Hypothalamic-hypophyseal System Research Articles

Differential Regulation of Cell Proliferation and Apoptosis by Melatonin Receptor Subtype-Signaling in the Adult Murine Brain

Background/Aims: Zeitgeber time (ZT)-dependent changes in cell proliferation and apoptosis are regulated by melatonin receptor (MT)-mediated signaling in the adult hippocampus and hypothalamic-hypophyseal system. There are two G-protein-coupled MT subtypes, MT1 and MT2. Therefore, the present study examined which MT subtype is required for the regulation of ZT-dependent changes in cell proliferation and/or apoptosis in the adult murine brain and pituitary. Methods: Adult melatonin-proficient (C3H) mice with targeted deletion of MT1 (MT1 KO) or MT2 (MT2 KO) were adapted to a 12-h light/12-h dark photoperiod and sacrificed at ZT00, ZT06, ZT12, and ZT18. Immunohistochemistry for Ki67 or activated caspase-3 served to quantify proliferating and apoptotic cells in the hippocampal subgranular zone (SGZ) and granule cell layer, the hypothalamic median eminence (ME), and the hypophyseal pars tuberalis. Results: ZT-dependent changes in cell proliferation were found exclusively in the SGZ and ME of MT1 KO mice, while apoptosis showed no ZT-dependent changes in the regions analyzed, neither in MT1 nor in MT2 KO mice. Comparison with our previous studies in C3H mice with functional MTs and MT1/2 KO mice revealed that MT2-mediated signaling is required and sufficient for ZT-dependent changes in cell proliferation in the SGZ and ME, while ZT-dependent changes in apoptosis require signaling from both MT subtypes. Conclusions: Our results indicate that generation and timing of ZT-dependent changes in cell proliferation and apoptosis by melatonin require different MT subtype constellations and emphasize the importance to shed light on the specific function of each receptor subtype in different tissues and physiological conditions.

Expression of corticotropin releasing factor (CRF), urocortin and CRF type 1 receptors in hypothalamic-hypophyseal systems under osmotic stimulation.

The expression of corticotropin releasing factor (CRF) and urocortin in hypothalamic magnocellular neurones increases in response to osmotic challenge. To gain a better understanding of the physiological roles of CRF and urocortin in fluid homeostasis, CRF, urocortin and CRF type 1 receptor (CRFR-1) gene expression was examined in the hypothalamic-hypophyseal system usingin situ and double-label in situ hybridization following chronic salt loading. CRFR-1 expression was further examined by immunohistochemistry and receptor binding. Ingestion of hypertonic saline by Sprague-Dawley rats for 7 days induced CRF mRNA exclusively in the oxytocin neurones of the magnocellular paraventricular nucleus (PVN) and the supraoptic nucleus (SON), but induced CRFR-1 mRNA in both oxytocin and vasopressin-containing magnocellular neurones. Hypertonic saline treatment also increased urocortin mRNA expression in the PVN and the SON. In the SON, urocortin was localized to vasopressin and oxytocin neurones but was rarely seen in CRF-positive cells. Changes in CRFR-1 mRNA expression in magnocellular neurones by hypertonic saline treatment were accompanied by changes in CRFR-1 protein levels and receptor binding. Hypertonic saline treatment increased CRFR-1-like immunoreactivity in the magnocellular PVN and SON, and decreased it in the parvocellular PVN. CRF receptor binding in the PVN and SON was also increased in response to osmotic stimulation. Finally, hypertonic saline treatment increased CRFR-1 mRNA, CRFR-1-like immunoreactivity and CRF receptor binding in the intermediate pituitary. These results demonstrate that the increase in the expression of CRF and urocortin message in magnocellular neurones induced by salt loading is accompanied by an increase in CRF receptor levels and binding in the hypothalamus and intermediate pituitary. Thus, CRF and urocortin may exert modulatory effects locally within magnocellular neurones as well as at the pituitary gland in response to osmotic stimulation.

