Role of the dorsomedial hypothalamus in glucocorticoid-mediated feedback inhibition of the hypothalamic–pituitary–adrenal axis (original) (raw)
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The role of corticosterone in human hypothalamic? pituitary?adrenal axis feedback
Clinical Endocrinology, 2006
Objective In humans, the glucocorticoid corticosterone circulates in blood at 10-20-fold lower levels than cortisol, but is found in higher relative amounts in postmortem brain samples. Access of cortisol and corticosterone to the central nervous system may not be equal. Additionally, the relative affinities for the glucocorticoid and mineralocorticoid receptors differ, such that corticosterone may play a significant role in human brain function. Design We measured cortisol and corticosterone levels in paired plasma and cerebrospinal fluid (CSF) samples. To test the relative potency of cortisol vs. corticosterone on hypothalamic-pituitaryadrenal (HPA) feedback, subjects underwent a three-phase, singleblind, randomized study assessing the postmetyrapone ACTH response over 3 h to an intravenous bolus of vehicle, cortisol or corticosterone (0·15 mg / kg and 0·04 mg / kg). Participants Outpatients undergoing diagnostic lumbar puncture who were subsequently deemed to be free of disease. Feedback was tested in healthy male volunteers. Measurements Plasma and CSF corticosterone to cortisol ratio was calculated and the ACTH response over time after the bolus glucocorticoid measured. Results Plasma corticosterone : cortisol was 0·069 ± 0·007; CSF corticosterone : cortisol was 0·387 ± 0·050 ( P < 0·001). Cortisol and corticosterone (0·15 mg / kg) suppressed ACTH vs. vehicle ( P = 0·002); there was no difference between corticosterone and cortisol. The 0·04 mg / kg dose had no effect on ACTH despite supraphysiological plasma corticosterone levels. Conclusions Corticosterone contributes almost 40% of total active glucocorticoids (cortisol and corticosterone) in the CSF. Significant effects on HPA axis suppression were only seen with supraphysiological levels of corticosterone, suggesting that corticosterone is not important in this model of nonstress-induced ACTH hypersecretion, in which the effect of cortisol predominates.
Mechanisms of rapid glucocorticoid feedback inhibition of the hypothalamic-pituitary-adrenal axis
2011
Stress activation of the hypothalamic -pituitary-adrenal (HPA) axis culminates in increased circulating corticosteroid concentrations. Stress-induced corticosteroids exert diverse actions in multiple target tissues over a broad range of timescales, ranging from rapid actions, which are induced within seconds to minutes and gene transcription independent, to slow actions, which are delayed, long lasting, and transcription dependent. Rapid corticosteroid actions in the brain include, among others, a fast negative feedback mechanism responsible for shutting down the activated HPA axis centrally. We provide a brief review of the cellular mechanisms responsible for rapid corticosteroid actions in different brain structures of the rat, including the hypothalamus, hippocampus, amygdala, and in the anterior pituitary. We propose a model for the direct feedback inhibition of the HPA axis by glucocorticoids in the hypothalamus. According to this model, glucocorticoids activate membrane glucocorticoid receptors to induce endocannabinoid synthesis in the hypothalamic paraventricular nucleus (PVN) and retrograde cannabinoid type I receptor-mediated suppression of the excitatory synaptic drive to PVN neuroendocrine cells. Rapid corticosteroid actions in the hippocampus, amygdala, and pituitary are mediated by diverse cellular mechanisms and may also contribute to the rapid negative feedback regulation of the HPA neuroendocrine axis as well as to the stress regulation of emotional and spatial memory formation.
Endocrinology, 2015
Glucocorticoids act rapidly at the paraventricular nucleus (PVN) to inhibit stress-excitatory neurons and limit excessive glucocorticoid secretion. The signaling mechanism underlying rapid feedback inhibition remains to be determined The present study was designed to test the hypothesis that the canonical glucocorticoid receptors (GR) is required for appropriate hypothalamic-pituitary-adrenal (HPA) axis regulation. Local PVN GR knockdown was achieved by breeding homozygous floxed GR mice with Sim1-cre recombinase transgenic mice. This genetic approach created mice with a knockdown of GR primarily confined to hypothalamic cell groups including the PVN, sparing GR expression in other HPA axis limbic regulatory regions and the pituitary. There were no differences in circadian nadir and peak corticosterone concentrations between male PVN GR KD mice and male littermate controls. However, reduction of PVN GR increased ACTH and corticosterone responses to acute, but not chronic stress, ind...
