9 Social Stress Effects on Hormones, Brain, and Behavior*scitechconnect.elsevier.com/.../03/Social-Stress-Effects.pdf · 2016-03-17 · Social Stress Effects on Hormones, Brain, and

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9 Social Stress Effects on Hormones, Brain, and Behavior*C R McKittrick, Drew University, Madison, NJ, USA

D C Blanchard, University of Hawaii, Honolulu, HI, USA

M P Hardy{, The Population Council, New York, NY, USA

R J Blanchard, University of Hawaii, Honolulu, HI, USA

� 2009 Elsevier Inc. All rights reserved.

Chapter Outline

9.1 Why Study Social Stress Effects? 334

9.1.1 Differences in Effects of Different Stressors 334

9.1.2 Social Stress as a Chronic or Recurrent Factor in Evolution 334

9.1.3 Social Stress Effects in People 335

9.2 Animal Models of Social Stress 335

9.2.1 Laboratory Models of Social Stress 335

9.2.1.1 Social defeat 335

9.2.1.2 Colony, or chronic defeat, models 336

9.2.1.3 Intermittent defeat 336

9.2.1.4 Social instability 336

9.2.1.5 Social disruption 336

9.2.1.6 Crowding 337

9.2.1.7 Social isolation 337

9.2.2 Naturalistic or Field Studies of Social Stress Effects 337

9.2.3 Studies of Social Stress Effects in Females 337

9.2.4 Social Stress Mechanisms and Markers 338

9.2.5 Scope of this Article 338

9.3 Behavioral Consequences of Social Stress 339

9.3.1 Agonistic Behaviors: Aggression and Defense 339

9.3.2 Emotional Behaviors Measured Outside the Agonistic Context 340

9.3.3 Social Stress Effects on Drinking and Drug-Taking Behaviors 341

9.3.4 Social Stress Effects on Sexual Behavior 341

9.3.5 Social Stress Effects on Other Social Behaviors 342

9.3.6 Social Stress Effects on Nonsocial Behaviors 342

9.3.7 Summary of Social Stress Effects on Behavior 343

9.4 Hormonal Aspects of Social Stress: HPA-Axis Function 343

9.4.1 Corticotropin and Glucocorticoids 343

9.4.1.1 Basal secretion 343

9.4.1.2 Reactivity and feedback control of HPA axis 345

9.4.2 Corticosteroid Receptors and CBG 346

9.4.3 Summary 346

9.5 Interactions between Hormones and Brain Systems in Social Stress 347

9.5.1 Neurotransmitter Systems 347

9.5.1.1 Serotonin 347

9.5.1.2 Norepinephrine 348

9.5.1.3 Dopamine 349

9.5.1.4 Amino acid transmitters 349

he authors would like to dedicate this chapter to the memory of Matthew P. Hardy, a wonderful colleague, collaborator, and friend.

e left us far too soon and will be missed.eceased.

333

334 Social Stress Effects on Hormones, Brain, and Behavior

9.5.1.5 CRH and vasopressin 350

9.5.1.6 Other neuropeptides 351

9.5.2 Immediate Early Gene Expression 351

9.5.3 Neuronal Structure and Survival 351

9.5.4 Summary 352

9.6 Reproductive Aspects of Social Stress: Hypothalamic–Pituitary–Gonadal Axis 352

9.6.1 Stress and Reproductive Functioning 353

9.6.1.1 Reproductive hormone levels in dominant males 354

9.6.1.2 Androgen levels in subordinate males 354

9.6.2 HPA/HPG Interactions in Socially Stressed Males 354

9.7 General Summary 356

References 356

Glossarydexamethasone suppression test (DST) It is a

pharmacological test that probes feedback

regulation of the hypothalamic–pituitary–

adrenal (HPA) axis. Under normal conditions,

glucocorticoid secretion is inhibited after

administration of the glucocorticoid receptor

agonist, dexamethasone. Nonsuppression

is an indicator of deficient regulation of the

HPA axis.

hypothalamic–pituitary–adrenal (HPA) axis This

is the hormonal cascade activated in

response to stress, which includes

corticotropin-releasing hormone (CRH) from

the hypothalamus, corticotropin (ACTH)

from the pituitary, and glucocorticoids from

the adrenal cortex (cortisol or corticosterone,

depending on the species).

hypothalamic–pituitary–gonadal (HPG) axis This

is the hormonal cascade that regulates the

secretion of sex steroids, which includes

gonadotropin-releasing hormone (GnRH) from

the hypothalamus, luteinizing hormone (LH)

and follicle-stimulating hormone (FSH) from the

pituitary, and either estrogens and progestins

from the ovary or testosterone from the testes.

9.1 Why Study Social Stress Effects?

9.1.1 Differences in Effects of DifferentStressors

Although stress has long been conceptualized in termsof a generic pattern of physiological responses, somerecent work indicates that different types of stressfulevents may produce qualitatively different patterns of

effects in both behavior and physiology: electric foot-shock and repeated social defeat have been reportedto produce opposite effects on systolic blood pressureand mean arterial blood pressure in male rats, withenhancement in the former situation and decrementsin the latter (Adams et al., 1987). While fear of apreviously received footshock produced both brady-cardia and immobility in almost all rat subjects, fearof a dominant rat produced bradycardia in about50% of subjects, and immobility primarily in theothers (Roozendaal et al., 1990). Similarly, whilewater deprivation had a duration-dependent anxio-lytic effect in the elevated plus maze, 1-h restraintwas anxiogenic in the same situation (McBlane andHandley, 1994). Social defeat produced a significantdecrease in variability indices for a number of car-diac electrical activity parameters, whereas threenonsocial stressors (restraint, shock-probe test, andswimming) either failed to change or increased theseindices (Sgoifo et al., 1999). While a variety of stres-sors tend to elicit self-grooming in the rat, the timecourse, form, and magnitude of these are differentwith different stressors (van Erp et al., 1994).

9.1.2 Social Stress as a Chronic orRecurrent Factor in Evolution

Differences in response to specific stressors suggest theadvisability of focusing research involving the biobe-havioral consequences of stress on those types of stres-sors that are most likely to be broadly representedacross mammalian species, including humans. In con-trast to many of the stressful manipulations used inlaboratory studies, social stress is a chronic or recurringfactor in the lives of virtually all higher animal species.Disputes over resources, including access to a sexual orreproductive partner, or in the process of setting up and

Social Stress Effects on Hormones, Brain, and Behavior 335

maintaining territoriality or dominance relationships,may involve agonistic behaviors that result in wound-ing, exhaustion, and sometimes even death. Even forthose species in which individuals are solitary exceptfor mating and rearing of young, spacing is based on theagonistic or avoidant behaviors that are seen whenconspecific encounters occur. Because social stresseffects are both common and powerful, they, alongwith response to predators, have provided much ofthe impetus for the evolution of stress mechanisms.These include both behavioral and physiological adap-tations, potentially differing for acute, as opposedto chronic, situations that may potentially influencevirtually every area of an animal’s life.

9.1.3 Social Stress Effects in People

Social stress is viewed as a major factor in the etiologyof a variety of psychopathologies, such as depressionand anxiety (e.g., Kessler, 1997; Patten, 1999); social andemotional stressors may also be involved in the etiol-ogyof post-traumatic stress disorder (PTSD) and acutestress disorder (American Psychiatric Association,2000). In addition to its effects on male (McGrady,1984) and female (Nepomnaschy et al., 2007) repro-duction, psychosocial stress also alters immunefunction (Godbout and Glaser, 2006) and increasesthe risk of cardiovascular disease and metabolic syn-drome (Ramachandruni et al., 2004; Abraham et al.,2007). Social stress in people is often evaluated interms of the number and magnitude of life events thatan individual experiences, and a general conclusionfrom this approach is that a plethora of moderatelystressful events can have as great an impact as a fewmajor events (Dohrenwend, 1973). Another importantindex, strongly associated with the number of stressfulevents that are likely to be experienced, is social status.Low social status is regarded as impacting almost everyarea of the individual’s life, with implications for accessto resources, safe living conditions, and healthcare.Whatis particularly interesting, however, is that thesematerialdifferences do not appear to account entirely for socialstatus effects. The ranking difference itself, and themeaning assigned by the individual to his/her statuswith reference to others, may provide stress that is addi-tional to (or interactive with) the material consequencesof low status (de Ridder, 2000; Ghaed and Gallo, 2007).

9.2 Animal Models of Social Stress

Animal models of social stress involve single, inter-mittent, or chronic exposure of a subject animal to a

conspecific, another member of the same species.The results of such exposure may be expected tovary with the subject species, and the age, gender,and previous history of the individual, as well as thecircumstances in which the exposure takes place.Most laboratory studies of social stress effects utilizerodents, typically laboratory rats or mice. However,hamsters – a variety of mouse species in addition tothe domesticated laboratory mouse – and otherrodents have also been used, albeit less frequently.Primates also serve as subjects of laboratory investi-gation of social stress effects, but their social andstress-related behaviors are more commonly obser-ved under natural or seminatural conditions.

Adult males are the subjects of a great majority ofsocial stress studies, as, indeed, they appear to befor work on animal models of stress-related psy-chopathologies in general (Blanchard et al., 1995;Tamashiro et al., 2005). With reference to social stresseffects, this may reflect that in most mammalianspecies males tend to create a dominance hierarchythat is much more visible than are the dominancerelationships of females, as the male hierarchy influ-ences a wider range of behaviors of the hierarchi-cal animals. In addition, for many species individualmale dyadic confrontations, particularly when theseoccur in the home cage or living area of one of themales, reliably produce fighting, in which the resi-dent has a major advantage. This phenomenon pro-vides a fast and reliable method of ensuring defeat inthe intruder, enabling some quantification of socialstress in terms of the characteristics of the fight, andits parameters (e.g., number and duration of sessions).

9.2.1 Laboratory Models of SocialStress

9.2.1.1 Social defeat

In general, two types of social stress situations areused in laboratory studies. The first involves individ-ual confrontations, typically separated by longerperiods in which the stressed intruder is returnedto its home cage or to a neutral site. These aretypically labeled social defeat tests, and, in order toreduce wounding and other physical concomitantsof the encounter, they may be followed by an addi-tional period in which the defeated animal is leftin the resident’s home cage, but protected by abarrier such as a wire mesh cage. These protectedexposures may be repeated, with or without actualphysical contact of the two animals, on successivetest days.


9.2.1.2 Colony, or chronic defeat, modelsThe other type of social stress situation involveschronic exposure of animals maintained in groupsor colonies. The physical and social environmentsand other parameters of these groups vary consider-ably, from standard animal cages in which multipleanimals of only one sex are housed, to seminaturalhabitats, including our Visible Burrow System (VBS)(see Blanchard and Blanchard (1990) for overview ofmodel), with tunnels and burrow systems includingboth male and female animals. The strength of ago-nistic interaction within these groups also appears tovary considerably, with housing with females andprovision of larger and more natural habitats tendingto produce higher levels of fighting. Various indicesof both the agonistic interactions, and other behaviorsmanifested by individual animals may be used toinfer a dominance hierarchy.

9.2.1.3 Intermittent defeatOther variants tend to fall between these two proto-cols. One frequently used variant involves caging twoanimals, usually male, in adjacent areas such that theyare chronically exposed to the sight, smell, and soundof the other, but with tactile contact precluded. Atintervals the barriers between the enclosures areremoved and the two animals are allowed to interactdirectly. In these encounters, one animal may be anexperienced fighter, and the other naive, such that itis very predictable that the naive male will bedefeated. In other variants, both males are naive, butthey quickly establish a victor and a defeated orsubmissive member of the pair. While this has muchin common with the social defeat model, that is,punctuated physical encounters, typically involvingfighting, the defeated animal is left in chronic sensory(except for tactile) contact with the victor such thatits exposure to this psychosocial stress is chronicrather than intermittent. A recent variant involvesallowing one animal to establish residency, for exam-ple, for 1 week, followed by brief exposure to anintruder in the resident’s home cage, then separationof resident and intruder within the home cage by abarrier, for 2 or 3 weeks. Additional confrontations atthe end of this period enable determination of domi-nant and subordinate status for the two, with theadded feature that if the initial resident is defeated,it will also have lost its territory in the process(reviewed in Bartolomucci et al. (2005)).

All of the above models are capable of providinganimals with a history of victory and a history ofdefeat, both of which potentially may be compared

to controls. For some of these, winners and losers aredirectly comparable with reference to housing con-ditions and prior social experience. For others, nota-bly the resident–intruder type social defeat models,the social disruption models, and those intermittentdefeat models in which an experienced animal ispaired with one that is naive, the winners typicallyhave much more social experience, and in a differentarena (i.e., their own home area rather than that ofthe other animal for social defeat, and in a varietyof locations for the social disruption models) thando the losers. The colony dominant–subordinate,intermittent defeat using initially naive animals, andthe social instability models, all involve someopportunities for agonistic interactions among ani-mals with initially equivalent experience. However,for those models, winning and losing may reflectindividual factors for the two animals, such thatcomparisons following victory or defeat experiencemust also take into account the possibility of preex-isting differences.