Cyproterone acetate and reversal of the impaired endometrial decidualization in streptozotocin-diabetic pseudopregnant rats

Reproductive dysfunction in the female diabetic rat is associated with impaired hypothalamic-hypophyseal system, anovulation, insufficiency of ovarian steroidogenesis and spontaneous failure of pregnancy. Formation of decidua, the highly modified endometrium of pregnancy and pseudopregnancy could only be achieved when the uterus was sensitized by a sequence of oestrogen and progesterone. In this study, we examined whether the impaired expression of endometrial decidualization in the pseudopregnant rat is linked with diabetes-associated hypersecretion of testosterone. Rats were made pseudopregnant by sterile mating. Diabetes was induced by streptozotocin on day 1 p.c. Deciduogenic stimulus was given on day 5 p.c. Treatment of cyproterone acetate (10 mg kg−1) was scheduled from day 5 through day 9 p.c. Animals were killed on day 10 p.c, and the degree of endometrial decidual growth, plasma levels of oestradiol, progesterone, ACTH and testosterone were determined. Results showed that compared to controls there was a concomitant drop in endometrial decidual growth concurrently with impaired levels of oestradiol and progesterone in diabetic pseudopregnant rats. ACTH and testosterone levels were, however, profoundly elevated. Cyproterone acetate treatment in the diabetic pseudopregnant rat resulted in a simultaneous elevation of oestradiol and progesterone, which eventually helped the endometrial differentiation to decidua in the diabetic pseudopregnant rat parallel to controls. Present experimental data suggest that diabetes-associated impaired endometrial decidualization in the pseudopregnant rat is possibly caused by testosterone-induced oestrogen deficiency.

O 2-supply to the kidneys and the production of erythropoietin

The concentration of erythropoietin (Ep) in blood increases little following a reduction of the renal blood flow (rbf). In the present study we examined whether a reduction of rbf in rats induces a lowering of the renal venous P O 2 . In addition, the combined effects of reduced rbf and hypobaric hypoxia on the production of Ep were studied. To lower rbf, silver clips with stepwisely reduced inner diameters were applied on both renal arteries. The P O 2 of renal venous blood descreased gradually to values below 10 mm Hg, when rbf was reduced from 80 to 10% of normal. Under these conditions plasma Ep increased only moderately from 20 ± 6 to 69 ± 24 mU/ml within 18–20 h. However, plasma Ep of rats exposed to hypobaric hypoxia (simulated altitude of 6000 m for 18–20 h) was 431 ± 68 mU/ml, when rbf was 100-80% of normal, compared to 931 ± 91 mU/ml, when rbf was reduced to 40-10%. Thus, a reduction of the blood flow to the kidney appears to be no major stimulus for the production of Ep, even when the P O 2 in the kidney becomes very low. However, plasma levels of Ep increase markedly, when the whole body O 2 offer is lowered. These results support the view that Ep production is not only dependent on the P O 2 in the kidney but also under the control of extrarenal O 2 sensitive mechanisms. For example, the hypothalamic-hypophyseal system is thought to influence the production of Ep.

Regulation of the fetoplacental unit. 3. Suppression of the fetoplacental unit by cortisol in relation to the maturity of the fetus

The present study investigates the suppression of free plasma oestriol by cortisol in mature and immature foetuses. 6 patients in the 32nd week of gestation and 6 patients in the 38th week received an infusion of 100 mg cortisol (Hydrocortison Hoechst) from 10 a.m. to 12 a.m. Blood specimens (5 ml) were drawn from 8 a.m. to 5 p.m. in 60 or 30 minutes intervals, respectively. Free plasma oestriol was measured by radioimmunoassay, total plasma cortisol by the protein binding method. In the 32nd week of gestation plasma oestriol rose from 501 +/- 240 ng/ml to 1035 +/- 301 ng/ml, whereas oestriol decreased from 5.2 +/- 1.0 ng/ml to 3.9 +/- 1.5 ng/ml (p less than 0.001). After an analogous rise of cortisol, oestriol levels in the 38th week were suppressed from 12.5 +/- 3.3 ng/ml to 4.0 +/- 1.6 ng/ml (p less than 0.001). The degree of oestriol suppression of 68 percent in the 38th week markedly exceeded that of the 32nd week (25%). According to these results, the hypothalamic-hypophyseal system of mature foetuses exhibits a higher sensitivity to the feed back action of cortisol than immature foetuses.

