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

ß 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

* The authors would like to dedicate this chapter to the memory of Matthew P. Hardy, a wonderful colleague, collaborator, and friend. He left us far too soon and will be missed. {Deceased.

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

Glossary effects in both behavior and physiology: electric foot- shock and repeated social defeat have been reported dexamethasone suppression test (DST) It is a to produce opposite effects on systolic blood pressure pharmacological test that probes feedback and mean arterial blood pressure in male rats, with regulation of the hypothalamic–pituitary– enhancement in the former situation and decrements adrenal (HPA) axis. Under normal conditions, in the latter (Adams et al., 1987). While fear of a glucocorticoid secretion is inhibited after previously received footshock produced both brady- administration of the glucocorticoid receptor cardia and immobility in almost all rat subjects, fear agonist, dexamethasone. Nonsuppression of a dominant rat produced bradycardia in about is an indicator of deficient regulation of the 50% of subjects, and immobility primarily in the HPA axis. others (Roozendaal et al., 1990). Similarly, while hypothalamic–pituitary–adrenal (HPA) axis This water deprivation had a duration-dependent anxio- is the hormonal cascade activated in lytic effect in the elevated plus maze, 1-h restraint response to stress, which includes was anxiogenic in the same situation (McBlane and corticotropin-releasing hormone (CRH) from Handley, 1994). Social defeat produced a significant the hypothalamus, corticotropin (ACTH) decrease in variability indices for a number of car- from the pituitary, and glucocorticoids from diac electrical activity parameters, whereas three the adrenal cortex (cortisol or corticosterone, nonsocial stressors (restraint, shock-probe test, and depending on the species). swimming) either failed to change or increased these hypothalamic–pituitary–gonadal (HPG) axis This indices (Sgoifo et al., 1999). While a variety of stres- is the hormonal cascade that regulates the sors tend to elicit self-grooming in the rat, the time secretion of sex steroids, which includes course, form, and magnitude of these are different gonadotropin-releasing hormone (GnRH) from with different stressors (van Erp et al., 1994). the hypothalamus, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary, and either estrogens and progestins 9.1.2 Social Stress as a Chronic or from the ovary or testosterone from the testes. Recurrent Factor in Evolution Differences in response to specific stressors suggest the advisability of focusing research involving the biobe- 9.1 Why Study Social Stress Effects? havioral consequences of stress on those types of stres- sors that are most likely to be broadly represented 9.1.1 Differences in Effects of Different across mammalian species, including humans. In con- Stressors trast to many of the stressful manipulations used in Although stress has long been conceptualized in terms laboratory studies, social stress is a chronic or recurring of a generic pattern of physiological responses, some factor in the lives of virtually all higher animal species. recent work indicates that different types of stressful Disputes over resources, including access to a sexual or events may produce qualitatively different patterns of reproductive partner, or in the process of setting up and Social Stress Effects on Hormones, Brain, and Behavior 335 maintaining territoriality or dominance relationships, conspecific, another member of the same species. may involve agonistic behaviors that result in wound- The results of such exposure may be expected to ing, exhaustion, and sometimes even death. Even for vary with the subject species, and the age, gender, those species in which individuals are solitary except and previous history of the individual, as well as the for mating and rearing of young, spacing is based on the circumstances in which the exposure takes place. agonistic or avoidant behaviors that are seen when Most laboratory studies of social stress effects utilize conspecific encounters occur. Because social stress rodents, typically laboratory rats or mice. However, effects are both common and powerful, they, along hamsters – a variety of mouse species in addition to with response to predators, have provided much of the domesticated laboratory mouse – and other the impetus for the evolution of stress mechanisms. rodents have also been used, albeit less frequently. These include both behavioral and physiological adap- Primates also serve as subjects of laboratory investi- tations, potentially differing for acute, as opposed gation of social stress effects, but their social and to chronic, situations that may potentially influence stress-related behaviors are more commonly obser- virtually every area of an animal’s life. ved under natural or seminatural conditions. Adult males are the subjects of a great majority of 9.1.3 Social Stress Effects in People social stress studies, as, indeed, they appear to be for work on animal models of stress-related psy- Social stress is viewed as a major factor in the etiology chopathologies in general (Blanchard et al., 1995; of a variety of psychopathologies, such as depression Tamashiro et al., 2005). With reference to social stress and anxiety (e.g., Kessler, 1997; Patten, 1999); social and effects, this may reflect that in most mammalian emotional stressors may also be involved in the etiol- species males tend to create a dominance hierarchy ogy of post-traumatic stress disorder (PTSD) and acute that is much more visible than are the dominance stress disorder (American Psychiatric Association, relationships of females, as the male hierarchy influ- 2000). In addition to its effects on male (McGrady, ences a wider range of behaviors of the hierarchi- 1984) and female (Nepomnaschy et al., 2007) repro- cal animals. In addition, for many species individual duction, psychosocial stress also alters immune male dyadic confrontations, particularly when these function (Godbout and Glaser, 2006) and increases occur in the home cage or living area of one of the the risk of cardiovascular disease and metabolic syn- males, reliably produce fighting, in which the resi- drome (Ramachandruni et al., 2004; Abraham et al., dent has a major advantage. This phenomenon pro- 2007). Social stress in people is often evaluated in vides a fast and reliable method of ensuring defeat in terms of the number and magnitude of life events that the intruder, enabling some quantification of social an individual experiences, and a general conclusion stress in terms of the characteristics of the fight, and from this approach is that a plethora of moderately its parameters (e.g., number and duration of sessions). stressful events can have as great an impact as a few major events (Dohrenwend, 1973). Another important index, strongly associated with the number of stressful 9.2.1 Laboratory Models of Social events that are likely to be experienced, is social status. Stress Lowsocialstatusisregardedasimpactingalmostevery 9.2.1.1 Social defeat area of the individual’s life, with implications for access In general, two types of social stress situations are to resources, safe living conditions, and healthcare. What used in laboratory studies. The first involves individ- is particularly interesting, however, is that these material ual confrontations, typically separated by longer differences do not appear to account entirely for social periods in which the stressed intruder is returned status effects. The ranking difference itself, and the to its home cage or to a neutral site. These are meaning assigned by the individual to his/her status typically labeled social defeat tests, and, in order to with reference to others, may provide stress that is addi- reduce wounding and other physical concomitants tional to (or interactive with) the material consequences of the encounter, they may be followed by an addi- of low status (de Ridder, 2000; Ghaed and Gallo, 2007). tional period in which the defeated animal is left in the resident’s home cage, but protected by a 9.2 Animal Models of Social Stress barrier such as a wire mesh cage. These protected exposures may be repeated, with or without actual Animal models of social stress involve single, inter- physical contact of the two animals, on successive mittent, or chronic exposure of a subject animal to a test days. 336 Social Stress Effects on Hormones, Brain, and Behavior

9.2.1.2 Colony, or chronic defeat, models to controls. For some of these, winners and losers are The other type of social stress situation involves directly comparable with reference to housing con- chronic exposure of animals maintained in groups ditions and prior social experience. For others, nota- or colonies. The physical and social environments bly the resident–intruder type social defeat models, and other parameters of these groups vary consider- the social disruption models, and those intermittent ably, from standard animal cages in which multiple defeat models in which an experienced animal is animals of only one sex are housed, to seminatural paired with one that is naive, the winners typically habitats, including our Visible Burrow System (VBS) have much more social experience, and in a different (see Blanchard and Blanchard (1990) for overview of arena (i.e., their own home area rather than that of model), with tunnels and burrow systems including the other animal for social defeat, and in a variety both male and female animals. The strength of ago- of locations for the social disruption models) than nistic interaction within these groups also appears to do the losers. The colony dominant–subordinate, vary considerably, with housing with females and intermittent defeat using initially naive animals, and provision of larger and more natural habitats tending the social instability models, all involve some to produce higher levels of fighting. Various indices opportunities for agonistic interactions among ani- of both the agonistic interactions, and other behaviors mals with initially equivalent experience. However, manifested by individual animals may be used to for those models, winning and losing may reflect infer a dominance hierarchy. individual factors for the two animals, such that comparisons following victory or defeat experience 9.2.1.3 Intermittent defeat must also take into account the possibility of preex- Other variants tend to fall between these two proto- isting differences. cols. One frequently used variant involves caging two animals, usually male, in adjacent areas such that they 9.2.1.4 Social instability are chronically exposed to the sight, smell, and sound Social instability models involve setting up social of the other, but with tactile contact precluded. At groups, and later mixing them. Since intruders intervals the barriers between the enclosures are into an established home area are typically attacked removed and the two animals are allowed to interact more strongly than are subordinates within a stable directly. In these encounters, one animal may be an social grouping, this procedure would be expected experienced fighter, and the other naive, such that it to involve a very high level of agonistic behavior. is very predictable that the naive male will be However, like crowding, this procedure does blur defeated. In other variants, both males are naive, but the distinction between dominant and subordinate, they quickly establish a victor and a defeated or or victorious and defeated, animals, in that animals submissive member of the pair. While this has much with only experience of victory, or only experience in common with the social defeat model, that is, of defeat, are unlikely to emerge from these pro- punctuated physical encounters, typically involving cedures. Moreover, the protocol may or may not fighting, the defeated animal is left in chronic sensory attempt to measure agonistic interactions for each (except for tactile) contact with the victor such that animal. its exposure to this psychosocial stress is chronic rather than intermittent. A recent variant involves allowing one animal to establish residency, for exam- 9.2.1.5 Social disruption ple, for 1 week, followed by brief exposure to an Social disruption is achieved by introducing a intruder in the resident’s home cage, then separation selected highly aggressive male or a succession of of resident and intruder within the home cage by a highly aggressive males into a stable social group barrier, for 2 or 3 weeks. Additional confrontations at (Padgett et al., 1998). As with social instability mod- the end of this period enable determination of domi- els, this procedure produces animals that are all likely nant and subordinate status for the two, with the to have been defeated in several of their agonistic added feature that if the initial resident is defeated, interactions, those involving the highly aggressive it will also have lost its territory in the process male intruders. However, some of the grouped sub- (reviewed in Bartolomucci et al. (2005)). jects may also have experience of victory, either All of the above models are capable of providing in within-group fights, or, on occasion, in agonistic animals with a history of victory and a history of encounters with the highly aggressive male intruders. defeat, both of which potentially may be compared Thus, for both social disruption and social instability Social Stress Effects on Hormones, Brain, and Behavior 337 models, although there is the possibility of dividing 9.2.2 Naturalistic or Field Studies of Social subjects into categories based on their own specific Stress Effects history of victory and defeat, it should be recognized Since a major focus of this chapter is on brain and that these experiences are likely to be less polarized endocrine effects of social stress, and these are much than those of the first three paradigms given above. more difficult to evaluate in animals in their natural environment, it will be laboratory models, such as the 9.2.1.6 Crowding above, that are emphasized. However, some field Additional variants of laboratory social stress models studies also involve sampling of blood, feces, and include crowding and social isolation. Properly other tissues providing indices of relevant hormone speaking, crowding should refer only to studies in levels. In these studies, the social stresses are typically which animals are placed together in housing situa- inferred from the subject animal’s position within the tions such that each has less than a standard amount group dominance hierarchy, or, more precisely, from of space. This may mean three rats in a cage meant for its recent activities with reference to moving up or one, or seven rats in a cage meant for 21. Since there is down in that hierarchy. While naturalistic studies little information on what are the optimum or even do provide a wider and more elaborate range of reasonable space requirements for most animal spe- behaviors for which social stress effects might be cies, the definition of crowding is necessarily some- described, and an expanded analysis of the conditions what arbitrary. In addition, the two examples given under which social agonistic behaviors generate little above illustrate that crowding measured as animals or great magnitude of stress, they generally lack a per unit area may be quite different than crowding as minimal stress control group for purposes of compar- number of interacting animals per housing unit, and it ison. Such studies typically compare animals that are might be expected that these two aspects of crowding high or low in a dominance hierarchy; moving up or would have differential effects. Crowding also implies down in the hierarchy, or, that show certain patterns that the mechanism of social stress is proximity, rather of endocrine levels or functioning. In field studies, than agonistic interaction per se, and crowding stress it is particularly difficult to measure physiological studies may or may not involve attempts to measure changes as a function of time, following agonistic agonistic reactions, and to identify dominant and sub- interaction or other stressful experience. ordinate animals within the groups.

