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The enzyme steroid 5α-reductase 2 (5αR2) catalyzes the conversion of testosterone into the potent androgen 5α-dihydrotestosterone. Previous investigations showed that 5αR2 is expressed in key brain areas for emotional and socio-affective reactivity, yet the role of this enzyme in behavioral regulation remains mostly unknown. Here, we profiled the behavioral characteristics of 5αR2 heterozygous (HZ) and knockout (KO) mice, as compared with their wild-type (WT) littermates. While male 5αR2 KO mice displayed no overt alterations in motoric, sensory, information-processing and anxiety-related behaviors, they exhibited deficits in neurobehavioral correlates of dominance (including aggression against intruders, mating, and tube dominance) as well as novelty-seeking and risk-taking responses. Furthermore, male 5αR2 KO mice exhibited reduced D(2)-like dopamine receptor binding in the shell of the nucleus accumbens - a well-recognized molecular signature of social dominance. Collectively, these results suggest that 5αR2 is involved in the establishment of social dominance and its behavioral manifestations. Further studies are warranted to understand how the metabolic actions of 5αR2 on steroid profile may be implicated in social ranking, impulse control, and the modulation of dopamine receptor expression in the nucleus accumbens.

Summary Growing evidence has indicated that gonadal and stress hormones interact to shape socially dominant behavior and externalizing psychopathology; however, such work to date has focused exclusively on the testosterone–cortisol interaction, despite expectations that estradiol should be associated with similar behavioral outcomes to testosterone. Here, we present the first empirical test of the hypothesis that adolescent males and females ( N = 105, ages 13–18) with high estradiol and low cortisol concentrations are at highest risk for externalizing problems, but – replicating previous work – only among adolescents high on pathological personality traits. Parents reported on youth psychopathology and personality, and hormone concentrations were measured via passive drool. Results confirmed the hypothesis: high estradiol was associated with more externalizing behaviors, but only when cortisol was low and personality traits of disagreeableness and emotional instability were high. Further, these associations held when controlling for testosterone concentrations. These findings provide the first empirical evidence of a hypothalamic pituitary adrenal (HPA) × hypothalamic pituitary gonadal (HPG) axis interaction that extends the “dual hormone” hypothesis beyond testosterone.

Population density is known to influence acute measures of hypothalamic-pituitary-adrenal (HPA) axis activity in a variety of species, including fish, deer, birds, and humans. However, the effects of population density on levels of chronic stress are unknown. Given the fact that exposure to chronically elevated levels of circulating glucocorticoids results in a host of health disparities in animals and humans alike, it is important to understand how population density may impact chronic stress. We assessed hair cortisol concentrations (HCCs), which are reliable indicators of chronic HPA axis activity, in rhesus monkeys (Macaca mulatta) to determine the influence of population density on these values. In Experiment 1, we compared HCCs of monkeys living in high-density (HD; 1 monkey/0.87m(2)) and low-density (LD; 1 monkey/63.37m(2)) environments (N=236 hair samples) and found that HD monkeys exhibited higher hair cortisol across all age categories (infant, juvenile, young adult, adult, and aged) except infancy and aged (F(5)=4.240, p=0.001), for which differences were nearly significant. HD monkeys also received more severe fight wounds than LD monkeys (χ(2)=26.053, p

Social stress has long been known to affect physical and psychological health in humans and a variety of animal species. In mice, disruption of the social hierarchy (social disruption, SDR) resulted in significant changes in the phenotype and function of immune cells taken from the spleen. Interestingly, there were considerable individual differences in the development of this splenic response to SDR. Studies have suggested that these individual differences were mediated by behavioral factors such as social hierarchy. To test this hypothesis, social status within cages of male mice was identified before and after SDR. Results showed that in the majority of the cages social order was stable over time. In addition, examination of the association between social status and splenic function showed that the splenic response to SDR in subordinate mice was significantly augmented compared to dominants. This relationship between subordinate social status and the splenic response to social stress was more notable in cages with stable social hierarchies. To sum up, the current study showed a role for socio-behavioral factors in determining the response to stress. This study further demonstrated the complexity of factors playing a role in mediating the physiological response to social stress resulting in considerable individual differences in the response to stress.

