Showing papers by "Bruce S. McEwen published in 1990"
TL;DR: It is demonstrated that gonadal steroids are necessary for the maintenance of normal adult CA1 hippocampal pyramidal cell structure and implies that CA1 pyramsidal cell dendritic spine density may fluctuate during the normal rat estrous cycle.
Abstract: Gonadal steroids are known to influence hippocampal physiology in adulthood. It is presently unknown whether gonadal steroids influence the morphology of hippocampal neurons in the adult intact rat brain. In order to determine whether female sex hormones influence hippocampal morphology in the intact adult, we performed Golgi impregnation on brains from ovariectomized rats and ovariectomized rats which received estradiol or estradiol and progesterone replacement. Removal of circulating gonadal steroids by ovariectomy of adult female rats resulted in a profound decrease in dendritic spine density in CA1 pyramidal cells of the hippocampus. Estradiol replacement prevented the observed decrease in dendritic spine density; progesterone augmented the effect of estradiol within a short time period (5 hr). Ovariectomy or gonadal steroid replacement did not affect spine density of CA3 pyramidal cells or granule cells of the dentate gyrus. These results demonstrate that gonadal steroids are necessary for the maintenance of normal adult CA1 hippocampal pyramidal cell structure. The short time course required to observe these effects (3 d for the estradiol effect and 5 hr for the progesterone effect) implies that CA1 pyramidal cell dendritic spine density may fluctuate during the normal (4-5 d) rat estrous cycle.
1,353 citations
TL;DR: These results demonstrate rapid and ongoing dendritic plasticity in a specific population of hippocampal neurons in experimentally unmanipulated animals.
Abstract: We have used Golgi-impregnated tissue to demonstrate that apical dendritic spine density in CA1 hippocampal pyramidal cells undergoes a cyclic fluctuation as estradiol and progesterone levels vary across the estrous cycle in the adult female rat We observed a 30% decrease in apical dendritic spine density over the 24-hr period between the late proestrus and the late estrus phases of the cycle Spine density then appears to cycle back to proestrus values over a period of several days In contrast, no significant changes in dendritic spine density across the estrous cycle occur in CA3 pyramidal cells or dentate gyrus granule cells These results demonstrate rapid and ongoing dendritic plasticity in a specific population of hippocampal neurons in experimentally unmanipulated animals
1,040 citations
TL;DR: The changes in dendritic morphology observed may be indicative of neurons in the early stages of degeneration, as prolonged exposure to high levels of corticosterone has been shown by others to result in a loss of CA3 pyramidal cells.
1,010 citations
TL;DR: Results show that dentate gyrus granule cells require glucocorticoids for their survival and for the maintenance of normal morphology and suggest that granule cell morphology and/or survival may undergo constant fluctuation in response to diurnal rhythms or stress-induced changes in glucOCorticoid levels.
348 citations
TL;DR: It is suggested that AS receptors in the brain, and especially the hippocampus, are more sensitive to circulating levels of glucocorticoids than the pituitary and there may be a greater capacity for physiological variations in type I receptor occupation in vivo than had previously been suggested.
247 citations
TL;DR: When spine density of VMN neurons was assessed throughout the estrous cycle, it was determined that spine density was significantly lower at diestrus than proestrus, and there were no differences between intact male and female rats observed in any parameter.
Abstract: Neurons in the adult rat ventromedial hypothalamic nucleus (VMN, 4–6 neurons per brain; 3–7 brains per group) were studied under various hormonal conditions using the single-section Golgi impregnation
239 citations
TL;DR: The rapid progesterone effect appears to be a direct and specific effect of this steroid on the receptor or membrane, because it was produced in vitro as well as in vivo and was not mimicked by a variety of other steroids.