9.2.1.4 Social instability

Social instability models involve setting up socialgroups, and later mixing them. Since intrudersinto an established home area are typically attackedmore strongly than are subordinates within a stablesocial grouping, this procedure would be expectedto involve a very high level of agonistic behavior.However, like crowding, this procedure does blurthe distinction between dominant and subordinate,or victorious and defeated, animals, in that animalswith only experience of victory, or only experienceof defeat, are unlikely to emerge from these pro-cedures. Moreover, the protocol may or may notattempt to measure agonistic interactions for eachanimal.

9.2.1.5 Social disruption

Social disruption is achieved by introducing aselected highly aggressive male or a succession ofhighly aggressive males into a stable social group(Padgett et al., 1998). As with social instability mod-els, this procedure produces animals that are all likelyto have been defeated in several of their agonisticinteractions, those involving the highly aggressivemale intruders. However, some of the grouped sub-jects may also have experience of victory, eitherin within-group fights, or, on occasion, in agonisticencounters with the highly aggressive male intruders.Thus, for both social disruption and social instability


models, although there is the possibility of dividingsubjects into categories based on their own specifichistory of victory and defeat, it should be recognizedthat these experiences are likely to be less polarizedthan those of the first three paradigms given above.

9.2.1.6 Crowding

Additional variants of laboratory social stress modelsinclude crowding and social isolation. Properlyspeaking, crowding should refer only to studies inwhich animals are placed together in housing situa-tions such that each has less than a standard amountof space. This may mean three rats in a cage meant forone, or seven rats in a cage meant for 21. Since there islittle information on what are the optimum or evenreasonable space requirements for most animal spe-cies, the definition of crowding is necessarily some-what arbitrary. In addition, the two examples givenabove illustrate that crowding measured as animalsper unit area may be quite different than crowding asnumber of interacting animals per housing unit, and itmight be expected that these two aspects of crowdingwould have differential effects. Crowding also impliesthat the mechanism of social stress is proximity, ratherthan agonistic interaction per se, and crowding stressstudies may or may not involve attempts to measureagonistic reactions, and to identify dominant and sub-ordinate animals within the groups.

9.2.1.7 Social isolation

It might be thought contradictory that both socialgrouping and social isolation may be stressful, sincethis differentiation seems to leave no normal situa-tion to serve as a minimal stress control. However,such a view does not take into account differences insocial organization between species or between sexeswithin the same species. Thus, although social group-ing appears to be more stressful for male rats, femalerats are more stressed by isolation (Brown andGruneberg, 1995; Haller et al., 1999; Palanza, 2001).Gender effects in protocols involving social isolationmay be quite complex. Thus, in contrast to moststudies of isolation effects, McCormick et al. (2008)reported a reduction in anxiety-like behavior (ALB)in adolescent female rats stressed by a combination ofisolation interspersed with partner housing in whichthe partners were intermittently changed. The choiceof which to consider the stressor, isolation or group-ing, may in some cases be based on associated behav-ioral changes rather than endocrine response (e.g.,Haller and Halasz, 1999).

9.2.2 Naturalistic or Field Studies of SocialStress Effects

Since a major focus of this chapter is on brain andendocrine effects of social stress, and these are muchmore difficult to evaluate in animals in their naturalenvironment, it will be laboratory models, such as theabove, that are emphasized. However, some fieldstudies also involve sampling of blood, feces, andother tissues providing indices of relevant hormonelevels. In these studies, the social stresses are typicallyinferred from the subject animal’s position within thegroup dominance hierarchy, or, more precisely, fromits recent activities with reference to moving up ordown in that hierarchy. While naturalistic studiesdo provide a wider and more elaborate range ofbehaviors for which social stress effects might bedescribed, and an expanded analysis of the conditionsunder which social agonistic behaviors generate littleor great magnitude of stress, they generally lack aminimal stress control group for purposes of compar-ison. Such studies typically compare animals that arehigh or low in a dominance hierarchy; moving up ordown in the hierarchy, or, that show certain patternsof endocrine levels or functioning. In field studies,it is particularly difficult to measure physiologicalchanges as a function of time, following agonisticinteraction or other stressful experience.

9.2.3 Studies of Social Stress Effects inFemales

As noted above, the vast majority of social stressstudies involves male subjects, as females of mostspecies show relatively little within-sex fighting. Inaddition, even when fighting between males andfemales is common, the females may appear to beonly a little stressed by it, in terms of measures suchas wounding, or subsequent avoidance of the male(Blanchard et al., 2001a). This may reflect the factthat in many of the more commonly used subjectspecies, male attack on females is inhibited, anddoes little damage. Female–female fighting maybecome more intense under some circumstances,however, such as during the week or so followingparturition. In addition, selection of highly aggressivemales, or of attackers subjected to physiologicalmanipulations, such as to make them more likely toshow intense attack, can be used to ensure a strongattack on females. These studies, while very interest-ing, tend to be cumbersome to run. Also, they maynot permit clear interpretation of male–female


differences in response to attack, since serious attackby males on females in species such as rats that showsexual dimorphism in size must either involve highmagnitude size differences, or the use of very small(young?) males.

In addition, females of many mammalian speciesshow a relatively specific inhibition of ovulation orother reduced reproductive functioning while insocial groups containing a dominant (reproductivelyactive) female. These nonreproductive females mayshow few other signs of stress or distress. Nonethe-less, the rapidity with which they may begin to cyclefollowing removal of the dominant female makes itclear that this suppression is a response, albeit a veryspecific one, to the social hierarchy.

9.2.4 Social Stress Mechanismsand Markers

This plethora of techniques for producing socialstress suggests the need for ways to evaluate whethersubjects have indeed experienced an adequate degreeof social stress. One approach may be to evaluate thespecific experiences that are regarded as mechanismsin the stress experience. Another is to examine beha-viors or physiological changes that may serve asrelatively specific markers or indices of stress.

With the possible exception of crowding, the majormechanism by which social experience is regarded asproducing stress is agonistic behavior. For laboratorymice and rats, the most commonly used subjectsof social stress laboratory research, this agonisticbehavior is a very obvious component of mostsocial-grouping studies. It may be measured directly,in terms of fighting within each specific male dyadwithin a group, or indirectly, in terms of woundson the combatants. Both techniques provide a goodindication of dominant or subordinate status, sinceoffensive attack, as is seen on the part of the dominantor the experienced victor, is aimed toward a differenttarget site on the body of its opponent than arethe attack bites of the defensive subordinate orexperienced loser (Blanchard and Blanchard, 1977).Measures of agonistic behavior that do not takeinto account crucial specifics, for example, a scorethat is summed for all fighting within a groupregardless of which animals fight, or overall woundingscores regardless of wound location, do not permitan analysis in terms of dominant/subordinate or win-ners as opposed to losers. All animals within sucha group may be compared to controls without agonis-tic experience but it is to be supposed that a good

deal of analytic precision is lost when this informa-tion is not available. Exceptions are females, forwhom overt fighting tends to be uncommon, exceptfor a few species such as hamsters and spottedhyenas, in which females are dominant to males andfemale–female fighting is common; and establishedor stable social groups, as may be the case in manyfield studies.

With reference to indices or markers of stress,the prototypical stress marker is activity of thehypothalamic–pituitary–adrenal (HPA) axis, typi-cally measured as the level of cortisol or corticoste-rone (CORT) in the plasma, saliva, or feces. As will beseen, while this marker is very consistent for mostlaboratory studies, there are some exceptions to thegeneral rule of high values for stressed subjects.Other commonly used indices of stress are changesin relevant organs (e.g., increased adrenal weight) andweight loss during the putatively stressful period.When all of these, plus direct measures of agonisticexperience are taken, they often covary consistently.Although not all such measures are taken in everystudy, they provide very useful indications that socialstress was indeed a factor in the experimental condi-tions imposed or a clear variate in the nonexperimen-tal situation in which observations were made.

9.2.5 Scope of this Article

This chapter will attempt to cover three broad aspectsof social stress effects: first, behavior; second, changesin brain systems; and third, endocrine changes. Somerecent work on social stress effects has tended to exam-ine these factors together, asking if animals that, forexample, show a particular pattern of endocrinechanges also show changes in behavior or in brainsystems. Such approaches are aimed at determiningthe mechanisms of interaction of these domains, andwe will attempt to sketch out these interactive effectswhenever possible. Our focus will be on changes ineach of these domains following social stress to rela-tively normal animals (e.g., not lesioned, drugged, orwith genetic modifications), examining them largely inthe context of laboratory research, although field stud-ies will also be considered. We will not attempt to dealwith a range of other stress-responsive systems thatare also interesting and potentially important, but arecovered in other chapters in this encyclopedia. Theseinclude analgesia, cardiovascular changes, autonomicfunctions, seizure manifestations, immune response,lipoprotein cholesterol, circadian rhythms, body tem-perature, and electrophysiological correlates.


9.3 Behavioral Consequences ofSocial Stress

9.3.1 Agonistic Behaviors: Aggressionand Defense

The immediate behavioral consequences of decisiveagonistic interactions comprise two groups of beha-viors – one that may be used to infer victory, the other,defeat. These have been intensively described inlaboratory rodents, beginning with the studies ofGrant and his colleagues about 40 years ago (GrantandChance, 1958; Grant, 1963; Grant andMacKintosh,1963), with further analyses in rats (e.g., Blanchard andBlanchard, 1977) and mice (e.g., Grimm, 1980). Suchstudies identified components such as lateral attack,chase, and standing on top of as aggressive elements,and flight/avoidance, defensive upright, and lying onthe back as defensive elements. For mice, in particular,the defensive upright is typically regarded as a submis-sive posture and is widely used to indicate defeat, as ittends to coincide with a cessation of aggressive beha-viors, and to recur as a conditioned response in situa-tions in which the animal has previously been attacked(Siegfried et al., 1984). Submissive behaviors have tradi-tionally (Lorenz, 1966) been interpreted as serving as acutoff for further attack, but appear not to be particu-larly effective in this role, except by concealing bodyareas that are the target for attack by the offensiveanimal (Blanchard and Blanchard, 1977; Pellis andPellis, 1992). Their inability to halt conspecific attackis illustrated by the fact that virtually all uses of socialdefeat models attempt to provide some protection forthe loser, which would not be necessary if its submissivepostures were effective in terminating physical attack.

Social defeat reduces social exploration, andincreases subordinate and fearful behaviors in socialsituations, in a range of species from great titsthrough laboratory rodents (Haller et al., 2002; VonFrijtag et al., 2002a; Wommack and Delville, 2007;Yamaguchi et al., 2005) to domestic swine (Carereet al., 2001; Pedersen et al., 2003). A number of recentreports indicate that social defeat in adolescence mayhave different effects. Delville, Wommack, and theirassociates report and confirm that early defeat stressproduces a premature transition from play fighting toadult forms of fighting in hamsters, with this acceler-ation most marked in the least submissive animals(Delville et al., 2003; Taravosh-Lahn and Delville,2004; Wommack and Delville, 2003; Wommack et al.,2003, 2004), whereas defeat in adult hamsters leads toreduced aggression and the development of patterns ofsubmissive behaviors (Wommack and Delville, 2007).

Young isolate-reared rats show more ultrasonic vocali-zations to an aggressive adult male and suffer moreinjuries in such encounters, suggesting that their behav-ioral deviations may serve as provocations for the adult(Von Frijtag et al., 2002a). However, changes in aggres-sion after social stress may be dependent on both thestressor and the incitement to aggression. Nakamuraet al. (2008) reported that as adults imprinting controlregion (ICR) mice weaned at 14 days of age showedenhanced aggression after food restriction, but not moreaggressionwith social instigation, compared to normallyweaned controls. In guinea pigs, sons of pre- and post-natally stressed mothers show infantilization of somebehaviors, such as more resting in body contact withconspecifics, that lasts to a later age than for controls(Kaiser and Sachser, 2001; Kaiser et al., 2003a). However,early pre- and postnatal stress masculinizes the behaviorof female guinea pigs (Kaiser et al., 2003b).

Subordinate behaviors include avoidance, immo-bility, crouching or freezing, and risk assessment(Blanchard and Blanchard, 1989; Blanchard et al.,1995, 2001a,b). The last category, risk assessment,involves information-gathering activities concerningpotential threat, and includes scanning as well as theassumption of low back postures while cautiouslyapproaching a threat stimulus (Blanchard et al.,1991a). These changes in aggressive and defensivebehavior may be further enhanced in a subset ofVBS subordinate rats that show a sharply reducedCORT response to restraint stress (see Section 9.4.1.2)(Blanchard et al., 1995, 2001b).