It was repeatedly shown that glucocorticoids increase aggressiveness when subjects are socially challenged. However, the interaction between challenge exposure and glucocorticoid effects was not investigated yet. We studied this interaction by assessing the effects of glucocorticoids in established colonies of rats, i.e. in rats that were not exposed to an acute social challenge. Aggressiveness was high immediately after colony formation but decreased sharply within 4 days and remained stable thereafter. Mild dominance relations were observed in 11 colonies (65%). Approximately three weeks after colony formation, rats remained undisturbed or were injected with vehicle or corticosterone. Routine colony life was followed for 1h after treatments. Injections per se induced a mild and transient behavioral activation: resting was reduced, whereas exploration, social and agonistic interactions were increased. The change lasted about 15min. Corticosterone--although plasma corticosterone levels were increased--had no specific effect, as the behavior of vehicle- and corticosterone-treated rats was similar. Social rank had a minor impact on the results. In contrast, the pro-aggressive effects of corticosterone were robust under conditions of social challenge and were maintained after repeated exposure to aggressive encounters. It occurs that an acute increase in glucocorticoids promotes social challenge-induced aggressiveness, but does not increase aggressiveness under routine conditions. We hypothesize that the pro-aggressive effects of glucocorticoids develop in conjunction with challenge-induced neuronal (e.g. monoaminergic) activation.

Men's testosterone is associated with several constructs that are linked to dominance rank, such as risk-taking, mating success, and aggression. However, no study has directly tested the relationship between men's self-perceived dominance and testosterone using an experimental design. We employed a within-subjects, double-blind, placebo-controlled paradigm to assess whether testosterone influences men's self-perceived dominance. Exogenous testosterone or a placebo was administered to healthy adult men and self-perceptions of physical dominance were subsequently assessed by having participants select what they believed to be their true face from an array of images digitally manipulated in masculinity. Men picked a more masculine version of their own face after testosterone versus placebo--an effect that was particularly pronounced among men with relatively low baseline testosterone. These findings indicate that a single administration of testosterone can rapidly modulate men's perceptions of their own physical dominance, which may explain links between testosterone and dominance-related behaviors.

Environmental enrichment may protect against some of the adverse behavioural and biological effects of stressors. However, unlike the effects seen in some species, among male mice housed in groups, enrichment may alter social stability, encourage competition and aggression, and thus promote the establishment of a stressful environment. A potent psychosocial stressor such as social defeat in mice promotes brain neurochemical changes as well as pro-inflammatory cytokine variations in the prefrontal cortex (PFC) and hippocampus. The present investigation demonstrated that enrichment in group-housed male mice, even in the relatively nonaggressive, although highly anxious BALB/cByJ strain encouraged the effects of a repeated social defeat stressor experienced 4 weeks later, especially with respect to corticosterone as well as hippocampal corticotropin-releasing hormone (CRH) and interleukin (IL)-6 variations. Moreover, within the hippocampus, enrichment itself was accompanied by modest reductions in the expression of the IL-1β receptor (IL-1r1). Thus, it seems that living in an enriched environment among group-housed male mice might promote a stressful environment that enhances basal hippocampal CRH and cytokine variations and increased vulnerability to further changes upon subsequent exposure to a social stressor.

A cascade of neuroendocrine events regulates the initiation and progression of female puberty. However, the factors that determine the timing of these events across individuals are still uncertain. While the consequences of puberty on subsequent emotional development and adult behavior have received significant attention, what is less understood are the social and environmental factors that actually alter the initiation and progression of puberty. In order to more fully understand what factors influence pubertal timing in females, the present study quantified social and emotional behavior; stress physiology; and growth and activity measures in juvenile female rhesus monkeys to determine what best predicts eventual puberty. Based on previous reports, we hypothesized that increased agonistic behavior resulting from subordinate status in their natal group, in combination with slowed growth, reduced prosocial behavior, and increased emotional reactivity would predict delayed puberty. The analyses were restricted to behavioral and physiological measures obtained prior to the onset of puberty, defined as menarche. Together, our findings indicate that higher rates of aggression but lower rates of submission received from group mates; slower weight gain; and greater emotional reactivity, evidenced by higher anxiety, distress and appeasing behaviors, and lower cortisol responsivity in response to a potentially threatening situation, predicts delayed puberty. Together the combination of these variables accounted for 58% of the variance in the age of menarche, 71% in age at first ovulation, and 45% in the duration of adolescent sterility. While early puberty may be more advantageous for the individual from a fertility standpoint, it presents significant health risks, including increased risk for a number of estrogen dependent cancers and as well as the emergence of mood disorders during adulthood. On the other hand, it is possible that increased emotional reactivity associated with delayed puberty could persist, increasing the risk for emotional dysregulation to socially challenging situations. The data argue for prospective studies that will determine how emotional reactivity shown to be important for pubertal timing is affected by early social experience and temperament, and how these stress-related variables contribute to body weight accumulation, affecting the neuroendocrine regulation of puberty.