Abstract: The ventromedial nuclei of the hypothalamus (VMN) are important for the control of feminine mating behavior, and hormone action within these nuclei has been causally related to behavior. Estradiol induces receptors for oxytocin in the VMN and in the area lateral to these nuclei over the course of 1 to 2 days, and progesterone causes, within 30 minutes of its application, a further increase in receptor binding and an expansion of the area covered by these receptors lateral to the VMN. The rapid progesterone effect appears to be a direct and specific effect of this steroid on the receptor or membrane, because it was produced in vitro as well as in vivo and was not mimicked by a variety of other steroids. The effect of progesterone occurred in the posterior part of the VMN, where oxytocin infusion facilitated feminine mating behavior; it did not take place in the anterior part of the VMN, where oxytocin infusion had no effect on mating behavior.
228 citations
TL;DR: There was, however, adaptation of the HPA axis to the chronic ethanol treatment, and there were no signs of impaired negative feedback control of glucocorticoid secretion in the chronic-ethanol-treated rats.
Abstract: The ability of chronic ethanol stress to alter hypothalamic-pituitary-adrenal (HPA) axis function in a manner similar to that previously reported for other chronic stress treatments was evaluated. Inj
164 citations
TL;DR: Changes in the morphological characteristics of pyramidal cells and granule cells of the hippocampal formation showed changes which were shown to be sexually dimorphic; treatment resulted in significantly greater numbers of both primary dendrites and apical excrescences.
Abstract: In an effort to determine if sex differences exist in the morphologic characteristics of pyramidal cells and granule cells of the hippocampal formation and whether sex plays a role in determining thyroid hormone sensitivity of these neuronal populations, we used single-section Golgi impregnation to examine the effects of neonatal thyroid hormone administration on hippocampal cells from the brains of adult rats of both sexes. Quantitative analyses of control brains revealed sex differences in the number of primary dendrites and the number of spines on the apical dendritic shaft of CA3 pyramidal cells. These differences showed opposite trends; females possessed more primary dendrites, whereas males showed more apical excrescences. Neonatal treatment with thyroid hormone resulted in long-lasting and dramatic changes of the entire CA3 pyramidal cell. CA3 pyramidal cells from thyroid hormone- treated animals showed significantly larger cell body areas, greater numbers of dendritic branchpoints, and longer dendrites. In addition, CA3 pyramidal cells from thyroid hormone-treated animals showed changes in the morphological characteristics which were shown to be sexually dimorphic; treatment resulted in significantly greater numbers of both primary dendrites and apical excrescences. These treatment differences occurred in both sexes and were of equal magnitude, regardless of sex. On the other hand, no sex differences in the morphologic parameters examined were detected for pyramidal cells in the CA1 region. Moreover, neonatal thyroid hormone treatment did not affect the cell body area, dendritic branch points, or the length of dendrites of these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
157 citations
TL;DR: The results suggest that spine density of the apical dendrites of CA1 pyramidal cells is specifically affected by thyroid hormone in adulthood, and it is likely that this morphological change results in altered hippocampal function.
118 citations
TL;DR: There are multiple mechanisms and agents involved in neuronal destruction or survival, and this article reviews some of the principal mechanisms and discusses them in relation to the contrasting effects of adrenal steroids on cell survival.
TL;DR: There may be considerable heterogeneity in the degree of activation of adrenal steroid receptor subtypes in immune, pituitary, and hippocampal tissue by endogenous and exogenous glucocorticoids.
Abstract: Type I and II adrenal steroid receptor binding was measured in spleen and thymus of adrenalectomized (ADX) rats and intact rats at basal levels of corticosterone after 1 h of restraint stress or after exogenous administration of dexamethasone (DEX). Concurrent receptor determinations were made in the hippocampus and pituitary. Receptor binding measures in immune tissues and pituitary were less responsive to varying levels of endogenous hormones than binding measures in hippocampus. Compared with ADX rats, type I binding in spleen and pituitary of intact rats at basal levels of corticosterone was unchanged, whereas type I binding in the hippocampus was significantly decreased. Furthermore, despite peak levels of corticosterone, type II binding in spleen, thymus, and pituitary of stressed rats was also unchanged, whereas type II binding in the hippocampus of stressed animals was significantly lower. In contrast, DEX, a well-known immunosuppressant, reduced type II binding in immune tissues more than in the hippocampus. Because a decrease in receptor binding measured in vitro may reflect receptor activation in vivo, these results suggest that there may be considerable heterogeneity in the degree of activation of adrenal steroid receptor subtypes in immune, pituitary, and hippocampal tissue by endogenous and exogenous glucocorticoids.