Most of the same changes are seen in subordinatetree shrews. Although the testing conditions (they arepaired with highly experienced fighters such thatthey are quickly and easily defeated) are such as tominimize any aggressive behaviors, they showincreased avoidance, immobility (measured as loco-motor activity in their home cage situation, in all buttactile contact with the dominant), and risk assess-ment, along with sleep disturbances (Flugge et al.,2001; Fuchs, 2005; Fuchs and Flugge, 2002; Fuchset al., 1996; Kramer et al., 1999; Von Kampen et al.,2000). Increases in particular defensive behaviors,such as the upright submissive posture, have alsobeen reported after defeat in both rats and mice, ashas risk assessment for subordinate cynomolgousfemale monkeys and socially stressed male mice(Beitia et al., 2005; Blanchard et al., 2001b; Chunget al., 1999; Siegfried et al., 1984; Kulling et al., 1987;Shively et al., 1997a,b). One potentially anomalousfinding is that enhanced scanning within a mixed-sexgroup has been reported for sugar glider dominants


(Mallick et al., 1994). As the dominant males weremoved to other groups where they became subordi-nates, scanning increased. While this may suggest thatscanning is a component of risk assessment to poten-tially attacking conspecifics, particularly in the lattersituation, this behavior is also highly functionalagainst nonconspecific threats, and in this species,dominant males in their own groups may take thelead in this type of risk assessment. Socially stressedrodents are less active and may show alterations incircadian rhythms and sleep (Lancel et al., 2003;Meerlo et al., 2002). Grouped (and presumablysocially stressed) pigs sleep more (Bornett et al.,2001). When mice are sorted into dominant residents,subordinate residents, dominant intruders, or resi-dent intruders on the basis of a protocol that affordsprior residency for one mouse followed by joint,noncontact habitation of a cage by both members ofa pair (reviewed in Bartolomucci et al. (2005)), sub-ordinates show reduced activity in the home situation(Bartolomucci et al., 2003).

9.3.2 Emotional Behaviors MeasuredOutside the Agonistic Context

Because of the strong association between stress and anarray of emotional disorders (e.g., Mineka and Zinbarg,1996), a major emphasis of social stress studies of ani-mals has been to evaluate emotionality. The anxietytest most commonly utilized in conjunction withsocially stressed animals is the elevated plus-maze.For subordinate rats, plus-maze findings tend to beextremely consistent, with a number of studies showingthat subordinates show more ALBs on this test, whilesocial victory decreases anxiety-like plus-maze behav-ior (Becker et al., 2001; Calfa et al., 2006; Haller andHalasz, 2000; Heinrichs et al., 1992, 1994; Lumley et al.,2000; McCormick et al., 2008; Menzaghi et al., 1994,1996; Palanza, 2001; Ruis et al., 1999; Sa-Rocha et al.,2006; Sterlemann et al., 2008). One interesting study,however, found that mild social stress normalizes theanxiety-like response of social isolates in the plus-mazetask (Haller and Hallasz, 1999).

Data from mouse studies were somewhat morevaried. Avgustinovich et al. (1997) reported thatc57BL/6J mice show enhanced plus-maze anxietyafter social defeat. However, Ferrari et al. (1998)found that among isolates, the more aggressivemales showed higher plus-maze anxiety, as did dom-inant males among group-housed animals. Theplus-maze anxiety measures of the Ferrari et al.(1998) test included risk-assessment measures, and

the aggressive isolates and grouped dominantsalso showed enhanced risk assessment, in additionto avoidance of open arms, the classical anxiety mea-sure of the elevated plus-maze test. This potentialrat–mouse difference may reduce to a difference inprocedure, in that, the rat studies compared sociallystressed (defeated) rats to controls, while the Ferrariet al., studies compared aggressive or dominantmice to controls. Possibly both winner and loseranimals are more anxious than those that have nothad aggressive experience. Other anxiety tasks thathave been shown to be responsive to social stresseffects are the black–white test (enhanced anxietyafter social defeat, Keeney and Hogg, 1999); openfield, and Porsolt’s test (reduced number of squarescrossed, and enhanced immobility, respectively;Kudryavtseva et al., 1991a). When placed in a novelenvironment, both resident and intruder dominantsfrom the mixed resident–cohabitation model (reviewedin Bartolomucci et al. (2005)) showed hyperactivityand reduced ALBs, whereas subordinates did notdiffer from controls (Bartolomucci et al., 2001).

After social defeat, immobility to a suddensilence was enhanced (Ruis et al., 1999). Similarly,stress-nonresponsive VBS subordinates show reducedactivity, including righting, to handling (Blanchard et al.,2001b), than controls, dominants, or stress-responsivesubordinates. However, a minimal physical-contactsocial defeat procedure failed to alter immobility formice in the forced swim test (Keeney and Hogg, 1999).Risk assessment is a pivotal defensive behavior thatdecreases with both high levels of defensiveness, or,when defensiveness declines toward a normal, non-defensive state (Blanchard et al., 1991a). It is very sensi-tive to subordination or defeat, but the direction ofchange is different for different situations, perhapsdepending on the level of threat experienced in thetest situation. The Ferrari et al. (1998) findings thataggressive and dominant mice show the highest levelsof risk assessment on the elevated plus-maze, are com-patible with a report by Avgustinovich et al. (1997) thatsocial defeat in mice may reduce peepings in this test,if the defensiveness of the latter, but not the former, isso great as to reduce risk assessment. Subordinatemice show enhanced risk assessment to social odorsin their own home cage, as do two of three VBSgroups (dominants and nonresponsive subordinates) ina stretch attend apparatus (Garbe and Kemble, 1994;Blanchard et al., 2001b).

Social defeat has also been consistently reportedto increase ultrasonic vocalizations to startle stimulisuch as strong air puffs, in rats (Vivian and Miczek,


1998, 1999), as well as to the situation in which theanimal has previously been defeated (Tornatzky andMiczek, 1994, 1995).

9.3.3 Social Stress Effects on Drinking andDrug-Taking Behaviors

Social stress is also viewed as an important factor indrug abuse and alcoholism, leading to many recentstudies of this relationship in animal models. Studiesin mice, rats, and monkeys provide a relativelyconsistent finding of enhanced alcohol intake forsocially stressed subordinates, particularly whenthis is measured in the grouped-housing situationitself (Blanchard et al., 1987; Higley et al, 1991,1998; Hilakivi-Clarke and Lister, 1992; Weisingeret al., 1989). This effect appears to be somewhatvariable for different strains of mice (Kudryavtsevaet al., 1991b), and with minimal physical-contactsocial defeat procedures (Keeney and Hogg, 1999)while Van Erp et al. (2001) and Van Erp and Miczek(2001) reported that social stress either suppressed orfailed to change alcohol intake in rats, measured ina different situation. Wolffgramm and Heyne (1991)found that dominant rats show less alcohol intakeeven when isolated, as well as in a contact-housingsituation that exposed subjects to other animals butprecluded direct physical contact. In partial contrast,the Blanchard et al. (1992) study found no differencebetween animals that subsequently became dominantor subordinate, prior to grouping, but that subordi-nates increased alcohol intake after grouping whiledominants did not. Similarly, Hilakivi-Clarke andLister (1992) found no differences in alcohol intakebetween dominant mice and controls. It might alsobe noted that the social stress in the monkey studieswas motherless rearing, while in the rat and mousestudies it involved some type of social agonisticexperience.

Similarly, social defeat was consistently reported toincrease cocaine self-administration (Covington andMiczek, 2001; Covington et al., 2005; Haney et al.,1995; Lemaire, et al., 1994; Miczek and Mutschler,1996; Tidey and Miczek, 1997). This fits well withfindings that social stress effects generalize to boththose of psychomotor stimulants (Covington andMiczek, 2001; Covington et al., 2005; Miczek et al.,1999) and pentylenetetrazole (Vivian et al., 1994) indrug discrimination tests, in that such similaritiesmay enable the social stressor to serve as a drugcue. However, social stress in adolescent hamsterswas reported not to cross-sensitize with cocaine

(Trzcinska et al., 2002). One potentially anomalousfinding is that social instability reduces the increasein amphetamine self-administration seen when malescohabit with females (Lemaire et al., 1994).

These increases in alcohol and drug-taking (diaz-epam as well as cocaine; Wolffgramm and Heyne,1991) as well as reinstatement of morphine-inducedplace preferences in mice with social defeat (Ribeirodo Couto et al., 2006), stand in contrast to the lack ofeffect for sucrose intake (Mole and Cooper, 1995) ordecreased sucrose preference in rats (Rygula et al.,2005, 2006). Socially defeated rats also show reducedanticipatory responses to sucrose reward (Von Frijtaget al., 2002), but this may be reward specific, in that,Van der Harst et al. (2005) reported impaired antici-patory behavior for sucrose but no change for anotherreward – an enriched cage. Other studies have showna reduction in reward motivation, specifically, foreating lab chow and drinking water, in subordinaterats in the VBS (Blanchard and Blanchard, 1989).This finding may have initially been confounded bythe presence of the dominant, since in that study foodand water were located in an area that the dominanttended to patrol, during lights-off period when mostconsumption occurs. However, later variants of theVBS provided food and water in each chamber, andstill found a reduction in subordinate weight, suggest-ing that food intake, at least, may still be reduced forthese animals (Blanchard et al., 1998). Tamashiroet al. (2006) also reported that VBS subordinate ratsshow decreased body weight, associated with eatingchanges. Social defeat reduced weight gain in norepi-nephrine transporter knockout (KO) mice (Halleret al., 2002), and in rats (Bhatnagar et al., 2006).Group-maintained pigs made fewer visits to a feeder,spent less time feeding, and showed reduced weightgain (Bornett et al., 2001).

9.3.4 Social Stress Effects on SexualBehavior

Social stress has relatively consistent effects on sexualbehavior. Using an unusual social stress paradigm inwhich dominant male mice are exposed to the sightand sound of their subordinates interacting with afemale, D’Amato et al. (2001) reported impaired sex-ual behaviors for the stressed dominant. More com-mon, however, are studies of social stress effects insubordi nate males. In Africa n cichlid fish (Parikhet al., 2006), la borator y mice ( D’Amato, 1988 ), deermice (Dewsbury, 1988), laboratory rats (Blanchardand Blanchard, 1989; Mizuno et al., 2006; Niikura


et al., 2002), domestic pigs (Pedersen et al., 2003), andlemurs (Perret, 1992) subordinates show reducedsexual behavior. It should be noted that this reductionmay also, at least in part, reflect the conditions underwhich the observations in several of these studieswere made, in groups or colonies such that the domi-nant is, or has recently been, present. Given thedegree to which proximity to a dominant animalinfluences subordinate behavior (see Section 9.3.5),and the existence of sneaker strategies for male mat-ing (Plaistow and Tsubaki, 2000), it is possible thatsubordinate males’ sexual behavior is better describedas transiently suppressed by the dominant. Whiledominant males do appear to disproportionatelyfather young in some studies, in others this is notthe case – findings that may reflect the existenceof female mate-selection strategies (e.g., Gagneuxet al., 1999) as well as male sneaker strategies, and ahost of postmating factors. Subordinates also showreductions and dominants increases in scent marking(Flugge et al., 1998; Fuchs et al., 1996; Mallick et al.,1994; Yamaguchi et al., 2005), which may be relatedto attraction of females as well as other aspects ofterritory marking.

Sexual behavior of subordinate females alsoappears to be inhibited, and this may occur in conjunc-tion with, or independently of, suppression of ovula-tion (Saltzman et al., 1997). The suppressionof ovulation in subordinate females is found in arange of rodent and primate species (naked mole-rats,Faulkes et al., 1990; hamsters, Gudermuth et al., 1992;Damaraland mole-rat, Bennett et al., 1996; mice,Marchlewska-Koj et al., 1994; and marmosets, Barrettet al., 1990; Saltzman et al., 1997). It is not clear to whatdegree this suppression might be ascribed to socialstress, as it may persist in response to particular pher-omones given off by the dominant female, otherwisenot present (Saltzman et al., 1997). As will be seen later(in Section 9.6.2), these subordinate females frequentlyhave lower, rather than higher, plasma glucococorti-coid values, further complicating the issue of whetherstress is involved.

9.3.5 Social Stress Effects on OtherSocial Behaviors

As might be expected, subordinates, socially defeatedmales, and dominants transferred from one group toanother (where they are very likely to become subor-dinate) show reduced affiliativeness and social con-tact (rat, Blanchard and Blanchard, 1989; Meerloet al., 1996b; female cynomolgous monkeys, Shively

et al., 1997a,b). Socially stressed animals appear toshow considerable sensitivity to relevant physical andbehavioral features of other animals, with subordi-nate male mice preferring the odors of familiar domi-nants to those of unfamiliar dominants (Rawleighet al., 1993), while subordinate female vervet monkeysshow a pattern of behavior changes in response to themenstrual cycle of the dominant female – a featurethat modulates the dominant’s defensiveness.

