Expression of the low affinity neurotrophin receptor, P75NGFR, in the rat forebrain, following unilateral bulbectomy

It has been hypothesized that the main olfactory bulb, with its relatively rich source of neurotrophins, may provide trophic support for neurons that project to the bulb. We monitored expression of the common, low affinity receptor for neurotrophins, p75NGFR, in the olfactory bulb and basal forebrain of unilaterally bulbectomized and sham-treated rats, 1-16 weeks post-surgery, using the monoclonal antibody MAb192. An induction of p75NGFR-immunoreactivity was observed in both the glomerular and olfactory nerve layers of the right, contralateral main olfactory bulb of lesioned animals. The naturally occurring regeneration taking place in the olfactory neuroepithelium is known to be altered by olfactory bulbectomy, with subsequent changes in the sensory input to the remaining bulb. These changes in expression of p75NGFR in the olfactory bulb support the hypothesis we have developed in previous papers, that changes in the extent of the peripheral input from the olfactory neuroepithelium to the main olfactory bulb regulate p75NGFR expression in both the glomerular and the olfactory nerve layers. Expression of p75NGFR in the basal forebrain of bulbectomized animals was found to be no different than sham-treated controls and does not support the hypothesis that the olfactory bulb provides trophic support to this region of the central nervous system.     

Failure of protein synthesis inhibition to block progesterone desensitization of lordosis in female rats

Progesterone's desensitization effect on lordosis has been shown to correlate with a decreased concentration of hypothalamic progestin receptors after progesterone injection. In a recent study, one group of investigators found that the protein synthesis inhibitor anisomycin appeared to block progesterone's desensitization effect. Despite decreased levels of cytoplasmic progestin receptors, progesterone + anisomycin-treated rats exhibited a high level of lordosis four hr after a second progesterone injection. Because this finding conflicts with a progestin receptor model of progesterone's desensitization effect, we investigated it further. In the first experiments, ovariectomized rats were injected with estradiol benzoate followed 24 hr later by either progesterone or vehicle. Anisomycin injected 3 hr after progesterone, at a dose that causes inhibition of hypothalamic protein synthesis for at least 4 hr, was without effect on progesterone desensitization a day later. In other experiments silastic implants containing estradiol were inserted into ovariectomized rats. Forty-five hr later, rats received progesterone or vehicle, followed by injections of anisomycin or saline. Rats receiving anisomycin + progesterone were still highly receptive at 30 hr while saline + progesterone controls were not. Furthermore, the results were similar 4 hr after a second injection of progesterone at 30 hr. In a related experiment, we confirmed that anisomycin delayed dramatically termination of the period of sexual receptivity. In this laboratory anisomycin does not seem to block progesterone's desensitization effect. However, with certain procedures anisomycin delays the termination of sexual receptivity. Thus it is important in investigations of the mechanism of progesterone's desensitization effect that animals be tested prior to the second progesterone injection to determine if they are actually responding to the progesterone.     

Changes in [3H]flunitrazepam binding in the brain of rats made tolerant to and dependent upon pentobarbital

Changes in benzodiazepine binding sites labeled by [3H]flunitrazepan (FNZ) in twenty discrete brain regions of rats made tolerant to and dependent upon pentobarbital were examined. Animals were rendered tolerant by intracerebroventricular (i.c.v.) infusion with pentobarbital (300 micrograms/ 10 microliters/ hr for six days) through pre-implanted cannulae connected to osmotic mini-pumps. The pentobarbital dependence was assessed 24 hr after abrupt withdrawal from pentobarbital. In the tolerant rats, a significant increase in [3H]FNZ binding sites was found in layer IV of frontal cortex and the molecular layer of olfactory bulb. [3H]FNZ binding sites in the pentobarbital dependent rats were significantly increased in layers I-III and V-VI of frontal cortex, caudate-putamen, olfactory tubercle, globus pallidus and ventral pallidum, in addition to those observed in the tolerant group. There was, however, no significant difference in the hippocampus and several regions in the hindbrain in either pentobarbital-treated group. Taken together with characteristics of subtypes of benzodiazepine receptors and changes in GABA-benzodiazepine receptor complexes elucidated in our previous studies, these findings suggest that both types of benzodiazepine receptors are involved in the development of pentobarbital intoxication mediated by GABAA receptors.     