An increasing body of evidence suggests that glucocorticoids--besides their well-known genomic effects--can affect neuronal function via mechanisms that do not involve the genome. Data obtained mainly in amphibians and birds suggest that such mechanisms play a role in the control of behavior. Acute glucocorticoid treatments increase aggressive behavior in rats, but the mechanism of action has not been investigated to date. To clarify the issue, we have assessed the aggressiveness of male rats after treating them with the corticosterone synthesis inhibitor metyrapone, corticosterone, and the protein synthesis inhibitor cycloheximide. Metyrapone applied intraperitoneally (i.p.) decreased the aggressiveness of residents faced with smaller opponents. Corticosterone administered i.p. 20 or 2 min before a 5-min encounter abolished these changes irrespective of the delay of behavioral testing. Thus, the effects of glucocorticoids on aggressive behavior occurred in less than 7 min (the delay and duration of testing taken together), and lasted more than 25 min. Corticosterone applied centrally (infused into the right lateral ventricle) also stimulated aggressive behavior rapidly, which shows that the effect was centrally mediated. The protein synthesis inhibitor cycloheximide did not affect the aggression-promoting effects of corticosterone when the hormone was injected 2 min before the aggressive encounter. Surprisingly, however, the effects were completely abolished when the hormone was injected 20 min before the encounter. These data suggest that glucocorticoids rapidly increase aggressive behavior via non-genomic mechanisms. In later phases of the aggressive encounter, aggressive behavior appears to be stimulated by genomic mechanisms.

Previous experiments with chronically coexisting groups of Long-Evans rats indicated differences in many aspects of blood cellular immunity between winner and loser rats. The present study investigated the specific hormonal response patterns of winners and losers in relation to changes in numbers of blood immune cells. At the beginning of a 7 day period of chronic confrontation, a partition wall was removed between two neighboring rat groups, each containing a male-female pair. Fights for dominance between the males resulted in fast establishment of stable dominance relationships. At day 7 of the confrontation, winner males showed stable concentrations of CBG (corticosteroid-binding globulin) and even reduced titers of total CORT (corticosterone). In contrast, a marked decrease in CBG and unaffected total CORT concentrations were determined in loser males. Increased norepinephrine (NE) and epinephrine (E) titers were evident only in losers. In addition, reduced testosterone titers were observed in the bitten loser male subgroup. All male subgroups lost body mass with most pronounced reductions in loser males. Confrontation caused a marked granulocytosis, especially in loser males. NE concentrations in loser males correlated with the percentage of granulocytes. Numbers of CD4 T-cells were lowered in all loser males and in non-biting winners. In not-bitten losers also a reduced number of CD8 T-cells was determined. Interestingly, higher pre-confrontational NE titers were detected in future bitten loser and future biting winner males relatively to not-bitten losers and non-biting winners. The present report indicates that differential hormonal response patterns may play an important role in some of the immunological differences observed between winner and loser males under stressful social conditions.

(1) Aggressive behavior, motor activity and defecation were examined simultaneously in wild male mice following daily ACTH administration. (2) Aggression increased during treatment on days 1–4 and decreased during treatment on days 4–7. (3) Motor activity, not associated with aggressive behavior, was decreased with ACTH. (4) Defecation was decreased with ACTH and increased in victors of both groups in comparison with losers. (5) Results are discussed with respect to the dissociable and time-dependent effects of ACTH and the construct of emotionality.