Changes in behavior in response to the presenceand proximity of a dominant have been shown forboth rodent and primate species. Some of thesechanges appear to involve efforts to become lessbehaviorally provocative, for example, selectivelylosing a tug of war for food when the competingdominant is close by (long-tailed macaque, Schaub,1995). In another intriguing finding, subordinaterhesus macaques showed no learning deficienciescompared to dominants when tested individually,but played dumb when tested together (Drea andWallen, 1999). The presence of a dominant appearsto produce anhedonia with reference to rewards(hamster, Kureta and Watanabe, 1996), a phenome-non that may or may not entirely account for theperformance deficiencies seen in such situations.

9.3.6 Social Stress Effects on NonsocialBehaviors

The degree to which social experience can resultin serious, indeed lethal, stress was shown in pioneer-ing studies by Barnett (1963), who reported thatintruders into wild rat colonies often died over aperiod of several days. Such stress deaths havebeen reported in a number of other rodent species(blind mole-rats, Zuri et al., 1998; naked mole-rats,Margulis et al., 1995; mice, Ebbesen et al., 1991),as well as for subordinates in laboratory rat VBScolonies (Blanchard and Blanchard, 1989). Otherspecies, such as lions (Schaller, 1972), hyenas(Kruuk, 1972), and chimpanzees (Wrangham andPeterson, 1996), also show lethal intraspecific fight-ing, but in these cases the death typically resultsdirectly from physical trauma, rather than fromstress per se. Weight loss and a reduction in weightgain are also commonly associated with subordina-tion in rodents (Blanchard and Blanchard, 1989;Blanchard et al., 1995, 2001a,b) and following socialdefeat (Haller et al., 1999; Meerlo et al., 1996b, 1997).While these may, in part, reflect eating reductions,they may also reflect enhanced metabolic demandsassociated with stress.


Decreases in locomotion, exploration, and celerityof movement are a very consistent finding with subor-dinate or socially defeated animals, including rats(Blanchard and Blanchard, 1989; Blanchard et al.,2001a,b; Meerlo et al., 1996a,b, 1997; Ruis et al., 1999;Tornatzky and Miczek, 1994), tree shrews (Fluggeet al., 2001; Fuchs, 2005; Fuchs and Flugge, 2002;Fuchs et al., 1996; Kramer et al., 1999; Van Kampenet al., 2000), and sugar gliders (Mallick et al., 1994).

Memoryand cognitive deficits are somewhat incon-sistently associated with social stress. Although para-doxical sleep deprivation leads to an impairment ofmemory in several learning/memory tasks, socialstress (maintenance in socially unstable conditions)did not produce deficits or interact with sleep depri-vation (Dametto et al., 2002; Dawood et al., 2004)reported a more complex relationship between socialstress and Y-maze memory performance, with habitu-ated but not nonhabituated mice showing poorer per-formance. In mountain chickadees, subordinates showless food caching and less-efficient cache retrieval, withreduced spatial memory task performance than domi-nants (Pravosudov et al., 2003). Ohl and Fuchs (1999)have suggested that the memory deficits seen aftersocial stress may be those involving hippocampalmediation (Ohl and Fuchs, 1999). These deficits donot appear in close correspondence with alternatingcycles of glucocorticoid elevation, suggesting alonger-term or indirect effect of stress on memoryprocesses (Ohl and Fuchs, 1998). A very intriguingfinding is that social stress may influence learningfunctions through mechanisms other than, or in addi-tion to, glucocorticoid increases, as exogenous admin-istration of these, to match the elevation seen withthe social stressor, failed to produce so profound orlasting a disruption of learning (Krugers et al., 1997;Ohl et al., 2000).

9.3.7 Summary of Social Stress Effectson Behavior

Social stress appears to be capable of altering a verywide range of behaviors. It facilitates the expression ofALBs in tests such as the elevated plus-maze, and, whenstrong or prolonged, may produce a pattern of behaviorchange that is very similar to many of the target symp-toms of depression (Blanchard et al., 1995). Social stressmay also alter substance-taking and enhance responsiv-ity to drugs of abuse. These changes, and other indica-tions of compromised social and sexual functioning, insocially stressed animals provide a potential link tobehavioral stress dysfunctions in humans.

9.4 Hormonal Aspects of SocialStress: HPA-Axis Function

The activity of the HPA axis has been studied inseveral different animal species in a variety of modelsof psychosocial stress. Not surprisingly, the majorityof studies indicates that the HPA axis is activated inlow-ranking animals in hierarchical social groups andin animals that have been defeated by a conspecific.However, activity and reactivity of the HPA axis havebeen shown to be modulated by a variety of differentfactors, including the species, gender, and behavioralstyle of the individuals.

9.4.1 Corticotropin and Glucocorticoids

9.4.1.1 Basal secretion

Most studies of dominance hierarchies in rodents,guinea pigs, and nonhuman primates have found ele-vated basal glucocorticoid secretion in subordinateanimals compared to dominants. Subordination hasbeen shown to increase CORTlevels in mice, rats, andhamsters (Louch andHigginbotham, 1967; Popova andNaumenko, 1972; Ely and Henry, 1978; Raab et al.,1986; Schuhr, 1987; Huhman et al., 1992; de Goeijet al., 1992; Blanchard et al., 1993; Ely et al., 1997;Bartolomucci et al., 2001), CORT and cortisol levelsin guinea pigs and tree shrews (von Holst, 1977;Sachser and Lick, 1989), and cortisol levels in squirrelmonkeys, cynomolgous macaques, and olive baboons(Manogue et al., 1975; Coe et al., 1979; Sapolsky, 1983;Shively et al., 1997a,b). The increased glucocorticoidlevels are often accompanied by weight loss, thymusinvolution, and/or adrenal hypertrophy (von Holst,1977; Raab et al., 1986; Sachser and Lick, 1989; deGoeij et al., 1992; Blanchard et al., 1993). Adrenocor-ticotropic hormone (ACTH) may also be elevated inthe subordinates (Huhman et al., 1991, 1992) althoughthat is not always the case (de Goeij et al., 1992).

Although in most social stress models, it is thesubordinates that appear to be most severely stressed,in many cases, the dominant animals show evidenceof HPA-axis activation as well. In the VBS model ofchronic social stress, for example, both dominant andsubordinate male rats have elevations in plasmaCORT in blood sampled immediately after removalfrom the burrow system (Blanchard et al., 1993, 1995;McKittrick et al., 1995). This suggests that boththe dominants and the subordinates are stressedwithin the context of the VBS. However, if blood issampled after the animals have been allowed to restin individual cages for 1h after removal from the


VBS, CORT remains high in the subordinates, butreturns to control levels in the dominants, indicatingmore efficient regulation of the HPA axis in theseanimals (McKittrick et al., 2000; Tamashiro et al.,2004, 2007b). In addition, in previous studies, allanimals housed in the VBS show some degree ofweight loss, thymus involution, and adrenal hy-pertrophy, although these effects are much morepronounced in the subordinate animals. It is possible,however, that some of these effects were exacerbatedby restricted access to food within the VBS and/orsomewhat higher levels of aggression in the colony-bred animals used in these studies. More recent itera-tions of the VBS (Tamashiro et al., 2004, 2007a,b)have used commercial Long-Evan rats and haveprovided additional food sources within the burrows;although stable hierarchies were formed and thesubordinates had elevated basal CORT and thymusinvolution, the mortality and morbidity within thesecolonies were greatly reduced. In addition, althoughdominant males had attenuated weight gain com-pared to controls, CORT levels and organ weightsdid not significantly differ from the control animals.Further studies by Tamashiro et al. (2007a) suggestthat weight loss alone can lead to an elevation ofCORT, but this effect is transient and is unlikely tocompletely account for the stress-induced increasein CORT seen in the subordinates.

Similarly, group housing of mice increases plas-ma CORT in both subordinates and dominants(Bartolomucci et al., 2001), although the glucocorti-coid concentrations may return to control levelsmore rapidly in dominants than in subordinates(Bronson, 1973). In studies using other models ofsocial stress, dominants as well as subordinates hadhigher CORT levels, decreased thymus weight, andincreased adrenal weights compared to single- orpair-housed controls, with the effects generally morepronounced in the subordinate animals (Louch andHigginbotham, 1967; Dijkstra et al., 1992).

In contrast to the above studies, dominant animalshave been found to have higher levels of basal glu-cocorticoids in social groups of dwarf mongoose, wilddogs, and marmosets (Saltzman, et al., 1994; Creelet al., 1996). These effects are observed primarily infemales and may be related to ovulatory cyclicity.In marmoset populations, low-ranking females areoften anovulatory and also have lower levels of corti-sol than normally cycling female of higher rank;in newly formed mixed-sex groups, cortisol levelsincrease if the female achieves dominant status but

decrease if the animal becomes an anovulatory sub-ordinate (Saltzman et al., 1994). Cortisol levelsin anovulatory subordinates are also lower than inovariectomized animals, suggesting factors otherthan ovarian hormones contribute to the regulationof cortisol in these animals (Saltzman et al., 1998).

This relationship between rank and cortisol levelsin females does not hold true for all primate species,however, since subordinate female cynomolgousmonkeys have higher cortisol levels than their domi-nant counterparts (Shively et al., 1997b). In addition,a study of female cotton-top tamarins showed nodifference in cortisol levels between high-rankingcycling and low-ranking noncycling, postpubertalfemales in the same natal group, although cortisollevels were higher in newly cycling females, reflect-ing a change of social status (Ziegler et al., 1995).Similar findings were obtained for black tufted-earmarmosets, with dominant and subordinate femalesin natal family groups showing similar levels of corti-sol, regardless of the cycling status (ovulatory oranovulatory) of the latter. Cortisol levels did, how-ever, increase following conflicts within the familygroup (Smith and French, 1997). Lactation status alsoappears to play a role in HPA activity in femalehyenas as well, as fecal corticosteroid levels weregenerally higher in lactating females, although theywere also increased in nonlactating females whosesocial status declined (Goymann et al., 2001).

Several other studies have indicated that thestability of social status and housing conditions in-fluences baseline HPA-axis activity. For example,housing marmosets in unstable peer groups led toan increase in morning cortisol measures in bothmales and females, although in both sexes, cortisollevels fell as the peer groups stabilized ( Johnsonet al., 1996). In olive baboon populations, rank pre-dicted cortisol levels only in stable hierarchies; inunstable hierarchies, cortisol increased with the fre-quency with which the animal was challenged bylower-ranking individuals but was not altered whenthe individual challenged other animals of higherrank (Sapolsky, 1992a). Similarly, plasma cortisollevels increased as squirrel monkeys were movedfrom individual housing to male peer groups – tomale–female groups (Mendoza et al., 1979). Theeffects were most pronounced in the higher-rankingmales, again suggesting increased HPA activity as aresult of repeated challenges by lower-ranking ani-mals. In rats, one complex model uses a combinationof mixed-sex housing and frequent colony


reorganization to induce a variety of physiologicalchanges indicative of HPA activation, includingincreased basal CORT, decreased thymus weight,and increased adrenal size (Klein et al., 1992). How-ever, social instability may have less predictableeffects in other scenarios, as in one study with rhesusmonkeys inoculated with the simian immunodefi-ciency virus (SIV), which showed that animals thatmet daily in unstable groups had lower plasma corti-sol levels than those that interacted within stablegroups, despite the fact that the animals in the unsta-ble condition showed behavioral signs of stress, aswell as altered immune function and shorter survivaltime (Capitanio et al., 1998). Therefore, althoughsocial instability is generally viewed as stressful, theeffects on basal HPA function and other stress-related parameters may vary considerably with theexperimental condition.

9.4.1.2 Reactivity and feedback control of

HPA axis

Socially subordinate animals are generally equallyor more reactive to a novel stressor compared totheir dominant counterparts, as shown in socialgroups of mice (Ely and Henry, 1978), rats (Dijkstraet al., 1992; Bhatnagar and Vining, 2003), hamsters(Huhman et al., 1992), guinea pigs (Haemisch, 1990),squirrel monkeys (Coe et al., 1979), and olive baboons(Sapolsky, 1983). However, under some circum-stances, subordinate animals have been shown tohave a less-robust response to stress than dominants(Manogue et al., 1975; de Goeij et al., 1992). Indeed,this is what we found in our VBS model of chronicsocial stress. The subordinate animals have a blun-ted CORT response to a novel restraint stressor;this effect is attributable to a subpopulation of sub-ordinates that have little or no CORT increase fol-lowing stressor exposure (Blanchard et al., 1995).These stress-nonresponsive subordinates appear to bethe most highly stressed in this model, showing greaterdecrements in insulin, glucose, testosterone, andcorticosteroid-binding globulin (CBG), compared tothe stress-responsive subordinates (McKittrick, 1996).

Similar subgroups of subordinates were also iden-tified in social groups of olive baboons. Subordinatesthat had a high number of consortships – a behaviormore typical of high-ranking animals – had largeHPA responses to stress, accompanied by higherbasal levels of cortisol (Virgin and Sapolsky, 1997).In contrast, the HPA response to an acute stressor wasblunted in another group of subordinates and basal

cortisol levels were also somewhat lower. Finally,a third group of particularly aggressive subordinateshad no elevation in basal cortisol; it is postulated thatthe initiation of aggressive actions played a role inattenuating glucocorticoid secretion (Virgin andSapolsky, 1997).

