Hypothalamo-pituitary-adrenal Response Research Articles

Prediabetes and mild hepatosteatosis are associated with blunted cortisol response to glucagon but not to growth hormone

BackgroundAlthough there is a close relationship between cortisol and growth hormone (GH) levels, glucose intolerance and hepatosteatosis, changes in GH and the hypothalamo-pituitary-adrenal (HPA) axis were not previously studied in prediabetes. The main purpose of the present study was to assess changes in GH and HPA axis and their relationship with hepatosteatosis in prediabetic patients. MethodsForty prediabetic patients, with body-mass index (BMI) 25–35kg/m2, and 23 healthy individuals, with normal glucose tolerance and similar age and BMI, were included. The 75g oral glucose tolerance test and glucagon stimulation test (GST) were used. ResultsNo significant differences were detected between prediabetic patients and healthy individuals in terms of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein-3 (IGFBP-3), IGF-1/IGFBP3 ratio or adrenocorticotropic hormone (ACTH). GH responses to GST did not differ between groups. On the other hand, peak cortisol and area under the curve (AUC) (cortisol) response on GST were significantly lower in prediabetic patients. Both peak GH and AUC (GH) response on GST correlated negatively with waist circumference and body weight. The degree of hepatosteatosis correlated negatively with peak cortisol, GH, AUC (cortisol) and AUC (GH) response on GST. ConclusionCortisol response to GST is decreased in prediabetic patients, with relatively well conserved GH response. This suggests altered HPA axis responsiveness in prediabetes, as is known in diabetes. Thus, HPA axis changes in patients with diabetes probably start before the development of diabetes as such.

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.

Stress response varies with plumage colour and local habitat in feral pigeons

Bird populations exposed to different extrinsic conditions often differ in the responsiveness of the hypothalamo–pituitary–adrenal (HPA) axis and thus in corticosterone response that individuals mount when facing stressful events. However, the contribution of genetic variation to among-individual variability in HPA axis responsiveness across different environmental conditions is poorly understood. Melanin-based coloured types provide reliable phenotypic markers of alternative genotypes underlying stress coping styles. Large variations in melanin-based colouration are heritable in feral pigeons. We tested whether melanin-based colouration is associated with variation in corticosterone stress response in feral pigeons. To this end, we examined how corticosterone response varies both within and between differently coloured individuals across different environmental conditions. Differently coloured individuals produced different stress-induced corticosterone levels in relation to their environmental conditions: dark pigeons exhibited a higher corticosterone when originating from rural habitats, while this was not observed in pale pigeons. This suggests that among-population variation in stress response is higher in dark pigeons, this variation possibly reflecting adjustment and/or (epi)genetic adaptation to environmental conditions. In addition, corticosterone response increased with the degree of melanin-based colouration in pigeons originating from rural habitats but not in pigeons originating from more urbanized populations, resulting in the coexistence of alternative stress responses in some populations, but not in others. Our results suggest that species with melanin-based variation in differently urbanized populations along rural–urban gradients are potentially good candidate systems for studying stress coping styles under alternative selective regimes.

Stress‐induced Neuroadaptations in the Paraventricular Hypothalamic Nucleus of Animals that Exhibit Persistent Avoidance

Individuals with PTSD exhibit increases in avoidance of trauma-related stimuli and blunted hypothalamo-pituitary adrenal (HPA) axis activation. Our laboratory has established a rodent model of traumatic stress that mimics the avoidance symptoms of PTSD. Animals are classified as ‘Avoiders' or ‘Non-Avoiders' based on avoidance of predator-odor paired context. We previously demonstrated that Avoiders exhibit an attenuated HPA response to predator odor. Glucocorticoids are the primary mediator of HPA negative feedback to the brain. Glucocorticoid receptor (GR) activation requires various accessory proteins that allow for translocation into the nucleus and transcriptional regulation of target genes. The FKBP5 gene, encoding binding protein FKBP51, is an important co-chaperone of the GR complex involved in regulating HPA negative feedback. FKBP51 prevents GR translocation to the nucleus, thus low FKBP5 results in enhanced negative feedback. We hypothesize that attenuated FKBP5 gene expression contributes to the hypofunctional HPA stress response in Avoiders. In this study, 50% of rats were classified as Avoiders. No differences in gene expression of the GR co-chaperones, Ncor1, FKBP5 and FKBP4 were noted in the paraventricular nucleus (PVN) of Non-Avoiders and Avoiders. There was a significant increase in NR3C1 (GR) gene expression in the PVN of Non-Avoiders compared to controls. These results suggest that stress-induced neuroadaptions in the GR complex may contribute to HPA dysfunction in Avoiders. The potential contribution of HPA dysfunction to stress-induced behaviors is the focus of current studies. This work was supported by NIH grants: AA018400 (NWG), AA023305 (NWG), and LSUHSC pilot grant (AMW).

