Showing papers by "Bruce S. McEwen published in 1998"
TL;DR: The long-term effect of the physiologic response to stress is reviewed, which I refer to as allostatic load, which is the ability to achieve stability through change.
Abstract: Over 60 years ago, Selye1 recognized the paradox that the physiologic systems activated by stress can not only protect and restore but also damage the body. What links these seemingly contradictory roles? How does stress influence the pathogenesis of disease, and what accounts for the variation in vulnerability to stress-related diseases among people with similar life experiences? How can stress-induced damage be quantified? These and many other questions still challenge investigators. This article reviews the long-term effect of the physiologic response to stress, which I refer to as allostatic load.2 Allostasis — the ability to achieve stability through change3 — . . .
5,932 citations
TL;DR: The relationship of allostatic load to genetic and developmental predispositions to disease is considered and examples will be given from research pertaining to autonomic, CNS, neuroendocrine, and immune system activity.
Abstract: Adaptation in the face of potentially stressful challenges involves activation of neural, neuroendocrine and neuroendocrine-immune mechanisms. This has been called "allostasis" or "stability through change" by Sterling and Eyer (Fisher S., Reason J. (eds): Handbook of Life Stress, Cognition and Health. J. Wiley Ltd. 1988, p. 631), and allostasis is an essential component of maintaining homeostasis. When these adaptive systems are turned on and turned off again efficiently and not too frequently, the body is able to cope effectively with challenges that it might not otherwise survive. However, there are a number of circumstances in which allostatic systems may either be overstimulated or not perform normally, and this condition has been termed "allostatic load" or the price of adaptation (McEwen and Stellar, Arch. Int. Med. 1993; 153: 2093.). Allostatic load can lead to disease over long periods. Types of allostatic load include (1) frequent activation of allostatic systems; (2) failure to shut off allostatic activity after stress; (3) inadequate response of allostatic systems leading to elevated activity of other, normally counter-regulated allostatic systems after stress. Examples will be given for each type of allostatic load from research pertaining to autonomic, CNS, neuroendocrine, and immune system activity. The relationship of allostatic load to genetic and developmental predispositions to disease is also considered.
3,876 citations
TL;DR: It is demonstrated that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls, and the degree of hippocampal atrophy correlated strongly with both the degree and current basal cortisol levels.
Abstract: Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Previously we related persistent cortisol increases to memory impairments in elderly humans studied over five years. Here we demonstrate that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.
1,564 citations
TL;DR: The results suggest that neurons are produced in the dentate gyrus of adult monkeys and that the rate of precursor cell proliferation can be affected by a stressful experience.
Abstract: Although granule cells continue to be added to the dentate gyrus of adult rats and tree shrews, this phenomenon has not been demonstrated in the dentate gyrus of adult primates. To determine whether neurons are produced in the dentate gyrus of adult primates, adult marmoset monkeys (Callithrix jacchus) were injected with BrdU and perfused 2 hr or 3 weeks later. BrdU is a thymidine analog that is incorporated into proliferating cells during S phase. A substantial number of cells in the dentate gyrus of adult monkeys incorporated BrdU and ≈80% of these cells had morphological characteristics of granule neurons and expressed a neuronal marker by the 3-week time point. Previous studies suggest that the proliferation of granule cell precursors in the adult dentate gyrus can be inhibited by stress in rats and tree shrews. To test whether an aversive experience has a similar effect on cell proliferation in the primate brain, adult marmoset monkeys were exposed to a resident-intruder model of stress. After 1 hr in this condition, the intruder monkeys were injected with BrdU and perfused 2 hr later. The number of proliferating cells in the dentate gyrus of the intruder monkeys was compared with that of unstressed control monkeys. We found that a single exposure to this stressful experience resulted in a significant reduction in the number of these proliferating cells. Our results suggest that neurons are produced in the dentate gyrus of adult monkeys and that the rate of precursor cell proliferation can be affected by a stressful experience.
