons who were moderately undernourished by a global 30% diet reduction during pregnancy and lactation. Sex differences in offspring outcomes in response to similar challenges are described. The data clearly show programming of increased HPA axis activity by moderate maternal undernutrition. Increased postnatal circulating cortisol concentrations are related to accelerated aging of the brain and cardiovascular systems. Future studies should address peripheral cortisol production and the influence of aging advantage in females. These data support the view that the HPA is an orchestrator of interactions of programming-aging mechanisms.

Metformin effectively restores the HPA axis function in diet-induced obese rats.

IntroductionThe hypothalamo-pituitary-adrenal (HPA) axis is perturbed in obesity. We previously reported presence of leptin resistance in the brainstem and uncoupling between central noradrenergic tone and the HPA axis in obesity-prone (DIO) rats. Metformin is shown to lower body weight and adiposity, but the underlying mechanism is unclear. We hypothesized that this is associated with restored HPA axis function.MethodsAdult male DIO rats were placed on either a regular chow or HF diet for 7 weeks. Starting week 4, the animals were given either a low dose (60mg/kg) or high dose (300mg/kg) of metformin in drinking water. In addition to body weight and feeding, we examined different arms of the HPA axis to test if metformin can reinstate its function and coupling. To understand potential mechanisms, leptin signaling in the brainstem and circulating free fatty acid levels were also assessed.ResultsMetformin treatment lowered weight gain, fat mass, caloric intake, and serum leptin levels. HPA axis activity as determined by corticotropin-releasing hormone in the median eminence and serum corticosterone was decreased by metformin in a dose-dependent manner, and so was norepinephrine (NE) in the paraventricular nucleus. Importantly, metformin completely normalized the NE-HPA axis uncoupling. While brainstem pSTAT-3 and SOCS-3, key markers of leptin signaling, were not different between groups, circulating saturated and unsaturated free fatty acids were reduced in HF-fed, metformin-treated animals.ConclusionsThese findings suggest that oral metformin can successfully correct HPA axis dysfunction that is associated with lowered circulating free fatty acids in DIO rats, thereby uncovering a novel effect of metformin in the treatment of obesity.

The effects of prenatal dexamethasone exposure and fructose challenge on pituitary-adrenocortical activity and anxiety-like behavior in female offspring

Prenatal glucocorticoid overexposure could largely influence pituitary-adrenal activity and anxiety-like behavior in offspring. Our aim was to study the possible potentiating effect of moderate dose of fructose – common ingredient of today’s diet – on prenatal glucocorticoid treatment-induced hypothalamo-pituitary-adrenal (HPA) axis changes. Pregnant female rats were treated with multiple dexamethasone (Dx) doses (3 x 0.5 mg/kg/b.m. Dx; 16th-18th gestational day). Half of female offspring from control and Dx treated dams were supplemented with 10% fructose solution, from weaning till adulthood. Immunohistochemistry, unbiased stereological evaluation and hormonal analysis are used to provide the morpho-functional state of pituitary and adrenal gland. Anxiety-like behavior was assessed using the light/dark box test and the elevated plus maze test. Prenatally Dx exposed females, with or without fructose consumption, had markedly reduced adrenocortical volume (p < 0.05) comparing to controls. Increased basal plasma ACTH level in these females (p < 0.05) maintained corticosterone concentration at control level produced by smaller adrenal glands. In parallel, anxiety-like behavior was shown by both tests used. In conclusion, prenatal Dx exposure cause negative psychophysiological outcome reflected in increased HPA axis activity and anxiety behavior in female offspring, while moderately increased fructose consumption failed to evoke any alteration or to potentiate effects of prenatal Dx exposure.

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.

Patterns of Circulating Corticosterone in a Population of Rattlesnakes Afflicted with Snake Fungal Disease: Stress Hormones as a Potential Mediator of Seasonal Cycles in Disease Severity and Outcomes.

Snake fungal disease (SFD) is an emerging threat to snake populations in the United States. Fungal pathogens are often associated with a physiological stress response mediated by the hypothalamo-pituitary-adrenal axis (HPA), and afflicted individuals may incur steep coping costs. The severity of SFD can vary seasonally; however, little is known regarding (1) how SFD infection relates to HPA activity and (2) how seasonal shifts in environment, life history, or HPA activity may interact to drive seasonal patterns of infection severity and outcomes. To test the hypothesis that SFD is associated with increased HPA activity and to identify potential environmental or physiological drivers of seasonal infection, we monitored baseline corticosterone, SFD infection severity, foraging success, body condition, and reproductive status in a field-active population of pigmy rattlesnakes. Both plasma corticosterone and the severity of clinical signs of SFD peaked in the winter. Corticosterone levels were also elevated in the fall before the seasonal rise in SFD severity. Severely symptomatic snakes were in low body condition and had elevated corticosterone levels compared to moderately infected and uninfected snakes. The monthly mean severity of SFD in the population was negatively related to population-wide estimates of body condition and temperature measured in the precedent month and positively correlated with corticosterone levels measured in the precedent month. Symptomatic females were less likely to enter reproductive bouts compared to asymptomatic females. We propose the hypothesis that the seasonal interplay among environment, host energetics, and HPA activity initiates trade-offs in the fall that drive the increase in SFD prevalence, symptom severity, and decline in condition observed in the population through winter.

