Interactive Report The Neurobiology Of Stress: From .
Brain Research 886 (2000) 172–189www.elsevier.com / locate / bresInteractive reportThe neurobiology of stress: from serendipity to clinical relevance 1Bruce S. McEwen*Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, Box 165, New York,NY 10021, USAAccepted 25 September 2000AbstractThe hormones and other physiological agents that mediate the effects of stress on the body have protective and adaptive effects in theshort run and yet can accelerate pathophysiology when they are over-produced or mismanaged. Here we consider the protective anddamaging effects of these mediators as they relate to the immune system and brain. ‘Stress’ is a principle focus, but this term is ratherimprecise. Therefore, the article begins by noting two new terms, allostasis and allostatic load that are intended to supplement and clarifythe meanings of ‘stress’ and ‘homeostasis’. For the immune system, acute stress enhances immune function whereas chronic stresssuppresses it. These effects can be beneficial for some types of immune responses and deleterious for others. A key mechanism involvesthe stress–hormone dependent translocation of immune cells in the blood to tissues and organs where an immune defense is needed. Forthe brain, acute stress enhances the memory of events that are potentially threatening to the organism. Chronic stress, on the other hand,causes adaptive plasticity in the brain, in which local neurotransmitters as well as systemic hormones interact to produce structural as wellas functional changes, involving the suppression of ongoing neurogenesis in the dentate gyrus and remodelling of dendrites in theAmmon’s horn. Under extreme conditions only does permanent damage ensue. Adrenal steroids tell only part of the story as far as howthe brain adapts, or shows damage, and local tissue modulators — cytokines for the immune response and excitatory amino acidneurotransmitters for the hippocampus. Moreover, comparison of the effects of experimenter-applied stressors and psychosocial stressorsshow that what animals do to each other is often more potent than what experimenters do to them. And yet, even then, the brain isresilient and capable of adaptive plasticity. Stress-induced structural changes in brain regions such as the hippocampus have clinicalramifications for disorders such as depression, post-traumatic stress disorder and individual differences in the aging process. 2000Elsevier Science B.V. All rights reserved.Keywords: Stress; Homeostasis; Allostasis; Immune function; Adaptive plasticity; Hippocampus; Dendrite; Neurotransmitter; Glucocorticoid; Adrenalectomy; Adrenal steroid; Learning; Memory; Cognitive function; Psychiatric disorder1. IntroductionStress is an aspect of our daily lives and conversations,and yet there is considerable ambiguity in the meaning ofthis word. The brain is the master controller of theinterpretation of what is stressful and the behavioral andphysiological responses that are produced. The brain isalso a target of stress, along with the immune system,metabolic and cardiovascular systems and other systems ofthe body. Stress hormones play a major role in mediatingboth adaptive and maladaptive responses, and they do soby interacting with specific aspects of the physiology ofeach tissue. What is often overlooked is that the stress1Published on the World Wide Web on 22 November 2000.*Tel.: 11-212-327-8624; fax: 11-212-327-8634.E-mail address: mcewen@rockvax.rockefeller.edu (B.S. McEwen).hormones are protective in the short run and yet canparticipate in damage when they are overproduced or notshut off when no longer needed.Animals are continually learning and some experiencesare classified as ‘stressful’ in part because stress hormonesare produced. Contrary to the late Hans Selye, whoemphasized physical stressors [133], psychological andexperiential factors are among the most powerful ofstressors: e.g., novelty, withholding of reward, and anticipation of punishment rather than the punishment itself areamong the most potent activators of HPA and ANS activity[89,90].Although stress is often thought about as bad anddamaging, recent studies paint a different picture as far asthe brain and also the immune system are concerned. Themain point is that the brain appears to handle repeatedstress over weeks by showing adaptive plasticity in which0006-8993 / 00 / – see front matter 2000 Elsevier Science B.V. All rights reserved.PII: S0006-8993( 00 )02950-4