Regulation of the fetoplacental unit. 2. Circadian changes in the sensitivity of the fetal hypothalamo-hypophyseal system for the feedback effect of cortisol

The present study investigates the significance of a circadian changing sensitivity on the feed back action of cortisol for the foetal hypothalamic hypophyseal system. 9 patients with uncomplicated courses of pregnancy in the 37th to 40th week volunteered in this study. All of them delivered healthy babies at term. 5 patients received a continuous infusion of 0.25 mg ACTH1-24 (Synacthen) in the morning from 10 a.m. to 4 p.m. (group I). To 4 patients an analogous ACTH infusion was applied in the evening from 8 p.m. to 2 a.m. (group II). Blood specimens (5 ml) were drawn from 8 a.m. to 5 p.m. in group I and from 5 p.m. to 3 a.m. in group II in 60 and 30 minutes intervals, respectively. Free plasma oestriol was measured by radioimmunoassay, total plasma cortisol by the protein binding method. In group I cortisol increased from 294.3 +/- 52.9 ng/ml to 774.5 +/- 170 ng/ml, whereas oestriol decreased from 13.1 +/- 6.1 ng/ml to 6.8 +/- 2.1 ng/ml (p less than 0.001). In group II cortisol rose from 267.5 +/- 76.2 ng/ml to 1010 +/- 284 ng/ml, whereas oestriol levels were suppressed from 21.7 +/- 10.5 ng/ml to 10.8 +/- 3.2 ng/ml (p less than 0.001). Two hours after starting ACTH infusion rising cortisol and falling oestriol concentrations were negatively correlated (r = -0.9657, p less than 0.001 in the morning; r = -0.9119, p less than 0.001 in the evening). Plasma oestriol levels were in the evening suppressed on an average of 10.9 ng/ml and exceeded the oestriol decrease in the morning (6.3 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of apomorphine, piribedil and haloperidol on adrenal ornithine decarboxylase activity of the rat

The administration of the dopaminergic drugs, apomorphine and piribedil to rats resulted in an increase in the activity of ornithine decarboxylase of the adrenal medulla and cortex. Pretreatment of the rats with the dopamine-receptor antagonist haloperidol caused a partial blockade of the apomorphine-induced effect at 4 hr in both adrenal medulla and cortex. At 6 hr, however, haloperidol did not block the effect of apomorphine and produced an increase in ornithine decarboxylase activity of both structures when administered alone. Hypophysectomy abolished the cortical ornithine decarboxylase response to apomorphine and haloperidol and the medullary response to haloperidol. The results suggest that the response of cortical ornithine decarboxylase activity to apomorphine and haloperidol is entirely mediated by the hypophysis and that the effect of apomorphine and the antagonistic action of haloperidol towards apomorphine in regard to the induction of adrenal medullary ornithine decarboxylase must be taking place at some central site independent of the hypothalamic-hypophyseal system.

Depolarization- and ionophore-induced release of octacosa somatostatin from stalk median eminence synaptosomes.

Species of somatostatin of higher molecular weight were present in the nerve terminals (synaptosomes) of ovine stalk median eminences and were released by depolarizing stimuli. One of these species was identified as the biologically active molecule octacosa somatostatin. Octacosa somatostatin appears therefore to be secreted into the hypothalamic-hypophyseal system, supporting the concept of a role for this peptide in regulating pituitary hormone secretion.

The hypothalamic-hypophyseal system and its evolutionary aspects in Scyliorhinus caniculus.

The peptidergic nature of most of the fibres of the neurosecretory system of Scyliorhinus caniculus has been demonstrated with the oxidation method of Naumann and Sterba (1976). Some of the fibres of this peptidergic system terminate on capillaries in the hypothalamic floor, some on neurointermediate cells. The evolutionary aspects of these observations are discussed.

Role of the Pineal Gland in Photoperiod-Induced Changes in Hypothalamic-Pituitary Sensitivity to Testosterone Feedback in Castrated Male Hamsters*

An exposure to short days induces testicular atrophy in intact, but not pinealectomized, golden hamsters. Since recent evidence suggests that an alteration in the sensitivity of the hypothalamic-hypophyseal system to steroid feedback may be one way in which the photoperiod acts to alter neuroendocrine- gonadal activity in seasonally breeding animals, the present investigation was designed to determine if the pineal gland is involved in this photic-induced change to steroid feedback. Castrated adult male hamsters that had been sham-pinealectomized (Sham-Px) or pinealectomized (Px) were maintained on either stimulatory long days [14 h of light, 10 h of darkness (LD 14:10)] or nonstimulatory short days (LD 6:18) for 8 weeks. The animals were then implanted with various sized testosteronefilled capsules and serum was collected 10 and 21 days later for hormone analysis. Capsules which contained 2 or 4 mm powdered testosterone maintained serum testosterone levels between about 0.8-1.5 ng/ml, and induced at leas...

