Showing papers by "Bruce S. McEwen published in 1992"
TL;DR: To the knowledge, this is the first demonstration of such short-term steroid-mediated synaptic plasticity occurring naturally in the adult mammalian brain.
Abstract: We have found that the density of synapses in the stratum radiatum of the hippocampal CA1 region in the adult female rat is sensitive to estradiol manipulation and fluctuates naturally as the levels of ovarian steroids vary during the 5 d estrous cycle. In both cases, low levels of estradiol are correlated with lower synapse density, while high estradiol levels are correlated with a higher density of synapses. These synaptic changes occur very rapidly in that within approximately 24 hr between the proestrus and estrus stages of the estrous cycle, we observe a 32% decrease in the density of hippocampal synapses. Synapse density then appears to cycle back to proestrus values over a period of several days. To our knowledge, this is the first demonstration of such short-term steroid-mediated synaptic plasticity occurring naturally in the adult mammalian brain.
1,238 citations
TL;DR: Repeated daily restraint stress for 21 days caused apical dendrites of CA3 pyramidal neurons to atrophy, while basal CA3 dendrite levels did not change.
1,225 citations
TL;DR: The results suggest that adrenal hormones normally suppress the birth of both glia and neurons in the adult rat dentate gyrus.
Abstract: The rat dentate gyrus is unusual among mammalian brain regions in that it shows cell birth well into adulthood. During development, dentate gyrus cell birth is regulated by adrenal steroids. However, it is presently unknown whether cell division in the adult is also mediated by these same factors. In order to determine whether this is the case, we combined adrenalectomy, with or without corticosterone (CORT) replacement, and 3H-thymidine autoradiography, Nissl staining, and immunohistochemistry for the glial cell markers vimentin and glial fibrillary acidic protein (GFAP) as well as for the neuronal marker neuron-specific enolase. Removal of circulating adrenal steroids resulted in a greater density of both GFAP-immunoreactive and vimentin- immunoreactive cells compared to sham-operated animals; CORT replacement prevented increases in both of these cell types. The increase in the density of vimentin-immunoreactive cells probably resulted from an increase in the birth of these cells, as adrenalectomized rats showed greater numbers of 3H-thymidine-labeled vimentin-positive cells compared to sham rats. In contrast, no changes in the number of 3H-thymidine-labeled GFAP-positive cells were observed with adrenalectomy, indicating that the increase in this cell type probably does not involve cell birth. In addition, the density of 3H- thymidine-labeled cells that were not immunoreactive for either glial cell marker and that showed neuronal characteristics was dramatically increased with adrenalectomy. These results suggest that adrenal hormones normally suppress the birth of both glia and neurons in the adult rat dentate gyrus.
636 citations
TL;DR: The data show that prenatal stress can cause permanent alterations in the behavior of both sexes in stressful situations but appears to cause a selective effect on the HPA axis in the female rat.
411 citations
TL;DR: Repeated daily restraint stress and daily corticosterone administration to adult male Sprague‐Dawley rats leads to decreases in the number of branch points and length of dendrites of CA3 pyramidal neurons of the hippocampal formation, consistent with a model in which stress‐ and cortic testosterone‐induced CA3 dendritic atrophy is produced by excitatory amino acids released from the mossy fibers.
Abstract: Repeated daily restraint stress and daily corticosterone administration to adult male Sprague-Dawley rats leads to decreases in the number of branch points and length of dendrites of CA3 pyramidal neurons of the hippocampal formation. This decrease is prevented by daily administration of the antiepileptic drug phenytoin (Dilantin), which is known to interfere with excitatory amino acid release and actions. Phenytoin had no obvious effect on behavior during and after stress and failed to prevent stress-induced reduction of body weight gain and stress-induced increases of adrenal weight relative to body weight; it also failed to attenuate glucocorticoid-induced diminution of the size of the thymus gland, indicating that it does not directly antagonize glucocorticoid actions. Stress- and corticosterone-induced effects on dendritic length and branch point number are more pronounced on the apical, as opposed to the basal, CA3 dendrites that receive the largest mossy fiber input from the dentate gyrus. Because phenytoin is also known to prevent ischemic damage, these results are consistent with a model in which stress- and corticosterone-induced CA3 dendritic atrophy is produced by excitatory amino acids released from the mossy fibers.