Structure and function of the peripheral-type benzodiazepine receptor in steroidogenic cells

Steroidogenesis depends on the rate of cholesterol transport from intracellular stores to the inner mitochondrial membrane cytochrome P-450 side-chain cleavage enzyme. Using steroidogenic cell submitochondrial fractions, mitochondrial preparations, various cell models, and animal models and with the help of pharmacological, biochemical, morphological, and molecular approaches, we provide evidence that the peripheral-type benzodiazepine receptor mediates the intramitochondrial cholesterol transport and the subsequent adrenal, gonadal, placental, and brain steroid biosynthesis.     

Temporal and spatial monitoring of exocytosis with native fluorescence imaging microscopy

The effects of maternal food deprivation for 16 hr on day 3 and again on day 5 of pregnancy on the development of adrenals and ovaries in the female offspring during postnatal life (8, 21, 30 and 60 days after birth) were examined. Experimental and control groups consisted of 6-15 animals. On day 8, the daughters of the deprived mothers had lower body weight than the control animals. Later, the differences between the groups disappeared. Maternal food deprivation alters the prepubertal dynamics of adrenal progesterone production in vitro, and in mature experimental females adrenal progesterone production is significantly (P < 0.05) lower than in the control. In deprived mothers' offspring, the postnatal development of the endocrine function of the ovaries was disturbed: on day 8, the ovarian progesterone production was 3.3 times less (P < 0.001) and ovarian estradiol production was 3.2 times less (P < 0.05) than in the control, and on day 30, a prepubertal peak in ovarian estradiol production in vitro was absent. Maternal food deprivation causes alterations in the prepubertal dynamics of blood concentrations of corticosterone, progesterone and estradiol and reduction in blood concentrations of progesterone (P < 0.05) and estradiol (P < 0.001) in mature individuals. It was concluded that maternal food deprivation before implantation disturbs the normal course of postnatal maturation of the ovarian endocrine functions and adrenal progesterone secretion in daughters.     

Hormonal regulation of epidermal growth factor receptor content and signaling in bovine mammary tissue

Mammary tissue from midpregnant heifers was cultured with epidermal growth factor (EGF) or transforming growth factor alpha for 1-3 days. After 1 day, 10 nM EGF or transforming growth factor alpha doubled DNA synthesis, whereas lower concentrations (0.1 or 1 nM) increased DNA synthesis 2- to 3-fold after 2-3 days in culture. In other studies, bovine mammary tissue was transplanted to ovariectomized athymic mice and treated for 10 days with saline, estradiol (1 microg/day), progesterone (1 mg/day), or estradiol + progesterone. Subsequent explant culture of the bovine tissue indicated that estradiol + progesterone augmented the ability of EGF to stimulate DNA synthesis. The increased response to EGF was associated with increased EGF binding and with increased EGF-induced tyrosine kinase that paralleled the increased EGF binding. In other studies, athymic mice bearing xenografted bovine mammary tissue were primed for 10 days with estradiol and progesterone, followed by 2-day treatment with saline (control), hydrocortisone (200 microg/day), PRL (1 mg/day), or hydrocortisone + PRL. Hydrocortisone and PRL alone decreased, and PRL + hydrocortisone eliminated, EGF-induced DNA synthesis. EGF receptor content was unaffected by hydrocortisone but was reduced by PRL or hydrocortisone + PRL. Furthermore, the ability of EGF to induce tyrosine kinase activity was decreased by PRL and by hydrocortisone + PRL. The decreased kinase activity was greater than the decrease in receptor binding, suggesting a specific modulation of EGF receptor kinase activity in response to lactogenic hormones.     