1,354 citations
TL;DR: The excess glucocorticoids and CRH, and the state of anticipatory anxiety, contribute to allostatic load, a new term that refers to the wear and tear on the body and brain arising from attempts to adapt to adversity.
428 citations
TL;DR: Findings of organ weight changes, enhanced basal CORT, and reduced CORT response to stress in a subgroup of animals are similar to many of the phenomena obtained with other intense, chronic stressors such as subordination, and suggest that repeated predator exposure produces a pattern of intense behavioral and endocrine response that is very slow to habituate.
297 citations
TL;DR: The findings suggest that estrogen can directly modulate specific OT and AVP systems through an ERbeta-mediated mechanism, in a tissue-specific manner.
Abstract: Evidence exists for the localization of the newly identified estrogen receptor β (ERβ) within the rat paraventricular nucleus (PVN) and supraoptic nucleus (SON), regions which lack ERα. Presently, we investigate whether ERβ-like-immunoreactivity (-ir) is found within cells of several major neuropeptide systems of these regions. Young adult Sprague–Dawley rats were ovariectomized (OVX), and 1 week later half of the animals received estradiol-17β (E). Dual-label immunocytochemistry was performed on adjacent sections by using an ERβ antibody, followed by an antibody to either oxytocin (OT), arginine-vasopressin (AVP), or corticotropin releasing hormone. Nuclear ERβ-ir was identified within SON and retrochiasmatic SON, and in specific PVN subnuclei: medial parvicellular part, ventral and dorsal zones, dorsal and lateral parvicellular parts, and in the posterior magnocellular part, medial and lateral zones. However, the ERβ-ir within magnocellular areas was noticeably less intense. OT-/ERβ-ir colocalization was confirmed in neurons of the parvicellular subnuclei, in both OVX and OVX+E brains (≈50% of OT and 25% of ERβ-labeled cells between bregma −1.78 and −2.00). In contrast, few PVN parvicellular neurons contained both AVP- and ERβ-ir. As well, very little overlap was observed in the distribution of cells containing corticotropin releasing hormone- or ERβ-ir. In the SON, most nuclear ERβ-ir colocalized with AVP-ir, whereas few OT-/ERβ-ir dual-labeled cells were observed. These findings suggest that estrogen can directly modulate specific OT and AVP systems through an ERβ-mediated mechanism, in a tissue-specific manner.
219 citations
TL;DR: 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.
158 citations
TL;DR: The existence of nonserotonergic cells that contain nuclear ERs or PRs within the female and male rat DRN, including estradiol‐inducible PRs is demonstrated, pointing to a species difference in ovarian steroid regulation of 5‐HT activity between the macaque and the rat, perhaps transsynaptically via local neurons in the rat brain.
Abstract: Estradiol and progesterone modulate central serotonergic activity; however, the mechanism(s) of action remain unclear Recently, estradiol-induced progestin receptors (PRs) have been localized within the majority of serotonin (5-HT) neurons in the female macaque dorsal raphe nucleus (DRN; Bethea [1994] Neuroendocrinology 60:50-61) In the present study, we investigated whether estrogen receptors (ERs) and/or PRs exist within 5-HT and/or non-5-HT cells in the female and male rat DRN and whether estradiol treatment alters the expression of these receptors Young adult female and male Sprague-Dawley rats were gonadectomized, and 1 week later, half of the animals received a subcutaneous Silastic implant of estradiol-17beta Animals were transcardially perfused 2 days later with acrolein and paraformaldehyde, and sequential dual-label immunocytochemistry was performed on adjacent sections by using either a PR antibody or an ERalpha antibody This was followed by an antibody to either the 5-HT-synthesizing enzyme, tryptophan hydroxylase (TPH), or to the astrocytic marker, glial fibrillary acidic protein (GFAP) Cells containing immunoreactivity (ir) for nuclear ERs or PRs were identified within the rat DRN in a region-specific distribution in both sexes No colocalization of nuclear ER-ir or PR-ir with cytoplasmic TPH-ir or GFAP-ir was observed in either sex or treatment, indicating that the steroid target cells are neither 5-HT neurons nor astrocytes Females were found to have approximately 30% more PR-labeled cells compared with males throughout the DRN (P < 005), but no sex difference was detected in the number of neurons demonstrating ER-ir In both sexes, 2 days of estradiol exposure decreased the number of cells with ER-ir, whereas it greatly increased the number of cells containing PR-ir in several DRN regions (P < 0005) Collectively, these findings demonstrate the existence of nonserotonergic cells that contain nuclear ERs or PRs within the female and male rat DRN, including estradiol-inducible PRs These findings point to a species difference in ovarian steroid regulation of 5-HT activity between the macaque and the rat, perhaps transsynaptically via local neurons in the rat brain
151 citations
TL;DR: The ability of 5-HT to modulate glutamatergic activity in auditory pathways to the amygdala is dependent on the presence of CORT and possibly glucocorticoid activation and modulates the processing of sensory information within the LA and thus may regulate amygdala-related functions.