9.2.3 Studies of Social Stress Effects in 9.2.1.7 Social isolation Females It might be thought contradictory that both social grouping and social isolation may be stressful, since As noted above, the vast majority of social stress this differentiation seems to leave no normal situa- studies involves male subjects, as females of most tion to serve as a minimal stress control. However, species show relatively little within-sex fighting. In such a view does not take into account differences in addition, even when fighting between males and social organization between species or between sexes females is common, the females may appear to be within the same species. Thus, although social group- only a little stressed by it, in terms of measures such ing appears to be more stressful for male rats, female as wounding, or subsequent avoidance of the male rats are more stressed by isolation (Brown and (Blanchard et al., 2001a). This may reflect the fact Gruneberg, 1995; Haller et al., 1999; Palanza, 2001). that in many of the more commonly used subject Gender effects in protocols involving social isolation species, male attack on females is inhibited, and may be quite complex. Thus, in contrast to most does little damage. Female–female fighting may studies of isolation effects, McCormick et al. (2008) become more intense under some circumstances, reported a reduction in anxiety-like behavior (ALB) however, such as during the week or so following in adolescent female rats stressed by a combination of parturition. In addition, selection of highly aggressive isolation interspersed with partner housing in which males, or of attackers subjected to physiological the partners were intermittently changed. The choice manipulations, such as to make them more likely to of which to consider the stressor, isolation or group- show intense attack, can be used to ensure a strong ing, may in some cases be based on associated behav- attack on females. These studies, while very interest- ioral changes rather than endocrine response (e.g., ing, tend to be cumbersome to run. Also, they may Haller and Halasz, 1999). not permit clear interpretation of male–female 338 Social Stress Effects on Hormones, Brain, and Behavior differences in response to attack, since serious attack deal of analytic precision is lost when this informa- by males on females in species such as rats that show tion is not available. Exceptions are females, for sexual dimorphism in size must either involve high whom overt fighting tends to be uncommon, except magnitude size differences, or the use of very small for a few species such as hamsters and spotted (young?) males. hyenas, in which females are dominant to males and In addition, females of many mammalian species female–female fighting is common; and established show a relatively specific inhibition of ovulation or or stable social groups, as may be the case in many other reduced reproductive functioning while in field studies. social groups containing a dominant (reproductively With reference to indices or markers of stress, active) female. These nonreproductive females may the prototypical stress marker is activity of the show few other signs of stress or distress. Nonethe- hypothalamic–pituitary–adrenal (HPA) axis, typi- less, the rapidity with which they may begin to cycle cally measured as the level of cortisol or corticoste- following removal of the dominant female makes it rone (CORT) in the plasma, saliva, or feces. As will be clear that this suppression is a response, albeit a very seen, while this marker is very consistent for most specific one, to the social hierarchy. laboratory studies, there are some exceptions to the general rule of high values for stressed subjects. Other commonly used indices of stress are changes 9.2.4 Social Stress Mechanisms in relevant organs (e.g., increased adrenal weight) and and Markers weight loss during the putatively stressful period. This plethora of techniques for producing social When all of these, plus direct measures of agonistic stress suggests the need for ways to evaluate whether experience are taken, they often covary consistently. subjects have indeed experienced an adequate degree Although not all such measures are taken in every of social stress. One approach may be to evaluate the study, they provide very useful indications that social specific experiences that are regarded as mechanisms stress was indeed a factor in the experimental condi- in the stress experience. Another is to examine beha- tions imposed or a clear variate in the nonexperimen- viors or physiological changes that may serve as tal situation in which observations were made. relatively specific markers or indices of stress. With the possible exception of crowding, the major 9.2.5 Scope of this Article mechanism by which social experience is regarded as producing stress is agonistic behavior. For laboratory This chapter will attempt to cover three broad aspects mice and rats, the most commonly used subjects of social stress effects: first, behavior; second, changes of social stress laboratory research, this agonistic in brain systems; and third, endocrine changes. Some behavior is a very obvious component of most recent work on social stress effects has tended to exam- social-grouping studies. It may be measured directly, ine these factors together, asking if animals that, for in terms of fighting within each specific male dyad example, show a particular pattern of endocrine within a group, or indirectly, in terms of wounds changes also show changes in behavior or in brain on the combatants. Both techniques provide a good systems. Such approaches are aimed at determining indication of dominant or subordinate status, since the mechanisms of interaction of these domains, and offensive attack, as is seen on the part of the dominant we will attempt to sketch out these interactive effects or the experienced victor, is aimed toward a different whenever possible. Our focus will be on changes in target site on the body of its opponent than are each of these domains following social stress to rela- the attack bites of the defensive subordinate or tively normal animals (e.g., not lesioned, drugged, or experienced loser (Blanchard and Blanchard, 1977). with genetic modifications), examining them largely in Measures of agonistic behavior that do not take the context of laboratory research, although field stud- into account crucial specifics, for example, a score ies will also be considered. We will not attempt to deal that is summed for all fighting within a group with a range of other stress-responsive systems that regardless of which animals fight, or overall wounding are also interesting and potentially important, but are scores regardless of wound location, do not permit covered in other chapters in this encyclopedia. These an analysis in terms of dominant/subordinate or win- include analgesia, cardiovascular changes, autonomic ners as opposed to losers. All animals within such functions, seizure manifestations, immune response, a group may be compared to controls without agonis- lipoprotein cholesterol, circadian rhythms, body tem- tic experience but it is to be supposed that a good perature, and electrophysiological correlates. Social Stress Effects on Hormones, Brain, and Behavior 339

9.3 Behavioral Consequences of Young isolate-reared rats show more ultrasonic vocali- Social Stress zations to an aggressive adult male and suffer more injuries in such encounters, suggesting that their behav- 9.3.1 Agonistic Behaviors: Aggression ioral deviations may serve as provocations for the adult and Defense (Von Frijtag et al., 2002a). However, changes in aggres- The immediate behavioral consequences of decisive sion after social stress may be dependent on both the agonistic interactions comprise two groups of beha- stressor and the incitement to aggression. Nakamura viors – one that may be used to infer victory, the other, et al. (2008) reported that as adults imprinting control defeat. These have been intensively described in region (ICR) mice weaned at 14 days of age showed laboratory rodents, beginning with the studies of enhanced aggression after food restriction, but not more Grant and his colleagues about 40 years ago (Grant aggression with social instigation, compared to normally and Chance, 1958; Grant, 1963; Grant and MacKintosh, weaned controls. In guinea pigs, sons of pre- and post- 1963), with further analyses in rats (e.g., Blanchard and natally stressed mothers show infantilization of some Blanchard, 1977) and mice (e.g., Grimm, 1980). Such behaviors, such as more resting in body contact with studies identified components such as lateral attack, conspecifics, that lasts to a later age than for controls chase, and standing on top of as aggressive elements, (Kaiser and Sachser, 2001; Kaiser et al., 2003a). However, and flight/avoidance, defensive upright, and lying on early pre- and postnatal stress masculinizes the behavior the back as defensive elements. For mice, in particular, of female guinea pigs (Kaiser et al., 2003b). the defensive upright is typically regarded as a submis- Subordinate behaviors include avoidance, immo- sive posture and is widely used to indicate defeat, as it bility, crouching or freezing, and risk assessment tends to coincide with a cessation of aggressive beha- (Blanchard and Blanchard, 1989; Blanchard et al., viors, and to recur as a conditioned response in situa- 1995, 2001a,b). The last category, risk assessment, tions in which the animal has previously been attacked involves information-gathering activities concerning (Siegfried et al., 1984). Submissive behaviors have tradi- potential threat, and includes scanning as well as the tionally (Lorenz, 1966) been interpreted as serving as a assumption of low back postures while cautiously cutoff for further attack, but appear not to be particu- approaching a threat stimulus (Blanchard et al., larly effective in this role, except by concealing body 1991a). These changes in aggressive and defensive areas that are the target for attack by the offensive behavior may be further enhanced in a subset of animal (Blanchard and Blanchard, 1977; Pellis and VBS subordinate rats that show a sharply reduced Pellis, 1992). Their inability to halt conspecific attack CORT response to restraint stress (see Section 9.4.1.2) is illustrated by the fact that virtually all uses of social (Blanchard et al., 1995, 2001b). defeat models attempt to provide some protection for Most of the same changes are seen in subordinate the loser, which would not be necessary if its submissive tree shrews. Although the testing conditions (they are postures were effective in terminating physical attack. paired with highly experienced fighters such that Social defeat reduces social exploration, and they are quickly and easily defeated) are such as to increases subordinate and fearful behaviors in social minimize any aggressive behaviors, they show situations, in a range of species from great tits increased avoidance, immobility (measured as loco- through laboratory rodents (Haller et al., 2002; Von motor activity in their home cage situation, in all but Frijtag et al., 2002a; Wommack and Delville, 2007; tactile contact with the dominant), and risk assess- Yamaguchi et al., 2005) to domestic swine (Carere ment, along with sleep disturbances (Flu¨gge et al., et al., 2001; Pedersen et al., 2003). A number of recent 2001; Fuchs, 2005; Fuchs and Flu¨gge, 2002; Fuchs reports indicate that social defeat in adolescence may et al., 1996; Kramer et al., 1999; Von Kampen et al., have different effects. Delville, Wommack, and their 2000). Increases in particular defensive behaviors, associates report and confirm that early defeat stress such as the upright submissive posture, have also produces a premature transition from play fighting to been reported after defeat in both rats and mice, as adult forms of fighting in hamsters, with this acceler- has risk assessment for subordinate cynomolgous ation most marked in the least submissive animals female monkeys and socially stressed male mice (Delville et al., 2003; Taravosh-Lahn and Delville, (Beitia et al., 2005; Blanchard et al., 2001b; Chung 2004; Wommack and Delville, 2003; Wommack et al., et al., 1999; Siegfried et al., 1984; Kulling et al., 1987; 2003, 2004), whereas defeat in adult hamsters leads to Shively et al., 1997a,b). One potentially anomalous reduced aggression and the development of patterns of finding is that enhanced scanning within a mixed-sex submissive behaviors (Wommack and Delville, 2007). group has been reported for sugar glider dominants 340 Social Stress Effects on Hormones, Brain, and Behavior