347 citations
TL;DR: Results suggest that the serotonergic system may be involved in modulating stress and corticosterone effects on dendritic morphology and that tianeptine is known to enhance neural uptake of serotonin.
333 citations
TL;DR: It was concluded that mesenteric fat tissue may respond to stress in a different manner from other fat depots, and glucocorticoids seem to be partly, but not solely, responsible for the changes observed in adipose tissue metabolism and distribution following exposure to uncontrollable stress.
223 citations
206 citations
TL;DR: Hormones secreted by the adrenals, gonads and thyroid play an important role in mediating how the environment shapes the structure and function of the brain during early development, adult life and senescence.
Abstract: Hormones secreted by the adrenals, gonads and thyroid play an important role in mediating how the environment shapes the structure and function of the brain during early development, adult life and se
206 citations
TL;DR: It is suggested that decreases in binding at 5-HT1A and 5- HT1B/1D receptors resulting from chronic exposure to high levels of CORT may also occur in animals that fail to adapt to chronic severe stress and play important roles in the etiology of depression.
Abstract: Quantitative autoradiography was used to evaluate the effects of adrenalectomy (ADX) and corticosterone (CORT) on binding at 5-HT1A and 5-HT1B receptors in the dorsal hippocampus
186 citations
TL;DR: The pituitary—adrenal axis is a prime target area for investigation of the events which accompany stress, and which may be related to the maladaptive state that results in depressive illness.
Abstract: The pituitary-adrenal axis participates in the diurnal response of the organism to the environment and in its response to stress. Circulating glucocorticoid and mineralocorticoid hormones act on cells in the brain via Type I and Type II receptors, which operate at the level of gene regulation, and mediate various feedback effects of adrenal steroids on brain chemistry and structure, including the operation of second-messenger generating systems, levels of structural proteins of glial cells, and the death and survival of neurons. The hippocampus is prominent in these effects, and it also displays the highest level of Type I receptors of any brain region. New concepts point to a special role of the hippocampus, a nexus of cognition and emotion, in the feedback actions of adrenal steroids during the diurnal rhythm, and in response to stress. The hippocampus is, therefore, a prime target area for investigation of the events which accompany stress, and which may be related to the maladaptive state that results in depressive illness. Initial studies are described which investigate the effects of tianeptine on pituitary-adrenal function, hippocampal morphology and Type I and Type II receptor levels.
TL;DR: Results with dexamethasone suggest that the DST in humans may primarily be a measure of type-II adrenal steroid receptor feedback inhibition at the level of the pituitary.
TL;DR: Much more needs to be learned to uncover basic cellular mechanisms and to account for the sometimes disturbing variability among studies and among individual animals in their susceptibility to negative effects of stress and in degenerative changes in the brain.
Abstract: The glucocorticoid cascade hypothesis of stress and aging is an attempt to formulate a causal relationship between the activity of the hypothalamicpituitary-adrenal axis (HPA axis) and the deleterious consequences of the actions of glucocorticoids upon the viability of cells in the brain as well as their structure and function. This chapter discusses the hypothesis in the light of old and new evidence on the aging of the HPA axis and the role of glucocorticoids in the generation of neural damage. The hypothesis is based on two lines of evidence: (1) that glucocorticoids cause hippocampal damage and (2) that hippocampal damage results in pituitary–adrenal hypersecretion. The chapter also presents some features of the results, such as a rat ages; there is a general decline in the plasticity of the brain to respond to environmental challenges, and with increasing age, there is increased vulnerability to stress-induced loss of hippocampal neurons. The glucocorticoid cascade hypothesis of stress and aging has served well as a stimulus and guide for research on endocrine factors in the aging of the brain; however, much more needs to be learned to uncover basic cellular mechanisms and to account for the sometimes disturbing variability among studies and among individual animals in their susceptibility to negative effects of stress and in degenerative changes in the brain.
TL;DR: There appear to be differences in the degree of sensitivity in the various brain regions to low and high levels of circulating adrenal steroids.