Two antiatherogenic effects of progesterone on human macrophages; inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids

The effects of progesterone and estradiol on cholesteryl ester (CE) formation by monocyte-derived human macrophages were examined. Formation was assessed from incorporation of 14C-cholesterol during a 20-h incubation with hormone and from that of 3H-oleate (3 h) after hormone removal. Progesterone inhibited cholesterol into CE and decreased CE cellular levels. Inhibition: 1) was reversed by progesterone removal; 2) was independent of the progesterone receptor (not blocked by the receptor antagonist RU40555); and 3) exhibited specific structural requirements; 11alpha-OH-progesterone was inhibitory, whereas its stereoisomer 11beta-OH-progesterone was not. In contrast to progesterone, estradiol was ineffective. We had reported that dexamethasone enhanced CE accumulation by human macrophages (1). In this study, we describe similar effects of the endogenous steroid, cortisol, and of the most widely prescribed glucocorticoid, prednisolone. Both steroids increased CE formation from two folds, in the presence of cholesterol-liposomes, to five folds, in the presence of modified low-density lipoprotein. Progesterone (0.1-1 micromol/L), added during glucocorticoid treatment, blocked this increase. The progesterone block: 1) was duplicated by the steroid receptor inhibitor RU40555; 2) was not reversed by hormone removal; and 3) reflected inhibition of glucocorticoid-induced increases in messenger RNA for acyl-CoA-cholesterol:acyl transferase. Thus, progesterone exerted two effects on macrophages: it acutely inhibited CE formation, and it prevented glucocorticoid-induced increases in acyl-CoA-cholesterol-acyl transferase gene expression and CE synthesis.     

Arrhythmogenic right ventricular dysplasia

Inorganic mercury (203Hg2+) was applied to the olfactory chambers or was given i.v. to pike (Esox lucius) and the uptake of the metal in the olfactory system and the brain was examined by autoradiography and gamma spectrometry. Application of 203Hg2+ in the olfactory chambers resulted in an accumulation of the metal in the olfactory nerves and the anterior parts of the olfactory bulbs of the brain. The levels of 203Hg2+ in other brain areas, such as the telencephalon, the optic tecti and the cerebellum, remained low. Application of 203Hg2+ in only one olfactory chamber resulted in an uptake of the metal only in the ipsilateral olfactory nerve and olfactory bulb. Intravenous injection of the 203Hg2+ resulted in a labelling of the olfactory system and the brain, which was much lower than of the blood. These results indicate that the 203Hg2+ is taken up in the olfactory neurones from the olfactory receptor cells in the olfactory rosettes and is transported to the terminal parts of the olfactory neurones in the olfactory bulbs. The uptake of mercury as well as some other metals in the olfactory system may result in noxious effects and this may be an important component in the toxicology of metals in fish.     

Olfactory bulb development is altered in small-eye (Sey) mice

Small-eye (Sey) is a spontaneous, semidominant murine mutation that results from a point mutation in the Pax-6 gene. Both the eyes and the olfactory system fail to develop in homozygotes and these animals die neonatally. Heterozygotes (Sey/+) have different degrees of eye abnormalities including decreased lens size and cataracts. In the present study, we examined whether one mutated allele of Pax-6 also affects olfactory system development. By 42 days of age, main olfactory bulb volume was significantly decreased in Sey/+ animals compared with wild-type littermates, and this effect was even more dramatic in 70-day-old animals. In contrast, there was no effect on accessory olfactory bulb, olfactory epithelial, or vomeronasal organ development at any age in Sey/+ animals, demonstrating the specificity of the effect. In the main olfactory bulb, the largest differences in laminar volume were found in the glomerular and granule cell layers. These layers contain the olfactory bulb interneurons, and a subpopulation of these cells were found to be Pax-6 immunoreactive. Examination of the neurochemical consequences of this mutation showed that the number of both tyrosine hydroxylase (TH)- and gamma-aminobutyric acid (GABA)-immunoreactive profiles were dramatically decreased in Sey/+ animals as compared with controls. In contrast, neither calretinin nor calbindin immunoreactivity was affected by this mutation. Dual-labeling immunohistochemistry showed that nearly all TH-immunoreactive cells and a subpopulation of GABA-immunoreactive cells coexpressed Pax-6. However, calretinin- and calbindin-immunoreactive cells were not Pax-6 immunopositive. These data indicate that two normal alleles of Pax-6 are required for normal olfactory bulb development and, as part of this effect, this gene may be involved in the development of specific neurotransmitter systems.     