(Mallick et al., 1994). As the dominant males were the aggressive isolates and grouped dominants moved to other groups where they became subordi- also showed enhanced risk assessment, in addition nates, scanning increased. While this may suggest that to avoidance of open arms, the classical anxiety mea- scanning is a component of risk assessment to poten- sure of the elevated plus-maze test. This potential tially attacking conspecifics, particularly in the latter rat–mouse difference may reduce to a difference in situation, this behavior is also highly functional procedure, in that, the rat studies compared socially against nonconspecific threats, and in this species, stressed (defeated) rats to controls, while the Ferrari dominant males in their own groups may take the et al., studies compared aggressive or dominant lead in this type of risk assessment. Socially stressed mice to controls. Possibly both winner and loser rodents are less active and may show alterations in animals are more anxious than those that have not circadian rhythms and sleep (Lancel et al., 2003; had aggressive experience. Other anxiety tasks that Meerlo et al., 2002). Grouped (and presumably have been shown to be responsive to social stress socially stressed) pigs sleep more (Bornett et al., effects are the black–white test (enhanced anxiety 2001). When mice are sorted into dominant residents, after social defeat, Keeney and Hogg, 1999); open subordinate residents, dominant intruders, or resi- field, and Porsolt’s test (reduced number of squares dent intruders on the basis of a protocol that affords crossed, and enhanced immobility, respectively; prior residency for one mouse followed by joint, Kudryavtseva et al., 1991a). When placed in a novel noncontact habitation of a cage by both members of environment, both resident and intruder dominants a pair (reviewed in Bartolomucci et al. (2005)), sub- from the mixed resident–cohabitation model (reviewed ordinates show reduced activity in the home situation in Bartolomucci et al. (2005)) showed hyperactivity (Bartolomucci et al., 2003). and reduced ALBs, whereas subordinates did not differ from controls (Bartolomucci et al., 2001). After social defeat, immobility to a sudden 9.3.2 Emotional Behaviors Measured silence was enhanced (Ruis et al., 1999). Similarly, Outside the Agonistic Context stress-nonresponsive VBS subordinates show reduced Because of the strong association between stress and an activity, including righting, to handling (Blanchard et al., array of emotional disorders (e.g., Mineka and Zinbarg, 2001b), than controls, dominants, or stress-responsive 1996), a major emphasis of social stress studies of ani- subordinates. However, a minimal physical-contact mals has been to evaluate emotionality. The anxiety social defeat procedure failed to alter immobility for test most commonly utilized in conjunction with mice in the forced swim test (Keeney and Hogg, 1999). socially stressed animals is the elevated plus-maze. Risk assessment is a pivotal defensive behavior that For subordinate rats, plus-maze findings tend to be decreases with both high levels of defensiveness, or, extremely consistent, with a number of studies showing when defensiveness declines toward a normal, non- that subordinates show more ALBs on this test, while defensive state (Blanchard et al., 1991a). It is very sensi- social victory decreases anxiety-like plus-maze behav- tive to subordination or defeat, but the direction of ior (Becker et al., 2001; Calfa et al., 2006; Haller and change is different for different situations, perhaps Halasz, 2000; Heinrichs et al., 1992, 1994; Lumley et al., depending on the level of threat experienced in the 2000; McCormick et al., 2008; Menzaghi et al., 1994, test situation. The Ferrari et al. (1998) findings that 1996; Palanza, 2001; Ruis et al., 1999; Sa´-Rocha et al., aggressive and dominant mice show the highest levels 2006; Sterlemann et al., 2008). One interesting study, of risk assessment on the elevated plus-maze, are com- however, found that mild social stress normalizes the patible with a report by Avgustinovich et al. (1997) that anxiety-like response of social isolates in the plus-maze social defeat in mice may reduce peepings in this test, task (Haller and Hallasz, 1999). if the defensiveness of the latter, but not the former, is Data from mouse studies were somewhat more so great as to reduce risk assessment. Subordinate varied. Avgustinovich et al. (1997) reported that mice show enhanced risk assessment to social odors c57BL/6J mice show enhanced plus-maze anxiety in their own home cage, as do two of three VBS after social defeat. However, Ferrari et al. (1998) groups (dominants and nonresponsive subordinates) in found that among isolates, the more aggressive a stretch attend apparatus (GarbeandKemble,1994; males showed higher plus-maze anxiety, as did dom- Blanchard et al., 2001b). inant males among group-housed animals. The Social defeat has also been consistently reported plus-maze anxiety measures of the Ferrari et al. to increase ultrasonic vocalizations to startle stimuli (1998) test included risk-assessment measures, and such as strong air puffs, in rats (Vivian and Miczek, Social Stress Effects on Hormones, Brain, and Behavior 341

1998, 1999), as well as to the situation in which the (Trzcinska et al., 2002). One potentially anomalous animal has previously been defeated (Tornatzky and finding is that social instability reduces the increase Miczek, 1994, 1995). in amphetamine self-administration seen when males cohabit with females (Lemaire et al., 1994). These increases in alcohol and drug-taking (diaz- 9.3.3 Social Stress Effects on Drinking and epam as well as cocaine; Wolffgramm and Heyne, Drug-Taking Behaviors 1991) as well as reinstatement of morphine-induced Social stress is also viewed as an important factor in place preferences in mice with social defeat (Ribeiro drug abuse and alcoholism, leading to many recent do Couto et al., 2006), stand in contrast to the lack of studies of this relationship in animal models. Studies effect for sucrose intake (Mole and Cooper, 1995)or in mice, rats, and monkeys provide a relatively decreased sucrose preference in rats (Rygula et al., consistent finding of enhanced alcohol intake for 2005, 2006). Socially defeated rats also show reduced socially stressed subordinates, particularly when anticipatory responses to sucrose reward (Von Frijtag this is measured in the grouped-housing situation et al., 2002), but this may be reward specific, in that, itself (Blanchard et al., 1987; Higley et al, 1991, Van der Harst et al. (2005) reported impaired antici- 1998; Hilakivi-Clarke and Lister, 1992; Weisinger patory behavior for sucrose but no change for another et al., 1989). This effect appears to be somewhat reward – an enriched cage. Other studies have shown variable for different strains of mice (Kudryavtseva a reduction in reward motivation, specifically, for et al., 1991b), and with minimal physical-contact eating lab chow and drinking water, in subordinate social defeat procedures (Keeney and Hogg, 1999) rats in the VBS (Blanchard and Blanchard, 1989). while Van Erp et al. (2001) and Van Erp and Miczek This finding may have initially been confounded by (2001) reported that social stress either suppressed or the presence of the dominant, since in that study food failed to change alcohol intake in rats, measured in and water were located in an area that the dominant a different situation. Wolffgramm and Heyne (1991) tended to patrol, during lights-off period when most found that dominant rats show less alcohol intake consumption occurs. However, later variants of the even when isolated, as well as in a contact-housing VBS provided food and water in each chamber, and situation that exposed subjects to other animals but still found a reduction in subordinate weight, suggest- precluded direct physical contact. In partial contrast, ing that food intake, at least, may still be reduced for the Blanchard et al. (1992) study found no difference these animals (Blanchard et al., 1998). Tamashiro between animals that subsequently became dominant et al. (2006) also reported that VBS subordinate rats or subordinate, prior to grouping, but that subordi- show decreased body weight, associated with eating nates increased alcohol intake after grouping while changes. Social defeat reduced weight gain in norepi- dominants did not. Similarly, Hilakivi-Clarke and nephrine transporter knockout (KO) mice (Haller Lister (1992) found no differences in alcohol intake et al., 2002), and in rats (Bhatnagar et al., 2006). between dominant mice and controls. It might also Group-maintained pigs made fewer visits to a feeder, be noted that the social stress in the monkey studies spent less time feeding, and showed reduced weight was motherless rearing, while in the rat and mouse gain (Bornett et al., 2001). studies it involved some type of social agonistic experience. 9.3.4 Social Stress Effects on Sexual Similarly, social defeat was consistently reported to Behavior increase cocaine self-administration (Covington and Miczek, 2001; Covington et al., 2005; Haney et al., Social stress has relatively consistent effects on sexual 1995; Lemaire, et al., 1994; Miczek and Mutschler, behavior. Using an unusual social stress paradigm in 1996; Tidey and Miczek, 1997). This fits well with which dominant male mice are exposed to the sight findings that social stress effects generalize to both and sound of their subordinates interacting with a those of psychomotor stimulants (Covington and female, D’Amato et al. (2001) reported impaired sex- Miczek, 2001; Covington et al., 2005; Miczek et al., ual behaviors for the stressed dominant. More com- 1999) and pentylenetetrazole (Vivian et al., 1994)in mon, however, are studies of social stress effects in drug discrimination tests, in that such similarities subordi nate males. In Africa n cichlid fish (Parikh may enable the social stressor to serve as a drug et al., 2006), la borator y mice ( D’Amato, 1988 ), deer cue. However, social stress in adolescent hamsters mice (Dewsbury, 1988), laboratory rats (Blanchard was reported not to cross-sensitize with cocaine and Blanchard, 1989; Mizuno et al., 2006; Niikura 342 Social Stress Effects on Hormones, Brain, and Behavior et al., 2002), domestic pigs (Pedersen et al., 2003), and et al., 1997a,b). Socially stressed animals appear to lemurs (Perret, 1992) subordinates show reduced show considerable sensitivity to relevant physical and sexual behavior. It should be noted that this reduction behavioral features of other animals, with subordi- may also, at least in part, reflect the conditions under nate male mice preferring the odors of familiar domi- which the observations in several of these studies nants to those of unfamiliar dominants (Rawleigh were made, in groups or colonies such that the domi- et al., 1993), while subordinate female vervet monkeys nant is, or has recently been, present. Given the show a pattern of behavior changes in response to the degree to which proximity to a dominant animal menstrual cycle of the dominant female – a feature influences subordinate behavior (see Section 9.3.5), that modulates the dominant’s defensiveness. and the existence of sneaker strategies for male mat- Changes in behavior in response to the presence ing (Plaistow and Tsubaki, 2000), it is possible that and proximity of a dominant have been shown for subordinate males’ sexual behavior is better described both rodent and primate species. Some of these as transiently suppressed by the dominant. While changes appear to involve efforts to become less dominant males do appear to disproportionately behaviorally provocative, for example, selectively father young in some studies, in others this is not losing a tug of war for food when the competing the case – findings that may reflect the existence dominant is close by (long-tailed macaque, Schaub, of female mate-selection strategies (e.g., Gagneux 1995). In another intriguing finding, subordinate et al., 1999) as well as male sneaker strategies, and a rhesus macaques showed no learning deficiencies host of postmating factors. Subordinates also show compared to dominants when tested individually, reductions and dominants increases in scent marking but played dumb when tested together (Drea and (Flu¨gge et al., 1998; Fuchs et al., 1996; Mallick et al., Wallen, 1999). The presence of a dominant appears 1994; Yamaguchi et al., 2005), which may be related to produce anhedonia with reference to rewards to attraction of females as well as other aspects of (hamster, Kureta and Watanabe, 1996), a phenome- territory marking. non that may or may not entirely account for the Sexual behavior of subordinate females also performance deficiencies seen in such situations. appears to be inhibited, and this may occur in conjunc- tion with, or independently of, suppression of ovula- 9.3.6 Social Stress Effects on Nonsocial tion (Saltzman et al., 1997). The suppression Behaviors of ovulation in subordinate females is found in a range of rodent and primate species (naked mole-rats, The degree to which social experience can result Faulkes et al., 1990;hamsters,Gudermuth et al., 1992; in serious, indeed lethal, stress was shown in pioneer- Damaraland mole-rat, Bennett et al., 1996;mice, ing studies by Barnett (1963), who reported that Marchlewska-Koj et al., 1994; and marmosets, Barrett intruders into wild rat colonies often died over a et al., 1990; Saltzman et al., 1997). It is not clear to what period of several days. Such stress deaths have degree this suppression might be ascribed to social been reported in a number of other rodent species stress, as it may persist in response to particular pher- (blind mole-rats, Zuri et al., 1998; naked mole-rats, omones given off by the dominant female, otherwise Margulis et al., 1995; mice, Ebbesen et al., 1991), not present (Saltzman et al., 1997). As will be seen later as well as for subordinates in laboratory rat VBS (in Section 9.6.2), these subordinate females frequently colonies (Blanchard and Blanchard, 1989). Other have lower, rather than higher, plasma glucococorti- species, such as lions (Schaller, 1972), hyenas coid values, further complicating the issue of whether (Kruuk, 1972), and chimpanzees (Wrangham and stress is involved. Peterson, 1996), also show lethal intraspecific fight- ing, but in these cases the death typically results directly from physical trauma, rather than from 9.3.5 Social Stress Effects on Other stress per se. Weight loss and a reduction in weight Social Behaviors gain are also commonly associated with subordina- As might be expected, subordinates, socially defeated tion in rodents (Blanchard and Blanchard, 1989; males, and dominants transferred from one group to Blanchard et al., 1995, 2001a,b) and following social another (where they are very likely to become subor- defeat (Haller et al., 1999; Meerlo et al., 1996b, 1997). dinate) show reduced affiliativeness and social con- While these may, in part, reflect eating reductions, tact (rat, Blanchard and Blanchard, 1989; Meerlo they may also reflect enhanced metabolic demands et al., 1996b; female cynomolgous monkeys, Shively associated with stress. Social Stress Effects on Hormones, Brain, and Behavior 343