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.

ACTH, Cortisol and IL-6 Levels in Athletes following Magnesium Supplementation.

SummaryBackgroundPhysical exercise activates the hypothalamo-pituitary-adrenal (HPA) axis and induces the body’s inflammatory response. Due to contemporary dietary habits and increased energy expenditure, athletes are susceptible to depletion of magnesium ions. The aim of our study was to investigate, through assessment of plasma ACTH, serum IL-6, and salivary/serum cortisol levels, if chronic magnesium supplementation might reduce damaging stress effects in amateur rugby players.MethodsRugby players (N=23) were randomly assigned to intervention and control group. Basal samples were collected before intervention group started a 4-week-long supplementation with magnesium (500 mg Mg/d). Blood and saliva sampling were done a day before the match (Day-1), on the morning of competition (Game), and during a six-day-long recovery period (Day1, Day3 and Day6). ACTH, serum/salivary cortisol, IL-6 and total/differential leukocytes counts were determined at each time point.ResultsThere was a statistically significant increase in ACTH concentration in intervention group compared to control group, while reductions in cortisol concentrations between the two groups were the greatest at Day-1 (p < 0.01) and at the day of competition (Game) (p < 0.01). Our results revealed that magnesium completely abolished the increase in IL-6 level noted in control group on Day1 and Day3 vs. Day-1 (p < 0.01) and also diminished the rise in neutrophil/lymphocyte ratio in intervention group vs. control group (p < 0.01).ConclusionsThese results suggest the possibly important influence magnesium supplementation might have on the change of parameters of HPA axis activity and reduction of immune response activation following strenuous physical exercise such as a rugby game.

Ecologically Relevant Cooling Early in Life Alters Prefledging Adrenocortical Response in Free-Living Songbirds.

In vertebrates, exposure to stressful stimuli early in development may alter the activity of the hypothalamo-pituitary-adrenal (HPA) axis, with the potential for fitness consequences later in life. For altricial species, whose young rely on their parents for food, warmth, and protection from predators, adult behavior can modify the impact of some stressors on their offspring after birth or hatching. We have shown that single bouts of cooling that normally occur when brooding females leave the nest elevate corticosterone secretion in very young free-living eastern bluebird (Sialia sialis) chicks. Thus, natural variation in maternal brooding patterns can result in differential exposure of offspring to cooling, and also to glucocorticoids, very early in development. We tested the hypothesis that exposure to repeated bouts of cooling (mimicking those that occur normally when females leave the nest) would alter the activity of the chicks' HPA axis later in life. We exposed free-living chicks to either four 18-min bouts of cooling or brooding temperatures (control) during the first week after hatching. Then, just before fledging (i.e., at least 7 d after the cooling treatments had ceased), we assessed their corticosterone responses to restraint. Repeatedly cooled chicks had a significantly lower corticosterone response to restraint than did control chicks but did not differ from controls in other measures of growth and development. Our data suggest that natural variation in maternal brooding patterns, and hence natural variation in the chicks' body temperature, can alter the activity of the HPA axis well beyond the brooding period.

Dexamethasone exposure affects paraventricular nucleus and pituitary corticotrophs in female rat fetuses: An unbiased stereological and immunohistochemical study.

The hypothalamic paraventricular nucleus (PVN) drives the stress response by activating the hypothalamo-pituitary-adrenal (HPA) axis, particularly vulnerable to glucocorticoid exposure during development. To evaluate the effects of fetal dexamethasone (Dx) exposure on the stereological features of PVN and HPA axis activity in female rat fetuses, pregnant rats received 0.5mg Dx/kg/b.w./day on days 16, 17 and 18 of pregnancy and 21-day-old fetuses were obtained; controls received the same volume of saline. In an unbiased stereological approach, Cavalieri's principle and an optical fractionator were used for estimating volume and total cell number of the PVN, respectively. The intensity of corticotropin-releasing hormone (CRH) immunoreactivity in the median eminence (ME) was determined by CRH optical density and the adrenocorticotropic hormone (ACTH) relative fluorescence signal intensity (RIF) in pituitary corticotrophs was measured using Image J. Significant reductions (p<0.05) in PVN volume and cell number were found in fetuses exposed to Dx. Additionally, CRH optical density in the ME and ACTH RIF (p<0.05) in the corticotrophs were decreased. The established results suggest that the reduced number of cells in the PVN after maternal Dx administration negatively affects the CRH content in the ME and the ACTH quantity in pituitary corticotrophs in near-term fetuses.