The HPA-axis response to an agonistic interactionappears to depend, in part, on the outcome of theencounter. After fighting between rats, CORT goesup more and stays higher longer in the losers com-pared to the winners (Koolhaas et al., 1983); a similarstudy showed that an animal that submits to a chal-lenger exhibits an increase in plasma CORT, whileplasma CORT declines if the other animal submits(Haller et al., 1996). The gender of the animal mayalso influence the magnitude of the stress response,as illustrated in wild dwarf mongooses, where malesubordinates had higher stress responses than maledominants, while in the females, the dominant wasmore responsive (Creel et al., 1996).

Social stress has also been shown to alter HPA-axisresponsiveness to ACTH, corticotropin-releasinghormone (CRH) and its secretagogs, as well asaffecting the feedback mechanisms regulating thetermination of the HPA-axis response. For example,in olive baboons, while the cortisol response toan acute stressor did not differ with social status,low-ranking males had a decreased ACTH responseto exogenous CRH and impaired negative feed-back following dexamethasone (DEX) administration(Sapolsky, 1983, 1989). Conversely, ACTH led to amorepronounced increase in glucocorticoid levels in subor-dinate compared to dominant mice (Ely and Henry,1978) and female cynomolgous macaques (Shively,1998). In some studies, social defeat enhanced theACTH, but not the CORT, response to intravenous(IV) CRH (Buwalda et al., 1999), while in others, socialsubordination led to blunted responses to CRH andimpaired DEX suppression (Pohorecky et al., 2004).Housing conditions after defeat appear to modulatethe consequences of defeat, as rats housed individuallyhad greater ACTH responses to CRH administrationand larger adrenals and smaller thymus weights thananimals housed in a group of familiar conspecifics (Ruiset al., 1999). The individually housed animals also hadimpaired DEX suppression of ACTH and CORT.

Administration of DEX reveals deficits in feed-back inhibition of the HPA axis in other social stressmodels as well. In addition to the olive baboons andrats mentioned above, both dominant and subordi-nate mice had impaired DEX suppression compared


to controls (Bartolomucci et al., 2004). Subordinatefemale cynomolgous monkeys also had less-efficientDEX suppression compared to dominants (Shively,1998), while marmosets housed in social groups had ablunted cortisol response to DEX, when compared topair-housed animals ( Johnson et al., 1996). Analysisof DEX-suppression in male cynomolgous macaquesindicated that those animals that were DEX-resistantwere also more than twice as likely to have comefrom unstable, rather than stable, social groups. How-ever, this result is in contrast with another study ofrhesus macaques, in which animals exposed to un-stable social groupings showed enhanced DEX sup-pression of cortisol, compared to animals exposedto stable social conditions (Capitanio et al., 1998). Itshould be noted that in the latter experiment, animalswere grouped together for only 100min per day,rather than being housed continuously in social groups;the differences in experimental design may account, inpart, for the seemingly contradictory results.

9.4.2 Corticosteroid Receptors and CBG

The biological effects of circulating glucocorticoidscan be modulated by alterations in the availability ofintracellular steroid receptors and in circulatinglevels of CBG. In both the VBS and tree shrewmodels of social stress, chronic subordination led toa decrease in the expression of glucocorticoid recep-tor (GR) mRNAs in hippocampus. In the tree shrew,13 days of psychosocial stress led to a decline in GRmRNA levels in CA1 and CA3 of the hippocampus insubordinates compared to unstressed control subor-dinates ( Johren et al., 1994). Similarly, subordinaterats housed in a VBS had lower mRNA levels of GRand mineralocorticoid receptor (MR) mRNA levelswere lower in CA1 (Chao et al., 1993). This down-regulation of gene expression does not appear totranslate into a corresponding change in GR bindingin the hippocampus, hypothalamus, or pituitary ofthe subordinates, although it is likely that subtledifferences in binding in selective hippocampalsubfields may not be detectable in homogenates ofwhole brain regions (Blanchard et al., 1995). How-ever, another group did find decreased GR bindingwithin the hippocampus and hypothalamus, but notthe pituitary, in rats killed 1 week after social defeat;by 3 weeks postdefeat, GR binding had returnedto control levels in all brain regions, but by thattime point, hippocampal MR binding had declinedsignificantly (Buwalda et al., 2001). A study of ratshoused in stable mixed-sex groups also demonstrated

a decrease in hippocampal MR binding, which wasproposed to be associated with impaired feedbackcontrol of the HPA-axis response in these animals(Maccari et al., 1991). The apparent stress-induceddownregulation of hippocampal GRs and/or MRsmay reflect a compensatory response to higher levelsof circulating glucocorticoids.

The effects of chronic social stress on plasmalevels of CBG have also been examined in the VBSmodel. Since glucocorticoids bound to CBG in bloodare not able to cross membranes in order to interactwith their intracellular receptors, alterations in CBGconcentrations may play an important role in regu-lating the bioavailability of circulating CORT. Com-pared to controls, all VBS-housed animals haddecreased circulating levels of CBG: this effect wasgreater in the subordinates than in the dominants,and was most pronounced in the stress-nonresponsivesubgroup of subordinates (McKittrick, 1996; Spenceret al., 1996). The observed decreases in CBG, par-ticularly in the nonresponders, combined with incre-ased CORT levels, may lead to higher levels offree bioactive CORT. This hypothesis is supportedby the observation that the concentration of plasmaCBG was significantly correlated with the number ofavailable (unoccupied) GRs in the spleen of the VBSanimals (Spencer et al., 1996). The increases in freeCORT may be short-lived in the animals with lowCBG concentrations, however, as low CBG levelsare correlated with an increased rate of glucocorti-coid clearance (Bright, 1995), most likely becauseCBG-bound CORT is not accessible to degradativeenzymes.

9.4.3 Summary

The above data indicate that, not surprisingly, socialsubordination and defeat appear to be stressful, lead-ing to HPA-axis activation. Chronic social stress canlead to long-term changes in HPA activity, includingpersistent elevations in basal glucocorticoids, abnor-mal responses to subsequent stressors, and impairedfeedback regulation. For the most part, these effectsare seen most clearly in subordinate animals housedin stable social groups; however, similar responseshave observed in dominant animals in such groups,and also in animals of all ranks in unstable socialgroupings. In addition to altering the levels of circu-lating glucocorticoids, social stress may also lead tochanges in central GR populations and in peripheralregulation of CBG, which may, in turn, modulate thebiological effectiveness of these steroids.


9.5 Interactions betweenHormones and Brain Systems inSocial Stress

The effects of psychosocial stressors on the brain area topic of considerable interest to many researchersfor several reasons. First of all, unlike many labora-tory stressors, the stressfulness of social conflict tendsto be primarily of psychological, rather than physical,origin. Although some wounding may occur in socialdominance or defeat paradigms, in most cases,a full-blown stress response can be generated in asubordinate or defeated animal merely throughvisual and/or olfactory contact with the previouslyencountered animal. The nonphysical nature ofsocial stressors makes them useful in generating mod-els of stress-related illnesses in humans, since rela-tively few people in modern society experiencesevere physical stressors in their lifetimes, while psy-chological stressors are relatively commonplace.Stressful life events have been associated with severalmental illnesses, including depression and otheraffective disorders; many of these disorders, in turn,appear to be linked to various neurochemical imbal-ances in the brain. Determining the effects of socialstress on neuronal transmission may provide cluesregarding how stress alters behavior and physiologyin animals and humans alike.

9.5.1 Neurotransmitter Systems

9.5.1.1 Serotonin

The transmitter system most widely studied in thecontext of social stress is the serotonergic system.Serotonin neurotransmission has been shown to bealtered by a variety of laboratory stressors, and sero-tonin (5-hydroxytryptamine; 5HT) also plays a rolein mediating many of the behaviors that contributeto, and are affected by, social status, including aggres-sion and sexual behavior. The majority of studiessuggest that 5HT systems are activated in responseto social stress. Examination of tissue concentrationsof 5HT and its metabolite, 5-hydroxyindole aceticacid (5HIAA), have shown elevated concentrationsof 5HIAA and/or increased 5HIAA/5HT ratios invarious brain regions of subordinate rats and mice,suggesting increased serotonergic activity. In the VBSmodel of social stress, levels of 5HIAA are higher insubordinates than in dominants and controls in limbicareas of the brain, such as the preoptic area, hippo-campus, and amygdala (Blanchard et al., 1991b). Sim-ilarly, submissive mice had increased 5HIAA in the

hypothalamus, hippocampus, and brainstem (Hilakiviet al., 1989), while repeated, but not single, socialdefeat increased the midbrain 5HIAA/5HT ratioin defeated Lewis rats (Berton et al., 1998, 1999),although these changes may habituate with time(Beitia et al., 2005). In addition, adult golden ham-sters that had been socially defeated during pubertyhad increased 5HT innervation of the lateral septumand anterior hypothalamus, suggesting that defeat ledto an increase in the capacity to release 5HT in theseareas (Delville et al., 1998). Social defeat has alsobeen shown to increase expression of c-fos in seroto-nergic neurons of the dorsal raphe nucleus, specifi-cally in subregions that are likely to play a role inthe behavioral and emotional responses to defeat(Gardner et al., 2005).

In addition to these rodent studies, various seroto-nergic parameters have been examined in nonhumanprimates. Subordinate talapoin monkeys had elevatedlevels of 5HIAA in their cerebrospinal fluid; this isbelieved to reflect increased 5HT neurotransmissionin the brain (Yodyingyuad et al., 1985). In cynomol-gous macaques, the stability of the social groupappeared to be more important than rank, as animalsthat had previously been housed in unstable socialgroups had lower 5HIAA and 5HT concentrations inthe prefrontal cortex, compared to animals main-tained in social groups; however, these changes mayhave reflected adaptive responses following termina-tion of the stressor, since the level of 5HT in theseanimals was lower in those that had been housed inunstable colonies more recently (Fontenot et al.,1995). Interestingly, one study showed that highlevels of 5HT in the blood was associated with domi-nant status in vervet monkeys, with 5HT levelsincreasing or decreasing as the animal experienced acorresponding rise or fall in rank (Raleigh et al.,1984). The relevance of these findings to central5HT neurotransmission is unclear, however, since itis likely that peripheral and central serotonergic sys-tems are regulated independently.

Both pre- and postsynaptic receptors and trans-porters for 5HT have been shown to be altered bysocial stress. Perhaps the most consistent findingsare a stress-related increase in binding to 5HT2A

receptors in cortex and a corresponding decrease in5HT1A receptors in the hippocampus (McKittricket al., 1995; Flugge, 1995; Berton et al., 1998). In addi-tion, in the VBS model, binding to presynaptic 5HT1A

autoreceptors is preferentially downregulated in themedian raphe of subordinate animals (McKittrick,1996). Further examination of the downregulation


of 5HT1A receptors in the hippocampus and else-where indicates that, in the tree shrew, this receptorsubtype is regulated not only by increased gluco-corticoid levels in the subordinates, but also bystress-induced suppression of testosterone, as bindingwas returned to control levels in most brain regions byexogenous administration of testosterone (Fluggeet al., 1998).

A single social defeat also led to a decreasein binding to the 5HT transporter in the hippocam-pus (Berton et al., 1999). The relationship of the5HT-transporter response to the severity of socialstress is unclear, however, since in our model, allVBS-housed animals show a similar decrease in5HT transporter binding, with the most pro-nounced effects occurring in the dominant animals(McKittrick et al., 2000). The dominant animals doappear to be somewhat stressed compared to the pair-housed controls, suggesting that the downregulationof 5HT transporters may be part of an adaptiveresponse to mild social stress; conversely, the decreasein binding may occur as simply as a result of agonisticinteractions between the animals, without regard tothe relative stressfulness of these encounters. How-ever, Filipenko et al. (2002) found that the expressionof 5HT transporter mRNAwas upregulated followingsocial defeat, suggesting that the stressor effects maybe model and/or species specific.

The functional effects of the changes in 5HTreceptors are unclear. Defeated rats exhibit a bluntedCORT response to the 5HT1A agonist 8-OH-DPAT,suggesting a functional subsensitivity of these recep-tors, a result that corresponds well with the observeddecrease in receptor number (Korte et al., 1995;Buwalda et al., 2005). In contrast, while an enhancedresponse to 5HT2A stimulation might be expected,the behavioral response to a 5HT2 agonist wasdecreased, rather than increased, in defeated rats(Benjamin et al., 1993). It should be noted, however,that in this particular experiment, the behavioralresponse was measured after a single social defeat,which does not lead to a measurable change in5HT2-binding capacity (Berton et al., 1999), suggest-ing that the desensitization may occur throughchanges in receptor-linked signal transduction path-ways or some other mechanism. Finally, in cyno-molgous monkeys, the hormonal responses to the5HT-releaser fenfluramine did not differ betweendominant and subordinate animals, indicating no dif-ferences in postsynaptic sensitivity to nonselectivestimulation of 5HT transmission (Botchin et al.,1994; Shively, 1998).

