Cheryl M. McCormick

Sex-specific effects of prenatal stress on hypothalamic-pituitary-adrenal responses to stress and brain glucocorticoid receptor density in adult rats

Previous research indicates that the offspring of dams exposed to stress during late gestation show altered hypothalamic-pituitary-adrenal (HPA) responses to stress. However, the results are inconsistent and a review of the literature suggests that the effects may differ depending upon the gender of the offspring. In the present study, we measured plasma adrenocorticotropin (ACTH) and corticosterone (B) levels prior to, and at 0, 20, 40 and 70 min following restraint stress in catheterized adult male and female offspring of dams stressed in the last week of gestation (i.e. days 15-19 of gestation). Prenatal stress significantly increased both plasma ACTH and B levels in response to restraint, but only in females; male offspring were largely unaffected. In addition, plasma corticosteroid-binding globulin (CBG) levels were significantly increased in prenatally-stressed females, but not in males. Despite these differences in plasma CBG, estimated free B levels following restraint were also significantly elevated in prenatally-stressed females. We then examined glucocorticoid receptor binding in a variety of forebrain structures. Prenatal stress had no effect on glucocorticoid receptor density in the hypothalamus or hippocampus in either males or females. Differences in glucocorticoid receptor density across groups were observed in the septum, frontal cortex, and amygdala. However, the pattern of observed differences across the groups was not consistent with the pattern of hormonal differences. In summary, the effect of prenatal stress on HPA function is substantially more marked in females than in males. Interestingly, a similar pattern of effects on HPA activity has been reported for prenatal alcohol exposure.

HPA function in adolescence: Role of sex hormones in its regulation and the enduring consequences of exposure to stressors

The hypothalamic-pituitary-adrenal (HPA) axis is one of the physiological systems involved in coping with stressors. There are functional shifts in the HPA axis and its regulation by sex hormones over the lifespan that allow the animal to meet the challenges of the internal and external environment that are specific to each stage of development. Sex differences in HPA function emerge over adolescence, a phenomenon reflecting the concomitant initiation of regulatory effects of sex hormones. The focus of this review is recent research on differences between adolescents and adults in HPA function and the enduring effects of exposure to stressors in adolescence. During adolescence, HPA function is characterized by a prolonged activation in response to stressors compared to adulthood, which may render ongoing development of the brain vulnerable. Although research has been scarce, there is a growing evidence that exposure to stressors in adolescence may alter behavioural responses to drugs and cognitive performance in adulthood. However, the effects reported appear to be stressor-specific and sex-specific. Such research may contribute toward understanding the increased risk for drug abuse and psychopathology that occurs over adolescence in people.

In your face: facial metrics predict aggressive behaviour in the laboratory and in varsity and professional hockey players

Facial characteristics are an important basis for judgements about gender, emotion, personality, motivational states and behavioural dispositions. Based on a recent finding of a sexual dimorphism in facial metrics that is independent of body size, we conducted three studies to examine the extent to which individual differences in the facial width-to-height ratio were associated with trait dominance (using a questionnaire) and aggression during a behavioural task and in a naturalistic setting (varsity and professional ice hockey). In study 1, men had a larger facial width-to-height ratio, higher scores of trait dominance, and were more reactively aggressive compared with women. Individual differences in the facial width-to-height ratio predicted reactive aggression in men, but not in women (predicted 15% of variance). In studies 2 (male varsity hockey players) and 3 (male professional hockey players), individual differences in the facial width-to-height ratio were positively related to aggressive behaviour as measured by the number of penalty minutes per game obtained over a season (predicted 29 and 9% of the variance, respectively). Together, these findings suggest that the sexually dimorphic facial width-to-height ratio may be an ‘honest signal’ of propensity for aggressive behaviour.

Effects of chronic social stress in adolescence on anxiety and neuroendocrine response to mild stress in male and female rats.