TL;DR: Results are consistent with the hypothesis that elevated levels of the enkephalins in the mesolimbic system may be necessary for antipsychotic activity and support the idea that the undesirable motoric signs and symptoms observed after chronic treatment with typical neuroleptics may not be the result of increased levels of enkephalin in the basal ganglia.
Abstract: We measured proenkephalin (PEK) mRNA levels in the anterior and medial aspects of the caudate-putamen (CPU) and in the nucleus accumbens (NAc) of the rat by in situ hybridization histochemistry after chronic treatment for 21 days with typical (haloperidol and prolixin) and atypical (molindone, thioridazine, and clozapine) neuroleptics. Chronic administration with these drugs resulted in PEK mRNA levels that were 60-80% higher than controls in the anterior and medial aspects of the CPU but only 25-30% over controls in the NAc. All three atypical neuroleptics studied increased PEK mRNA in the following order: anterior-CPU, thioridazine greater than clozapine and molindone; medial-CPU, thioridazine and molindone greater than clozapine; and NAc, thioridazine much greater than molindone and clozapine. Chronic treatment with the specific dopamine D2 antagonist sulpiride also caused elevation in PEK mRNA levels in all three brain regions studied whereas the specific serotonin S2 receptor blocker, cinanserin, had no significant effects on PEK mRNA levels. These results are consistent with the hypothesis that elevated levels of the enkephalins in the mesolimbic system may be necessary for antipsychotic activity. They also support the idea that the undesirable motoric signs and symptoms observed after chronic treatment with typical neuroleptics may not be the result of increased levels of enkephalins in the basal ganglia because atypical neuroleptics which are almost totally devoid of these side effects caused similar increases in PEK mRNA in the CPU.
TL;DR: The results demonstrate that in the striatum the preproenkephalin mRNA is expressed at a high level and is regulated by glucocorticoids, and provides evidence for regulation by nonglucorticoid mechanisms as well.
Abstract: Glucocorticoids regulate the level of preproenkephalin mRNA expression in a number of cell systems. This study investigated the expression of preproenkephalin mRNA in the brain and its regulation by glucocorticoids in vivo. Two different methods for mRNA quantitation were employed. Total RNA isolated from dissected brain tissue was analyzed in an RNAse T2 protection assay. In addition, we have used in situ hybridization to brain sections to assess the expression of preproenkephalin mRNA. The results demonstrate that in the striatum the preproenkephalin mRNA is expressed at a high level and is regulated by glucocorticoids. There is a decrease in striatal preproenkephalin mRNA after adrenalectomy (ADX), and ADX animals replaced with corticosterone express higher levels of striatal preproenkephalin mRNA than ADX animals. By in situ hybridization we have determined that the corticosterone-induced increase in striatal preproenkephalin mRNA is evident after 16 h, but not after 2 h, of corticosterone replacement...
TL;DR: Quantitative analyses revealed significant increases in the density of GFAP‐immunostained astrocytes and in the cross‐sectional cell body area and the number of primary processes in Golgi‐impregnated astroCytes of the basal forebrain and hippocampus of animals treated neonatally with thyroid hormone.