Decreases in locomotion, exploration, and celerity 9.4 Hormonal Aspects of Social of movement are a very consistent finding with subor- Stress: HPA-Axis Function dinate or socially defeated animals, including rats (Blanchard and Blanchard, 1989; Blanchard et al., The activity of the HPA axis has been studied in 2001a,b; Meerlo et al., 1996a,b, 1997; Ruis et al., 1999; several different animal species in a variety of models Tornatzky and Miczek, 1994), tree shrews (Flu¨gge of psychosocial stress. Not surprisingly, the majority et al., 2001; Fuchs, 2005; Fuchs and Flu¨gge, 2002; of studies indicates that the HPA axis is activated in Fuchs et al., 1996; Kramer et al., 1999; Van Kampen low-ranking animals in hierarchical social groups and et al., 2000), and sugar gliders (Mallick et al., 1994). in animals that have been defeated by a conspecific. Memory and cognitive deficits are somewhat incon- However, activity and reactivity of the HPA axis have sistently associated with social stress. Although para- been shown to be modulated by a variety of different doxical sleep deprivation leads to an impairment of factors, including the species, gender, and behavioral memory in several learning/memory tasks, social style of the individuals. stress (maintenance in socially unstable conditions) did not produce deficits or interact with sleep depri- 9.4.1 Corticotropin and Glucocorticoids vation (Dametto et al., 2002; Dawood et al., 2004) reported a more complex relationship between social 9.4.1.1 Basal secretion stress and Y-maze memory performance, with habitu- Most studies of dominance hierarchies in rodents, ated but not nonhabituated mice showing poorer per- guinea pigs, and nonhuman primates have found ele- formance. In mountain chickadees, subordinates show vated basal glucocorticoid secretion in subordinate less food caching and less-efficient cache retrieval, with animals compared to dominants. Subordination has reduced spatial memory task performance than domi- been shown to increase CORT levels in mice, rats, and nants (Pravosudov et al., 2003). Ohl and Fuchs (1999) hamsters (Louch and Higginbotham, 1967; Popova and have suggested that the memory deficits seen after Naumenko, 1972; Ely and Henry, 1978; Raab et al., social stress may be those involving hippocampal 1986; Schuhr, 1987; Huhman et al., 1992; de Goeij mediation (Ohl and Fuchs, 1999). These deficits do et al., 1992; Blanchard et al., 1993; Ely et al., 1997; not appear in close correspondence with alternating Bartolomucci et al., 2001), CORT and cortisol levels cycles of glucocorticoid elevation, suggesting a in guinea pigs and tree shrews (von Holst, 1977; longer-term or indirect effect of stress on memory Sachser and Lick, 1989), and cortisol levels in squirrel processes (Ohl and Fuchs, 1998). A very intriguing monkeys, cynomolgous macaques, and olive baboons finding is that social stress may influence learning (Manogue et al., 1975; Coe et al., 1979; Sapolsky, 1983; functions through mechanisms other than, or in addi- Shively et al., 1997a,b). The increased glucocorticoid tion to, glucocorticoid increases, as exogenous admin- levels are often accompanied by weight loss, thymus istration of these, to match the elevation seen with involution, and/or adrenal hypertrophy (von Holst, the social stressor, failed to produce so profound or 1977; Raab et al., 1986; Sachser and Lick, 1989; de lasting a disruption of learning (Krugers et al., 1997; Goeij et al., 1992; Blanchard et al., 1993). Adrenocor- Ohl et al., 2000). ticotropic hormone (ACTH) may also be elevated in the subordinates (Huhman et al., 1991, 1992) although that is not always the case (de Goeij et al., 1992). 9.3.7 Summary of Social Stress Effects Although in most social stress models, it is the on Behavior subordinates that appear to be most severely stressed, Social stress appears to be capable of altering a very in many cases, the dominant animals show evidence wide range of behaviors. It facilitates the expression of of HPA-axis activation as well. In the VBS model of ALBs in tests such as the elevated plus-maze, and, when chronic social stress, for example, both dominant and strong or prolonged, may produce a pattern of behavior subordinate male rats have elevations in plasma change that is very similar to many of the target symp- CORT in blood sampled immediately after removal toms of depression (Blanchard et al., 1995). Social stress from the burrow system (Blanchard et al., 1993, 1995; may also alter substance-taking and enhance responsiv- McKittrick et al., 1995). This suggests that both ity to drugs of abuse. These changes, and other indica- the dominants and the subordinates are stressed tions of compromised social and sexual functioning, in within the context of the VBS. However, if blood is socially stressed animals provide a potential link to sampled after the animals have been allowed to rest behavioral stress dysfunctions in humans. in individual cages for 1h after removal from the 344 Social Stress Effects on Hormones, Brain, and Behavior

VBS, CORT remains high in the subordinates, but decrease if the animal becomes an anovulatory sub- returns to control levels in the dominants, indicating ordinate (Saltzman et al., 1994). Cortisol levels more efficient regulation of the HPA axis in these in anovulatory subordinates are also lower than in animals (McKittrick et al., 2000; Tamashiro et al., ovariectomized animals, suggesting factors other 2004, 2007b). In addition, in previous studies, all than ovarian hormones contribute to the regulation animals housed in the VBS show some degree of of cortisol in these animals (Saltzman et al., 1998). weight loss, thymus involution, and adrenal hy- This relationship between rank and cortisol levels pertrophy, although these effects are much more in females does not hold true for all primate species, pronounced in the subordinate animals. It is possible, however, since subordinate female cynomolgous however, that some of these effects were exacerbated monkeys have higher cortisol levels than their domi- by restricted access to food within the VBS and/or nant counterparts (Shively et al., 1997b). In addition, somewhat higher levels of aggression in the colony- a study of female cotton-top tamarins showed no bred animals used in these studies. More recent itera- difference in cortisol levels between high-ranking tions of the VBS (Tamashiro et al., 2004, 2007a,b) cycling and low-ranking noncycling, postpubertal have used commercial Long-Evan rats and have females in the same natal group, although cortisol provided additional food sources within the burrows; levels were higher in newly cycling females, reflect- although stable hierarchies were formed and the ing a change of social status (Ziegler et al., 1995). subordinates had elevated basal CORT and thymus Similar findings were obtained for black tufted-ear involution, the mortality and morbidity within these marmosets, with dominant and subordinate females colonies were greatly reduced. In addition, although in natal family groups showing similar levels of corti- dominant males had attenuated weight gain com- sol, regardless of the cycling status (ovulatory or pared to controls, CORT levels and organ weights anovulatory) of the latter. Cortisol levels did, how- did not significantly differ from the control animals. ever, increase following conflicts within the family Further studies by Tamashiro et al. (2007a) suggest group (Smith and French, 1997). Lactation status also that weight loss alone can lead to an elevation of appears to play a role in HPA activity in female CORT, but this effect is transient and is unlikely to hyenas as well, as fecal corticosteroid levels were completely account for the stress-induced increase generally higher in lactating females, although they in CORT seen in the subordinates. were also increased in nonlactating females whose Similarly, group housing of mice increases plas- social status declined (Goymann et al., 2001). ma CORT in both subordinates and dominants Several other studies have indicated that the (Bartolomucci et al., 2001), although the glucocorti- stability of social status and housing conditions in- coid concentrations may return to control levels fluences baseline HPA-axis activity. For example, more rapidly in dominants than in subordinates housing marmosets in unstable peer groups led to (Bronson, 1973). In studies using other models of an increase in morning cortisol measures in both social stress, dominants as well as subordinates had males and females, although in both sexes, cortisol higher CORT levels, decreased thymus weight, and levels fell as the peer groups stabilized ( Johnson increased adrenal weights compared to single- or et al., 1996). In olive baboon populations, rank pre- pair-housed controls, with the effects generally more dicted cortisol levels only in stable hierarchies; in pronounced in the subordinate animals (Louch and unstable hierarchies, cortisol increased with the fre- Higginbotham, 1967; Dijkstra et al., 1992). quency with which the animal was challenged by In contrast to the above studies, dominant animals lower-ranking individuals but was not altered when have been found to have higher levels of basal glu- the individual challenged other animals of higher cocorticoids in social groups of dwarf mongoose, wild rank (Sapolsky, 1992a). Similarly, plasma cortisol dogs, and marmosets (Saltzman, et al., 1994; Creel levels increased as squirrel monkeys were moved et al., 1996). These effects are observed primarily in from individual housing to male peer groups – to females and may be related to ovulatory cyclicity. male–female groups (Mendoza et al., 1979). The In marmoset populations, low-ranking females are effects were most pronounced in the higher-ranking often anovulatory and also have lower levels of corti- males, again suggesting increased HPA activity as a sol than normally cycling female of higher rank; result of repeated challenges by lower-ranking ani- in newly formed mixed-sex groups, cortisol levels mals. In rats, one complex model uses a combination increase if the female achieves dominant status but of mixed-sex housing and frequent colony Social Stress Effects on Hormones, Brain, and Behavior 345 reorganization to induce a variety of physiological cortisol levels were also somewhat lower. Finally, changes indicative of HPA activation, including a third group of particularly aggressive subordinates increased basal CORT, decreased thymus weight, had no elevation in basal cortisol; it is postulated that and increased adrenal size (Klein et al., 1992). How- the initiation of aggressive actions played a role in ever, social instability may have less predictable attenuating glucocorticoid secretion (Virgin and effects in other scenarios, as in one study with rhesus Sapolsky, 1997). monkeys inoculated with the simian immunodefi- The HPA-axis response to an agonistic interaction ciency virus (SIV), which showed that animals that appears to depend, in part, on the outcome of the met daily in unstable groups had lower plasma corti- encounter. After fighting between rats, CORT goes sol levels than those that interacted within stable up more and stays higher longer in the losers com- groups, despite the fact that the animals in the unsta- pared to the winners (Koolhaas et al., 1983); a similar ble condition showed behavioral signs of stress, as study showed that an animal that submits to a chal- well as altered immune function and shorter survival lenger exhibits an increase in plasma CORT, while time (Capitanio et al., 1998). Therefore, although plasma CORT declines if the other animal submits social instability is generally viewed as stressful, the (Haller et al., 1996). The gender of the animal may effects on basal HPA function and other stress- also influence the magnitude of the stress response, related parameters may vary considerably with the as illustrated in wild dwarf mongooses, where male experimental condition. subordinates had higher stress responses than male dominants, while in the females, the dominant was 9.4.1.2 Reactivity and feedback control of more responsive (Creel et al., 1996). HPA axis Social stress has also been shown to alter HPA-axis Socially subordinate animals are generally equally responsiveness to ACTH, corticotropin-releasing or more reactive to a novel stressor compared to hormone (CRH) and its secretagogs, as well as their dominant counterparts, as shown in social affecting the feedback mechanisms regulating the groups of mice (Ely and Henry, 1978), rats (Dijkstra termination of the HPA-axis response. For example, et al., 1992; Bhatnagar and Vining, 2003), hamsters in olive baboons, while the cortisol response to (Huhman et al., 1992), guinea pigs (Haemisch, 1990), an acute stressor did not differ with social status, squirrel monkeys (Coe et al., 1979), and olive baboons low-ranking males had a decreased ACTH response (Sapolsky, 1983). However, under some circum- to exogenous CRH and impaired negative feed- stances, subordinate animals have been shown to back following dexamethasone (DEX) administration have a less-robust response to stress than dominants (Sapolsky, 1983, 1989). Conversely, ACTH led to a more (Manogue et al., 1975; de Goeij et al., 1992). Indeed, pronounced increase in glucocorticoid levels in subor- this is what we found in our VBS model of chronic dinate compared to dominant mice (Ely and Henry, social stress. The subordinate animals have a blun- 1978) and female cynomolgous macaques (Shively, ted CORT response to a novel restraint stressor; 1998). In some studies, social defeat enhanced the this effect is attributable to a subpopulation of sub- ACTH, but not the CORT, response to intravenous ordinates that have little or no CORT increase fol- (IV) CRH (Buwalda et al., 1999), while in others, social lowing stressor exposure (Blanchard et al., 1995). subordination led to blunted responses to CRH and These stress-nonresponsive subordinates appear to be impaired DEX suppression (Pohorecky et al., 2004). the most highly stressed in this model, showing greater Housing conditions after defeat appear to modulate decrements in insulin, glucose, testosterone, and the consequences of defeat, as rats housed individually corticosteroid-binding globulin (CBG), compared to had greater ACTH responses to CRH administration the stress-responsive subordinates (McKittrick, 1996). and larger adrenals and smaller thymus weights than Similar subgroups of subordinates were also iden- animals housed in a group of familiar conspecifics (Ruis tified in social groups of olive baboons. Subordinates et al., 1999). The individually housed animals also had that had a high number of consortships – a behavior impaired DEX suppression of ACTH and CORT. more typical of high-ranking animals – had large Administration of DEX reveals deficits in feed- HPA responses to stress, accompanied by higher back inhibition of the HPA axis in other social stress basal levels of cortisol (Virgin and Sapolsky, 1997). models as well. In addition to the olive baboons and In contrast, the HPA response to an acute stressor was rats mentioned above, both dominant and subordi- blunted in another group of subordinates and basal nate mice had impaired DEX suppression compared 346 Social Stress Effects on Hormones, Brain, and Behavior to controls (Bartolomucci et al., 2004). Subordinate a decrease in hippocampal MR binding, which was female cynomolgous monkeys also had less-efficient proposed to be associated with impaired feedback DEX suppression compared to dominants (Shively, control of the HPA-axis response in these animals 1998), while marmosets housed in social groups had a (Maccari et al., 1991). The apparent stress-induced blunted cortisol response to DEX, when compared to downregulation of hippocampal GRs and/or MRs pair-housed animals ( Johnson et al., 1996). Analysis may reflect a compensatory response to higher levels of DEX-suppression in male cynomolgous macaques of circulating glucocorticoids. indicated that those animals that were DEX-resistant The effects of chronic social stress on plasma were also more than twice as likely to have come levels of CBG have also been examined in the VBS from unstable, rather than stable, social groups. How- model. Since glucocorticoids bound to CBG in blood ever, this result is in contrast with another study of are not able to cross membranes in order to interact rhesus macaques, in which animals exposed to un- with their intracellular receptors, alterations in CBG stable social groupings showed enhanced DEX sup- concentrations may play an important role in regu- pression of cortisol, compared to animals exposed lating the bioavailability of circulating CORT. Com- to stable social conditions (Capitanio et al., 1998). It pared to controls, all VBS-housed animals had should be noted that in the latter experiment, animals decreased circulating levels of CBG: this effect was were grouped together for only 100min per day, greater in the subordinates than in the dominants, rather than being housed continuously in social groups; and was most pronounced in the stress-nonresponsive the differences in experimental design may account, in subgroup of subordinates (McKittrick, 1996; Spencer part, for the seemingly contradictory results. et al., 1996). The observed decreases in CBG, par- ticularly in the nonresponders, combined with incre- ased CORT levels, may lead to higher levels of 9.4.2 Corticosteroid Receptors and CBG free bioactive CORT. This hypothesis is supported The biological effects of circulating glucocorticoids by the observation that the concentration of plasma can be modulated by alterations in the availability of CBG was significantly correlated with the number of intracellular steroid receptors and in circulating available (unoccupied) GRs in the spleen of the VBS levels of CBG. In both the VBS and tree shrew animals (Spencer et al., 1996). The increases in free models of social stress, chronic subordination led to CORT may be short-lived in the animals with low a decrease in the expression of glucocorticoid recep- CBG concentrations, however, as low CBG levels tor (GR) mRNAs in hippocampus. In the tree shrew, are correlated with an increased rate of glucocorti- 13 days of psychosocial stress led to a decline in GR coid clearance (Bright, 1995), most likely because mRNA levels in CA1 and CA3 of the hippocampus in CBG-bound CORT is not accessible to degradative subordinates compared to unstressed control subor- enzymes. dinates ( Jo¨hren et al., 1994). Similarly, subordinate rats housed in a VBS had lower mRNA levels of GR 9.4.3 Summary and mineralocorticoid receptor (MR) mRNA levels were lower in CA1 (Chao et al., 1993). This down- The above data indicate that, not surprisingly, social regulation of gene expression does not appear to subordination and defeat appear to be stressful, lead- translate into a corresponding change in GR binding ing to HPA-axis activation. Chronic social stress can in the hippocampus, hypothalamus, or pituitary of lead to long-term changes in HPA activity, including the subordinates, although it is likely that subtle persistent elevations in basal glucocorticoids, abnor- differences in binding in selective hippocampal mal responses to subsequent stressors, and impaired subfields may not be detectable in homogenates of feedback regulation. For the most part, these effects whole brain regions (Blanchard et al., 1995). How- are seen most clearly in subordinate animals housed ever, another group did find decreased GR binding in stable social groups; however, similar responses within the hippocampus and hypothalamus, but not have observed in dominant animals in such groups, the pituitary, in rats killed 1 week after social defeat; and also in animals of all ranks in unstable social by 3 weeks postdefeat, GR binding had returned groupings. In addition to altering the levels of circu- to control levels in all brain regions, but by that lating glucocorticoids, social stress may also lead to time point, hippocampal MR binding had declined changes in central GR populations and in peripheral significantly (Buwalda et al., 2001). A study of rats regulation of CBG, which may, in turn, modulate the housed in stable mixed-sex groups also demonstrated biological effectiveness of these steroids. Social Stress Effects on Hormones, Brain, and Behavior 347