Relationships between estrogen receptor and estradiol-stimulated progesterone synthesis in the rabbit corpus luteum

The effects of estradiol on luteal estrogen receptor and steroidogenesis were examined on Days 9 through 11 of pseudopregnancy. In normal pseudopregnant rabbits, unoccupied cytoplasmic and total nuclear estrogen receptor were 2.6 +/- 0.4 fmol/microgram DNA and 0.4 +/- 0.1 fmol/microgram DNA, respectively, on Day 10 of pseudopregnancy. An i.v. injection of 4 micrograms of estradiol caused the translocation of cytoplasmic receptor and a 6.6-fold increment in total nuclear receptor within 15 min, which was followed by rapid processing of the nuclear receptor. Both cytoplasmic and nuclear estrogen receptor returned to normal values within 24 h, and during this period, serum progesterone did not change significantly. Withdrawal of an estradiol implant from animals on Day 9 of pseudopregnancy initiated a marked decline in serum progesterone within 24 h. Following an injection of saline or of 4 micrograms estradiol on Day 10, unoccupied cytoplasmic estrogen receptor in saline- and estradiol-injected rabbits was 1.0 +/- 0.1 fmol/microgram DNA and 1.9 +/- 0.1 fmol/microgram DNA, respectively, on Day 11 of pseudopregnancy. Associated with the increase in cytoplasmic receptor there was an increase in serum progesterone (8.2 +/- 1.5 ng/ml), in contrast to saline-injected animals in which serum progesterone continued to decline (1.6 +/- 0.4 ng/ml). Despite the significant differences in cytoplasmic receptor and in progesterone synthesis, total nuclear estrogen receptor was not different in these animals. These data suggest that in corpora lutea already secreting progesterone at high rates during midpseudopregnancy, the rapid translocation of available estrogen receptor does not cause further stimulation of progesterone synthesis. However, if steroidogenesis is first reduced experimentally, then an injection of 4 micrograms of estradiol can readily stimulate progesterone synthesis, and this stimulation is associated with an increase in cytoplasmic receptor.     

Environmentally induced changes in peripheral benzodiazepine receptors are stressor and tissue specific

The stress-induced changes in peripheral benzodiazepine receptors (PBR) can be observed in a number of different tissues, depending upon the nature and chronicity of the aversive experience. In addition, virtually all stress procedures that cause rapid changes in PBR simultaneously increase the physical activity or metabolic rate of the subjects. The present study analyzed the contributions of rapid alterations in activity or metabolic rate with and without aversive stimulation and their subsequent impact on PBR. Mechanically induced increases in activity by forced running stress results in a significant reduction in [3H]Ro 5-4864 binding to PBR in olfactory bulb, opposite to the PBR changes in this tissue following forced cold-water swim stress. Pharmacological induction of increased locomotor activity as well as metabolic rate by d-amphetamine causes a significant increase in cardiac PBR binding, again, opposite to the response typically observed following inescapable shock stress. Finally, administration of the anxiogenic beta-carboline, FG-7142, causes increases in both hippocampus and adrenal gland PBR binding reminiscent of acute noise stress exposure. These experiments demonstrate that increased locomotor activity or metabolic rate alone is not a necessary and sufficient condition for previous stress-induced changes in PBR. Conversely, increased metabolic rate coupled with an aversive stimulus appears to be an important factor for inducing stress-like changes in PBR. This data, coupled with previous reports, suggests that rapid alterations in these sites are stressor and tissue dependent. Finally, we propose that the PBR may be involved in many aspects of the stress response including: a) a blowarning system in adrenal gland, b) participation in stress-induced hypertension via renal PBR, and c) a modulator of stress-induced immunosuppression and subsequent recovery of function or recuperation by actions on immune cells.     