Abstract: The lateral nucleus of the amygdala (LA) receives excitatory (glutamatergic) inputs from thalamic and cortical sensory processing areas and is believed to be involved in evaluation of the affective significance of sensory events. We examined whether serotonin (5-HT) affects excitatory transmission in auditory afferents to the LA and, if so, whether this modulation of sensory transmission is regulated by the stress hormone corticosterone (CORT). Neuronal activity in the LA was elicited via iontophoretic ejection of L-glutamate or synaptically via electrical stimulation of auditory afferent pathways. In the intact rat, iontophoretically applied 5-HT inhibited both synaptically and glutamate-evoked action potentials in most neurons examined. However, after adrenalectomy (ADX), which eliminates endogenous CORT, 5-HT no longer inhibited evoked activity in the LA. High-CORT doses given to ADX animals reinstated the inhibition of excitatory transmission of 5-HT, whereas low-CORT doses had little effect. Immunocytochemical labeling of the glucocorticoid receptor in the intact rat demonstrated nuclear staining throughout several amygdala regions, including the LA. However, after ADX, no nuclear labeling was visible. With a high replacement dose of CORT (5 or 10 mg) after ADX, dense nuclear staining returned, but with a low replacement dose (1 mg/kg), there was only light nuclear staining. Thus, the ability of 5-HT to modulate glutamatergic activity in auditory pathways to the amygdala is dependent on the presence of CORT and possibly glucocorticoid activation. Via this mechanism, 5-HT modulates the processing of sensory information within the LA and thus may regulate amygdala-related functions.
151 citations
TL;DR: Results indicate a meaningful relationship between receptor expression and known sensitivity to glucocorticoid exposure, and thymic T cells were found to have higher levels of GR than T cells isolated from the spleen.
TL;DR: The extent to which adrenal steroids regulate hippocampal neurotrophic and growth-associated factors, appears to be dependent both on the adrenal steroid receptor subtype activated and on the hippocampal subregion examined.
Abstract: Adrenal steroids and neurotrophic factors are important modulators of neuronal plasticity, function, and survival in the rat hippocampus. Adrenal steroids act through two receptor subtypes, the glucocorticoid receptor (GR) and the mineralocorticoid receptor, and activation of each receptor subtype has distinct biochemical and physiological consequences. Adrenal steroids may exert their effects on neuronal structure and function through the regulation of expression of neurotrophic and growth-associated factors. We have examined adrenal steroid regulation of the neurotrophins brain-derived neurotrophic factor, neurotrophin-3, and basic fibroblast growth factor, as well as the growth associated protein GAP-43, through activation of GR or mineralocorticoid receptor with selective agonists. Our findings indicated that in CA2 pyramidal cells, adrenalectomy resulted in decreases in the levels of basic fibroblast growth factor and neurotrophin-3 messenger RNA, which were prevented by activation of mineralocortico...
TL;DR: It is concluded that neurotrophins, GAP-43 and MAP2 are not likely to be directly related to the chronic stress-induced dendritic atrophy or the prevention of the atrophy by tianeptine.