Interaction between the hypothalamic-hypophyseal system and thyroid gland at different age periods

Age differences in interaction between the hypothalamic-hypophyseal system and the thyroid gland were studied with consideration to both direct and feedback control. In old age significant disturbances affect both direct and feedback components of this system; the sensitivity of thyroid tissue to TSH and of the hypothalamus and pituitary to the action of T4 is increased. The increased sensitivity of the hypothalamic-hypophyseal system to T4 is largely determined by activation of the deiodination of T4 by the adenohypophysis. The reactivity of the thyroid gland and hypothalamic-hypophyseal complex to the corresponding factors is reduced.

Morphological aspects of the hypothalamic-hypophyseal system

The ultrastruct of the tanycyte ependyma in male 160-180 g Wistar albino rats was studied under normal conditions and in experiments involving long-term suppression of ACTH secretion and its long-term stimulation. The former was accomplished by daily (for 8 days) intraperitoneal administration of dexamethasone phosphate at low (5 microgram/100 g) and high (100 microgram/100 g) concentrations. The effectiveness of suppression of the hypothalamic-hypophyseal-adrenal system in the experimental animals was judged by their reaction to two-minute ether stress (determination of plasma corticosterone) and by the results of measurement of the adrenal weights. Stimulation of ACTH secretion was achieved by bilateral adrenalectomy; the animals were examined on days 8, 10, 14, and 22 following the operation. The results obtained were in agreement with the previously established fact that there is a negative correlation between tanycyte activity and hypophyseal adrenocorticotropic function (Akmayed and Fidelina, 1974). They also testified to the predominant involvement of the median eminence tanycyte ependyma (beta-tanycytes according to the author's nomenclature) in these relationships. It is supposed that correlations are regulated by a feedback mechanism and attest to the involvement of beta-tanycytes in the inhibiting control of hypophyseal adrenocorticotrophic function. The mechanism of this control may be explained alternatively: either the tanycytes transport ACTH-suppression substances (catecholamines, corticosteroids, ACTH) from the CSF to the hypophyseal portal system or they themselves secrete substances possessing ACTH-suppressive activity. The authors distinguish several types of vesicles in the beta-tanycytes, the number of which changed with experimentally induced shifts in hypophyseal adrenocorticotrophic function. These vesicles are discussed in connection with the transport and secretory activity of the tanycytes and are considered to be a possible substrate of the hypothalamic inhibiting effect on ACTH secretion.

Morphological aspects of the hypothalamic-hypophyseal system. VI. The tanycytes: their relation to the sexual differentiation of the hypothalamus. An enzyme-histochemical study.

Enzyme-histochemical methods were used to study the metabolic activity of specialized ependyma of the ventrolateral walls and floor of the third ventricle in young male and female rats during the "critical period" of sexual differentiation of the hypothalamus (one week after birth). Histochemical tests were conducted for glutamic dehydrogenase, lactic dehydrogenase, glucose-6-phosphate dehydrogenase, glycerophosphate dehydrogenase and NADH2-dehydrogenase. Enzyme activity was judged by cytospectrophotometry. All the data were treated statistically. It was found that the specialized ependyma of the ventrolateral wall and floor of the third ventricle (median eminence) in rats differed in their enzyme behaviour in males and females during the "critical period" of sexual differentiation of the hypothalamus. At the level of the arcuate nucleus (alpha2-tanycytes) and the medial part of the median eminence (beta2-tanycytes) the ependyma was characterized by similar indices of metabolic activity in males and females in the decisive terms of the "critical period" (days 3, 5, and 7). On day 5 metabolic activity of these cells was reduced both in the males and in the females. Prominent sexual differences in the intensity of the enzyme reactions studied were noted in the ependyma of the lateral parts of the median eminence (beta1-tanycytes) in the "critical period". On day 5 metabolic activity of beta1-tanycytes was reduced in males and increased in females. It is suggested that these differences are caused by the receptor nature of beta1 tanycytes and suggest their implication in the mechanisms of sexual differentiation of hypothalamus.