Abstract: Quantitative autoradiography was used to evaluate the time course and reversibility of corticosterone (CORT)-induced decreases in binding at 5-HT1A receptors in the dorsal hippocampus, cortex and septum of the male rat. Continuous exposure to high levels of CORT decreased binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin at 5-HT1A receptors in the dentate gyrus and in the oriens and lacunosum moleculare layers of CA4 after 16 to 48 h. CORT-induced decreases in binding were also observed in the dorsal lateral septum after 2-4 days, and in the intermediate lateral septum after 4-8 days of exposure to high levels of CORT. When CORT pellets that had remained in rats for 8 days were removed 3 weeks prior to sacrifice, binding at 5-HT1A receptors increased in comparison to control values in the oriens and lacunosum moleculare layers of CA2, and in layers 4-6 of the parietal/temporal cortex. These increases in binding were associated with very low serum CORT levels, and resembled increases previously observed in those areas in ADX rats. Although removal of CORT reversed the decreases in binding in the septum, no significant increases above control values were observed. Thus, there appear to be differences in the degree of sensitivity in the various brain regions to low and high levels of circulating adrenal steroids.
TL;DR: The present data is consistent with a similar mechanism occurring in at least some parts of the brain, although the hippocampus appears to be an important exception because it does not appear to be differentially responsive to aldosterone in spite of its high 11‐DH activity and immunoreactivity.
Abstract: The dehydrogenase form of 11 β-hydroxysteroid dehydrogenase (11-DH) which catalyzes the oxidation of the biologically active steroid, corticosterone, to its inactive metabolite, 11-dehydrocorticosterone, is found in rat brain. The distribution and localization of 11-DH-like labeling in the rat brain was examined by immunocytochemistry. 11-DH-like immunostaining was found in all subfields of the hippocampus and in many other parts of the brain, including the preoptic area (POA), central nucleus of the amygdala, bed nucleus of the stria terminalis (NIST) and the cerebral cortex. Percentages of 11-DH-positive cells ranged from 10% in the POA and NIST to 50% to 60% in the hippocampus. When combined with neuronal or glial markers, 11-DH-like immunostaining was found to be predominantly localized within neurons, ranging from 10% or less glial labeling in hippocampus, amgydala and cortex to 22% glial labeling in the POA and NIST. Immunostaining was present in both the cytoplasmic and nuclear components of some cells in addition to their projections. In the kidney, 11-DH has been postulated to be a key component in a mechanism by which aldosterone gains access to renal Type I receptors despite the presence of much higher concentrations of glucocorticoids. The present data is consistent with a similar mechanism occurring in at least some parts of the brain, although the hippocampus appears to be an important exception because it does not appear to be differentially responsive to aldosterone in spite of its high 11-DH activity and immunoreactivity. However, the hippocampus is not implicated in neural control of salt appetite and fluid balance, whereas some of the other brain regions like the POA, NIST and amygdala are believed to be involved. Other aspects of 11-DH localization must therefore be examined in future studies, including the co-presence of mineraiocorticoid receptors and 11-DH in the same or adjacent cells and the possible significance of the relatively high glial localization of 11-DH immunoreactivity in the POA and NIST.
TL;DR: There is a sex difference in the level of binding in the very caudal ventromedial nucleus of the hypothalamus in males and females, and these effects may be functionally related to GABAergic control of female sexual behavior.