Using a rat model of adolescent social stress (SS, daily 1 h isolation and change of cage partner, 30-45 days of age), we have reported sex-specific effects on neuroendocrine function over the course of SS, and enduring effects of SS in females, and not males, on drug-related behaviour. Here, we investigated both the immediate and enduring impact of SS in adolescence on anxiety-like behaviour in the elevated plus maze (EPM) and determined the temporal pattern of corticosterone release after confinement to the open arm of the EPM. When tested as adolescents, SS decreased anxiety-like behaviour in females and had no effect in males. When tested as adults several weeks after the chronic stress, overall, SS tended to increase anxiety-like behaviour in both sexes. However, estrous cycle moderated the effect in females, in that reduced anxiety-like behaviour was observed for SS females in the estrous group. Confinement to the open arm of the EPM increased plasma corticosterone concentrations, which declined markedly upon return to home cage for all except adolescent control males for which corticosterone concentrations at 45 and 90 min were elevated compared other groups. Among controls, anxiety-like behaviour decreased in females and increased in males with age, and confinement to the open arm of the EPM led to a greater increase in corticosterone concentrations in adult males compared to adolescent males. In sum, modest effects of adolescent social stress were observable several weeks after the stress exposure, indicating that sex-specific developmental trajectories and vulnerability to anxiety may be shaped by experiences in adolescence.

Investigations of HPA function and the enduring consequences of stressors in adolescence in animal models.

Developmental differences in hypothalamic-pituitary-adrenal (HPA) axis responsiveness to stressors and ongoing development of glucocorticoid-sensitive brain regions in adolescence suggest that similar to the neonatal period of ontogeny, adolescence may also be a sensitive period for programming effects of stressors on the central nervous system. Although research on this period of life is scarce compared to early life and adulthood, the available research indicates that effects of stress exposure during adolescence differ from, and may be longer-lasting than, effects of the same stress exposure in adulthood. Research progress in animal models in this field is reviewed including HPA function and the enduring effects of stress exposures in adolescence on sensitivity to drugs of abuse, learning and memory, and emotional behaviour in adulthood. The effects of adolescent stress depend on a number of factors, including the age, gender, the duration of stress exposure, the type of stressor, and the time between stress exposure and testing.

Corticosterone release in response to repeated, short episodes of neonatal isolation : evidence of sensitization

Repeated isolation of neonatal rats produces persistent changes in physiology and behavior. In Experiment 1, we examined changes in plasma corticosterone (CORT) levels as a possible mechanism for the effects of isolation. Pups that were isolated from their mother and the nest for 1 h per day on postnatal days (PND) 2–9 were compared to control litters of pups that were either nonhandled or handled but not isolated. On PND 2, compared to nonhandled pups, handled pups had elevated CORT levels that returned to baseline levels within 30 to 60 min of return to the home cage. No significant elevation of CORT levels were found in handled pups on PND 9. The CORT levels of isolated pups were over twice those of nonhandled pups on PND 2 and four times those of nonhandled pups on PND 9. In Experiment 2, we investigated whether the increased CORT release in response to isolation on PND 9 was the result of the pups treatment on the previous six days as against an effect of maturation. Plasma CORT levels were measured in rat pups that were either isolated, handled or nonhandled on PNDs 2–8 during the conditions of isolation, handling and nonhandling on PND 9. There were no differences among the groups in basal plasma levels of CORT. Handling on PND 9 did not result in elevated CORT levels in any of the groups. All three groups showed a significant increase in plasma CORT levels after isolation on PND 9. However, the CORT response to isolation of pups previously isolated on PND 2–8 were significantly higher than pups that were either handled or nonhandled on PNDs 2–8. Thus, daily episodes of isolation potentiate the hypothalamic‐pituitary‐adrenal response to stress.

Adolescent development, hypothalamic-pituitary-adrenal function, and programming of adult learning and memory

Chronic exposure to stress is known to affect learning and memory in adults through the release of glucocorticoid hormones by the hypothalamic-pituitary-adrenal (HPA) axis. In adults, glucocorticoids alter synaptic structure and function in brain regions that express high levels of glucocorticoid receptors and that mediate goal-directed behaviour and learning and memory. In contrast to relatively transient effects of stress on cognitive function in adulthood, exposure to high levels of glucocorticoids in early life can produce enduring changes through substantial remodeling of the developing nervous system. Adolescence is another time of significant brain development and maturation of the HPA axis, thereby providing another opportunity for glucocorticoids to exert programming effects on neurocircuitry involved in learning and memory. These topics are reviewed, as is the emerging research evidence in rodent models highlighting that adolescence may be a period of increased vulnerability compared to adulthood in which exposure to high levels of glucocorticoids results in enduring changes in adult cognitive function.