Abstract: Previous studies have shown that developing neurons of the basal forebrain and hippocampus are sensitive to thyroid hormone (Gould and Butcher: J. Neurosci., 9:3347-3358, 1989; Rami et al: Neuroscience, 19:1217-1226, 1986). In order to determine whether or not thyroid hormone influences the development of astrocytes in brain regions where neurons are affected, we performed vimentin and glial fibrillary acidic protein (GFAP) immunocytochemical and single-section Golgi-impregnation analyses on the basal forebrain and hippocampus of control and neonatally thyroid hormone treated rats. For purposes of comparison, glial cells of the pontomesencephalotegmental (PMT) region, a region where developing neurons are not morphologically affected by thyroid hormone imbalances (Gould and Butcher, op. cit.), were also examined. Neonatal thyroid hormone treatment resulted in a premature disappearance of vimentin-immunoreactive radial glia in the basal forebrain and hippocampus. In addition, a premature appearance of GFAP-immunoreactive astrocytes with mature morphological characteristics was observed in the basal forebrain and hippocampus of thyroid hormone treated animals. Quantitative analyses revealed significant increases in the density of GFAP-immunostained astrocytes and in the cross-sectional cell body area and the number of primary processes in Golgi-impregnated astrocytes of the basal forebrain and hippocampus of animals treated neonatally with thyroid hormone. In contrast, no changes in any of these parameters were observed in glial cells of the PMT region with neonatal thyroid hormone treatment.
01 Jan 1990
TL;DR: The brain has been recognized as a complex target tissue for genomic effects of steroid hormones, which bring about long-lasting alterations in brain structure and neurochemistry as well as changes in behaviour and neuroendocrine function.
Abstract: For over four decades steroids have been regarded first as facilitators of enzymic reactions and subsequently as activators of genomic activity. The brain, long studied in terms of its bioelectric properties and anatomical connectivity, has now been recognized as a complex target tissue for genomic effects of steroid hormones, which bring about long-lasting alterations in brain structure and neurochemistry as well as changes in behaviour and neuroendocrine function. Studies of steroid effects on brain bioelectric activity have also shown rapid effects which are difficult to explain by a strictly genomic mechanism. One way to distinguish between genomic and non-genomic effects is by the time course, with extremely rapid effects being non-genomic and delayed effects being genomic. Effects with onset latencies of minutes to an hour may be due to either mechanism. Examples illustrating genomic actions include delayed effects of oestrogen which alter oxytocin and GABAA receptors and induce spines on dendrites and delayed glucocorticoid effects on neuronal survival. There are also examples of apparent genomic effects of oestradiol which interact with rapid and apparently non-genomic effects of progesterone: progesterone rapidly promotes spread of oestrogen-induced oxytocin receptors in ventromedial hypothalamus and rapidly modifies oestrogen-regulated GABAA receptor density in hypothalamus. The former effect is one produced by progesterone itself whereas the latter effect may be related to the ability of progesterone metabolites to interact with the chloride channel of the GABAA-benzodiazepine receptor complex.
TL;DR: It is shown that both destruction of nigral dopamine neurons by 6-hydroxydopamine and chronic treatment with haloperidol increase the content of D 2 mRNA and D 2 receptors within distinct parts of the striatum.
TL;DR: The distribution of muscarinic cholinergic receptors in the brain of three avian species was investigated by quantitative autoradiography and demonstrated that the binding of NMS in the three species is saturable in the nanomolar range and has a high affinity.