9.5 Interactions between hypothalamus, hippocampus, and brainstem (Hilakivi Hormones and Brain Systems in et al., 1989), while repeated, but not single, social Social Stress defeat increased the midbrain 5HIAA/5HT ratio in defeated Lewis rats (Berton et al., 1998, 1999), The effects of psychosocial stressors on the brain are although these changes may habituate with time a topic of considerable interest to many researchers (Beitia et al., 2005). In addition, adult golden ham- for several reasons. First of all, unlike many labora- sters that had been socially defeated during puberty tory stressors, the stressfulness of social conflict tends had increased 5HT innervation of the lateral septum to be primarily of psychological, rather than physical, and anterior hypothalamus, suggesting that defeat led origin. Although some wounding may occur in social to an increase in the capacity to release 5HT in these dominance or defeat paradigms, in most cases, areas (Delville et al., 1998). Social defeat has also a full-blown stress response can be generated in a been shown to increase expression of c-fos in seroto- subordinate or defeated animal merely through nergic neurons of the dorsal raphe´ nucleus, specifi- visual and/or olfactory contact with the previously cally in subregions that are likely to play a role in encountered animal. The nonphysical nature of the behavioral and emotional responses to defeat social stressors makes them useful in generating mod- (Gardner et al., 2005). els of stress-related illnesses in humans, since rela- In addition to these rodent studies, various seroto- tively few people in modern society experience nergic parameters have been examined in nonhuman severe physical stressors in their lifetimes, while psy- primates. Subordinate talapoin monkeys had elevated chological stressors are relatively commonplace. levels of 5HIAA in their cerebrospinal fluid; this is Stressful life events have been associated with several believed to reflect increased 5HT neurotransmission mental illnesses, including depression and other in the brain (Yodyingyuad et al., 1985). In cynomol- affective disorders; many of these disorders, in turn, gous macaques, the stability of the social group appear to be linked to various neurochemical imbal- appeared to be more important than rank, as animals ances in the brain. Determining the effects of social that had previously been housed in unstable social stress on neuronal transmission may provide clues groups had lower 5HIAA and 5HT concentrations in regarding how stress alters behavior and physiology the prefrontal cortex, compared to animals main- in animals and humans alike. tained in social groups; however, these changes may have reflected adaptive responses following termina- 9.5.1 Neurotransmitter Systems tion of the stressor, since the level of 5HT in these animals was lower in those that had been housed in 9.5.1.1 Serotonin unstable colonies more recently (Fontenot et al., The transmitter system most widely studied in the 1995). Interestingly, one study showed that high context of social stress is the serotonergic system. levels of 5HT in the blood was associated with domi- Serotonin neurotransmission has been shown to be nant status in vervet monkeys, with 5HT levels altered by a variety of laboratory stressors, and sero- increasing or decreasing as the animal experienced a tonin (5-hydroxytryptamine; 5HT) also plays a role corresponding rise or fall in rank (Raleigh et al., in mediating many of the behaviors that contribute 1984). The relevance of these findings to central to, and are affected by, social status, including aggres- 5HT neurotransmission is unclear, however, since it sion and sexual behavior. The majority of studies is likely that peripheral and central serotonergic sys- suggest that 5HT systems are activated in response tems are regulated independently. to social stress. Examination of tissue concentrations Both pre- and postsynaptic receptors and trans- of 5HT and its metabolite, 5-hydroxyindole acetic porters for 5HT have been shown to be altered by acid (5HIAA), have shown elevated concentrations social stress. Perhaps the most consistent findings of 5HIAA and/or increased 5HIAA/5HT ratios in are a stress-related increase in binding to 5HT2A various brain regions of subordinate rats and mice, receptors in cortex and a corresponding decrease in suggesting increased serotonergic activity. In the VBS 5HT1A receptors in the hippocampus (McKittrick model of social stress, levels of 5HIAA are higher in et al., 1995; Flu¨gge, 1995; Berton et al., 1998). In addi- subordinates than in dominants and controls in limbic tion, in the VBS model, binding to presynaptic 5HT1A areas of the brain, such as the preoptic area, hippo- autoreceptors is preferentially downregulated in the campus, and amygdala (Blanchard et al., 1991b). Sim- median raphe of subordinate animals (McKittrick, ilarly, submissive mice had increased 5HIAA in the 1996). Further examination of the downregulation 348 Social Stress Effects on Hormones, Brain, and Behavior