Impaired steroidogenesis in the luteal phase of the reproductive cycle and during pregnancy in rhesus monkeys immunized with the beta-subunit of ovine luteinizing hormone

Monkeys immunized with the beta-subunit of ovine luteinizing hormone (oLH beta) develop antibodies which cross react with rhesus chorionic gonadotropin (rhCG) and luteinizing hormone (rhLH). Immunization causes shortened menstrual cycles and reduced fertility. Fertility can be restored by administration of medroxyprogesterone acetate (MPA) during the first 5 weeks of pregnancy. In the present study, we have measured the effects of circulating oLH beta-antibodies on peripheral estradiol, progesterone and 17 alpha OH-progesterone (17OH-P) concentrations throughout the menstrual cycle and during gestation in monkeys which became pregnant following MPA-treatment. Progesterone concentrations were markedly reduced during the luteal phase in cycling animals and the luteal phase of the cycle was significantly shorter as compared to non-immunized controls. Concentrations of estradiol and 17OH-P in the peripheral circulation were not affected by the oLH beta-antibodies. In immunized monkeys which became pregnant following MPA-treatment, progesterone and 17OH-P levels were consistently lower and estradiol concentrations were increased during the second and third trimesters. Our results show that circulating antibodies to oLH beta have multiple endocrinological effects. Corpus luteum function is impaired in cycling monkeys and during the early part of pregnancy. In addition, the pattern of steroid secretion remains abnormal in pregnant monkeys even after the luteal-placental shift.     

Fetal and maternal endocrine responses to experimental intrauterine infection in rhesus monkeys

OBJECTIVE: Our purpose was to describe the temporal and quantitative relationships among intrauterine infection, fetal-placental steroid biosynthesis, and preterm labor in a nonhuman primate model. STUDY DESIGN: On approximately day 130 of gestation (term 167 days) chronically instrumented rhesus monkeys (Macaca mulatta) were infected with 10(6) colony-forming units of group B streptococci either by intraamniotic (n = 4) or choriodecidual (n = 2) inoculation. As controls, four additionally chronically instrumented noninfected monkeys were followed up to spontaneous parturition. Amniotic fluid and maternal and fetal arterial blood were serially sampled in all monkeys (both before and after infection) for progesterone, estrone, estradiol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and cortisol by specific radioimmunoassays, and uterine activity was continuously recorded. RESULTS: Spontaneous parturition was preceded by gradual and significant increases in the plasma concentrations of fetal dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione and fetal and maternal levels of estrone, estradiol, and progesterone but not by changes in cortisol. In contrast, infection-associated parturition (either intraamniotic or choriodecidual) was characterized by abrupt increases in fetal dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, progesterone, and cortisol but not by increases in maternal or fetal estrone or estradiol. Infection-associated steroid changes occurred concurrently with or after increases in uterine activity. CONCLUSION: Infection-associated preterm parturition is associated with dramatic increases in fetal adrenal steroid biosynthesis but not by corresponding increases in placental estrogen biosynthesis. This suggests that fetal stress in accompanied by placental dysfunction and that infection-associated parturition is not dependent on the increased estrogen biosynthesis observed in spontaneous parturition.     

Development of 5'-nucleotidase staining in the olfactory bulbs of normal and naris-occluded rats

The distribution of the adenosine-producing ecto-enzyme 5'-nucleotidase was investigated histochemically in the developing rat olfactory bulb. Rat pups underwent either unilateral surgical occlusion of the right external naris or sham surgery on postnatal day 1. At 10, 20, or 30 days postpartum, horizontal sections of the olfactory bulb were reacted histochemically to reveal the locus and intensity of 5'-nucleotidase activity. Relative staining levels were determined by optical densitometry in standardized bulb regions. A marked, age-related increase in staining density was observed. Reaction product was found primarily in neuropil areas. The P10 and P20 control animals did not exhibit right/left differences in bulb staining; however, some laterality was observed in P30 animals. Inter-glomerular and regional variations were observed throughout the developmental period, including (1) differences between neighboring glomeruli; (2) a gradient in the dorsal-ventral axis of the bulb; and (3) a higher staining density in the medial-caudal portion of the bulb. In subjects with occluded nares, asymmetries in right/left bulb 5'-nucleotidase staining patterns were detected throughout development. Bulbs ipsilateral to the blocked nares exhibited increased staining density, suggesting that the procedure enhanced enzymatic activity. Understanding these variations in 5'-nucleotidase staining may be important for a complete understanding of the mechanisms of olfactory bulb maturation and may give insight into the possible role of this enzyme in synaptic malleability during nervous system development and regeneration.     