Nicotine modulates multiple regions in the limbic stress network regulating activation of hypophysiotrophic neurons in hypothalamic paraventricular nucleus

Nicotine intake affects CNS responses to stressors. We reported that nicotine self-administration (SA) augmented the hypothalamo-pituitary-adrenal (HPA) stress response, in part because of the altered neurotransmission and neuropeptide expression within hypothalamic paraventricular nucleus (PVN). Limbic-PVN interactions involving medial prefrontal cortex, amygdala, and bed nucleus of the stria terminalis (BST) greatly impact the HPA stress response. Therefore, we investigated the effects of nicotine SA on stress-induced neuronal activation in limbic-PVN network, using c-Fos protein immunohistochemistry and retrograde tracing. Nicotine decreased stress-induced c-Fos in prelimbic cortex (PrL), anteroventral BST (avBST), and peri-PVN, but increased c-Fos induction in medial amygdala (MeA), locus coeruleus, and PVN. Fluoro-gold (FG) was injected into avBST or PVN, as GABAergic neurons in avBST projecting to PVN corticotrophin-releasing factor neurons relay information from both PrL glutamatergic and MeA GABAergic neurons. The stress-induced c-Fos expression in retrograde-labeled FG+ neurons was decreased in PrL by nicotine, but increased in MeA, and also reduced in avBST. Therefore, within limbic-PVN network, nicotine SA exerts selective regional effects on neuronal activation by stress. These findings expand the mechanistic framework by demonstrating altered limbic-BST-PVN interactions underlying the disinhibition of PVN corticotrophin-releasing factor neurons, an essential component of the amplified HPA response to stress by nicotine.

Here today, not gone tomorrow: long-term effects of corticosterone

There is a growing body of evidence from across animal taxa that exposure to elevated levels of glucocorticoids during development can have profound long-term effects upon physiological and behavioral phenotypes. Several avian studies have revealed that the degree to which an individual’s hypothalamo–pituitary–adrenal (HPA) axis responds to stressful stimuli as an adult may in effect have been ‘programmed’ or set as a result of that individual’s corticosterone exposure in ovo or as a nestling. Developmental exposure to corticosterone may also have effects upon avian ‘personalities’ or coping styles, and evidence from mammalian studies suggests that these long-term effects are mediated epigenetically via altered expression of relevant DNA sequences. Although there does not appear to be a consistent across-species pattern, developmental exposure to elevated corticosterone levels may shape adult coping style with such exposure, resulting in adults that are more timid and with increased HPA axis responsiveness to stress than those individuals that were exposed to relatively little corticosterone as nestlings. Recent work in Florida Scrub-jays (Aphelocoma coerulescens) has found that baseline corticosterone levels in nestlings at 11 days post-hatch explained 84% of the variation in ‘personality’ (bold vs. timid) when those individuals were tested at approximately 7 months of age. The overall ‘personality’ scores at 7–8 months of age were based upon tests that evaluated and combined the Jays’ responses to three tests: two startle and one neophobia stimuli. Here, we present findings on some of the factors that contribute to corticosterone levels of nestling Florida Scrub-jays, both within and among broods. Our prior and continuing research, as this overview will present, suggests that maternal attentiveness at the nest and paternal provisioning are important factors that mediate nestling corticosterone levels.