Neonatal sex hormones have `organizational' effects on the hypothalamic-pituitary-adrenal axis of male rats

Sex hormones have activational effects on the hypothalamic-pituitary-adrenal (HPA) axis in adulthood: For example, corticosterone release is influenced by gonadal status. These experiments investigated whether sex hormones have organizational effects on the HPA axis of male rats: Do sex hormones have relatively permanent effects on its development? In adults, both neonatal (neoGDX) and adult gonadectomy (adult GDX) resulted in elevated corticosterone (CORT) levels in response to stress compared to intact rats. Five days of testosterone propionate (TP) replacement was not as effective at attenuating CORT levels in neoGDX rats as in adult GDX rats. Neonatal GDX elevated corticosterone binding globulin (CBG) levels, whereas adult GDX was without effect. In Experiment 2 the effects of neonatal gonadectomy and neonatal treatment with either TP, estradiol benzoate (EB), or oil vehicle was examined. Despite 14 days of hormone replacement, neoGDX showed elevated CORT levels in response to stress compared to all other groups. A single neonatal dose of TP or EB in neoGDX rats eliminated the increased responsiveness. Neonatal TP and EB were without effect in sham-operated rats. Plasma CBG levels were elevated in neoGDX groups regardless of neonatal hormone treatment. Corticosteroid receptor binding levels were examined in various brain areas and the pituitary in two groups most different in their androgen experience: NeoGDX and shams that did not receive treatments as adults. NeoGDX had lower levels of glucocorticoid receptor, and higher levels of mineralocorticoid receptor binding in the pituitary. No other receptor differences were found. These experiments suggest that neonatal sex hormones influence the sensitivity of the HPA axis to sex hormones in adulthood and, thus, that they have organizational effects in addition to activational effects on HPA function.

Testosterone responses to competition predict future aggressive behaviour at a cost to reward in men

The extent to which trait factors (baseline testosterone concentrations, trait dominance) and state factors (change in social status, change in testosterone concentrations) would predict reactive aggression in a subsequent task that involved provocation was examined in 99 participants (39 men and 60 women). Participants first competed in same-sex dyads on a Number Tracing Task for which the outcome (win or loss) was rigged. After the competition, participants performed the Point Subtraction Aggression Paradigm (PSAP), a behavioural measure of reactive aggression against an opponent (actually a computer program). Trait dominance predicted baseline testosterone in men, but not women, and men made more aggressive responses than did women. Baseline testosterone concentrations did not predict aggressive behaviour in either men or women. Winners and losers did not differ in competition-induced change in testosterone. However, change in testosterone concentrations predicted aggressive responses in the PSAP for men in the loss condition, and aggressive responses were made at a cost to obtaining reward points. For men in the win condition, aggressive responses were predicted by an interaction between trait dominance and change in testosterone concentrations. These findings suggest that situational changes in testosterone concentrations modulate future aggressive behaviour in men.

Aggressive behavior and change in salivary testosterone concentrations predict willingness to engage in a competitive task

The current study investigated relationships among aggressive behavior, change in salivary testosterone concentrations, and willingness to engage in a competitive task. Thirty-eight male participants provided saliva samples before and after performing the Point Subtraction Aggression Paradigm (a laboratory measure that provides opportunity for aggressive and defensive behavior while working for reward; all three involve pressing specific response keys). Baseline testosterone concentrations were not associated with aggressive responding. However, aggressive responding (but not point reward or point protection responding) predicted the pre- to post-PSAP change in testosterone: Those with the highest aggressive responding had the largest percent increase in testosterone concentrations. Together, aggressive responding and change in testosterone predicted willingness to compete following the PSAP. Controlling for aggression, men who showed a rise in testosterone were more likely to choose to compete again (p=0.03) and controlling for testosterone change, men who showed the highest level of aggressive responding were more likely to choose the non-competitive task (p=0.02). These results indicate that situation-specific aggressive behavior and testosterone responsiveness are functionally relevant predictors of future social behavior.