Journal Article•
TL;DR: Researchers have revealed a wide array of neurochemical and structural effects of ovarian steroids that provide a foundation for understanding hormone effects on mood, behavior, and cognition in the menstrual cycle, during reproductive transitions and in depressive illness.
Abstract: Ovarian steroids produce a variety of effects on the brain, influencing diverse nonreproductive processes such as cognitive function, motor activity, seizure susceptibility, and pain sensitivity, as well as pathological processes such as Parkinson's disease and Alzheimer's disease. Studies of ovarian hormone effects on animal brains have revealed a wide array of neurochemical and structural effects of ovarian steroids, which are reviewed in this article. These studies provide a foundation for understanding hormone effects on mood, behavior, and cognition in the menstrual cycle, during reproductive transitions and in depressive illness.
TL;DR: One of the references in this manuscript is incorrect and should read: 18.
Abstract: Nature Neurosci. 1, 69– 73 One of the references in this manuscript is incorrect. Reference 18 should read: 18. Convit, A. et al Specific hippocampal volume reductions in individuals at risk for Alzheimer's disease. Neurobiol. Aging 18, 131–138 (1997).
TL;DR: Comparisons of patterns of stress response with those of other chronic stress models such as learned helplessness and chronic mild stress suggest that, in terms of adrenal and gonadal steroid hormone response, subordination constitutes a more severe stressor.
Abstract: Subordination constitutes a natural and often chronic stress condition for males of virtually all species of social mammals. Subordinate male rats of mixed-sex groups maintained in visible burrow systems show high-magnitude changes in adrenal and gonadal steroid hormones and, in a subpopulation, disruptions in hypothalamic pituitary adrenal axis function. Changes in brain serotonin systems have been extensively documented in both colony subordinates and colony dominants, with other regional neurotransmitter system changes also indicated. The group experience seems to change a variety of behaviors both inside the colony situation and in tests run outside the colonies and may disrupt the relationship found in controls between hypothalamic pituitary adrenal response to an acute stressor and defensive behavior. Comparisons of these patterns of stress response with those of other chronic stress models such as learned helplessness and chronic mild stress suggest that, in terms of adrenal and gonadal steroid hormone response, subordination constitutes a more severe stressor. Some involvement of the serotonin system has been demonstrated for both subordination and more traditional models, and other systems may prove to be involved in both. However, a central feature of both learned helplessness and chronic mild stress paradigms is a specific criterion behavior or behaviors, emphasized as models for particular psychopathologies. Thus, learned helplessness and chronic mild stress studies have tended to emphasize the effects of pharmacological agents on these models, whereas work with subordination has been focused on analysis of the biobehavioral stress process itself.
TL;DR: There is autoregulation of each receptor subtype, such that activation of GR regulates GR mRNA levels and MR activation regulates MR mRNA expression, and there is evidence that aldosterone, acting through MR, can affect the expression of GR mRNA.
Abstract: Adrenal steroids can have prodigious effects on the structure, function, and survival of hippocampal neurons. In the rat hippocampus, the actions of adrenal steroids are mediated by two receptor types, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Using in situ hybridization, we have examined the regulation of the messenger RNAs (mRNAs) encoding the glucocorticoid and mineralocorticoid receptors, by aldosterone, which acts selectively through MR, and by RU28362, which acts selectively through GR. Our results demonstrate that there is autoregulation of each receptor subtype, such that activation of GR regulates GR mRNA levels and MR activation regulates MR mRNA expression. In addition, there is evidence that aldosterone, acting through MR, can affect the expression of GR mRNA. The extent to which a specific agonist can produce a significant change in the expression of a particular steroid receptor mRNA varies between the different subfields of the hippocampus.
TL;DR: Results indicate that chronic binge cocaine administration leads to sustained activation of the HPA axis and alters processes underlying individual vulnerability to stress.