New Aspects of the Immunoregulation by the Hypothalamo-Pituitary-Adrenal (HPA) Axis

One of the basic neuro-immune-endocrine interaction is the hypothalamo-pituitary-adrenal axis (HPA) to harmonize immune response to inflammatory stressors. Immune defense mechanisms mediated by cytokines and other humoral factors play particularly important roles in this communication. They are also potent activators in the CNS and factors of the HPA axis, like an increased secretion of glucocorticoids (GC). They can act as major feedback regulator of the vertebrate immune response via suppression of a wide range of cytokines, as well as interferons. Increases in systemic GC levels, however, often play dual role: do not suppress all cytokines since inhibition of a particular cytokine may result in elevated production of others. External stimuli/acute stress can compromise activation of the HPA axis and activate immune processes for defense, redirecting leukocytes from the circulation to the environment/organism interface. Overall it results in release of danger-associated molecular patterns (DAMPs) to activate cells of the innate immune system, which is resolved by neural, hormonal or immune mechanisms. The chronic stress leads to chronic immune arousal and subsequent sterile, low-grade inflammation, which has been identified in most stress-related or civilized disorders in humans. The role of pituitary-gonadal axis in the activation of HPA axis results in a gender difference in HPA response to immunological challenges: e.g. can be varied during the estrus cycle, pregnancy or lactation. That corresponds to the results of recent experimental data that reveals an important role of certain neurotramsitters (such as dopamine) in immune regulation. Internal constitutional-factors of neuro-immune-endocrine interaction, such as corticotropin-releasing hormone (CRH) and its receptors (CRF-R1 and CRF-R2), melanocortin peptides, glucocorticoids or pro-inflammatory cytokines can also act as an immunoregulator, since their receptors is present in lymphoid organs, also in peripheral blood and organs that are enhanced under inflammatory conditions. In spite of series experimental data, the role of CRH and other members of its family, as well as its receptors in inflammation are still controversial. This dual role may be due to different CRF receptors and altered functionality. There are several putative mechanisms or ports of entry, in which the cytokines may affect HPA activity and CRH release. Some influences of cytokines on the HPA axis may be exerted by an indirect way. The aim of our review was to summarize and outline of key interacting agents based upon recent experimental results.

Inhibiting influence of testosterone on stress responsiveness during adolescence

The maturation of the hypothalamo-pituitary-adrenal (HPA) axis is a key-component of the changes that occur during adolescence. In guinea pigs, HPA responsiveness during late adolescence depends strongly on the quantity and quality of social interactions: Males that lived in a large mixed-sex colony over the course of adolescence exhibit a lower stress response than males that were kept in pairs (one male/one female). Since colony-housed males have higher testosterone (T) levels than pair-housed males, and inhibiting effects of T on HPA function are well known, we tested the hypothesis that the decrease in stress responsiveness found in colony-housed males is due to their high T concentrations. We manipulated T levels in two experiments: 1) gonadectomy/sham-gonadectomy of colony-housed males (which usually have high T levels), 2) application of T undecanoate/vehicle to pair-housed males (which usually have low T levels). As expected, gonadectomized males showed a significantly increased stress response in comparison with sham-gonadectomized males, and T-injected males had a significantly lower stress response than vehicle-injected males. Both experiments thus confirm an inhibiting effect of T on HPA responsiveness during adolescence, which can mediate the influence of social interactions. The reduction in stress responsiveness is hypothesized to have a biologically adaptive value: A sudden increase in glucocorticoid concentrations can enhance aggressive behavior. Thus, pair-housed males might be adapted to aggressively defend their female (‘resource defense strategy’), whereas colony-housed males display little aggressive behavior and are capable of integrating themselves into a colony (‘queuing strategy’).

The development of endotoxin tolerance, and the role of hypothalamo-pituitary-adrenal function and glucocorticoids in Pekin ducks

Endotoxin tolerance represents a state of abated immunological responsiveness to pyrogens, which, in mammals, leads to the decline or abolition of the fever response. The development of endotoxin tolerance in birds is not well understood; consequently, the impact of repeated pathogenic exposure on the avian febrile response, and thus on the ability of birds to fight recurrent infection, is not known. We determined the effect of repeated injections of lipopolysaccharide (LPS) on the febrile response of Pekin ducks. We gave ducks five injections of LPS, spaced 1, 4 or 10 days apart, and recorded their core body temperature with abdominally implanted temperature data loggers. Once we established that Pekin ducks developed endotoxin tolerance, we investigated the effect of repeated injections of LPS on the central and peripheral segments of the hypothalamo-pituitary-adrenal (HPA) axis in an attempt to elucidate the role of glucocorticoids in the modulation of the febrile response during the tolerant period. When our ducks became tolerant to LPS, they had significantly higher basal levels of plasma corticosterone (CORT, the principal glucocorticoid in birds), and their HPA response to treatment with LPS was blunted. We propose that the augmented levels of basal plasma CORT resulted from sensitized HPA function, and this, in turn, contributed to the development of endotoxin tolerance. Regulation of the circulating level of CORT might be a possible target for the re-establishment of appropriate immune responses in birds.