9.5.1.2 NorepinephrineThe effects of chronic social stress on both pre- andpostsynaptic elements of noradrenergic neurotrans-mission have been studied in both rat and tree shrewmodels of psychosocial stress. Messenger mRNAlevels of tyrosine hydroxylase, the rate-limitingenzyme in catecholamine synthesis, were shown tobe selectively increased in noradrenergic, but notdopaminergic, brain regions; in some cases, theincreased mRNA levels in the locus ceruleus (LC)were accompanied by a corresponding increase inimmunoreactive tyrosine hydroxylase protein (Bradyet al., 1994; Watanabe et al., 1995). Since several dif-ferent stress paradigms have shown that the LC nor-adrenergic system is activated by stress, the changes intyrosine hydroxylase probably reflect an upregulationof synthetic capacity as a result of increased neuronalactivity and transmitter release.

Functional alterations in noradrenergic systemsare also a consequence of social stress. Followingthree days of social crowding, male rats exhibiteda blunted CORT response to both isoprenaline, ab-adrenergic receptor agonist, and clonidine, ana2-adrenergic agonist; the hypothalamic histamineresponse to these two drugs was also attenuated(Bugajski et al., 1993). However, crowding had littleeffect on the CORT response to a1-adrenoceptoragonist phenylephrine, suggesting that the variousadrenergic receptor populations are differentiallyregulated as a result of social crowding.

Adrenergic receptor subtypes are affected by sub-ordination stress as well, as shown in the tree shrewmodel. After 10 days of social stress, a2-adrenoceptorbinding was downregulated in the subordinatescompared to dominants in several brain regions,including periaqueductal gray (PAG), the periforni-cal region of hypothalamus, medial amygdala, thenucleus of the solitary tract (STN), and the dorsalmotor nucleus of the vagus (DMV); in addition,low-affinity binding sites were present in the STN,PAG, and medial amygdala of the dominants but notthe subordinates (Flugge et al., 1992). Time-coursestudies indicate that these receptors have differenttemporal patterns of regulation within individualbrain regions. For example, in LC and DMV, bindingwas decreased after only 2 days of psychosocial stressand remained low throughout the period of subor-dination (Flugge, 1996). Binding in STN was simi-larly downregulated, although these changes werenot apparent until day 21. In contrast, the responseof a2-receptors in the prefrontal cortex was biphasic,with a transient decrease in binding at day 10,


followed by a return to control values by day 21, and asubsequent increase in binding at day 28. In addition,binding affinity of various a2-adrenoceptor subtypeswas altered in temporal and regional patterns distinctfrom the changes in receptor number. Further stu-dies with this model have shown that a2A- anda2C-receptor mRNA expression and binding alsohave regionally specific upregulation; the changes ina2C-binding appear to be transient, while the upre-gulation of the a2A-receptor persists at least 10 daysafter stressor cessation (Flugge et al., 2003).

b-Adrenergic receptors are also regulated in asimilar complex manner in this model. Both b1- andb2-adrenoceptors are transiently downregulated inthe prefrontal cortex after 2 days of subordinationand upregulated in the pulvinar nucleus after 10and 28 days respectively; however, b1-adrenoceptorsare also decreased in the parietal cortex and hippo-campus at 28 days (Flugge et al., 1997). In addition,the affinity for b-adrenergic receptors was decreasedin the cortex and hippocampus following 21 daysof psychosocial stress. These complex changes inregional populations of adrenergic receptor subtypesindicate that the function of various noradrenergiccircuits may be differentially regulated in response tochronic stress; furthermore, this regulation may occurvia changes in receptor turnover, synthesis, andconformation.

9.5.1.3 Dopamine

Unlike 5HT and norepinephrine, dopamine (DA)has only recently been considered to be a stress-responsive neurotransmitter. As a result, studiesfocusing on the effects of social stress on dopaminer-gic systems are relatively rare. In mice, dominantsdid have lower brainstem DA content than subordi-nate or control animals in one study (Hilakivi et al.,1989), while Beitia et al. (2005) observed a transientincrease in hypothalamic dihydroxyphenylaceticacid: DA ratios following chronic social defeat. Inmonkey and rat social hierarchies, tissue content ofDA and its metabolites were unaffected by rank(Blanchard et al., 1991b; Fontenot et al., 1995). Asimilar lack of effect was observed on the regulationof tyrosine hydroxylase in dopaminergic nuclei ofthe ventral tegmental area (VTA) and substantianigra, in contrast to the increase in tyrosine hydroxy-lase mRNA and protein seen in noradrenergic nuclei(Watanabe et al., 1995).

More recent studies looking at dynamic changesin dopaminergic neurotransmission have demon-strated activation of the mesolimbic pathway in

response to social stress. In previously defeated rats,the threat of defeat elicits an increase in extracellularDA content in both the prefrontal cortex andthe nucleus accumbens, as measured using in vivomicrodialysis (Tidey and Miczek, 1996, 1997), indi-cating that these limbic areas are responsive to sti-muli associated with social stressors. In these areas,the dopaminergic responsiveness to subsequent socialencounters has also been shown to be altered insocially defeated mice, although the nature of thesealterations depends on both the nature of the socialinteraction and the sex of the other animal (Cabibet al., 2000). Chronic, but not acute, defeat in miceincreased the basal firing rate of dopaminergic neu-rons in the VTA, with this increase persisting forseveral weeks only in mice that also demonstratepersistent physiological and behavior changes follow-ing stress (Krishnan et al., 2007).

In nonhuman primates, binding and function ofthe D2 DA receptor subtype is decreased in sociallysubordinate female cynomolgous monkeys. Theseanimals have decreased D2 receptor-binding capac-ity in the basal ganglia, as indicated by positronemission tomography (PET) scanning after injectionwith 18-fluoroclebopride; in addition, the subordi-nates exhibited a blunted prolactin response to theD2 antagonist, haloperidol, indicating a functionalsubsensitivity of these receptors (Shively et al.,1997a,b; Shively, 1998). In contrast, D2 receptor bind-ing is increased in the nucleus accumbens of sub-ordinate VBS animals (Lucas et al., 2004). D2binding is also increased in the dorsal striatum ofthe nonresponsive subordinates, in conjunction withdecreased binding to the DA transporter. DA trans-porter binding is also reduced in subordinate treeshrews in the caudate nucleus and putamen, withno changes in the nucleus accumbens or VTA orsubstantia nigra (Isovich et al., 2000). The alteredDA receptor and transporter densities are likely toreflect compensatory changes in response to dimin-ished activity of the mesolimbic DA system in theseanimals. Decreased DA tone may represent a mal-adaptive response in these animals, and be associatedwith the anhedonia observed in other models ofchronic social stress (e.g., Rygula et al., 2005).

9.5.1.4 Amino acid transmitters

Very few studies have examined the effects of socialstress on components of excitatory amino acid neu-rotransmission. However, Krugers et al. (1993) foundthat a single social defeat was sufficient to lead tochanges in the ratio of N-methyl-D-aspartic acid


(NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in theCA3 area of the hippocampus of rats: specifically,binding of [3H]CGP39653 to NMDA receptors wasincreased in the stratum radiatum of CA3, while [3H]CNQX binding to AMPA receptors was decreased inthis and other areas of hippocampus.

There also appear to be alterations in GABA-Areceptors following defeat in mice. Northern blotanalysis of both a1 and g2 GABA-A subunits hasshown that mRNA levels of both subunits areincreased in cortex at 4 h postdefeat and remainelevated for at least 72h, before falling to controllevels after 7 days (Kang et al., 1991). SubunitmRNA levels were unchanged in the cerebellumand hippocampus, while no changes were observedin any region in the brains of the resident animals thatdefeated the intruder mice. The increase in subunitexpression is likely to reflect a general upregulationof the GABA-A receptor, but it may also indicatechanges in the subunit composition, and thus theelectrical and pharmacological properties, of thereceptors.

9.5.1.5 CRH and vasopressin

CRH and arginine-vasopressin (AVP) are known tobe involved in the initiation and modulation of HPA-axis activity; in addition, extrahypothalamic CRHand AVP circuits have been implicated in the media-tion of stress-related and social behaviors, respec-tively. As a result, the effect of social stressors onthe expression and release of these two neuropep-tides has been studied in a variety of animal models.Social subjugation, either in adulthood or in puberty,led to reduction in AVP stores in the anterior hypo-thalamus of hamsters as determined by both fiberimmunostaining and radioimmunoassay (RIA) ofextracts from tissue micropunches, suggesting decre-ased AVP release within this brain region, which isinvolved in aggressive behavior in this species (Ferriset al., 1989; Delville et al., 1998). Conversely, mea-surement of AVP in samples collected using in vivomicrodialysis, indicates that social defeat enhancesrelease of this peptide in another area of the hypo-thalamus, the paraventricular nucleus (PVN), whereit is believed to play a role in the modulation of theHPA-axis response (Wotjak et al., 1996). Similarly,AVP immunostaining was increased in the zonaexterna of the median eminence (ZEME), a projec-tion area of neurons originating in the PVN, in sub-ordinate colony-housed male rats (de Goeij et al.,1992). Inescapable interaction with the dominant

after administration of the neuronal transportblocker, colchicine, did not alter the AVP immunore-activity in ZEME in subordinate rats, however, sug-gesting that the encounter with the dominant did notlead to AVP release in this area. In contrast, AVPcontent was reduced in colchicine-treated animalsfollowing a single defeat, indicating that AVP releaseand content are regulated differentially followingacute and chronic social stress.

We used the VBS model to investigate the effectsof chronic social stress on mRNA for AVP and CRH.mRNA levels for AVP were unaffected by socialstress in the PVN, but were significantly decreasedin the medial amygdala, whereas CRH mRNA wasincreased in the central amygdala (Albeck et al.,1996). The changes in CRH mRNA in the PVNwere a bit more complex. Mixed-sex housing inthe VBS increased CRH mRNA content in PVN inboth dominant and subordinate males compared topair-housed controls, but only in those animals thatretained relatively normal CORT responses to anacute stressor. It was hypothesized, at the time, thatincreased CRH expression contributed to the incre-ased basal CORTobserved in the VBS animals; how-ever, a subsequent study by Choi et al. (2006)demonstrated that the elevated CORT in subordi-nates could occur independently of any changes inhypothalamic CRH mRNA levels. This dissociationbetween hypothalamic CRH and CORT was alsoseen in mice, where chronic defeat was associatedwith elevated plasma CORT, despite control levelsof CRH mRNA in the PVN (Keeney et al., 2006).Dysfunction at the level of the hypothalamic CRHneurons may still contribute to the HPA-axis hypor-esponsiveness in the stress-nonresponsive subordi-nates of the VBS, however, since CRH mRNAcontent was significantly lower in these animals com-pared to the other groups (Albeck et al., 1996).

The receptors for CRH have been shown to bedifferentially regulated in the tree shrew model ofsocial stress. After 24 days of psychosocial stress, sub-ordinates show a downregulation of CRH receptorsin brain regions involved in HPA-axis regulation,including the anterior pituitary, dentate gyrus, andCA1-CA3 of the hippocampus; binding was alsodecreased in the superior colliculus (Fuchs andFlugge, 1995). Conversely, both the number of bind-ing sites and the affinity of CRH receptors wereincreased in other areas of the brain, including thefrontal and cingulate cortex, the claustrocortex,the central and lateral nucleus of amygdala, and thechoroid plexus. However, in all regions except the


claustrocortex and the central amygdala, this increasein receptor number was partially offset by a decreasein binding affinity.

Overall, it appears that social stress activates theAVP and CRH neuropeptide circuits that are directlyassociated with activation and regulation of the HPAaxis; an apparent increase in presynaptic activity isaccompanied by a corresponding downregulation ofthe postsynaptic elements, at least in the case ofCRH. In contrast, evidence from both hamsters andrats indicates that subordination and defeat inhibitthe extrahypothalamic AVP circuits involved inaggressive and sexual behavior. Finally, while CRHmRNA is upregulated in extrahypothalamic areas,the net effect of social stress on CRH neurotransmis-sion in these areas is less clear, since the number andaffinity of the postsynaptic receptors are altered in acomplex manner.