of 5HT1A receptors in the hippocampus and else- 9.5.1.2 Norepinephrine where indicates that, in the tree shrew, this receptor The effects of chronic social stress on both pre- and subtype is regulated not only by increased gluco- postsynaptic elements of noradrenergic neurotrans- corticoid levels in the subordinates, but also by mission have been studied in both rat and tree shrew stress-induced suppression of testosterone, as binding models of psychosocial stress. Messenger mRNA was returned to control levels in most brain regions by levels of tyrosine hydroxylase, the rate-limiting exogenous administration of testosterone (Flu¨gge enzyme in catecholamine synthesis, were shown to et al., 1998). be selectively increased in noradrenergic, but not A single social defeat also led to a decrease dopaminergic, brain regions; in some cases, the in binding to the 5HT transporter in the hippocam- increased mRNA levels in the locus ceruleus (LC) pus (Berton et al., 1999). The relationship of the were accompanied by a corresponding increase in 5HT-transporter response to the severity of social immunoreactive tyrosine hydroxylase protein (Brady stress is unclear, however, since in our model, all et al., 1994; Watanabe et al., 1995). Since several dif- VBS-housed animals show a similar decrease in ferent stress paradigms have shown that the LC nor- 5HT transporter binding, with the most pro- adrenergic system is activated by stress, the changes in nounced effects occurring in the dominant animals tyrosine hydroxylase probably reflect an upregulation (McKittrick et al., 2000). The dominant animals do of synthetic capacity as a result of increased neuronal appear to be somewhat stressed compared to the pair- activity and transmitter release. housed controls, suggesting that the downregulation Functional alterations in noradrenergic systems of 5HT transporters may be part of an adaptive are also a consequence of social stress. Following response to mild social stress; conversely, the decrease three days of social crowding, male rats exhibited in binding may occur as simply as a result of agonistic a blunted CORT response to both isoprenaline, a interactions between the animals, without regard to b-adrenergic receptor agonist, and clonidine, an the relative stressfulness of these encounters. How- a2-adrenergic agonist; the hypothalamic histamine ever, Filipenko et al. (2002) found that the expression response to these two drugs was also attenuated of 5HT transporter mRNAwas upregulated following (Bugajski et al., 1993). However, crowding had little social defeat, suggesting that the stressor effects may effect on the CORT response to a1-adrenoceptor be model and/or species specific. agonist phenylephrine, suggesting that the various The functional effects of the changes in 5HT adrenergic receptor populations are differentially receptors are unclear. Defeated rats exhibit a blunted regulated as a result of social crowding. CORT response to the 5HT1A agonist 8-OH-DPAT, Adrenergic receptor subtypes are affected by sub- suggesting a functional subsensitivity of these recep- ordination stress as well, as shown in the tree shrew tors, a result that corresponds well with the observed model. After 10 days of social stress, a2-adrenoceptor decrease in receptor number (Korte et al., 1995; binding was downregulated in the subordinates Buwalda et al., 2005). In contrast, while an enhanced compared to dominants in several brain regions, response to 5HT2A stimulation might be expected, including periaqueductal gray (PAG), the periforni- the behavioral response to a 5HT2 agonist was cal region of hypothalamus, medial amygdala, the decreased, rather than increased, in defeated rats nucleus of the solitary tract (STN), and the dorsal (Benjamin et al., 1993). It should be noted, however, motor nucleus of the vagus (DMV); in addition, that in this particular experiment, the behavioral low-affinity binding sites were present in the STN, response was measured after a single social defeat, PAG, and medial amygdala of the dominants but not which does not lead to a measurable change in the subordinates (Flu¨gge et al., 1992). Time-course 5HT2-binding capacity (Berton et al., 1999), suggest- studies indicate that these receptors have different ing that the desensitization may occur through temporal patterns of regulation within individual changes in receptor-linked signal transduction path- brain regions. For example, in LC and DMV, binding ways or some other mechanism. Finally, in cyno- was decreased after only 2 days of psychosocial stress molgous monkeys, the hormonal responses to the and remained low throughout the period of subor- 5HT-releaser fenfluramine did not differ between dination (Flu¨gge, 1996). Binding in STN was simi- dominant and subordinate animals, indicating no dif- larly downregulated, although these changes were ferences in postsynaptic sensitivity to nonselective not apparent until day 21. In contrast, the response stimulation of 5HT transmission (Botchin et al., of a2-receptors in the prefrontal cortex was biphasic, 1994; Shively, 1998). with a transient decrease in binding at day 10, Social Stress Effects on Hormones, Brain, and Behavior 349 followed by a return to control values by day 21, and a response to social stress. In previously defeated rats, subsequent increase in binding at day 28. In addition, the threat of defeat elicits an increase in extracellular binding affinity of various a2-adrenoceptor subtypes DA content in both the prefrontal cortex and was altered in temporal and regional patterns distinct the nucleus accumbens, as measured using in vivo from the changes in receptor number. Further stu- microdialysis (Tidey and Miczek, 1996, 1997), indi- dies with this model have shown that a2A- and cating that these limbic areas are responsive to sti- a2C-receptor mRNA expression and binding also muli associated with social stressors. In these areas, have regionally specific upregulation; the changes in the dopaminergic responsiveness to subsequent social a2C-binding appear to be transient, while the upre- encounters has also been shown to be altered in gulation of the a2A-receptor persists at least 10 days socially defeated mice, although the nature of these after stressor cessation (Flu¨gge et al., 2003). alterations depends on both the nature of the social b-Adrenergic receptors are also regulated in a interaction and the sex of the other animal (Cabib similar complex manner in this model. Both b1- and et al., 2000). Chronic, but not acute, defeat in mice b2-adrenoceptors are transiently downregulated in increased the basal firing rate of dopaminergic neu- the prefrontal cortex after 2 days of subordination rons in the VTA, with this increase persisting for and upregulated in the pulvinar nucleus after 10 several weeks only in mice that also demonstrate and 28 days respectively; however, b1-adrenoceptors persistent physiological and behavior changes follow- are also decreased in the parietal cortex and hippo- ing stress (Krishnan et al., 2007). campus at 28 days (Flu¨gge et al., 1997). In addition, In nonhuman primates, binding and function of the affinity for b-adrenergic receptors was decreased the D2 DA receptor subtype is decreased in socially in the cortex and hippocampus following 21 days subordinate female cynomolgous monkeys. These of psychosocial stress. These complex changes in animals have decreased D2 receptor-binding capac- regional populations of adrenergic receptor subtypes ity in the basal ganglia, as indicated by positron indicate that the function of various noradrenergic emission tomography (PET) scanning after injection circuits may be differentially regulated in response to with 18-fluoroclebopride; in addition, the subordi- chronic stress; furthermore, this regulation may occur nates exhibited a blunted prolactin response to the via changes in receptor turnover, synthesis, and D2 antagonist, haloperidol, indicating a functional conformation. subsensitivity of these receptors (Shively et al., 1997a,b; Shively, 1998). In contrast, D2 receptor bind- 9.5.1.3 Dopamine ing is increased in the nucleus accumbens of sub- Unlike 5HT and norepinephrine, dopamine (DA) ordinate VBS animals (Lucas et al., 2004). D2 has only recently been considered to be a stress- binding is also increased in the dorsal striatum of responsive neurotransmitter. As a result, studies the nonresponsive subordinates, in conjunction with focusing on the effects of social stress on dopaminer- decreased binding to the DA transporter. DA trans- gic systems are relatively rare. In mice, dominants porter binding is also reduced in subordinate tree did have lower brainstem DA content than subordi- shrews in the caudate nucleus and putamen, with nate or control animals in one study (Hilakivi et al., no changes in the nucleus accumbens or VTA or 1989), while Beitia et al. (2005) observed a transient substantia nigra (Isovich et al., 2000). The altered increase in hypothalamic dihydroxyphenylacetic DA receptor and transporter densities are likely to acid: DA ratios following chronic social defeat. In reflect compensatory changes in response to dimin- monkey and rat social hierarchies, tissue content of ished activity of the mesolimbic DA system in these DA and its metabolites were unaffected by rank animals. Decreased DA tone may represent a mal- (Blanchard et al., 1991b; Fontenot et al., 1995). A adaptive response in these animals, and be associated similar lack of effect was observed on the regulation with the anhedonia observed in other models of of tyrosine hydroxylase in dopaminergic nuclei of chronic social stress (e.g., Rygula et al., 2005). the ventral tegmental area (VTA) and substantia nigra, in contrast to the increase in tyrosine hydroxy- 9.5.1.4 Amino acid transmitters lase mRNA and protein seen in noradrenergic nuclei Very few studies have examined the effects of social (Watanabe et al., 1995). stress on components of excitatory amino acid neu- More recent studies looking at dynamic changes rotransmission. However, Krugers et al. (1993) found in dopaminergic neurotransmission have demon- that a single social defeat was sufficient to lead to strated activation of the mesolimbic pathway in changes in the ratio of N-methyl-D-aspartic acid 350 Social Stress Effects on Hormones, Brain, and Behavior