A Common Substrate for Prefrontal and Hippocampal Inhibition of the Neuroendocrine Stress Response

A network of interconnected limbic forebrain cell groups, including the medial prefrontal cortex (mPFC) and hippocampal formation (HF), is known to shape adaptive responses to emotionally stressful experiences, including output of the hypothalamo-pituitary-adrenal (HPA) axis. While disruption of limbic HPA-inhibitory systems is implicated in stress-related psychiatric and systemic illnesses, progress in the field has been hampered by a lack of a systems-level understanding of the organization that provides for this regulation. Using rats, we first localized cell groups afferent to the paraventricular hypothalamic nucleus (PVH) (the initiator of HPA responses to stress) whose engagement following acute (30 min) restraint was diminished by excitotoxin lesions of the ventral subiculum, a component of the HF. This identified a candidate relay for imparting HF influences in a circumscribed portion of the anterior bed nucleus of the stria terminalis (aBST), which we previously identified as a GABAergic relay subserving mPFC inhibition of the stress axis. Anatomical tracing experiments then indicated that extrinsic projections from HF and mPFC converge onto regions of aBST that contain neurons that are both stress sensitive and PVH projecting. Two final experiments provided evidence that (1) HPA-inhibitory influences of mPFC and HF are additive and (2) aBST plays a more prominent inhibitory role than ventral subiculum over stress-induced HPA endpoints. These findings support the view that stress-inhibitory influences of mPFC and HF are exerted principally via convergence onto a common relay, as opposed to a serial, parallel, or more complex multisynaptic network.

Neuroendocrine control of maternal stress responses and fetal programming by stress in pregnancy

The major changes in highly dynamic neuroendocrine systems that are essential for establishing and maintaining pregnancy are outlined from studies on rodents. These changes optimise the internal environment to provide the life support system for the placenta, embryo and fetus. These include automatic prevention of further pregnancy, blood volume expansion, increased appetite and energy storage. The brain regulates these changes, in response to steroid (estrogens, progesterone) and peptide (lactogens, relaxin) hormone signals. Activation of inhibitory endogenous opioid mechanisms in the brain in late pregnancy restrains premature secretion of oxytocin, and attenuates hypothalamo-pituitary-adrenal (HPA) responses to stress. This opioid mechanism is activated by allopregnanolone, a neuroactive progesterone metabolite. The significance of reduced HPA axis responses in shifting maternal metabolic balance, and in protecting the fetuses from adverse programming of HPA axis stress responsiveness and anxious behaviour in later life is critically discussed. Experimental studies showing sex-dependent fetal programming by maternal stress or glucocorticoid exposure in late pregnancy are reviewed. The possibility of over-writing programming in offspring through neurosteroid administration is discussed. The impact of maternal stress on placental function is considered in the context of reconciling studies that show offspring programming by stress in very early or late pregnancy produce similar phenotypes in the offspring.

A Role for the Androgen Metabolite, 5alpha Androstane 3beta, 17beta Diol (3?-Diol) in the Regulation of the Hypothalamo-Pituitary?Adrenal Axis

Activation of the hypothalamo-pituitary–adrenal (HPA) axis is a basic reaction of animals to environmental perturbations that threaten homeostasis. These responses are ultimately regulated by neurons residing within the paraventricular nucleus (PVN) of the hypothalamus. Within the PVN, corticotrophin-releasing hormone (CRH), vasopressin (AVP), and oxytocin (OT) expressing neurons are critical as they can regulate both neuroendocrine and autonomic responses. Estradiol (E2) and testosterone (T) are well known reproductive hormones; however, they have also been shown to modulate stress reactivity. In rodent models, evidence shows that under some conditions E2 enhances stress activated adrenocorticotropic hormone (ACTH) and corticosterone secretion. In contrast, T decreases the gain of the HPA axis. The modulatory role of testosterone was originally thought to be via 5 alpha reduction to the potent androgen dihydrotestosterone (DHT) and its subsequent binding to the androgen receptor, whereas E2 effects were thought to be mediated by estrogen receptors alpha (ERalpha) and beta (ERbeta). However, DHT has been shown to be metabolized to the ERbeta agonist, 5α- androstane 3β, 17β Diol (3β-Diol). The actions of 3β-Diol on the HPA axis are mediated by ERbeta which inhibits the PVN response to stressors. In gonadectomized rats, ERbeta agonists reduce CORT and ACTH responses to restraint stress, an effect that is also present in wild-type but not ERbeta-knockout mice. The neurobiological mechanisms underlying the ability of ERbeta to alter HPA reactivity are not currently known. CRH, AVP, and OT have all been shown to be regulated by estradiol and recent studies indicate an important role of ERbeta in these regulatory processes. Moreover, activation of the CRH and AVP promoters has been shown to occur by 3β-Diol binding to ERbeta and this is thought to occur through alternate pathways of gene regulation. Based on available data, a novel and important role of 3β-Diol in the regulation of the HPA axis is suggested.