Effect of the ergot derivative lisuride hydrogen maleate on serum prolactin concentrations in female rats.

The influence of a new synthetic ergot derivative, lisuride hydrogen maleate (LHM) on serum prolactin (PRL) concentrations was investigated in female rats using different test models: 1. in reserpine (R)-pretreated intact females, and 2. in ovariectomized (OVX) estradiol benzoate (E2)-primed animals with or without an additional pretreatment with R. In all the models used LHM was strongly effective in lowering serum PRL. Doses from 0.025 to 0.5 mg/kg LHM, given orally as well as subcutaneously, suppressed serum PRL. Depending on the dose used, the serum PRL was lowered to a different extent for up to 12 h. LHM was at least as effective as the well-known potent inhibitor of PRL secretion CB-154 in lowering serum PRL in OVX rats primed with E2. The effects of R, E2, and LHM are described in relation to their mode of action within the hypothalamic-hypophyseal system which regulates PRL secretion. While the increase in serum PRL induced by R seems to be directly relatable to its known catecholamine depletion, the circadian rhythm of PRL secretion induced by E2 seems to be influenced or mediated by central neural mechanisms. The effects of LHM on serum PRL in these test models can be related to its dopaminergic action and constitute further evidence for the central functions of dopaminergic mechanisms in the regulation of PRL secretion.

Pineal factors other than melatonin

Some sheep pineal factors other than melatonin are described. A “nonmelatonin” antigonadotropic activity has been detected by application of the inhibition of compensatory ovarian hypertrophy (COH) in unilaterally ovariectomized adult Charles River CD-1 mice. The factor has been extracted from sheep pineals under rather simple and mild experimental conditions. This antigonadotropic activity has been partially purified by gel filtration and ultrafiltration and was localized on paper chromatograms and paper electropherograms. Inhibitory and stimulatory activities on the hypothalamic-hypophyseal system in vitro have been detected in sheep pineal fractions obtained after gel filtration and ultrafiltration. A substance with distinct fluorescence characteristics, which could not be detected in sheep cerebral cortex extracts and which differs from melatonin, has been isolated from a low molecular Sephadex G-25 fraction of an extract of sheep pineals.

Morphological aspects of the hypothalamic-hypophyseal system. IV. Medial basal hypothalamus. An experimental morphological study.

Morphological aspects of the hypothalamic-hypophyseal system. IV. Medial basal hypothalamus. An experimental morphological study.

Compensatory ovarian hypertrophy as a function of age and neonatal androgenization.

Compensatory ovarian hypertrophy (COH) was examined in 144 normal or neonatally androgenized Sprague-Dawley female rats. Injections of either oil or 1.25 mg testosterone propionate (TP) were given on day 5. Left ovariectomy or sham-operation was performed on day 1, 10, 25, or 40, and the right ovary was removed 9 days later. Significant COH was found in the normal female on days 10, 34, and 49, but not on day 19. No significant hypertrophy was found until day 34 in the TP-treated females, after which a decrease in rate of ovarian growth and percentage of COH was observed. Even on days 34 and 49 androgenized females displayed less COH than controls. The results suggest that the sensitivity of the normal female's hypothalamichypophyseal system to ovarian secretions varies during prepuberal development and that neonatal androgen can impair the responsiveness of this system to changes in ovarian secretions. (Endocrinology 90: 1309, 1972)

Comparative anatomy and the evolution of the neurosecretory hypothalamic-hypophyseal system.

Comparative anatomy and the evolution of the neurosecretory hypothalamic-hypophyseal system.

Morphological aspects of the hypothalamic-hypophyseal system. 3. Vascularity of the hypothalamus, with special reference to its quantitative aspects.

Morphological aspects of the hypothalamic-hypophyseal system. 3. Vascularity of the hypothalamus, with special reference to its quantitative aspects.

Morphological aspects of the hypothalamic-hypophyseal system

Morphological aspects of the hypothalamic-hypophyseal system