(NMDA) and alpha-amino-3-hydroxy-5-methyl- after administration of the neuronal transport 4-isoxazolepropionic acid (AMPA) receptors in the blocker, colchicine, did not alter the AVP immunore- CA3 area of the hippocampus of rats: specifically, activity in ZEME in subordinate rats, however, sug- binding of [3H]CGP39653 to NMDA receptors was gesting that the encounter with the dominant did not increased in the stratum radiatum of CA3, while [3H] lead to AVP release in this area. In contrast, AVP CNQX binding to AMPA receptors was decreased in content was reduced in colchicine-treated animals this and other areas of hippocampus. following a single defeat, indicating that AVP release There also appear to be alterations in GABA-A and content are regulated differentially following receptors following defeat in mice. Northern blot acute and chronic social stress. analysis of both a1 and g2 GABA-A subunits has We used the VBS model to investigate the effects shown that mRNA levels of both subunits are of chronic social stress on mRNA for AVP and CRH. increased in cortex at 4 h postdefeat and remain mRNA levels for AVP were unaffected by social elevated for at least 72h, before falling to control stress in the PVN, but were significantly decreased levels after 7 days (Kang et al., 1991). Subunit in the medial amygdala, whereas CRH mRNA was mRNA levels were unchanged in the cerebellum increased in the central amygdala (Albeck et al., and hippocampus, while no changes were observed 1996). The changes in CRH mRNA in the PVN in any region in the brains of the resident animals that were a bit more complex. Mixed-sex housing in defeated the intruder mice. The increase in subunit the VBS increased CRH mRNA content in PVN in expression is likely to reflect a general upregulation both dominant and subordinate males compared to of the GABA-A receptor, but it may also indicate pair-housed controls, but only in those animals that changes in the subunit composition, and thus the retained relatively normal CORT responses to an electrical and pharmacological properties, of the acute stressor. It was hypothesized, at the time, that receptors. increased CRH expression contributed to the incre- ased basal CORT observed in the VBS animals; how- 9.5.1.5 CRH and vasopressin ever, a subsequent study by Choi et al. (2006) CRH and arginine-vasopressin (AVP) are known to demonstrated that the elevated CORT in subordi- be involved in the initiation and modulation of HPA- nates could occur independently of any changes in axis activity; in addition, extrahypothalamic CRH hypothalamic CRH mRNA levels. This dissociation and AVP circuits have been implicated in the media- between hypothalamic CRH and CORT was also tion of stress-related and social behaviors, respec- seen in mice, where chronic defeat was associated tively. As a result, the effect of social stressors on with elevated plasma CORT, despite control levels the expression and release of these two neuropep- of CRH mRNA in the PVN (Keeney et al., 2006). tides has been studied in a variety of animal models. Dysfunction at the level of the hypothalamic CRH Social subjugation, either in adulthood or in puberty, neurons may still contribute to the HPA-axis hypor- led to reduction in AVP stores in the anterior hypo- esponsiveness in the stress-nonresponsive subordi- thalamus of hamsters as determined by both fiber nates of the VBS, however, since CRH mRNA immunostaining and radioimmunoassay (RIA) of content was significantly lower in these animals com- extracts from tissue micropunches, suggesting decre- pared to the other groups (Albeck et al., 1996). ased AVP release within this brain region, which is The receptors for CRH have been shown to be involved in aggressive behavior in this species (Ferris differentially regulated in the tree shrew model of et al., 1989; Delville et al., 1998). Conversely, mea- social stress. After 24 days of psychosocial stress, sub- surement of AVP in samples collected using in vivo ordinates show a downregulation of CRH receptors microdialysis, indicates that social defeat enhances in brain regions involved in HPA-axis regulation, release of this peptide in another area of the hypo- including the anterior pituitary, dentate gyrus, and thalamus, the paraventricular nucleus (PVN), where CA1-CA3 of the hippocampus; binding was also it is believed to play a role in the modulation of the decreased in the superior colliculus (Fuchs and HPA-axis response (Wotjak et al., 1996). Similarly, Flu¨gge, 1995). Conversely, both the number of bind- AVP immunostaining was increased in the zona ing sites and the affinity of CRH receptors were externa of the median eminence (ZEME), a projec- increased in other areas of the brain, including the tion area of neurons originating in the PVN, in sub- frontal and cingulate cortex, the claustrocortex, ordinate colony-housed male rats (de Goeij et al., the central and lateral nucleus of amygdala, and the 1992). Inescapable interaction with the dominant choroid plexus. However, in all regions except the Social Stress Effects on Hormones, Brain, and Behavior 351 claustrocortex and the central amygdala, this increase expression has been studied in several different in receptor number was partially offset by a decrease species. In mice, defeat has been shown to increase in binding affinity. c-fos-like immunoreactivity in limbic and sensory Overall, it appears that social stress activates the relay areas, such as the cingulate cortex, lateral AVP and CRH neuropeptide circuits that are directly septum, bed nucleus of the stria terminalis (BNST), associated with activation and regulation of the HPA hippocampus, hypothalamus, amygdala, PAG, dorsal axis; an apparent increase in presynaptic activity is raphe, LC, and several brainstem sensory nuclei accompanied by a corresponding downregulation of (Matsuda et al., 1996; Nikulina et al., 1998). After a the postsynaptic elements, at least in the case of single defeat, c-fos expression returned to baseline CRH. In contrast, evidence from both hamsters and levels within 24 h, but with chronic defeat, a more rats indicates that subordination and defeat inhibit prolonged increase was observed (Matsuda et al., the extrahypothalamic AVP circuits involved in 1996). In contrast, while similar circuits were acti- aggressive and sexual behavior. Finally, while CRH vated in rats following a single defeat (e.g., Gardner mRNA is upregulated in extrahypothalamic areas, et al., 2005), the c-fos response in these animals the net effect of social stress on CRH neurotransmis- adapted with repeated defeat, so that c-fos expression sion in these areas is less clear, since the number and was increased only in BNST, PVN of hypothala- affinity of the postsynaptic receptors are altered in a mus, medial amygdala, and the medial and dorsal complex manner. raphe nuclei (Martinez et al., 1998). Similarly, in male Syrian hamsters, the c-fos response to repeated defeat habituated in the supraoptic nucleus, lateral 9.5.1.6 Other neuropeptides septum, central amygdala, and amygdalohippocam- The regulation of other stress-related peptides has pal area but remained high in the anterior and ven- been investigated in our VBS model of chronic social tromedial hypothalamic nuclei, dorsal PAG, and stress. Galanin, a 29-amino-acid neuropeptide, can be dorsal raphe (Kollack-Walker et al., 1999). However, found in approximately 80% of the tyrosine hydrox- the response in the PVN of hypothalamus adapted ylase-containing neurons in the LC. Chronic social with chronic defeat but remained significant in the stress leads to an increase in mRNA levels of pre- LC in hamsters, while the converse was true in rats. progalanin in the LC of the subordinate animals These variations may be related not only to differ- (Holmes et al., 1995). The levels of mRNA were ences among experimental protocols, but also to spe- positively correlated with the number of wounds cies-specific differences in the behavioral and per animal and negatively correlated with body cognitive response to social defeat. weight gain, suggesting that the degree of galanin gene expression was associated with the severity of the stress. The increase in preprogalanin mRNA in 9.5.3 Neuronal Structure and Survival the subordinate animals parallels that observed in Several studies have indicated that chronic stress tyrosine hydroxylase mRNA (see Section 9.5.1.3), affects neurons in the hippocampal formation in a indicating that the two mRNAs may be upregulated variety of ways, leading to alterations in dendritic mor- in tandem as the result of a stress-induced increase in phology, cell survival, and neurogenesis. A recent the activity of LC neurons. In addition, mRNA levels examination of the morphology of hippocampal neu- of proopiomelanocortin (POMC), the precursor to rons has found that significant shrinkage of the apical ACTH and b-endorphin, were increased in the ante- dendritic arbors of CA3 pyramidal neurons is seen in rior pituitary of subordinate rats (Brady et al., 1994). all animals in the VBS (McKittrick et al., 2000). There Again, the magnitude of the response correlated is a decrease in arbor complexity (branch points) in with wounding and weight loss, and also adrenal both dominants and subordinates while dominants weight, suggesting that the POMC response reflected have a reduction in total dendritic length as well. The stressor severity. observation that these changes occur to a similar (or greater) extent in dominants as well as in the more severely stressed subordinates suggests that dendritic 9.5.2 Immediate Early Gene Expression remodeling may be a common response to chronic Expression of immediate early genes, such as c-fos,is activation of the HPA axis but does not vary signifi- often used as an identifier of neural circuits activated cantly with the severity of the stress. This conclusion is by a given stimulus. The effect of social defeat on c-fos supported by data showing similar degrees of dendritic 352 Social Stress Effects on Hormones, Brain, and Behavior atrophy in animals subjected either to the relatively Indeed, several groups have characterized the wide- mild stressor of repeated restraint or to a more spread changes in gene expression associated with severe chronic variable stress regimen (Magarin˜os chronic social stress using proteomic and genomic and McEwen, 1995). analyses (cf. Carboni et al., 2006; Feldker et al., A study of tree shrews has shown similar dendritic 2006; Kroes et al., 2006; the details of these studies atrophy in subordinates compared to unstressed con- are beyond the scope of the current review). Overall, trols, although pyramidal cell morphology in domi- social stress, like other stressors, seems to induce a nant animals was not examined (Magarin˜os et al., net stimulation of serotonergic and noradrenergic 1996). In addition to dendritic atrophy, chronic social neurons, although the functional outcome of incre- stress also led to a time-dependent increase in the ased transmitter release is likely to be modulated by staining intensity of the nucleoplasm of CA1 and region- and time-specific factors in receptor popula- CA3 pyramidal cells, indicating alterations in nuclear tions. Few studies have been conducted examining chromatin structure, but these changes were not the effects of social stress on other classical transmit- accompanied by signs of neuronal degeneration or ter systems, although social stress has been shown to cell loss (Fuchs et al., 1995, 2001;Vollmann-Honsdorf modify various aspects of dopaminergic, GABAergic, et al., 1997). However, the number of bromodeoxyur- and excitatory amino acid transmission. In neuropep- idine (BrdU)-labeled cells was decreased within the tide systems, CRH and AVP pathways involved in the dentate gyrus of subordinate tree shrews, compared HPA-axis response appear to be activated by social to controls, indicating that neurogenesis in this part stress, while extrahypothalamic AVP and CRH are of the hippocampus is inhibited by chronic social inhibited and stimulated, respectively, although the stress (Gould et al., 1997). Neurogenesis in the den- effects on CRH may only exist in the context of tate gyrus was also reduced in mice following social abnormal HPA-axis responsivity. Chronic social defeat (Mitra et al., 2006; Yap et al., 2006). In contrast, stress can alter the morphology of hippocampal neu- dominant animals had increased neurogenesis in a rons, which may affect learning and memory pro- variant of the VBS that used Sprague–Dawley rats, cesses in these animals. Finally, although there is no although subordinates did not differ from controls; evidence that chronic subordination actively incre- markers of cell proliferation were not increased, ases neurodegeneration (i.e., by inducing apoptotic suggesting that the increase in new neurons was processes), it has been shown to retard neurogenesis due to enhanced survival rather than proliferation within the dentate gyrus by compromising cell sur- (Kozorovitskiy and Gould, 2004). vival. Together, these results indicate that social stress Far more pronounced pathological changes were can have profound consequences on the brain; further found in the hippocampus of vervet monkeys that study is needed to determine which of these changes died spontaneously at a primate center in Kenya. are adaptive and which can lead to pathological These animals exhibited signs of severe stress, such changes in brain function and behavior. as gastric ulcers and enlarged adrenals, and several also showed evidence of social conflict, such as bite marks. When compared to animals euthanized for 9.6 Reproductive Aspects of Social other reasons, the stressed monkeys showed evidence Stress: Hypothalamic–Pituitary– of neurodegeneration in Ammon’s horn, especially Gonadal Axis CA3, including reduced perikarya size, dispersed Nissl bodies, increased vesicle number, and decreased It is well established that stress suppresses repro- dendritic width (Uno et al., 1989). However, it must ductive function (Selye, 1950; Bliss et al., 1972; Rose be noted that these animals are presumed to have and Sachar, 1981). The concept of stress, however, died from stress-related causes, which indicates a embraces a large range of diverse phenomena, and severity of stress much greater than that seen in further subdivision of terms is helpful for the sake most other social stress paradigms. of clarity. Stressors are the aversive conditions or stimuli that provoke responses in animals which, in total, are termed the stress response. The stress res- 9.5.4 Summary ponse was first called the general adaptation syn- As described above, social stress leads to many drome by its discoverer, Hans Selye (1946),in changes in the brain, affecting neuronal structure reference to physiological adjustments made to com- and survival as well as neurochemical transmission. pensate for the stressor and preserve the internal Social Stress Effects on Hormones, Brain, and Behavior 353 milieu in the body. The adjustments, while adaptive for males compared to females. This is attributable to in the short term, can have harmful effects in the the higher levels of testosterone in males, relative to chronic setting (Shanks et al., 1998) The postulated females, and the role of testosterone in promoting adaptive value of the stress response traces its evo- the aggressive behavior that leads to stressful attacks lutionary origin to the flight-or-fight cascade of (Monaghan and Glickman, 1992). Female hyenas, neuroendocrine events that ensue when an animal which are unusually aggressive due to high levels of confronts a potential predator (Sapolsky, 1992b). In androgen production by the adrenal gland, are an the threatened animal, the sequential rapid release exception to the rule ( Jenks et al., 1995). In females, of CRH from hypothalamic neurons and ACTH there is abundant evidence that social interactions by the pituitary stimulates a massive outpouring of can play a role in suppressing reproductive function, glucocorticoid from the adrenal gland, which serves including both reductions in sexual