2010
Almost all hormones are secreted in an episodic manner, producing fluctuations in hormone plasma concentrations over a timescale measured in minutes or hours, known as an ultradian rhythm. For some hormones, such as gonadotrophin-releasing hormone, growth hormone, and insulin, this ultradian rhythm has been shown to be of fundamental importance for normal physiological function. Corticosterone is the major effector hormone of the rat hypothalamic-pituitary-adrenal (HPA) axis and in unstressed conditions it too exhibits an ultradian rhythm, with pulses occurring approximately every 60 minutes. The aim of this research was to develop a novel model of corticosterone replacement for use in adrenalectomised (ADX) rats to investigate the physiological significance of corticosterone pulsatility. Chronic indwelling cannulae were surgically inserted into the right jugular and right femoral veins of ADX male Sprague-Dawley rats, and exteriorised through the scalp. Five days later these freely-moving animals were connected to a programmable infusion system. Each animal received two separate infusions of corticosterone 2- hydroxypropyl-β-cyclodextrin via the femoral cannula: first a constant infusion (42 μg active corticosterone/hour) lasting 12 hours; second a pulsatile infusion of one pulse/hour for 12 hours. Each pulse was achieved by programming the infusion pump to deliver 42 μg active corticosterone in 20 minutes, followed by a pause of 40 minutes. During both infusions the animals were connected to an automated blood microsampling system (ABS), and blood samples were taken via the jugular cannulae at 10 minute intervals. Plasma corticosterone levels were determined by radioimmunoassay. This model was subsequently further refined to incorporate variations in pulse amplitude which recreate the circadian rhythm of corticosterone secretion. A final experiment showed ADX animals which underwent long-term administration (126 hours) of a constant level of corticosterone had a significantly smaller thymus gland (P=0.02) compared with animals which had received the same amount of corticosterone presented as an hourly pulse. This model is the first corticosterone replacement system capable of closely mimicking the amplitude and frequency of the ultradian pattern of endogenous corticosterone pulses seen in adrenal-intact animals. It has a wide range of potential applications for further investigation into the question of the significance of glucocorticoid pulsatility.
Journal of Neuroendocrinology, 2008
Negative feedback effect of glucocorticoids on the hypothalamopituitary-adrenocortical (HPA) axis is mediated via a complex network of spatially and temporally distinct elements (1, 2). Glucocorticoids inhibit adrenocorticotrophic hormone (ACTH) secretion in rapid (short)-, intermediate-and long-term time domains that involve their action through membrane bound (3) and nuclear receptors (2, 4), respectively. In addition to a putative binding site on the plasma membrane, two types of nuclear corticosteroid receptors have been identified in the rat brain (5). Type I mineralocorticoid receptors have a high affinity for corticosterone (CORT) and are found predominantly in the limbic formation and in the septum. Type II glucocorticoid receptors (GR) have a lower affinity for CORT and are available for steroid binding under basal nonstressed conditions in widespread brain areas including the hypothalamus (6-8). To reveal brain site(s) where glucocorticoids exert their negative feedback on the HPA axis is a major question in stress physiology. Pioneer studies in the 1960s used large implants of steroids and measured ACTH or CORT plasma concentration as an index of HPA activity (9-11). These studies, however, have one major limitation, the 'implantation paradox' (12). Steroids, implanted into the brain parenchyma can reach the portal circulation and act within the pituitary to inhibit ACTH and, subsequently, CORT secretion. Some of these problems have been circumvented by using small capillary steroid implants and assaying corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) mRNA levels in the paraventricular nucleus (PVN) (13, 14). Although these studies provided evidence favouring the PVN as the major hypothalamic target of corticosteroid feedback, the question remained as to whether glucocorticoids act directly on CRH neurones or indirectly, through an inhibitory network.