Abstract: Acute cocaine administration activates behavioral and neuroendocrine processes associated with the stress response. However, much less is known about the effects of chronic, long-term cocaine administration on neuroendocrine adaptations and individual vulnerability to stress. We hypothesized that chronic ‘binge’ cocaine administration may serve as a chronic pharmacological stressor leading to a hyperactivity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and alterations in its feedback mechanisms. In order to test this hypothesis, the effects of long-term (3 and 6 weeks) ‘binge’ pattern cocaine administration (3×15 mg/kg cocaine, i.p., daily, during the early phase of the light cycle) on body weight, adrenal gland weight, basal and stress-induced activity of the corticosterone (CORT) and basal plasma testosterone (T) levels were measured. Both 3 and 6 weeks ‘binge’ cocaine administration decreased body weight gain, increased the weight of adrenal glands and increased basal CORT levels. Plasma T levels were suppressed by both 3 and 6 weeks of cocaine treatment. No correlation was found between elevated CORT and low T levels at any time point. Neither chronic saline nor cocaine administration altered stress-induced CORT secretion. CORT levels 60 min following the restraint stress (recovery) were significantly lower than pre-stress basal levels after 3 and 6 weeks of cocaine, but not saline, administration. Moreover, initial individual differences in stress-induced CORT response, i.e. low and high responsivity to restraint prior to any saline or cocaine injections, were maintained in control rats but became diminished in cocaine-treated rats. These results indicate that chronic binge cocaine administration leads to sustained activation of the HPA axis and alters processes underlying individual vulnerability to stress.
TL;DR: The neurobiological correlates of individual rats' propensities to develop drug‐intake are enhanced and some putative mechanisms for the dopaminergic hyperactivity that characterizes drug‐prone animals are provided.
Abstract: Rats exposed to a low-light, low-noise, novel environment exhibit differences in individual locomotor response to the novelty stressor. The categorization of rats in a locomotor screening procedure as low- (LR) or high-responders (HR), where LRs are in the low locomotor range while HRs belong to the high locomotor range, is significant in that HRs show higher activity in mesencephalic dopaminergic projection neurons, and also show a higher propensity to self-administer psychostimulants and other drugs of abuse compared with LRs. In this study, we examined the neurobiological basis of dopaminergic hyperactivity by comparing in HRs and LRs the steady-state differences in regulatory inputs to mesencephalic (substantia nigra and ventral tegmental area: VTA) dopaminergic neurons. In particular, using in situ hybridization, we studied levels of mRNA for tyrosine hydroxylase (TH) and cholecystokinin (CCK) in the mesencephalon, and for preprodynorphin (DYN), preproenkephalin (PPE), and preprotachykinin (PPT) in the striatum and nucleus accumbens (Acb). We also evaluated TH levels by radioimmunocytochemistry (TH-RIC) in striatal, accumbal and mesencephalic regions. HRs versus LRs had lower levels of neurochemicals belonging to the intrinsic inhibitory input to dopaminergic neurons in the VTA, e.g. lower TH-RIC (–25%) and CCK-mRNA (–48%). In contrast, HRs showed higher levels of parameters belonging to extrinsic facilitating inputs, e.g. higher PPE-mRNA (+ 37%). In addition, HRs had higher DYN-mRNA in Acb (+ 61%), which has been shown to be positively correlated with higher dopaminergic activity. These results enhance our knowledge of the neurobiological correlates of individual rats' propensities to develop drug-intake and provide some putative mechanisms for the dopaminergic hyperactivity that characterizes drug-prone animals.
TL;DR: CGRP appears to mediate at least two separate functions on subpopulations of thymocytes and T cells via two different CGRP receptors within the gland, which exemplify the phenomenon of differential regional regulation of immunity by the autonomic and neuroendocrine systems.