9.5.1.6 Other neuropeptides

The regulation of other stress-related peptides hasbeen investigated in our VBS model of chronic socialstress. Galanin, a 29-amino-acid neuropeptide, can befound in approximately 80% of the tyrosine hydrox-ylase-containing neurons in the LC. Chronic socialstress leads to an increase in mRNA levels of pre-progalanin in the LC of the subordinate animals(Holmes et al., 1995). The levels of mRNA werepositively correlated with the number of woundsper animal and negatively correlated with bodyweight gain, suggesting that the degree of galaningene expression was associated with the severity ofthe stress. The increase in preprogalanin mRNA inthe subordinate animals parallels that observed intyrosine hydroxylase mRNA (see Section 9.5.1.3),indicating that the two mRNAs may be upregulatedin tandem as the result of a stress-induced increase inthe activity of LC neurons. In addition, mRNA levelsof proopiomelanocortin (POMC), the precursor toACTH and b-endorphin, were increased in the ante-rior pituitary of subordinate rats (Brady et al., 1994).Again, the magnitude of the response correlatedwith wounding and weight loss, and also adrenalweight, suggesting that the POMC response reflectedstressor severity.

9.5.2 Immediate Early Gene Expression

Expression of immediate early genes, such as c-fos, isoften used as an identifier of neural circuits activatedby a given stimulus. The effect of social defeat on c-fos

expression has been studied in several differentspecies. In mice, defeat has been shown to increasec-fos-like immunoreactivity in limbic and sensoryrelay areas, such as the cingulate cortex, lateralseptum, bed nucleus of the stria terminalis (BNST),hippocampus, hypothalamus, amygdala, PAG, dorsalraphe, LC, and several brainstem sensory nuclei(Matsuda et al., 1996; Nikulina et al., 1998). After asingle defeat, c-fos expression returned to baselinelevels within 24 h, but with chronic defeat, a moreprolonged increase was observed (Matsuda et al.,1996). In contrast, while similar circuits were acti-vated in rats following a single defeat (e.g., Gardneret al., 2005), the c-fos response in these animalsadapted with repeated defeat, so that c-fos expressionwas increased only in BNST, PVN of hypothala-mus, medial amygdala, and the medial and dorsalraphe nuclei (Martinez et al., 1998). Similarly, inmale Syrian hamsters, the c-fos response to repeateddefeat habituated in the supraoptic nucleus, lateralseptum, central amygdala, and amygdalohippocam-pal area but remained high in the anterior and ven-tromedial hypothalamic nuclei, dorsal PAG, anddorsal raphe (Kollack-Walker et al., 1999). However,the response in the PVN of hypothalamus adaptedwith chronic defeat but remained significant in theLC in hamsters, while the converse was true in rats.These variations may be related not only to differ-ences among experimental protocols, but also to spe-cies-specific differences in the behavioral andcognitive response to social defeat.

9.5.3 Neuronal Structure and Survival

Several studies have indicated that chronic stressaffects neurons in the hippocampal formation in avariety of ways, leading to alterations in dendritic mor-phology, cell survival, and neurogenesis. A recentexamination of the morphology of hippocampal neu-rons has found that significant shrinkage of the apicaldendritic arbors of CA3 pyramidal neurons is seen inall animals in the VBS (McKittrick et al., 2000). Thereis a decrease in arbor complexity (branch points) inboth dominants and subordinates while dominantshave a reduction in total dendritic length as well. Theobservation that these changes occur to a similar (orgreater) extent in dominants as well as in the moreseverely stressed subordinates suggests that dendriticremodeling may be a common response to chronicactivation of the HPA axis but does not vary signifi-cantly with the severity of the stress. This conclusion issupported by data showing similar degrees of dendritic


atrophy in animals subjected either to the relativelymild stressor of repeated restraint or to a moresevere chronic variable stress regimen (Magarinosand McEwen, 1995).

A study of tree shrews has shown similar dendriticatrophy in subordinates compared to unstressed con-trols, although pyramidal cell morphology in domi-nant animals was not examined (Magarinos et al.,1996). In addition to dendritic atrophy, chronic socialstress also led to a time-dependent increase in thestaining intensity of the nucleoplasm of CA1 andCA3 pyramidal cells, indicating alterations in nuclearchromatin structure, but these changes were notaccompanied by signs of neuronal degeneration orcell loss (Fuchs et al., 1995, 2001;Vollmann-Honsdorfet al., 1997). However, the number of bromodeoxyur-idine (BrdU)-labeled cells was decreased within thedentate gyrus of subordinate tree shrews, comparedto controls, indicating that neurogenesis in this partof the hippocampus is inhibited by chronic socialstress (Gould et al., 1997). Neurogenesis in the den-tate gyrus was also reduced in mice following socialdefeat (Mitra et al., 2006; Yap et al., 2006). In contrast,dominant animals had increased neurogenesis in avariant of the VBS that used Sprague–Dawley rats,although subordinates did not differ from controls;markers of cell proliferation were not increased,suggesting that the increase in new neurons wasdue to enhanced survival rather than proliferation(Kozorovitskiy and Gould, 2004).

Far more pronounced pathological changes werefound in the hippocampus of vervet monkeys thatdied spontaneously at a primate center in Kenya.These animals exhibited signs of severe stress, suchas gastric ulcers and enlarged adrenals, and severalalso showed evidence of social conflict, such as bitemarks. When compared to animals euthanized forother reasons, the stressed monkeys showed evidenceof neurodegeneration in Ammon’s horn, especiallyCA3, including reduced perikarya size, dispersedNissl bodies, increased vesicle number, and decreaseddendritic width (Uno et al., 1989). However, it mustbe noted that these animals are presumed to havedied from stress-related causes, which indicates aseverity of stress much greater than that seen inmost other social stress paradigms.

9.5.4 Summary

As described above, social stress leads to manychanges in the brain, affecting neuronal structureand survival as well as neurochemical transmission.

Indeed, several groups have characterized the wide-spread changes in gene expression associated withchronic social stress using proteomic and genomicanalyses (cf. Carboni et al., 2006; Feldker et al.,2006; Kroes et al., 2006; the details of these studiesare beyond the scope of the current review). Overall,social stress, like other stressors, seems to induce anet stimulation of serotonergic and noradrenergicneurons, although the functional outcome of incre-ased transmitter release is likely to be modulated byregion- and time-specific factors in receptor popula-tions. Few studies have been conducted examiningthe effects of social stress on other classical transmit-ter systems, although social stress has been shown tomodify various aspects of dopaminergic, GABAergic,and excitatory amino acid transmission. In neuropep-tide systems, CRH and AVP pathways involved in theHPA-axis response appear to be activated by socialstress, while extrahypothalamic AVP and CRH areinhibited and stimulated, respectively, although theeffects on CRH may only exist in the context ofabnormal HPA-axis responsivity. Chronic socialstress can alter the morphology of hippocampal neu-rons, which may affect learning and memory pro-cesses in these animals. Finally, although there is noevidence that chronic subordination actively incre-ases neurodegeneration (i.e., by inducing apoptoticprocesses), it has been shown to retard neurogenesiswithin the dentate gyrus by compromising cell sur-vival. Together, these results indicate that social stresscan have profound consequences on the brain; furtherstudy is needed to determine which of these changesare adaptive and which can lead to pathologicalchanges in brain function and behavior.

9.6 Reproductive Aspects of SocialStress: Hypothalamic–Pituitary–Gonadal Axis

It is well established that stress suppresses repro-ductive function (Selye, 1950; Bliss et al., 1972; Roseand Sachar, 1981). The concept of stress, however,embraces a large range of diverse phenomena, andfurther subdivision of terms is helpful for the sakeof clarity. Stressors are the aversive conditions orstimuli that provoke responses in animals which, intotal, are termed the stress response. The stress res-ponse was first called the general adaptation syn-drome by its discoverer, Hans Selye (1946), inreference to physiological adjustments made to com-pensate for the stressor and preserve the internal


milieu in the body. The adjustments, while adaptivein the short term, can have harmful effects in thechronic setting (Shanks et al., 1998) The postulatedadaptive value of the stress response traces its evo-lutionary origin to the flight-or-fight cascade ofneuroendocrine events that ensue when an animalconfronts a potential predator (Sapolsky, 1992b). Inthe threatened animal, the sequential rapid releaseof CRH from hypothalamic neurons and ACTHby the pituitary stimulates a massive outpouring ofglucocorticoid from the adrenal gland, which servesto mobilize glucose in the blood for needed energy(Hers, 1986; Munck and Guyre, 1986). Simulta-neously, heightened sympathetic nervous systemactivity and release of epinephrine and norepineph-rine increase the heart rate, and secretion of endor-phins blunts the sensation of pain should tissue injurybe inflicted (Hedman et al., 1990). It is thought thatthe stress response is survival-related in the presenceof a predator but harmful when it occurs inappropri-ately and is prolonged.

9.6.1 Stress and Reproductive Functioning

Evidence from studies of numerous animal specieshas shown that suppression of reproductive func-tion is associated with the stress response. Here theadaptive significance may lie in the preservationof the species, with the stress response providinga physiological cue that external conditions areunfavorable for reproduction (Handelsman andDong, 1992). Naturally occurring social stressors,the focus of this chapter, appear to fall broadly intotwo categories: crowding (e.g., in snowshoe hares,Boonstra and Singleton (1993)) and subordinatestatus in social dominance hierarchies (which will betermed social stress). In both cases, competition forfood or access to a mate leads to aggressive encountersbetween individuals that, when repeated and unpre-dictable, become an aversive stimulus or stressor.Stress-induced elevations in glucocorticoids havebeen implicated as the principal mediators of theinhibition in reproductive function, both directly –through reductions in the gonadal responsivenessto gonadotrophins (Charpenet et al., 1981; Orr andMann, 1992) – and indirectly – through inhibitionof the gonadotrophins themselves (Sapolsky, 1985;Norman and Smith, 1992; Akimbami et al., 1994).

The association between social stress andglucocorticoid mediated inhibition of reproductivefunction has been established for both sexes(Marchlewska-Koj, 1997), but is defined more clearly

for males compared to females. This is attributable tothe higher levels of testosterone in males, relative tofemales, and the role of testosterone in promotingthe aggressive behavior that leads to stressful attacks(Monaghan and Glickman, 1992). Female hyenas,which are unusually aggressive due to high levels ofandrogen production by the adrenal gland, are anexception to the rule ( Jenks et al., 1995). In females,there is abundant evidence that social interactionscan play a role in suppressing reproductive function,including both reductions in sexual behavior andsuppression of ovulation (Saltzman et al., 1994). Asnoted under Section 9.4.1, alterations in ovulationand changes in HPA-axis activity are both associatedwith social stratification in females of a number ofprimate species, but the relationships among thesefactors appear to be complex and to differ from onespecies to another.

In males, the ability to impose social stress on asubordinate is one mechanism of sexual selection. Ifthe dominant male suppresses reproductive functionin the subordinate males, his exclusive access to femalesensures preferential perpetuation of the dominant’sgenes. Consistent with this hypothesis, crowding exp-eriments have provided a dramatic demonstration ofthe consequences of social stress (reviewed by Bronson(1989)). At the start of such experiments, one or twobreeding pairs of mice are put into a large, physicallycomplex cage and allowed to breed. Aggression bet-ween males increases as the population size andits density increase. Eventually, the population sizewithin the cage self-regulates, at which point reproduc-tion by all but a few adult animals, the dominants,stops entirely.

In populations where there is social stratificationamong individuals, low-ranking animals generallyhave lower reproductive fitness and engage in fewersexual encounters than high-ranking individuals(Calhoun, 1962; von Holst, 1977; Sapolsky, 1982;Blanchard and Blanchard, 1990). The stressful natureof subordination is likely to play a role in the inhibi-tion of male reproductive function in these situations.Subordinate males often have lower testosteronetiters compared to dominants, particularly duringestablishment of social hierarchies (Rose et al., 1971;Coe et al., 1979; Mendoza et al., 1979; von Holstet al., 1983; Sachser and Prove, 1986; Sachser andLick, 1989; Dijkstra et al., 1992). Defeat by a conspe-cific can lead to a rapid decline of plasma testosterone(Rose et al., 1975; von Holst, 1977; Schuurman, 1980;Sachser and Lick, 1989, 1991), whereas social vict-ories may lead to an increase in testosterone levels in


dominants (Coe et al., 1982; Bernstein et al., 1983;Sachser and Prove, 1986). In addition, subordinateanimals also have a larger and more prolonged inhi-bition of testosterone and gonadotrophins followingexposure to other, nonsocial stressors, while domi-nants may have a smaller decline or a transient risein testosterone (Bronson, 1973; Sapolsky, 1986).

9.6.1.1 Reproductive hormone levels in

dominant males

Aggressiveness has been found to be positively corre-lated with testosterone levels in primates. However,increased aggression is not necessarily correlatedwithdominance in these populations (Sapolsky, 1982;Bernstein et al., 1983). In rodents, castration decreasesaggressive behaviors, an effect that can be reversed bytestosterone replacement (Brain, 1983). Clampingtestosterone levels by castration and steroid replace-ment has been shown to have no behavioral effect oncompetitive interactions and agonistic behavior. Inprimates, social defeat seems to play a role in perpe-tuating the difference in testosterone levels betweendominant and subordinate animals, as the differencesare most prominent during hierarchy formation, butmay disappear when the hierarchy has stabilizedand aggressive encounters become less frequent(Rose et al., 1971; Sapolsky, 1982; Coe et al., 1982).