Endocrine response of gilts to various common stressors: A comparison of indicators and methods of analysis

The first aim of the present study was to determine whether various common events encountered by pigs in commercial farms or experimental units induce activation of the sympathetic and hypothalamo-pituitary-adrenal (HPA) axes. The second aim was to compare the efficiency of various indicators and methods of analysis to detect the occurrence of a stress reaction. Responses to two blood sampling methods, immobilization by snaring, brief electric shocks, loud noise, ear tagging, tattooing, biopsy, pen relocation or delayed feeding time have been evaluated. Series of blood and saliva samplings (from 10 min before to 120 min after stressor application) were collected for each stressor on a total of 8 catheterized sows. Plasma glucose, lactate, cortisol and ACTH levels as well as salivary cortisol were measured. Acute increases of cortisol or ACTH (at least at time points +5 or +15 min) were observed for intense noise, electric shocks, ear tagging, tattooing, biopsy, cava blood sampling, snaring and pen relocation. Snaring, relocation and vena cava blood sampling generated longer stress responses whereas delayed meal and tail blood sampling had no influence. Plasma lactate was also significantly increased in several time-points after stressor application contrarily to plasma glucose. Comparison of successive time points with the starting basal level and comparison with the control group were more sensitive methods to detect a stress response to moderate stressors like electric shocks and tattooing, than comparing the area under the curve. These data confirmed that salivary cortisol is a good indicator to measure the HPA response to a stressor, provided that post-treatment levels can be compared with pre-treatment levels.

Reduced stress responsiveness in pregnancy: Relationship with pattern of forebrain c-fos mRNA expression

Stress-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis is known to be attenuated during late pregnancy and throughout lactation. To investigate the neural basis of this stress hyporesponsiveness we examined the changes in the restraint-induced HPA response and accompanying forebrain expression of c-fos mRNA that occur in rats between days 16 (D16) and 19 (D19) of gestation, times associated with declining levels of progesterone, a potential mediating factor. Compared to D16, the D19 group showed a significantly attenuated release of ACTH following 30min restraint. This reduced HPA response was accompanied by significantly lower levels of restraint-induced c-fos mRNA expression in the hypothalamic paraventricular nucleus. Other areas of the forebrain, including medial amygdala, piriform cortex, and ventrolateral septum, showed low c-fos mRNA expression in non-stressed (control) animals and a large increase following restraint, the magnitude of which was similar between D16 and D19 animals indicating no involvement in the differential HPA response to stress. However, a markedly different pattern of c-fos mRNA expression was observed in other brain areas, including barrel cortex and CA1 ventral and CA3 regions of the ventral hippocampus: D19 animals had low control expression which was increased by restraint, but D16 control animals had raised c-fos mRNA expression which was not further elevated by stress. These data demonstrate that region-specific changes in basal and stress-induced cellular activity occur during a period of late gestation coincident with attenuated HPA responsiveness. These changes in neuronal activity may contribute to the adaptive processes that prepare the mother for parturition and lactation.