Decline of hippocampal stress reactivity and neuronal ensemble coherence in a mouse model of depression

Dysregulations of stress systems, especially the hypothalamo–pituitary–adrenal (HPA) axis, have been commonly reported in major depression. Consistent results emphasized the role of the hippocampus in regulating stress systems and restoring an operative control on HPA axis following antidepressant treatments. However, very little is known about how the hippocampus integrates stress-related information and reacts to stressors beforehand. We therefore aimed to assess activations of hippocampal neuronal ensembles during stress-related experiences and evaluated the effects of a mouse model of depression, the Unpredictable Chronic Mild Stress (UCMS), and an antidepressant treatment (fluoxetine, 20mgkg−1day−1, ip) in BALB/cByJ mice. The UCMS induced a depression-like syndrome characterized by a reduced weight gain, a progressive deterioration of the coat, an altered stress-coping strategy in behavioural tests and HPA axis dysregulations. Chronic fluoxetine had no effect in control non-stressed mice per se but reversed the syndrome induced by the UCMS, including an improvement of the HPA-system alterations. Neuronal activation was then assessed by immediate early-gene (c-fos) expression in different subfields of the CA3 and dentate gyrus (DG) along the dorso–ventral axis of the hippocampus, as they can support different computational functions. Our results showed that the hippocampus reacts to stressors by adjusting activations of cell ensembles. A pre-treatment with dexamethasone (DEX), a glucocorticoid receptor (GR) agonist that produced a delayed inhibition of the HPA axis activity, reduced novelty-related activations in the proximal CA3 (CA3c) and the DG of the dorsal hippocampus. All these effects were compromised by the UCMS, particularly by altering activation coherences within the dorsal CA3–DG network, but were rescued by chronic fluoxetine. Our study indicates therefore that variations of CA3–DG cell ensemble activation may contribute to stress integration in the hippocampus and that dysfunctions of this process may foster HPA-system dysregulations and depression-related states. It suggests that pharmacological interventions aiming to consolidate CA3–DG neural network might improve stress reactivity and possibly benefit to patients with major depression.

Exercise and the Hypothalamo-Pituitary-Adrenal Axis.

Exercise represents a potent physiological stimulus upon the hypothalamo-pituitary adrenal (HPA) axis. Two major factors modulate the HPA axis response to exercise: intensity and duration. Endurance training per se does not induce permanent hypercortisolism as endurance-trained subjects have similar biological markers of HPA axis activity in resting condition as healthy untrained men. However, during a challenge of the HPA axis, endurance-trained subjects demonstrate an adaptation of the HPA axis activity to repeated exercise resulting from decreased tissular sensitivity to glucocorticoids. A great diversity of other mechanisms is involved in this adaptation, acting potentially at all levels in the cascade and leading to the biological effects of cortisol.

Increased adrenal responsiveness and delayed hatching date in relation to polychlorinated biphenyl exposure in Arctic-breeding black-legged kittiwakes (Rissa tridactyla)

High levels of environmental contaminants such as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and mercury (Hg) have been reported in some Arctic top predators such as seabirds. Chronic exposure to these contaminants might alter the response to environmental changes through interference with the regulation of corticosterone (CORT), a glucocorticoid stress hormone released by the hypothalamo–pituitary–adrenal (HPA) axis. Positive and negative relationships between CORT and environmental contaminants have been reported in polar seabirds. However, patterns appear inconclusive and it is difficult to attribute these relationships to a dysfunction of the HPA axis or to other confounding effects. In order to explore the relationships between the HPA axis activity and contaminants, we tested whether different aspects of the HPA axis of an Arctic seabird, the black-legged kittiwakes Rissa tridactyla, would be related to blood Hg, PCB and OCP concentrations. Male kittiwakes were caught during the incubation period in Svalbard and were subjected to different stress series: (1) a capture-restraint stress protocol, (2) an injection of dexamethasone (DEX) that enabled to test the efficacy of the HPA negative feedback and (3) an injection of adrenocorticotropic hormone (ACTH) that informed on the adrenal responsiveness. The HPA axis activity was unrelated to ΣOCPs and Hg. However, birds with high concentrations of ΣPCBs released more CORT after the ACTH injection. It is suggested that ΣPCBs may increase the number of ACTH-receptors on the adrenals. Additionally, hatching date was delayed in males with higher concentrations of ΣPCBs and ΣOCPs. This study gives new evidence that PCBs and adrenal activity may be related. Thus high PCB burden may make individuals more prone to other stressors such as ongoing climate change.