B.S. McEwen / Brain Research 886 (2000) 172 – 189local neurotransmitters as well as systemic hormonesinteract to produce structural as well as functional changes.Likewise, the immune system responds to acute stress byshowing enhanced responses, and this is mediated byadrenal steroids and catecholamines, as well as by locallyproduced cytokines and cell adhesion molecules. Thus,systemic levels of adrenal steroids and catecholamines, theclassical stress hormones, do not tell the whole story as faras how the brain adapts. Moreover, comparison of theeffects of experimenter-applied stressors and psychosocialstressors show that what animals do to each other is oftenmore potent than what we, as experimenters, do to them.Yet, even then, there is reason to believe that the brain isresilient and capable of adaptive plasticity. The changes inthe brain and immune system produced by acute andrepeated stress and the underlying mechanisms have turnedout to have unexpected clinical ramifications. After discussing these, the article will consider future directions of thisresearch and consider important unanswered questions.2. Protective and damaging effects of stressmediators: homeostasis and allostasisBefore discussing the brain and its adaptive responses tostress, it is important to consider the definition of some keyterms. Stress is often defined as a threat, real or implied, tohomeostasis, and homeostasis refers to the maintenance ofa narrow range of vital physiological parameters necessaryfor survival. In common usage, stress usually refers to anevent or succession of events that cause a response, oftenin the form of ‘distress’ but also, in some cases, referringto a challenge that leads to a feeling of exhilaration, as in‘good’ stress. But, the term ‘stress’ is full of ambiguities. Itis often used to mean the event (stressor) or the response(stress response). It is frequently used in the negative senseof ‘distress’, and sometimes it is used to describe a chronicstate of imbalance in the response to stress. In this article,‘stress’ will be used to describe an event or events that areinterpreted as threatening to an individual and which elicitphysiological and behavioral responses. The brain is thekey organ involved in interpretation and responding topotential stressors. But before considering its role, thefollowing are some additional key terms and the way theyare used in this article.2.1. Stress responseThe most commonly studied physiological systems thatrespond to stress are the HPA axis and the autonomicnervous system, particularly the sympathetic response ofthe adrenal medulla and sympathetic nerves. These systems respond in daily life according to stressful events aswell as to the diurnal cycle of rest and activity. Thus, thesesystems do more than respond to ‘stressors’ even thoughthey are frequently identified as ‘stress response systems’.173Behaviorally, the response to stress may consist of fightor-flight reactions or potentially health-related behaviorssuch as eating, alcohol consumption, smoking and otherforms of substance abuse. Another type of reaction to apotentially stressful situation is an increased state ofvigilance, accompanied, at least in our own species, byenhanced anxiety and worrying, particularly when thethreat is ill-defined or imaginary and when there is no clearalternative behavioral response that would end the threat.The behavioral responses to stress and these states ofanxiety are both capable of exacerbating and potentiatingthe production of the physiological mediators of healthoutcomes.2.2. HomeostasisHomeostasis, in a strict sense, applies to a limitednumber of systems like pH, body temperature and oxygentension, components of the internal milieu, that are trulyessential for life and are, therefore, maintained over anarrow range, as a result of their critical role in survival.These systems are not activated or varied in order to helpthe individual adapt to its environment. In contrast,systems that show ‘variation to meet perceived / anticipateddemands’ [145] characterizes the state of the organism in achanging world and reflects the operation of most bodysystems in meeting environmental challenges, e.g., throughfluctuating hormones, heart rate and blood pressure, cytokines of the immune system, and other tissue mediatorslike neurotransmitters and hormones. Those mediators aremost certainly not held constant, although their levels mayusually operate within a range, and they participate inprocesses leading to adaptation as well as contributing topathophysiology when they are produced insufficiently orin excess, i.e., outside of the normal range.2.3. AllostasisAllostasis is a term introduced by Sterling and Eyer[145] to characterize how blood pressure and heart rateresponses vary with experiences and time of day and alsoto describe changes in the set point of these parameters inhypertension. The change in set point was used by them asthe primary example that distinguishes allostasis fromhomeostasis. Yet there is a much broader implication ofwhat they wrote. In their paper, they state: ‘‘Allostasisemphasizes that the internal milieu varies to meet perceived and anticipated demand’’. This led us [100] todefine allostasis more broadly than the idea of a changingset point, namely, as the process for actively maintaininghomeostasis. This is important because, in our view, thesystems that vary according to demand, like the HPA axisand ANS, actually help maintain those systems that aretruly homeostatic. Moreover, large variations in the HPAaxis and ANS do not lead directly to death as would largedeviations in oxygen tension and pH.