Nicotine self‐administration differentially modulates glutamate and GABA transmission in hypothalamic paraventricular nucleus to enhance the hypothalamic–pituitary–adrenal response to stress

The mechanisms by which chronic nicotine self-administration augments hypothalamo-pituitary-adrenal (HPA) responses to stress are only partially understood. Nicotine self-administration alters neuropeptide expression in corticotropin-releasing factor (CRF) neurons within paraventricular nucleus (PVN) and increases PVN responsiveness to norepinephrine during mild footshock stress. Glutamate and GABA also modulate CRF neurons, but their roles in enhanced HPA responsiveness to footshock during chronic self-administration are unknown. We show that nicotine self-administration augmented footshock-induced PVN glutamate release, but further decreased GABA release. In these rats, intra-PVN kynurenic acid, a glutamate receptor antagonist, blocked enhanced adrenocorticotropic hormone and corticosterone responses to footshock. In contrast, peri-PVN kynurenic acid, which decreases activity of GABA afferents to PVN, enhanced footshock-induced corticosterone secretion only in control rats self-administering saline. Additionally, in rats self-administering nicotine, footshock-induced elevation of corticosterone was significantly less than in controls after intra-PVN saclofen (GABA-B receptor antagonist). Therefore, the exaggerated reduction in GABA release by footshock during nicotine self-administration disinhibits CRF neurons. This disinhibition combined with enhanced glutamate input provides a new mechanism for HPA sensitization to stress by chronic nicotine self-administration. This mechanism, which does not preserve homeostatic plasticity, supports the concept that smoking functions as a chronic stressor that sensitizes the HPA to stress.

Dual Roles for Perivascular Macrophages in Immune-to-Brain Signaling

Cytokines produced during infection/inflammation activate adaptive central nervous system (CNS) responses, including acute stress responses mediated by the hypothalamo-pituitary-adrenal (HPA) axis. The mechanisms by which cytokines engage HPA control circuitry remain unclear, though stimulated release of prostanoids from neighboring vascular cells has been implicated in this regard. How specific vascular cell types, endothelial cells (ECs) versus perivascular cells (PVCs; a subset of brain-resident macrophages), participate in this response remains unsettled. We exploited the phagocytic activity of PVCs to deplete them in rats by central injection of a liposome-encapsulated proapoptotic drug. This manipulation abrogated CNS and hormonal indices of HPA activation under immune challenge conditions (interleukin-1) that activated prostanoid synthesis only in PVCs, while enhancing these responses to stimuli (lipopolysaccharide) that engaged prostanoid production by ECs as well. Thus, PVCs provide both prostanoid-mediated drive to the HPA axis and an anti-inflammatory action that constrains endothelial and overall CNS responses to inflammatory insults.

Stress sensitivity is increased in transgenic rats with low brain angiotensinogen

AT(1) blockers attenuate hypothalamo-pituitary-adrenal (HPA) axis reactivity in hypertension independently of their potency to lower blood pressure. A reduced pituitary sensitivity to CRH and a downregulation of hypothalamic CRH expression have been suggested to influence HPA axis activity during chronic AT(1) blockade. This study was aimed at confirming the role of central angiotensin II in regulating HPA reactivity by using the transgenic rat TGR(ASrAOGEN), a model featuring low levels of brain angiotensinogen. Different stress tests were performed to determine HPA reactivity in TGR(ASrAOGEN) and appropriate controls. In TGR(ASrAOGEN), blood pressure was diminished compared to controls. The corticosterone response to a CRH or ACTH challenge and a forced swim test was more distinct in TGR(ASrAOGEN) than it was in controls and occurred independently of a concurrent enhancement in ACTH. Using quantitative real-time PCR, we found increased mRNA levels of melanocortin 2 (Mc2r) and AT(2) receptors (Agtr2) in the adrenals of TGR(ASrAOGEN), whereas mRNA levels of Crh, Pomc, and AT(1) receptors (Agtr1) remained unchanged in hypothalami and pituitary glands. Since stress responses were increased rather than attenuated in TGR(ASrAOGEN), we conclude that the reduced HPA reactivity during AT(1) blockade could not be mimicked in a specific transgenic rat model featuring a centrally inactivated renin-angiotensin-aldosterone system. The ACTH independency of the enhanced corticosterone release during CRH test and the enhanced corticosterone response to ACTH rather indicates an adrenal mechanism. The upregulation of adrenal MC2 and AT(2) receptors seems to be involved in the stimulated facilitation of adrenal corticosterone release for effectuating the stimulated stress responses.