Abstract: In order to clarify the neuroanatomical basis for postulated muscarinic cholinergic control of a wide array of physiological processes in birds, the distribution of muscarinic cholinergic receptors in the brain of three avian species was investigated by quantitative autoradiography. The species consisted of two passerines (songbirds), the European starling (Sturnus vulgaris) and the song sparrow (Melospiza melodia), and one galliform, the Japanese quail (Coturnix coturnix japonica). [3H]N-methyl scopolamine (NMS), a muscarinic cholinergic antagonist was used as the ligand to label the receptors. Initial experiments demonstrated that the binding of this ligand in the three species is saturable in the nanomolar range and has a high affinity (Kd = +/- 0.6 nM). Displacement experiments revealed that three muscarinic ligands competed in an order of potency characteristic of the mammalian muscarinic receptor (i.e., atropine greater than oxotremorine greater than carbachol) for NMS binding in the avian brain. In all three species, portions of the basal ganglia, such as the parolfactory lobe and the paleostriatum augmentatum, exhibited the highest density of binding. On the other hand, the paleostriatum primitivum, the avian homologue of the mammalian globus pallidus, contained very few binding sites. Other telencephalic sites, such as the ventral and dorsal hyperstriatum, also revealed relatively high receptor density. However, the neostriatum and especially the ectostriatum showed much lower levels. In the hypothalamus, in all three species, specific binding could be observed in the ventromedial nucleus and adjacent areas. The paraventricular nucleus also showed moderate levels of binding density, especially in the two songbird taxa. At a more rostral level, the preoptic area showed low levels of binding. In the quail, the sexually dimorphic nucleus of the preoptic area was clearly outlined in the autoradiograms by the low level of binding sites compared to the surrounding areas. In the two passerine species, nuclei of the song system were identified by either high or low levels of NMS binding. High binding defined area X and the mesencephalic nucleus, intercollicularis (ICo). In contrast, the robust nucleus of the archistriatum and the magnocellular nucleus of the anterior neostriatum showed low levels of binding in comparison with the surrounding tissue. None of these nuclei were visible in the quail autoradiograms except for ICo, which appeared as in the passerines as a heavily labelled area surrounding the lightly labelled nucleus mesencephalicus lateralis pars dorsalis. In all three species, the hippocampal complex was devoid of NMS binding except for two lateral dark bands that were present along the entire rostral to caudal extent of the hippocampus.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: The ability of daily CORT injection to mimic the effects of repeated stress, but inability of CORT ingestion at high doses in the drinking water to do so, suggests that the time course of Cort elevation and the coincidence of some type of stress may be important for the suppression of cyclic AMP‐generating systems in brain.
Abstract: Manipulation of the hypothalamic-pituitary-adrenal axis selectively alters alpha-adrenergic potentiation of the cyclic AMP response to beta-adrenergic receptor stimulation in rat cerebral cortex. Calcium has been implicated in this alpha-receptor-mediated response, which may involve activation of phospholipases A2 and C and/or calmodulin-dependent adenylate cyclase. We therefore investigated the effects of stress and corticosterone (CORT) on membrane calmodulin-dependent adenylate cyclase and noradrenaline-stimulated cyclic AMP accumulation in brain slices. Repeated stress for 21 days selectively attenuated the adenylate cyclase response to calcium/calmodulin in cerebral cortex membranes, without affecting basal or forskolin-stimulated enzyme activity. There was no such effect in hippocampal membranes. The same pattern of response was elicited by daily CORT injection (50 mg/kg s.c.) for 21 days, while vehicle injection had no effect. CORT in the drinking water (400 micrograms/ml) elicited the same reduction of body weight as CORT injections, but had no effect on calmodulin adenylate cyclase. In parallel with calmodulin adenylate cyclase, cyclic AMP accumulation elicited by noradrenaline in slices of cerebral cortex was suppressed by both stress and daily CORT injections, with smaller effects observed with CORT in the drinking water. Unlike calmodulin adenylate cyclase, noradrenaline-stimulated cyclic AMP accumulation in hippocampus showed the same suppression as that in cerebral cortex. These results are discussed in relation to the differential mode of coupling of alpha-adrenergic receptors to cyclic AMP-generating systems between brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: It is suggested that chronic ECS has a trophic effect on Type I receptors and that the higher levels of corticosterone resulting from chronic E CS do not induce adrenal steroid receptor down-regulation.
TL;DR: The hypothesis that decreased striatal protachykinin mRNA levels may not be directly linked to development of extrapyramidal side effects is suggested.
TL;DR: In this article, quantitative autoradiography was used to evaluate the effects of testosterone on the binding of [ 3 H] 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) at 5-HT 1A receptors in the brains of castrated male rats.
TL;DR: It is suggested that the effects of testosterone on sexual and other social behaviors in male rats may be mediated, at least in part, by decreases in the activation of 5-HT3 receptors in the amygdala.