behavior and to mobilize glucose in the blood for needed energy suppression of ovulation (Saltzman et al., 1994). As (Hers, 1986; Munck and Guyre, 1986). Simulta- noted under Section 9.4.1, alterations in ovulation neously, heightened sympathetic nervous system and changes in HPA-axis activity are both associated activity and release of epinephrine and norepineph- with social stratification in females of a number of rine increase the heart rate, and secretion of endor- primate species, but the relationships among these phins blunts the sensation of pain should tissue injury factors appear to be complex and to differ from one be inflicted (Hedman et al., 1990). It is thought that species to another. the stress response is survival-related in the presence In males, the ability to impose social stress on a of a predator but harmful when it occurs inappropri- subordinate is one mechanism of sexual selection. If ately and is prolonged. the dominant male suppresses reproductive function in the subordinate males, his exclusive access to females ensures preferential perpetuation of the dominant’s 9.6.1 Stress and Reproductive Functioning genes. Consistent with this hypothesis, crowding exp- Evidence from studies of numerous animal species eriments have provided a dramatic demonstration of has shown that suppression of reproductive func- the consequences of social stress (reviewed by Bronson tion is associated with the stress response. Here the (1989)). At the start of such experiments, one or two adaptive significance may lie in the preservation breeding pairs of mice are put into a large, physically of the species, with the stress response providing complex cage and allowed to breed. Aggression bet- a physiological cue that external conditions are ween males increases as the population size and unfavorable for reproduction (Handelsman and its density increase. Eventually, the population size Dong, 1992). Naturally occurring social stressors, within the cage self-regulates, at which point reproduc- the focus of this chapter, appear to fall broadly into tion by all but a few adult animals, the dominants, two categories: crowding (e.g., in snowshoe hares, stops entirely. Boonstra and Singleton (1993)) and subordinate In populations where there is social stratification status in social dominance hierarchies (which will be among individuals, low-ranking animals generally termed social stress). In both cases, competition for have lower reproductive fitness and engage in fewer food or access to a mate leads to aggressive encounters sexual encounters than high-ranking individuals between individuals that, when repeated and unpre- (Calhoun, 1962; von Holst, 1977; Sapolsky, 1982; dictable, become an aversive stimulus or stressor. Blanchard and Blanchard, 1990). The stressful nature Stress-induced elevations in glucocorticoids have of subordination is likely to play a role in the inhibi- been implicated as the principal mediators of the tion of male reproductive function in these situations. inhibition in reproductive function, both directly – Subordinate males often have lower testosterone through reductions in the gonadal responsiveness titers compared to dominants, particularly during to gonadotrophins (Charpenet et al., 1981; Orr and establishment of social hierarchies (Rose et al., 1971; Mann, 1992) – and indirectly – through inhibition Coe et al., 1979; Mendoza et al., 1979; von Holst of the gonadotrophins themselves (Sapolsky, 1985; et al., 1983; Sachser and Pro¨ve, 1986; Sachser and Norman and Smith, 1992; Akimbami et al., 1994). Lick, 1989; Dijkstra et al., 1992). Defeat by a conspe- The association between social stress and cific can lead to a rapid decline of plasma testosterone glucocorticoid mediated inhibition of reproductive (Rose et al., 1975; von Holst, 1977; Schuurman, 1980; function has been established for both sexes Sachser and Lick, 1989, 1991), whereas social vict- (Marchlewska-Koj, 1997), but is defined more clearly ories may lead to an increase in testosterone levels in 354 Social Stress Effects on Hormones, Brain, and Behavior dominants (Coe et al., 1982; Bernstein et al., 1983; controls rats housed in standard rat cages with a Sachser and Pro¨ve, 1986). In addition, subordinate female (Blanchard et al., 1993). LH as well as testos- animals also have a larger and more prolonged inhi- terone was also lower in the subordinate animals, bition of testosterone and gonadotrophins following suggesting overall suppression of the HPG axis; exposure to other, nonsocial stressors, while domi- these decreases did not become apparent until at nants may have a smaller decline or a transient rise least day 7 of colony housing (Hardy et al., 2002). in testosterone (Bronson, 1973; Sapolsky, 1986). As with the dominant animals (see above), the lower activity is context dependent, rather than character- 9.6.1.1 Reproductive hormone levels in istic of individual animals. The decrease in testoster- dominant males one in these animals is likely to be the result of the Aggressiveness has been found to be positively corre- stress-induced increases in CORT, acting indirectly lated with testosterone levels in primates. However, to suppress LH secretion, and directly on the Leydig increased aggression is not necessarily correlated with cells themselves (see Section 9.6.2). dominance in these populations (Sapolsky, 1982; Similar reductions in testicular androgen produc- Bernstein et al., 1983). In rodents, castration decreases tion have been shown for other animal populations aggressive behaviors, an effect that can be reversed by with hierarchical social structures (Mendoza et al., testosterone replacement (Brain, 1983). Clamping 1979; Coe et al., 1979; von Holst et al., 1983; Sachser testosterone levels by castration and steroid replace- and Pro¨ve, 1986). Repeated agonistic encounters may ment has been shown to have no behavioral effect on play a role in maintaining the low testosterone levels competitive interactions and agonistic behavior. In in the subordinate animals. In a wide variety of rodent primates, social defeat seems to play a role in perpe- models, laboratory stressors have been shown to lead tuating the difference in testosterone levels between to a rapid suppression of testosterone secretion (Gray dominant and subordinate animals, as the differences et al., 1978; Tache´ et al., 1980; Charpenet et al., 1981; are most prominent during hierarchy formation, but Collu et al., 1984b; Armario and Castellanos, 1984; may disappear when the hierarchy has stabilized Bidzinska et al., 1993; Srivastava et al., 1993). Simi- and aggressive encounters become less frequent larly, stress leads to a decline in plasma testosterone (Rose et al., 1971; Sapolsky, 1982; Coe et al., 1982). levels in primates, including man (Aakvaag et al., Although the majority of agonistic encounters in the 1978; Coe et al., 1978; Wheeler et al., 1984; Sapolsky, VBS occur within the first fewdays of colony formation, 1985; Norman and Smith, 1992). Although many of there is still a low, but significant, degree of fight- these changes in androgen levels may be associated ing throughout the remainder of the housing period with elevated glucocorticoid secretion, stress may (Blanchard et al., 1995). Significant increases in LH decrease androgen levels through glucocorticoid- and testosterone were found in dominant males, com- independent mechanisms as well (Gray et al., 1978; pared to controls, on day 4, when the hierarchy was still Tache´ et al., 1980; Rivest and Rivier, 1991). being established, but the values of these hormones returned to control levels by days 7 and 14, when the 9.6.2 HPA/HPG Interactions in Socially hierarchy, and the level of fighting, had stabilized Stressed Males (Hardy et al., 2002). These data suggest that in the dominant males, increased hypothalamic–pituitary– Regulation of testosterone secretion in socially gonadal (HPG) activity is context-dependent and stressed animals is complex, as both stress and gluco- occurs in response to the transient increase in aggres- corticoids have been shown to affect testosterone sion, rather than being a characteristic of the individual synthesis and secretion at several different levels. animals who go on to become dominant (in which case, ACTH and CRH have been shown to inhibit test- testosterone should be higher at all time points). In osterone secretion in animals and man (Schaison situations where there is continued fighting in social et al., 1978; Vreeburg et al., 1984; Rivier and Vale, groups, however, the difference in testosterone between 1985; Mann et al., 1987), with a concomitant decrease socialranksismaintained(Sachser and Pro¨ve, 1986). in LH in some cases (Vreeburg et al., 1984; Rivier and Vale, 1985). These effects can be blocked by adrenal- 9.6.1.2 Androgen levels in subordinate males ectomy (Vreeburg et al., 1984; Rivier and Vale, 1985; In rats housed in the VBS, chronic social stress leads Mann et al., 1987) or inhibition of cortisol synthesis to declines in circulating levels of testosterone in with metyrapone (Schaison et al., 1978), suggesting a subordinate males, as compared to dominants and primary role of glucocorticoids. In rats and humans, Social Stress Effects on Hormones, Brain, and Behavior 355 glucocorticoid administration leads to a reduction Leydig cells contain high concentrations of 11b-HSD, in testosterone levels (Doerr and Pirke, 1976; an enzyme that oxidatively inactivates CORT. It has Schaison et al., 1978; Mann et al., 1987; Urban been postulated that this enzyme serves to modulate et al., 1991) while GRs on the Leydig cells in the the effects of CORT by regulating intracellular glu- testis provide a possible anatomical substrate for cocorticoid concentrations (Monder et al., 1994a). In this effect (Stalker et al., 1989). Glucocorticoids act the VBS, subordinate rats were shown to have lower directly on the testes by inhibiting Leydig cell sensi- testicular 11b-HSD activity than dominants and con- tivity to gonadotropins. DEX and CORT treatment trols (Monder et al., 1994b), indicating that chronic reduce basal testosterone levels and decrease binding social stress may lead to decreased testosterone pro- to testicular LH/human chorionic gonadotropin duction via a decrease in the protective effects of (hCG) receptors (Bambino and Hsueh, 1981; Mann 11b-HSD within the testes. Indeed, recent studies et al., 1987). The functional significance of the dec- by Hu et al. (2008b) have shown that administration rease in LH receptor is shown by the blunted androg- of CORTalong with an inhibitor of 11b-HSD leads to enic response to hCG in glucocorticoid-treated animals elevation of serum CORT above that seen with and humans (Bambino and Hsueh, 1981; Mann et al., CORT alone. At the same time, serum testosterone 1987; Schaison et al., 1978). Incubation with various declined, with no effects on LH, suggesting that the natural and synthetic glucocorticoids leads to a similar suppression of testosterone was a result of a CORT- decrease in steroidogenesis in cultured testicular cells, mediated increased inhibition of synthesis, rather an effect that can be reversed by the GR antagonist than a decrease in stimulation. The ability of CORT mefipristone (RU 486) (Bambino and Hsueh, 1981; Orr to inhibit 11b-HSD appears to be independent of and Mann, 1992). activation of intracellular GRs, although the exact In contrast to exogenous glucocorticoids, the dec- mechanism remains unclear (Hu et al., 2008a). Addi- rease in testosterone synthesis following stress does not tional glucocorticoid-independent mechanisms of appear to be mediated by alterations in LH/hCG stress-induced testosterone suppression, which may receptor binding (Tache´ et al., 1980; Orr and Mann, involve endogenous opiates and/or nitric oxide, 1990). The responses of the testes from stressed ani- may also contribute to the suppression of testosterone mals, to gonadotropin stimulation is blunted, however, in VBS animals (Kostic et al., 1998, 1999). both in vivo (Charpenet et al., 1981; Sapolsky, 1985)and Although stress has been shown to decrease LH in vitro (Charpenet et al., 1981; Collu et al., 1984a; secretion in some instances (Bronson, 1973; Gray Orr and Mann, 1990). Testosterone synthesis following et al., 1978; Tache´ et al., 1980; Sapolsky, 1985; Rivier incubation of Leydig cells with hCG, dibutyryl cAMP, et al., 1986; Lo´pez-Caldero´n et al., 1991; Rivest and or cholera toxin is decreased in stressed rats, despite Rivier, 1991; Norman and Smith, 1992), a decrease in comparable levels of cellular cAMP production; testosterone is not always accompanied by a con- similarly, basal cAMP content in Leydig cells is comitant decrease in plasma LH (Puri et al., 1981; comparable between stressed and unstressed rats Charpenet et al., 1981; Mann and Orr, 1990; (Charpenet et al., 1981). This suggests that the stress- Akimbami et al., 1994; Orr and Mann, 1992). Decreases induced impairment in testicular sensitivity to gona- in LH, when observed, appear to be a result of decre- dotropins occurs at a site distal to second-messenger ased hypothalamic gonadotropin-releasing hormone production, perhaps at the level of second messenger– (GnRH) stimulation (Coe et al., 1982; Bidzinska et al., effector coupling. Changes in coupling, in turn, may 1993) and increased opioid-mediated inhibition of affect the synthetic capacity of the testes, since central LH release (Sapolsky and Krey, 1988; Bidzinska stress has been shown to decrease the activities et al., 1993; Akimbami et al., 1994). The inhibitory (Vmax) of 17-hydroxylase-17,20-lyase, and 3-hydroxy- effects of the opioid system appear to be mediated steroid dehydrogenase (3-HSD), which are involved in primarily through m-andk-receptor subtypes testosterone steroidogenesis (Srivastava et al., 1993; (Sapolsky and Krey, 1988).Thestress-inducedtestos- Akimbami et al., 1994). Similar inhibition of androgen terone suppression can also be blocked by peripheral synthetic enzyme activity has been induced by gluco- opioid-receptor antagonism. corticoids in vitro (Welsh et al., 1982; Hales and Payne, The exact mechanism of testosterone suppression in 1989; Agular et al., 1992). the VBS animals is not known. Further studies will be The inhibitory effects of glucocorticoids on tes- necessary to elucidate the temporal progression of the tosterone synthesis may also be regulated by changes changes in testosterone, and the testicular synthetic in the bioavailability of CORT to the testes. Testicular capacity and responsiveness to gonadotropin. It is likely 356 Social Stress Effects on Hormones, Brain, and Behavior that the stress-related changes in testosterone secre- Acknowledgments tion involve a combination of the central and periph- eral effects of stress and glucocorticoids described The authors would like to acknowledge the partici- above, including central inhibition of GnRH and LH, pation of Randall R. Sakai, Kellie L.K. Tamashiro, decreased testicular responsiveness to LH, and dec- Mary M.N. Nguyen, and Bruce S. McEwen in the reased testicular degradation of CORT. Visible Burrow System (VBS) work reported here. Supported by NSF IBN 28543.

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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 environmental manipulations, 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 College and her PhD from Rockefeller University, with qualifications in neuroscience, biochemistry and gene expression, and cell biology.

D. Caroline Blanchard received her PhD from the University of Hawaii. She has served as president of the International Society 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, Go¨ttingen, 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 the Journal 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 Workshop LLC, a biennial international meeting for scientists working on male fertility and infertility. Hardy received his undergraduate 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 on ethoexperimental 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, Go¨ttingen, and Tel Aviv.