A single exposure to an acute stressor has lasting consequences for the hypothalamo–pituitary–adrenal response to stress in free-living birds

In vertebrates, activation of the hypothalamo–pituitary–adrenal (HPA) axis in response to unpredictable events results in elevated glucocorticoid secretion. Repeated exposure to stressors alters subsequent glucocorticoid secretion, either by inducing chronic stress or as a result of habituation. However, most studies of repeated stress focus on the impacts of multiple and frequent exposures to acute stressors, and few have been carried out in free-living animals. We investigated whether a single exposure to a novel stressor was sufficient to produce long-lasting alterations in HPA function in free-living eastern bluebirds ( Sialia sialis). We subjected adult females to a capture/restraint protocol in which we collected serial blood samples over an hour of restraint to be analyzed for corticosterone. We administered this protocol to three groups of females during the nestling phase of their first and/or second brood of the season: Repeaters (sampled during brood 1 and brood 2), Naïve-Brood 1 (sampled only during brood 1), and Naïve-Brood 2 (sampled only during brood 2). Repeaters had attenuated corticosterone responses to the second restraint bout compared to the first, and in brood 2, Repeaters had lower responses than Naïve-Brood 2 females. However, Naïve-Brood 1 and Naïve-Brood 2 birds did not differ in their responses to restraint. Thus, as little as one prior experience with an acute stressor was sufficient to alter subsequent HPA responsiveness, and this effect was not due to a natural change in HPA responsiveness as the breeding season progressed. These data may have important implications for understanding how acute stressors can alter a free-living animal’s ability to cope in the face of subsequent stressors, and for longitudinal field studies in which individuals are repeatedly sampled for glucocorticoid responsiveness.

Reduced Hypothalamo‐pituitary‐adrenal Axis Stress Responses in Late Pregnancy

In late pregnancy, the hypothalamo-pituitary-adrenal (HPA) axis is less responsive to a range of psychological and physical stressors as a result of reduced central drive to the corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN). Most stressors activate the brain stem noradrenergic system, which innervates the majority of networks involved in regulating stress responses, including the PVN. Forced swimming, systemic interleukin-1beta (IL-1beta), and cholecystokinin (CCK) all activate brain stem noradrenergic cell groups, stimulate noradrenaline release in the PVN, and activate the HPA axis in nonpregnant rats. However, in late pregnancy we have shown that forced swimming and IL-1beta fail to evoke noradrenaline release in the PVN and hence HPA axis responses are suppressed. HPA axis responses to IL-1beta and CCK can be reinstated in pregnant rats by systemic administration of the opioid receptor antagonist naloxone, and when infused directly into the PVN, naloxone restores noradrenaline release in the PVN following IL-1beta treatment. Adrenaline release into the blood following stress is also attenuated in late pregnancy, despite increased adrenomedullary expression of tyrosine hydroxylase mRNA at this time. This review describes the mechanisms underlying attenuated HPA axis stress responses in pregnancy, focusing on the role of endogenous opioids and the central noradrenergic system.

Noradrenergic Innervation of the Dorsal Medial Prefrontal Cortex Modulates Hypothalamo-Pituitary-Adrenal Responses to Acute Emotional Stress

The medial prefrontal cortex (mPFC) has been proposed to play a role in the inhibition of hypothalamo-pituitary-adrenal (HPA) responses to emotional stress via influences on neuroendocrine effector mechanisms housed in the paraventricular hypothalamic nucleus (PVH). Previous work also suggests an involvement of the locus ceruleus (LC) in behavioral and neuroendocrine responses to a variety of acute stressors. The LC issues a widespread set of noradrenergic projections, and its innervation of the prefrontal cortex plays an important role in the modulation of working memory and attention. Because these operations are likely to be critical for stimulus selection, evaluation, and comparison with past experience in mounting adaptive responses to emotional stress, it follows that the LC-to-mPFC pathway might also be involved in regulating HPA activity under such conditions. Therefore, in the present study, we assessed the effects of selectively ablating noradrenergic inputs into the mPFC, using the axonally transported catecholamine immunotoxin, saporin-conjugated antiserum to dopamine-beta-hydroxylase, on acute restraint stress-induced activation of HPA output. Immunotoxin injections in the dorsal mPFC (centered in the prelimbic cortex) attenuated increments in restraint-induced Fos and corticotropin-releasing factor mRNA expression in the neurosecretory region of PVH, as well as HPA secretory responses. Stress-induced Fos expression in dorsal mPFC was enhanced after noradrenergic deafferentation and was negatively correlated with stress-induced PVH activation, independent of lesion status. These findings identify the LC as an upstream component of a circuitry providing for dorsal mPFC modulation of emotional stress-induced HPA activation.