TL;DR: It is concluded that [3H]ZK 91587 is a useful ligand for further studies on putative mineralocorticoid responsive cells in brain, due to its high affinity, stability and lack of cross reactivity with glucocortioid receptors.
TL;DR: Results demonstrate that alterations which occur in a neuropeptide system as a consequence to 6-OHDA-induced denervation of the striatum can respond to NGF administration in a topographical fashion.
TL;DR: It is likely that inhibitory neural input plays a role in determining the threshold level of E2‐induced CPR, which is sufficient to trigger lordosis behavior, suggesting the presence of a threshold level controlling the expression of feminine sexual behavior.
Abstract: Sex differences in the induction of cytosolic progestin receptors (CPR) by estrogen priming were correlated with the sex differences in behavioral responses. We evaluated the temporal relationship between CPR in several brain regions and pituitary and the time-course of 17beta-estradiol (E(2)) activation of female sexual behavior in gonadectomized male and female rats implanted with subcutaneous E(2) Silastic capsules for 6 h, 24 h and 48 h. Both CPR levels and mating behavior increase monotonically with the time of E(2) exposure. Induction of CPR was observed in the periventricular region of the preoptic area (PVPOA), arcuate nucleus (ARC), ventromedial nuclei (VMN) and pituitary in both sexes. A small induction of CPR was found in parietal cortex. The VMN in female rats showed a significant E(2)-induced CPR increase at all times of exposure, while in male rats this induction was only significant after 24 h. Significant sex differences in absolute CPR levels and E(2)-induced receptors were found in the following structures: VMN, 18 h after 6 h of E(2) treatment and after 24 h and 48 h of continuous E(2) exposure; PVPOA, only after 48 h of continuous E(2) exposure; ARC at 24 h and 48 h; and pituitary after all E(2) treatment. Mating behavior was tested under two conditions: E(2) alone (2 h after removal of E(2) capsules) and E(2)+progesterone (2 h after a progesterone injection given 10 min after concluding the first test). Receptivity was first observed after 24 h E(2) exposure in female rats, whereas in male rats a small response appeared only after 48 h of E(2) exposure. After progesterone priming, the time of E(2) exposure necessary for expression of female sexual behavior was reduced to 6 h in females and 24 h in males. The appearance of mating behavior appears to follow that of inducible CPR in the VMN in both sexes. In addition, the CPR levels associated with the first receptivity either by male rats (16.6 fmol/mg protein) or female rats (15.3 fmol/mg protein) are very similar suggesting the presence of a threshold level controlling the expression of feminine sexual behavior. It is likely that inhibitory neural input plays a role in determining the threshold level of E(2)-induced CPR, which is sufficient to trigger lordosis behavior.
TL;DR: The data suggest that sigma receptor activity, directly or indirectly, affects proenkephalin and protachykinin mRNA expression in striatal neurons.
TL;DR: Pharmacologically characterized a glucocorticoid binding site present in AtT20 mouse pituitary cells, a cell line extensively used in studying Type II glucoc Corticoid receptor function and should prove of use in elucidating the relationships between glucocORTicoid receptors activation and different responses in both AtT 20 cells and other glucocortsicoid responsive tissues.
Journal Article•
TL;DR: It is concluded that age-related degeneration of neural tissue is the complex result of multiple factors which synergize to cause neural destruction, including endogenous excitatory amino acids, calcium ions, endogenous proteolytic enzymes, free radicals and circulating glucocorticoids.
Abstract: In their study of the neuroendocrine aspects of cerebral aging the authors review the effect of glucocorticoids, their participation in the mechanisms of neuronal loss and their beneficial and destructive effects. They discuss the treatment strategies for showing the destructive aspects of aging and the effect of acetyl-L-carnitine in rats. They conclude that age-related degeneration of neural tissue is the complex result of multiple factors which synergize to cause neural destruction, including endogenous excitatory amino acids, calcium ions, endogenous proteolytic enzymes, free radicals and circulating glucocorticoids. It is considered that acetyl-L-carnitine may have protective effects in rats.