Blockade of adrenal compensatory hypertrophy by unilateral hypothalamic lesions
Brain Research Bulletin, 1985
MARUBAYASHI, U., J. ANTUNES-RODRIGUES AND S. M. MCCANN. Blockade of adrenal compensarory hypertrophy by unilateral hypothalamic lesions. BRAIN RES BULL 14(4) 297-300, 1985.-To determine if unilateral hypothalamic lesions block adrenal compensatory hypertrophy (ACH), such lesions were produced unilaterally under stereotaxic guidance using direct cathodal current in rats just after the left adrenal gland was removed. The animals were sacrificed one week later and the degree of the ACH of the remaining adrenal gland was determined. Animals without lesions uniformly showed ACH in terms of an absolute increase in adrenal weight of the remaining gland as compared to the one excised or if calculated as mg adrenal weight/l00 g body weight. On the other hand, lesions in the region lateral to the paraventricular nucleus, lateral to the median eminence or in the region between these two loci prevented ACH in roughly 5&X of the animals whether the lesion was placed on the same or opposite side of the hypothalamus. Some lesions in the mid-line in the vicinity of the pamventricular nucleus also resulted in blockade of ACH. We speculate that the blockade is due to a partial elimination of CRF and/or vasopressin/oxytocinergic pathways which are activated by the fall in plasma corticosterone after removal of an adrenal gland.
1987
The effect of glucocorticoid on the production of corticotropin-releasing factor (CRE) and vasopressm in the paraventricular nucleus of the hypothalamus (PVH) was examined immunocytochemically, lntraperitoneal administration of dexamethasone sulfate in a dose of 0.1 mg/day suppressed the immunorcactivity of CRF and vasopressin in the medial parvocellular divisions of the PVH of the rat subsequent to bilateral adrenalectomy. In the magnoccllular divisions, suppression of vasopressin-immunoreactivity was not observed. These results suggest that the vasopressin in the medial parvocellular divisions plays a distinct role from that in the magnocellular divisions, the former having functional significance in the hypothalamo-hypophysio-adrenal axis.
Journal of Endocrinological Investigation, 1998
The aim of the present study was to determine the role of the endogenous sex steroid environment in the hypothalamo-corticotrope (HC) function in both sham-operated (SHAM) and bilaterally adrenalectomized (ADX) rats. For this purpose adult rats of both sexes were used 3 and 6 weeks after either SHAM or ADX. The results indicate that: a) in SHAM animals, basal plasma ACTH levels were significantly higher in females than in males, and this sexual dimorphism was overridden by ADX, regardless of the time postsurgery; b) although basal anterior pituitary (AP) ACTH content was similar in SHAM animals of both sexes, 3-and 6-week ADX induced higher AP ACTH in males than in females; c) at 3-and 6weeks, ADX rats of hoth sexes had an AVP:CRH ratio (r), in the median eminence (ME) and medial basal hypothalamus (MBH), increased several fold over the respective SHAM-value and, although no sexual dimorphism was found at week 3 post-ADX, by 6-weeks post ADX, these ratios were sig
Journal of Endocrinology, 1968
The adrenal response to adrenocorticotrophin (ACTH), as determined by the secretion of corticosterone into adrenal vein blood,was measured in hypophysectomized rats in the presence of low and high levels of corticosterone in the peripheral circulation. To ensure that the level of corticosterone was low in the peripheral blood, the animals were hypophysectomized 24 hr. before the experiment, and one adrenal was removed before the start of infusion of ACTH. After the onset of the infusion the effluent from the remaining gland was collected in a receptacle, thus preventing any corticosterone produced under the influence of ACTH from reaching the general circulation. To study the effect of a high level of circulating corticosterone on the adrenal response to ACTH, corticosterone was injected subcutaneously, in beeswax and arachis oil, before the start of infusion of ACTH. In these experiments, too, the steroid secreted under the influence of ACTH was prevented from entering the general circulation. The peripheral levels attained by the injection of corticosterone were within the range observed during surgical stress, i.e. about 40 \g=m\g./100 ml.blood. When the corticosterone levels were within this range the response to a continuous infusion of ACTH was reduced by approximately 22 % when compared with animals which had received no corticosterone and whose peripheral corticosterone levels were hardly measurable. These results suggest that corticosterone is probably involved in a direct feedback mechanism of adrenocortical secretion in the rat as its inhibitory effect on the response to ACTH can be demonstrated at peripheral levels of corticosterone which are within the range found during surgical stress. * Determined by weight. t P for 'ACTH' v. 'ACTH'+corticosterone, < 0-025 (corrected) and <0-05 (uncorrected).