A blurring of life-history lines: Immune function, molt and reproduction in a highly stable environment

Rufous-collared sparrows (Zonotrichia capensis peruviensis) from valleys in the Atacama Desert of Chile, live in an extremely stable environment, and exhibit overlap in molt and reproduction, with valley-specific differences in the proportion of birds engaged in both. To better understand the mechanistic pathways underlying the timing of life-history transitions, we examined the relationships among baseline and stress-induced levels of corticosterone (CORT), testosterone, and bacteria-killing ability of the blood plasma (BKA), as well as haemosporidian parasite infections and the genetic structure of two groups of sparrows from separate valleys over the course of a year. Birds neither molting nor breeding had the lowest BKA, but there were no differences among the other three categories of molt-reproductive stage. BKA varied over the year, with birds in May/June exhibiting significantly lower levels of BKA than the rest of the year. We also documented differences in the direction of the relationship between CORT and BKA at different times during the year. The direction of these relationships coincides with some trends in molt and reproductive stage, but differs enough to indicate that these birds exhibit individual-level plasticity, or population-level variability, in coordinating hypothalamo–pituitary–adrenal axis activity with life-history stage. We found weak preliminary evidence for genetic differentiation between the two populations, but not enough to indicate genetic isolation. No birds were infected with haemosporidia, which may be indicative of reduced parasite pressure in deserts. The data suggest that these birds may not trade off among different life-history components, but rather are able to invest in multiple life-history components based on their condition.

Sleep in prenatally restraint stressed rats, a model of mixed anxiety-depressive disorder.

Prenatal restraint stress (PRS) can induce persisting changes in individual's development. PRS increases anxiety and depression-like behaviors and induces changes in the hypothalamo-pituitary-adrenal (HPA) axis in adult PRS rats after exposure to stress. Since adaptive capabilities also depend on temporal organization and synchronization with the external environment, we studied the effects of PRS on circadian rhythms, including the sleep-wake cycle, that are parameters altered in depression. Using a restraint stress during gestation, we showed that PRS induced phase advances in hormonal/behavioral circadian rhythms in adult rats, and an increase in the amount of paradoxical sleep, positively correlated to plasma corticosterone levels. Plasma corticosterone levels were also correlated with immobility in the forced swimming test, indicating a depressive-like profile in the PRS rats. We observed comorbidity with anxiety-like profile on PRS rats that was correlated with a reduced release of glutamate in the ventral hippocampus. Pharmacological approaches aimed at modulating glutamate release may represent a novel therapeutic strategy to treat stress-related disorders. Finally, since depressed patients exhibit changes in HPA axis activity and in circadian rhythmicity as well as in the paradoxical sleep regulation, we suggest that PRS could represent an original animal model of depression.

Central 5-alpha reduction of testosterone is required for testosterone's inhibition of the hypothalamo-pituitary–adrenal axis response to restraint stress in adult male rats

In rodents, the hypothalamo-pituitary–adrenal (HPA) axis is controlled by a precise regulatory mechanism that is influenced by circulating gonadal and adrenal hormones. In males, gonadectomy increases the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) response to stressors, and androgen replacement returns the response to that of the intact male. Testosterone (T) actions in regulating HPA activity may be through aromatization to estradiol, or by 5α-reduction to the more potent androgen, dihydrotestosterone (DHT). To determine if the latter pathway is involved, we assessed the function of the HPA axis response to restraint stress following hormone treatments, or after peripheral or central treatment with the 5α-reductase inhibitor, finasteride. Initially, we examined the timecourse whereby gonadectomy alters the CORT response to restraint stress. Enhanced CORT responses were evident within 48h following gonadectomy. Correspondingly, treatment of intact male rats with the 5α-reductase inhibitor, finasteride, for 48h, enhanced the CORT and ACTH response to restraint stress. Peripheral injections of gonadectomized male rats with DHT or T for 48h reduced the ACTH and CORT response to restraint stress. The effects of T, but not DHT, could be blocked by the third ventricle administration of finasteride prior to stress application. These data indicate that the actions of T in modulating HPA axis activity involve 5α-reductase within the central nervous system. These results further our understanding of how T acts to modulate the neuroendocrine stress responses and indicate that 5α reduction to DHT is a necessary step for T action.