174B.S. McEwen / Brain Research 886 (2000) 172 – 189Therefore, we propose that allostasis is a much betterterm for physiological coping mechanisms than is homeostasis, which should be reserved for the parameters that areessentially maintained for survival. Therefore, allostasis isthe process that keeps the organism alive and functioning,i.e., maintaining homeostasis or ‘maintaining stabilitythrough change’ and promoting adaptation and coping, atleast in the short run [94,99].We note, however, that another view of homeostasis isthat it can also mean the operation of coordinated physiological processes which maintain most of the steady statesof the organism [16]. In this interpretation, homeostasisand allostasis might seem to mean almost the same thing.The problem with this use of ‘homeostasis’ is that it doesnot distinguish between those systems essential for life andthose that maintain them.What are some examples of allostasis? Sterling and Eyer[145] used variations in blood pressure as an example: e.g.,in the morning, blood pressure rises when we get out ofbed and blood flow is maintained to the brain when westand up in order to keep us conscious. This type ofallostasis helps to maintain oxygen tension in the brain.There are other examples: e.g., catecholamine andglucocorticoid elevations during physical activity mobilizeand replenish, respectively, energy stores needed for brainand body function under challenge. These adaptationsmaintain essential metabolism and body temperature.Examples of allostasis go beyond the immediate controlof body temperature and pH to broader aspects of individual survival, e.g., from pathogens or physical danger.In the immune system, we will see below that acutestress-induced release of catecholamines and glucocorticoids facilitates the movement of immune cells to parts ofthe body where they are needed to fight an infection or toproduce other immune responses [25]. Finally, in the brain,glucocorticoids and catecholamines act in concert topromote the formation of memories of events of potentiallydangerous situations so that the individual can avoid themin the future [125]. Yet, each of these adaptive processeshas a potential cost to the body when allostasis is eithercalled upon too often or is inefficiently managed, and thatcost is referred to as ‘allostatic load’.2.4. Allostatic loadWhereas allostasis refers to the process of adaptation tochallenges, ‘allostatic load’ refers to the price the bodypays for being forced to adapt to adverse psychosocial orphysical situations, and it represents either the presence oftoo much allostasis or the inefficient operation of theallostasis response systems, which must be turned on andthen turned off again after the stressful situation is over.What are the damaging, as well as the adaptive effects, indifferent systems? For example, glucocorticoids, so-namedbecause of their ability to promote conversion of proteinand lipids to usable carbohydrates, serve the body well inthe short run by replenishing energy reserves after a periodof activity, like running away from a predator. Glucocorticoids also act on the brain to increase appetite for foodand to increase locomotor activity and food seekingbehavior [69], thus regulating behaviors which controlenergy input and expenditure. This is very useful when wedo manual labor or play active sports, but it is notbeneficial when we grab a pizza and a beer while watchingtelevision or writing a paper. Inactivity and lack of energyexpenditure creates a situation where chronically-elevatedglucocorticoids that may result from either poor sleep,ongoing stress, or as side effects of rich diet can impedethe action of insulin to promote glucose uptake. One of theresults of this interaction is that insulin levels increase,and, together, insulin and glucocorticoid elevations promote the deposition of body fat and this combination ofhormones also promotes the formation of atheroscleroticplaques in the coronary arteries [6].For the heart, we see a similar paradox. Getting out ofbed in the morning requires an increase in blood pressureand a reapportioning of blood flow to the head so we canstand up and not faint [145]. Our blood pressure rises andfalls during the day as physical and emotional demandschange, providing adequate blood flow as needed. Yetrepeatedly elevated blood pressure promotes generation ofatherosclerotic plaques, particularly when combined with asupply of cholesterol and lipids and oxygen free radicalsthat damage the coronary artery walls [87]. Beta adrenergicreceptor blockers are known to inhibit this cascade ofevents and to slow down the atherosclerosis that isaccelerated in dominant male cynomologus monkeys exposed to an unstable dominance hierarchy [88]. Thus,catecholamines and the combination of glucocorticoids andinsulin can have dangerous effects on the body, besidestheir important short-term adaptive roles [6].We now shall consider protective and damaging effectsof mediators of allostasis in the immune system and brain,two systems that are less well-understood.3. Stress and immune functionThe immune system is regulated by neural input fromsensory, sympathetic and parasympathetic nerves [7], aswell as by circulating hormones, of which the glucocorticoids are among the most prominent [97,142]. Longregarded as inhibitors of immune function, adrenal steroidshave now been recognized as having biphasic effects uponimmune function, as shown recently in studies of delayedtype hypersensitivity (DTH) [25,28]. This makes moresense, because the organism’s response to acute challengeis in other respects protective. Under acute stress, energyreserves are mobilized, vegetative processes and reproduction are suppressed, and the body is made ready for fight orflight, which may involve wounding. Thus the immune