Although the majority of agonistic encounters in theVBS occurwithin the first fewdays of colony formation,there is still a low, but significant, degree of fight-ing throughout the remainder of the housing period(Blanchard et al., 1995). Significant increases in LHand testosterone were found in dominant males, com-pared to controls, on day 4, when the hierarchy was stillbeing established, but the values of these hormonesreturned to control levels by days 7 and 14, when thehierarchy, and the level of fighting, had stabilized(Hardy et al., 2002). These data suggest that in thedominant males, increased hypothalamic–pituitary–gonadal (HPG) activity is context-dependent andoccurs in response to the transient increase in aggres-sion, rather than being a characteristic of the individualanimals who go on to become dominant (in which case,testosterone should be higher at all time points). Insituations where there is continued fighting in socialgroups, however, the difference in testosterone betweensocial ranks is maintained (Sachser and Prove, 1986).

9.6.1.2 Androgen levels in subordinate males

In rats housed in the VBS, chronic social stress leadsto declines in circulating levels of testosterone insubordinate males, as compared to dominants and

controls rats housed in standard rat cages with afemale (Blanchard et al., 1993). LH as well as testos-terone was also lower in the subordinate animals,suggesting overall suppression of the HPG axis;these decreases did not become apparent until atleast day 7 of colony housing (Hardy et al., 2002).As with the dominant animals (see above), the loweractivity is context dependent, rather than character-istic of individual animals. The decrease in testoster-one in these animals is likely to be the result of thestress-induced increases in CORT, acting indirectlyto suppress LH secretion, and directly on the Leydigcells themselves (see Section 9.6.2).

Similar reductions in testicular androgen produc-tion have been shown for other animal populationswith hierarchical social structures (Mendoza et al.,1979; Coe et al., 1979; von Holst et al., 1983; Sachserand Prove, 1986). Repeated agonistic encounters mayplay a role in maintaining the low testosterone levelsin the subordinate animals. In a wide variety of rodentmodels, laboratory stressors have been shown to leadto a rapid suppression of testosterone secretion (Grayet al., 1978; Tache et al., 1980; Charpenet et al., 1981;Collu et al., 1984b; Armario and Castellanos, 1984;Bidzinska et al., 1993; Srivastava et al., 1993). Simi-larly, stress leads to a decline in plasma testosteronelevels in primates, including man (Aakvaag et al.,1978; Coe et al., 1978; Wheeler et al., 1984; Sapolsky,1985; Norman and Smith, 1992). Although many ofthese changes in androgen levels may be associatedwith elevated glucocorticoid secretion, stress maydecrease androgen levels through glucocorticoid-independent mechanisms as well (Gray et al., 1978;Tache et al., 1980; Rivest and Rivier, 1991).

9.6.2 HPA/HPG Interactions in SociallyStressed Males

Regulation of testosterone secretion in sociallystressed animals is complex, as both stress and gluco-corticoids have been shown to affect testosteronesynthesis and secretion at several different levels.ACTH and CRH have been shown to inhibit test-osterone secretion in animals and man (Schaisonet al., 1978; Vreeburg et al., 1984; Rivier and Vale,1985; Mann et al., 1987), with a concomitant decreasein LH in some cases (Vreeburg et al., 1984; Rivier andVale, 1985). These effects can be blocked by adrenal-ectomy (Vreeburg et al., 1984; Rivier and Vale, 1985;Mann et al., 1987) or inhibition of cortisol synthesiswith metyrapone (Schaison et al., 1978), suggesting aprimary role of glucocorticoids. In rats and humans,


glucocorticoid administration leads to a reductionin testosterone levels (Doerr and Pirke, 1976;Schaison et al., 1978; Mann et al., 1987; Urbanet al., 1991) while GRs on the Leydig cells in thetestis provide a possible anatomical substrate forthis effect (Stalker et al., 1989). Glucocorticoids actdirectly on the testes by inhibiting Leydig cell sensi-tivity to gonadotropins. DEX and CORT treatmentreduce basal testosterone levels and decrease bindingto testicular LH/human chorionic gonadotropin(hCG) receptors (Bambino and Hsueh, 1981; Mannet al., 1987). The functional significance of the dec-rease in LH receptor is shown by the blunted androg-enic response to hCG in glucocorticoid-treated animalsand humans (Bambino and Hsueh, 1981; Mann et al.,1987; Schaison et al., 1978). Incubation with variousnatural and synthetic glucocorticoids leads to a similardecrease in steroidogenesis in cultured testicular cells,an effect that can be reversed by the GR antagonistmefipristone (RU 486) (Bambino and Hsueh, 1981; Orrand Mann, 1992).

In contrast to exogenous glucocorticoids, the dec-rease in testosterone synthesis following stress does notappear to be mediated by alterations in LH/hCGreceptor binding (Tache et al., 1980; Orr and Mann,1990). The responses of the testes from stressed ani-mals, to gonadotropin stimulation is blunted, however,both in vivo (Charpenet et al., 1981; Sapolsky, 1985) andin vitro (Charpenet et al., 1981; Collu et al., 1984a;Orr andMann, 1990). Testosterone synthesis followingincubation of Leydig cells with hCG, dibutyryl cAMP,or cholera toxin is decreased in stressed rats, despitecomparable levels of cellular cAMP production;similarly, basal cAMP content in Leydig cells iscomparable between stressed and unstressed rats(Charpenet et al., 1981). This suggests that the stress-induced impairment in testicular sensitivity to gona-dotropins occurs at a site distal to second-messengerproduction, perhaps at the level of second messenger–effector coupling. Changes in coupling, in turn, mayaffect the synthetic capacity of the testes, sincestress has been shown to decrease the activities(Vmax) of 17-hydroxylase-17,20-lyase, and 3-hydroxy-steroid dehydrogenase (3-HSD), which are involved intestosterone steroidogenesis (Srivastava et al., 1993;Akimbami et al., 1994). Similar inhibition of androgensynthetic enzyme activity has been induced by gluco-corticoids in vitro (Welsh et al., 1982; Hales and Payne,1989; Agular et al., 1992).

The inhibitory effects of glucocorticoids on tes-tosterone synthesis may also be regulated by changesin the bioavailability of CORT to the testes. Testicular

Leydig cells contain high concentrations of 11b-HSD,an enzyme that oxidatively inactivates CORT. It hasbeen postulated that this enzyme serves to modulatethe effects of CORT by regulating intracellular glu-cocorticoid concentrations (Monder et al., 1994a). Inthe VBS, subordinate rats were shown to have lowertesticular 11b-HSD activity than dominants and con-trols (Monder et al., 1994b), indicating that chronicsocial stress may lead to decreased testosterone pro-duction via a decrease in the protective effects of11b-HSD within the testes. Indeed, recent studiesby Hu et al. (2008b) have shown that administrationof CORTalong with an inhibitor of 11b-HSD leads toelevation of serum CORT above that seen withCORT alone. At the same time, serum testosteronedeclined, with no effects on LH, suggesting that thesuppression of testosterone was a result of a CORT-mediated increased inhibition of synthesis, ratherthan a decrease in stimulation. The ability of CORTto inhibit 11b-HSD appears to be independent ofactivation of intracellular GRs, although the exactmechanism remains unclear (Hu et al., 2008a). Addi-tional glucocorticoid-independent mechanisms ofstress-induced testosterone suppression, which mayinvolve endogenous opiates and/or nitric oxide,may also contribute to the suppression of testosteronein VBS animals (Kostic et al., 1998, 1999).

Although stress has been shown to decrease LHsecretion in some instances (Bronson, 1973; Grayet al., 1978; Tache et al., 1980; Sapolsky, 1985; Rivieret al., 1986; Lopez-Calderon et al., 1991; Rivest andRivier, 1991; Norman and Smith, 1992), a decrease intestosterone is not always accompanied by a con-comitant decrease in plasma LH (Puri et al., 1981;Charpenet et al., 1981; Mann and Orr, 1990;Akimbami et al., 1994; Orr andMann, 1992). Decreasesin LH, when observed, appear to be a result of decre-ased hypothalamic gonadotropin-releasing hormone(GnRH) stimulation (Coe et al., 1982; Bidzinska et al.,1993) and increased opioid-mediated inhibition ofcentral LH release (Sapolsky andKrey, 1988; Bidzinskaet al., 1993; Akimbami et al., 1994). The inhibitoryeffects of the opioid system appear to be mediatedprimarily through m- and k-receptor subtypes(Sapolsky and Krey, 1988). The stress-induced testos-terone suppression can also be blocked by peripheralopioid-receptor antagonism.

The exactmechanismof testosterone suppression inthe VBS animals is not known. Further studies will benecessary to elucidate the temporal progression of thechanges in testosterone, and the testicular syntheticcapacity and responsiveness to gonadotropin. It is likely


that the stress-related changes in testosterone secre-tion involve a combination of the central and periph-eral effects of stress and glucocorticoids describedabove, including central inhibition of GnRH and LH,decreased testicular responsiveness to LH, and dec-reased testicular degradation of CORT.

9.7 General Summary

Social stress effects are currently evaluated in a vari-ety of laboratory models. These may differ consider-ably in the intensity of the stress produced, and in thedegree to which they afford dominant and subordi-nate or victorious and defeated animals that canlegitimately be compared with each other, as well aswith controls. Although HPA-axis activity is stronglyassociated with social, as with other, stressors, it doesnot always differentiate dominant from subordinateanimals. Moreover, some social stressors appear toproduce effects in addition to those that are mediatedby HPA-axis activity.

In general, there is good agreement between find-ings with respect to behavioral, neurochemical,and hormonal sequelae of social stress in animalmodels, as compared to the range of behavioral andmedical conditions involving similar changes inhighly stressed people. This provides some degreeof validation for social stress paradigms, and strength-ens the need for finer analysis of social stress effectsand mechanisms in animal models. Nonetheless, it isnot clear that laboratory animal models of socialstress, necessarily providing only a restricted rangeof behavioral options and opportunities for bothwinners and losers, afford the same range of stress-response and stress-reduction mechanisms that mayappear in the same species under more natural con-ditions. This emphasizes the value of attempts toincorporate enhanced social and environmental com-plexity into laboratory models, suggesting that thesemay provide a more complete range of behavioraland physiological stress effects, including bothdestructive and ameliorative mechanisms. The com-plex interplay of behavioral and physiologicalmechanisms in social stress suggests that researchusing only nonsocial stressors may be too simplisticto accurately model the stress mechanisms operativein humans. In recognition of this, research usingsocial stressors has burgeoned in recent years andcontinues to hold promise for elucidating themechanisms underlying stress-related health pro-blems in human populations.

Acknowledgments

The authors would like to acknowledge the partici-pation of Randall R. Sakai, Kellie L.K. Tamashiro,Mary M.N. Nguyen, and Bruce S. McEwen in theVisible Burrow System (VBS) work reported here.Supported by NSF IBN 28543.

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Biographical Sketch

Christina R. McKittrick is an associate professor of biology and director of the neuroscience program at Drew University.She is interested in how various central neurotransmitter systems are affected by pharmacological and environmentalmanipulations, and how these changes, in turn, are related to behavior. Her current research is focused on the biological

consequences of stress and the neurochemical effects of drug abuse. She received her BS in biology from Davidson Collegeand her PhD from Rockefeller University, with qualifications in neuroscience, biochemistry and gene expression, and cellbiology.

D. Caroline Blanchard received her PhD from the University of Hawaii. She has served as president of the InternationalSociety for Research on Aggression. Her research interests are on biological and behavioral analyses of emotional

behaviors, including emotions and emotional psychopathologies in people. Long-time faculty at the University of Hawaii,Caroline Blanchard has also worked in laboratories in Moscow, Bergen, Tokyo, Gottingen, and Tel Aviv.

Matthew P. Hardy was a senior scientist at the Population Council’s Center for Biomedical Research before his unexpected

death on 4 November 2007. He studied androgen secretion and male reproductive health, stress and reproduction,environmental toxicants and male fertility, as well as male contraception. For 5 years he served as co-editor-in-chief of theJournal of Andrology; he was also co-editor-in-chief of Archives of Andrology and was on the board of reviewing editors for the

Biology of Reproduction. At the time of his death he was serving as the president/managing partner of the Testis WorkshopLLC, a biennial international meeting for scientists working on male fertility and infertility. Hardy received hisundergraduate degree from Oberlin College and a PhD from the University of Virginia. Before joining the Council in 1991,

Hardy worked at Johns Hopkins University. Photo by Ben Asen # 2008 Population Council Inc.

Robert J. Blanchard received his PhD from the University of Iowa. He has served as president of the International Society

for Research on Aggression, and of the International Behavioral Neurosciences Society. His research interests focus onethoexperimental analysis of natural patterns of emotional behaviors. Long-time faculty at the University of Hawaii,Robert Blanchard has also worked in laboratories in Moscow, Bergen, Tokyo, Gottingen, and Tel Aviv.

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