Abstract: The gonadal steroids estradiol and progesterone have previously been shown to modulate the specific binding of the GABA(A) agonist, [(3) H]muscimol, in the CA1 region of the hippocampus, the ventromedial nucleus of the hypothalamus and the midbrain central gray of ovariectomized female rats. In this report we show a sex difference in the level of binding in the very caudal ventromedial nucleus of the hypothalamus. In contrast to females, there is no steroid modulation of [(3) H]muscimol binding in the ventromedial nucleus of the hypothalamus and midbrain central gray of males. These effects may be functionally related to GABAergic control of female sexual behavior. In contrast, steroid modulation of [(3) H]muscimol binding in the CA1 region of the hippocampus occurred to the same degree in males and females, and there was no difference in the level of binding in any region of the hippocampus between gonadectomized males and females. Incubation of brain slices with progesterone or its metabolite 5α-3α-pregnanolone dissolved in ethanol, produced a significant increase in [(3) H]muscimol binding in most brain regions as compared to control brain slices treated with ethanol alone. Moreover, there was also a marked increase in [(3) H]muscimol binding in all brain areas in the control condition which contained 100 mM ethanol, as compared to brain slices not preincubated with ethanol. The increase in binding after in vitro treatment with either progesterone or 5α-3α-pregnanolone is notably different from that seen after progesterone given in vivo 4 h prior to assay in that it is not site-specific, does not depend on prior treatment with estradiol and shows no sex difference. These results suggest different mechanisms for progesterone effects on the GABA(A) receptor when administered in vivo as compared to in vitro.
TL;DR: Results indicate that CORT and the selective type II receptor agonist RU28362 specifically stimulate carbohydrate ingestion after SC or PVN administration, while DEX has no effect on feeding.
TL;DR: The behavioral insensitivity of male rats to ovarian hormones, in particular to P, may be related to sex differences affecting the modulation of OTR binding.
Abstract: The facilitation of sexual receptivity by oxytocin (OT) in female rats is related to the regulation of oxytocin receptors (OTR) by ovarian steroids in the ventromedial nuclei (VMN) of the hypothalamus. In a previous study, we have shown that estradiol benzoate (EB) causes a twofold increase in OTR binding in the VMN. Progesterone (P) then modulates levels of the estrogen-induced OTR and increases the area occupied by the receptors by acting on the neuronal membrane. In the present study, we compared the effects of EB and P on OTR binding between males and females. In both sexes, EB increased the density of OTR and the area covered by the receptors at the level of the medial and caudal VMN. In estrogen-primed females, P further increased OTR levels in the medial VMN and the area covered by OTR at the level of the caudal VMN. By contrast, P did not modulate OTR binding in estrogen-primed males. Thus, the behavioral insensitivity of male rats to ovarian hormones, in particular to P, may be related to sex differences affecting the modulation of OTR binding.
TL;DR: The relatively high percentage of pyknotic cells that were GR-immunoreactive suggests that adrenal steroids influence cell survival directly through GRs, while the relatively low percentage of [(3)H]thymidine-labeled cells expressing GRs indicates that adrenals influence cell birth indirectly through an as yet unidentified mechanism.
TL;DR: An example of hormone-dependent neuronal plasticity that has been related to a behavioral response is the central oxytocin (OT) system, which facilitates mating behavior in female rats only if they have been treated successively with E, and P.
Abstract: Recent research has shown that steroid hormones produce important structural and chemical changes in the adult brain. Within hormone-sensitive brain regions, gonadal and adrenal steroids increase the number and length of dendritic spines'V2 and induce ne~ropeptides,~.~ enzyme^,^.^ and receptors.'-' An example of hormone-dependent neuronal plasticity that has been related to a behavioral response is the central oxytocin (OT) system. Estradiol (E,) induces receptors for OT (OTR) within the ventromedial nucleus of the hypothalamus (VMN) that are then transported toward OT-containing terminal fields located outside the boundaries of the VMN.IosI' However, the additional action of progesterone (P) is required for a maximal spread of the receptors. Progesterone rapidly increases the area covered by the estrogen-induced OTR by acting directly on the receptors or on the surrounding neuronal membrane.I2 The modulation of OTR binding by P may correspond to an activation of the receptors because OT facilitates mating behavior in female rats only if they have been treated successively with E, and P.lo Moreover, OT facilitates female mating only when infused into the caudal part of the ventromedial hypothalamus where P modulates OTR binding. I'
TL;DR: Both male and female aged rats exhibit levels of GAP-43 mRNA in hippocampal pyramidal cells lower than those of their younger counterparts, reflecting perhaps the ongoing neurogenesis and synaptic plasticity characteristic of this brain region.
Journal Article•
01 Jan 1992
TL;DR: It is concluded that binding of a natural agonist steroid may be a prerequisite for type I receptor transformation and translocation from the cytoplasm into the nuclear fraction.