T cell-mediated xenograft rejection: specific tolerance is probably required for long term xenograft survival

We have previously demonstrated that the most rostral part of the subventricular zone (SVZ) is a source of neuronal progenitor cells whose progeny are destined to become interneurons of the olfactory bulb. To determine whether the number of newly generated neurons in the adult olfactory bulb could be increased by the administration of an exogenous factor, brain-derived neurotrophic factor (BDNF) was infused for 12 days into the right lateral ventricle of adult rat brains. The production of new cells was monitored by either the intraventricular infusion or intraperitoneal injection of the cell proliferation marker BrdU. In both experimental paradigms we observed significantly more BrdU-labeled cells in the olfactory bulbs on the BDNF-infused side than in the olfactory bulb of PBS-infused animals. Analysis of the BDNF-infused brains of animals injected intraperitoneally with BrdU demonstrated a 100% increase in the number of BrdU-labeled cells in the bulb, the preponderance ( approximately 90%) of which were double-labeled with a neuron-specific antibody. These results demonstrate that the generation and/or survival of new neurons in the adult brain can be increased substantially by an exogenous factor. Furthermore, the SVZ, and in particular the rostral part, may constitute a reserve pool of progenitor cells available for neuronal replacement in the diseased or damaged brain.     

Preproenkephalin mRNA is regulated by an interaction between steroid hormones and nociceptive stimulation

The expression of preproenkephalin (PPE) mRNA has previously been shown to be regulated by steroid hormones in the ventromedial nucleus of the hypothalamus (VMH) and to be regulated by noxious stimuli in the dorsal horn of the spinal cord (DH). The present in situ hybridization study in ovariectomized rats showed that PPE mRNA expression in both the VMH and the lumbar DH, responds to the interaction between a noxious peripheral stimulus and ovarian steroid hormones. In the VMH, either estradiol or estradiol + progesterone increased the mean PPE mRNA content per cell by 100% compared with vehicle-treated rats. Unilateral hindpaw injection of 5% formalin, as compared to saline, significantly increased mean PPE mRNA content per VMH cell in rats treated with vehicle or estradiol but not those treated with estradiol + progesterone. Regression analysis for mean PPE mRNA content per VMH cell as a function of intensity of hindpaw inflammation showed a significant positive correlation coefficient after vehicle and estradiol treatment (P < 0.02) but a strong trend towards a negative correlation coefficient after estradiol + progesterone treatment (P < 0.06). ANOVA for homogeneity of regression coefficients showed a significant difference across hormone groups (P < 0.01). In the lumbar DH, mean PPE mRNA content per cell was greater in rats injected with formalin than with saline and was greatest in rats given steroids + formalin. Mean PPE mRNA content per DH cell was greater ipsilateral than contralateral to the formalin injection in estradiol-treated rats, but no laterality difference was seen in the other hormone groups. No significant differences in mean PPE mRNA levels per DH cell were found among the rats treated with saline + hormone, saline + vehicle, formalin + vehicle, or uninjected rats. For all hormone groups combined, mean PPE mRNA per DH cell showed a significant positive regression on intensity of hindpaw inflammation (P < 0.05). Taken together these data are consistent with reports of increased pain threshold during pregnancy, descending control of antinociception from the basomedial hypothalamus and positive correlations between VMH levels of PPE mRNA and lordosis, a behavior evoked by somatosensory stimulation below nociceptive threshold.     