B.S. McEwen / Brain Research 886 (2000) 172 – 189defense system should acutely gear up to protect theorganism from infections and accelerate wound healing.A primary underlying mechanism for these effects is thetranslocation or ‘trafficking’ of immune cells between theblood and different primary, secondary and tertiary immune tissues (see [7,142]). Elevations of stress hormones,both glucocorticoids and catecholamines, direct the movement of various cell types of the immune system. Lymphocytes, monocytes and NK cells are all reduced in numberin blood and increased in number in tissues, such as theskin, as a result of acute stress or acute glucocorticoidadministration [27,29] (see Fig. 1).Once immune cells have marginated and begun to enterthe tissue, other factors become involved as local mediators of further activation of immune function. Interferongamma is an important factor in the stress-enhancement ofthe DTH response, and this has been shown by a lack of astress effect in mice lacking the receptor for IFN gamma[30]. Furthermore, immunoneutralization of IFN gamma innormal mice also blocks the stress effect. Thus, althoughIFN gamma is not required for the baseline DTH response,it is evidently important for the manifestations of theeffects of acute stress. IFN gamma is known to induceexpression of antigen-presenting and cell-adhesion molecules on endothelial cells and macrophages and celladhesion molecules on leukocytes. It is also significant thatglucocorticoids induce IFN gamma receptors on monocytes. (For discussion and refererences, see [30]).What about the effects of chronic stress? Acute stressshows a dose dependency to activate the DTH response,and this is related to the magnitude of glucocorticoidsecretion [28]. Exogenous glucocorticoids mimic this dosedependency, but at higher glucocorticoid doses, there is anFig. 1. Immune cells are depleted reversibly from the blood duringstress-induced elevation of glucocorticoids and marginate on blood vesselwalls and enter tissues such as the skin. From [26].175Fig. 2. Physiological doses of corticosterone mimic effects of stress inenhancing the DTH response in the ear, whereas high doses of corticosterone and dexamethasone, which does not bind to CBG, suppresses theDTH response. From [25].inverted U dose response curve and suppression of theDTH response is seen [25] (see Fig. 2). Dexamethasone,which does not bind to serum corticosteroid bindingglobulin (CBG), mimics the suppressive effects of highdose glucocorticoids [25]. Chronic stress over 3–5 weeksproduces a suppression of the DTH response and alsosuppressed the initial sensitization of the response [28] (seeFig. 3). An important factor in this suppression is the lackof immune cell trafficking, and this may be due, at least inpart, to habituation of the corticosterone response to stress[28].These findings are relevant to the extensive literature onthe effects of stress on immune function in animals andhumans [142]. Enhancement of immune function, in thecase of an autoimmune disease, may be deleterious,whereas it may be beneficial where there is a pathogeninvolved; conversely, suppression of immune function maybe beneficial where an autoimmune disorder is concerned,whereas it may be dangerous where a pathogen is involved[25]. Thus, the immune system exemplifies the contrastingaspects of ‘protection’ and ‘damage’ and the effects ofstress and stress hormones are highly relevant to humandisease. Now we turn to the brain and consider how ithandles both acute and repeated stress.Fig. 3. Acute stress enhances, whereas chronic stress suppresses, theDTH response. From [25,28].
176B.S. McEwen / Brain Research 886 (2000) 172 – 1894. Stress, adaptive plasticity and the hippocampusThe brain is the key to interpreting and responding topotentially stressful events; it is also a target for the actionsof stress hormones, particularly glucocorticoids. In theshort run, acute elevation of both glucocorticoids andcatecholamines facilitates the formati
Interactive report The neurobiology of stress: from serendipity to clinical relevance1 Bruce S. McEwen* Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology,The Rockefeller University, 1230York Avenue,Box 165,New York, .
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Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. Crawford M., Marsh D. The driving force : food in human evolution and the future.
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. 3 Crawford M., Marsh D. The driving force : food in human evolution and the future.