Abstract: In the course of our studies, we have shown the presence of calcitonin gene related peptide (CGRP) by immunocytochemistry in cell bodies and nerve fibers of the murine thymus and in a sparce innervation of the spleen. Receptors for CGRP have been characterized within these glands, and their activation by physiological levels of CGRP was found to suppress Con A-stimulated proliferation of thymocytes and splenic T cells as well as antigen-specific T-cell proliferation. This suppression is blocked by the antagonist for CGRP (CGRP 8-37). Within the thymus cultures, the antagonist CGRP (8-37) alone enhanced proliferation of thymocytes during Con A stimulation, most likely by inhibiting the endogenous release of CGRP into the culture medium by resident thymocytes. Some of the CGRP-induced suppression of mitogenic stimulation of thymocytes, but not of splenocytes, was due to apoptosis. The antagonist, CGRP(8-37), did not block apoptosis caused by Con A or CGRP but rather enhanced it. Flow cytometric analysis of CGRP-treated cultures using antibodies to cluster determinates (CD) showed that the majority of thymocytes undergoing apoptosis induced by CGRP were of the CD4/CD8 double-positive type. These data indicate that apoptosis in the thymocytes is mediated by a CGRP receptor not sensitive to the antagonist CGRP(8-37). Because proliferation of thymocytes and splenocytes induced by Con A is blocked by this antagonist and splenocytes are refractory to CGRP induced apoptosis, CGRP appears to mediate at least two separate functions on subpopulations of thymocytes and T cells via two different CGRP receptors within the gland. These effects of a neuropeptide exemplify the phenomenon of differential regional regulation of immunity by the autonomic and neuroendocrine systems.
TL;DR: Results lend support to the hypothesis that corticosteroid receptors, and in particular the Type I receptor subtype, play a central role in the regulation of circadian and circannual rhythms of the HPA.
TL;DR: Chronic stress increases the vulnerability to develop psychostimulant selfadministration in a glucocorticoid-responsive manner, and rats have been shown to intravenously self-administer CORT, which suggests an important role of CORT in reward related brain processes.
Abstract: [Extract] Chronic stress or high glucocorticoid levels have been shown to affect fundamental brain functions, including emotions, cognition, and reward/reinforcement, and may be associated with psychiatric disorders (McEwen, 1998; Piazza and LeMoal, 1997). Stress and glucocorticoids (GCs) have also been suggested as major factors influencing drug addiction (Kreek, 1996; Piazza and LeMoal, 1997). For example, chronic stress increases the vulnerability to develop psychostimulant selfadministration in a glucocorticoid-responsive manner (for a review, see Piazza and LeMoal, 1997). Moreover, rats have been shown to intravenously self-administer corticosterone (CORT) (see Piazza and LeMoal, 1997), which suggests an important role of CORT in reward related brain processes.
TL;DR: The data from this study and the previous study indicate that damage induces CGRP-LI expression in interneurons and nonprincipal cells in the area of damage, and it is hypothesize that C GRP expression in surviving neurons within damage-related regions of the hippocampus is likely to be an important, and possibly a protective, component of the response of the nervous system to injury.
Journal Article•
TL;DR: An important action of ovarian hormones is the regulation of synapse turnover in the hippocampus as exhibited during the fourth or fifth day of a female rat's estrus cycle.
Abstract: Ovarian steroids have numerous effects on the brain throughout the life span, beginning during gestation and continuing into senescence. Ovarian steroids have widespread effects on catecholaminergic neurons and serotonergic pathways and on the basal forebrain cholinergic system. Another important action of ovarian hormones is the regulation of synapse turnover in the hippocampus as exhibited during the fourth or fifth day of a female rat's estrus cycle. In the human brain, estrogen replacement therapy is associated with improvements in episodic and declarative memory, which depend on the hippocampus, and is involved in the processing of emotional information. Because of their widespread influences on neuronal systems, ovarian steroids are important factors to consider in the treatment of depressive illness.
TL;DR: The data indicate that males contain higher levels of preproenkephalin mRNA per neuron than females, and that estrogen causes an upward shift in the amount of mRNA expressed per cell, females demonstrating a greater response to estrogen than males.
TL;DR: The present results suggest that NMDA receptors in the inferior colliculus, presumably in the subnucleus of external cortex may play the critical role in the initiation of audiogenic seizures in PTU-treated rats.