In vivo studies on the role of the peripheral benzodiazepine receptor (PBR) in steroidogenesis

In various steroidogenic cell models, mitochondrial preparations and submitochondrial fractions, the expression of the mitochondrial 18 kDa peripheral-type benzodiazepine receptor (PBR) protein confers the ability to take up and release, upon ligand activation, cholesterol. Thus, cholesterol becomes available to P450scc on the inner mitochondrial membrane. These in vitro studies were validated by in vivo experiments. Treatment of rats with ginkgolide B (GKB), specifically reduced the ligand binding capacity, protein, and mRNA expression of the adrenocortical PBR and circulating glucocorticoid levels. Treatment with GKB also resulted in inhibition of PBR protein synthesis and corticosterone production by isolated adrenocortical cells in response to ACTH. The ontogeny of both PBR binding capacity and protein directly paralleled that of ACTH-inducible steroidogenesis in rat adrenal cells and in rats injected with ACTH. In addition, the previously described suppression of luteal progesterone synthesis in the pregnant rat by continuous in vivo administration of a gonadotropin-releasing hormone agonist may be due to decreased luteal PBR ligand binding and mRNA. These results suggest that (i) PBR is an absolute prerequisite for adrenocortical and luteal steroidogenesis, (ii) regulation of adrenal PBR expression may be used as a tool to control circulating glucocorticoid levels and (iii) the stress hypo-responsive period of neonatal rats may result from decreased adrenal cortical PBR expression.     

Spatial organization and plasticity of the primary and secondary olfactory projections in goldfish

Crystals of the lipophilic tracer DiI were applied to discrete regions of the olfactory epithelium of goldfish to trace the primary sensory projection to the olfactory bulb. Receptors from the anterior half of the sensory sheet project primarily to glomeruli in the medial half of the bulb and receptors in the posterior half terminate mainly within the lateral half of the bulb. This pattern disappeared following ablation of selected, discrete epithelial regions. In order to investigate reorganization of secondary olfactory projections, unoperated control and unilaterally bulbectomized animals received injections of [3H]proline into the right olfactory bulb. Densities of silver grains per unit area were determined within six different forebrain nuclei in both the right and left hemispheres of each animal. Of the six areas examined, three demonstrated a significantly greater density of afferent innervation from the ipsilateral versus contralateral bulb; a difference which disappeared in two of these three regions after bulbectomy. Thus, for at least two forebrain nuclei, bulb removal caused a change in the afferent input from the spared olfactory bulb to those regions. We conclude that both primary and secondary olfactory projections in goldfish are capable of some degree of reorganization following insult.     

Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: a paradox

Repeated stress induces atrophy, or remodeling, of apical dendrites in hippocampal CA3 pyramidal neurons. In rats, the stress effect is blocked by adrenal steroid synthesis inhibitors, and mimicked by daily injection of corticosterone. We report that non-invasive administration of corticosterone in the drinking water (400 micrograms/ml) also produced atrophy of apical dendrites in CA3. Unexpectedly, the combination of daily stress and oral corticosterone negated the effects of either treatment alone, and no changes in the apical dendritic length or branching pattern of CA3 pyramidal neurons were observed compared to control unstressed rats.     

Progesterone regulates proliferation of endothelial cells

The use of steroid hormones in postmenopausal replacement therapy has been associated with prevention of cardiovascular disease. Although the contribution of estradiol to endothelial cell function has been addressed, little information is available on the effect of progestins on this cell type. Here, we provide direct evidence for the presence of functional nuclear progesterone receptor in endothelial cells and demonstrate that physiological levels of progesterone inhibit proliferation through a nuclear receptor-mediated mechanism. The effects of progesterone were blocked by pretreatment with a progesterone receptor antagonist, and progesterone receptor-deficient endothelial cells failed to respond to the hormone. We evaluated the effect of progesterone by analysis of aorta re-endothelialization experiments in wild-type and progesterone receptor knockout mice. The rate of re-endothelialization was significantly decreased in wild-type mice when in the presence of progesterone, whereas there was no difference between control and progesterone-treated progesterone receptor knockout mice. FACS analysis showed that progestins arrest endothelial cell cycle in G1. The lag in cell cycle progression involved reduction in cyclin-dependent kinase activity, as shown by down-regulation in retinoblastoma protein phosphorylation. In addition, treatment of endothelial cells with progestins altered the expression of cyclin E and A in accordance with G1 arrest. These results have important implications to our current knowledge of the effect of steroids on endothelial cell function and to the overall contribution of progesterone to vascular repair.