Vasopressin needs an audience: neuropeptide elicited stress responses are contingent upon perceived social evaluative threats

The nonapeptide arginine vasopressin (AVP) plays an important role in hypothalamus-pituitary-adrenal axis regulation and also functions as a social hormone in a wide variety of species, from voles to humans. In the current report we use a variety of stress inducing tasks, including the Trier Social Stress Test (TSST) and intranasal administration of AVP to show that intranasal administration of this neuropeptide leads to a significant increase in salivary cortisol and pulse rate, specifically in conditions where subjects perform tasks in the presence of a social evaluative threat (task performance could be negatively judged by others). In contrast, in conditions without a social evaluative threat (no task condition, modified TSST without audience and bike ergometry), subjects receiving AVP did not differ from subjects receiving placebo. Thus exogenous AVP's influence is contingent upon a circumscribed set of initial conditions that constitute a direct threat to the maintenance of our social selves. Stress evoked by social threat is an integral part of social life and is related to self-esteem and in extreme forms, to poor mental health (e.g., social phobia). Our findings suggest that AVP is a key component in the circuit that interlaces stress and social threat and findings offer inroads to our understanding of individual differences in sociability and in stress response elicited in threatening social situations.     

Social cognition under stress: Differential effects of stress-induced cortisol elevations in healthy young men and women

Humans as social beings often have to perform complex social cognitive tasks while under stress (e.g., during a social conflict). Previous research has established that the brain regions responsible for social cognitive tasks are target regions for stress hormones. However, little experimental research has been done testing the acute effects of stress on social cognition. Here, we investigated whether stress exposure and the ensuing glucocorticoid (i.e., cortisol) elevations affect social cognition. Thirty-two men and 32 women were exposed to either a psychosocial stress or a non-stressful control test before assessing their social cognition using the Reading the Mind in the Eyes Test (RMET) and the Movie for the Assessment of Social Cognition (MASC). Results showed differential effects of stress-induced cortisol responses among men and women for the MASC, but not the RMET. Among men, high cortisol responders displayed elevated MASC scores compared with low cortisol responders. Moreover, for stressed men a positive association between the magnitude of the cortisol responses to the stressor and MASC scores emerged. Among women, enhanced MASC scores were found for low cortisol responders relative to high cortisol responders and non-stressed controls. A strong negative association between cortisol reactivity and MASC scores was found among women. These results imply sex specific effects of glucocorticoids on social cognition and partially support the idea of sex differences in biobehavioral stress responses, with men engaging in fight-or-flight responses while women may react to stress with tending and befriending behavior.     

Coping with an Acute Psychosocial Challenge: Behavioral and Physiological Responses in Young Women

Despite the relevance of behavior in understanding individual differences in the strategies used to cope with stressors, behavioral responses and their relationships with psychobiological changes have received little attention. In this study on young women, we aimed at analyzing the associations among different components of the stress response and behavioral coping using a laboratory psychosocial stressor. The Ethological Coding System for Interviews, as well as neuroendocrine, autonomic and mood parameters, were used to measure the stress response in 34 young women (17 free-cycling women in their early follicular phase and 17 oral contraceptive users) subjected to the Trier Social Stress Test (TSST) and a control condition in a crossover design. No significant differences in cardiac autonomic, negative mood and anxiety responses to the stressor were observed between the two groups of women. However, women in the follicular phase showed a higher cortisol response and a larger decrease in positive mood during the social stress episode, as well as greater anxiety overall. Interestingly, the amount of displacement behavior exhibited during the speaking task of the TSST was positively related to anxiety levels preceding the test, but negatively related to baseline and stress response values of heart rate. Moreover, the amount of submissive behavior was negatively related to basal cortisol levels. Finally, eye contact and low-aggressiveness behaviors were associated with a worsening in mood. Overall, these findings emphasize the close relationship between coping behavior and psychobiological reactions, as well as the role of individual variations in the strategy of coping with a psychosocial stressor.     

Acute stress impairs recall after interference in older people,but not in young people

Stress has been associated with negative changes observed during the aging process. However, very little research has been carried out on the role of age in acute stress effects on memory. We aimed to explore the role of age and sex in the relationship between hypothalamus–pituitary–adrenal axis (HPA-axis) and sympathetic nervous system (SNS) reactivity to psychosocial stress and short-term declarative memory performance. To do so, sixty-seven participants divided into two age groups (each group with a similar number of men and women) were exposed to the Trier Social Stress Test (TSST) and a control condition in a crossover design. Memory performance was assessed by the Rey Auditory Verbal Learning Test (RAVLT). As expected, worse memory performance was associated with age; but more interestingly, the stressor impaired recall after interference only in the older group. In addition, this effect was negatively correlated with the alpha-amylase over cortisol ratio, which has recently been suggested as a good marker of stress system dysregulation. However, we failed to find sex differences in memory performance. These results show that age moderates stress-induced effects on declarative memory, and they point out the importance of studying both of the physiological systems involved in the stress response together.     

The Combined Propranolol/TSST Paradigm – A New Method for Psychoneuroendocrinology

Upon perception of a stimulus as stressful, the human brain reacts with the activation of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), to mobilize energy resources to better cope with the stressor. Since the perception of the stressor is the initial stimulus, a synchronicity between the subjective perception of stress and the physiological stress reactivity should be expected. However, according to a recent meta-analysis, these associations are weak and inconsistent. The goal of the current study was to investigate the interaction between the SNS, HPA and subjective stress perceptions, by introducing an experimental manipulation of this interaction. For this purpose, we combined the SNS inhibitor propranolol with the Trier Social Stress Test, and measured endocrinological and psychological responses to the stressor. Thirty healthy male participants were recruited and randomly assigned to either a propranolol (PROP; n = 15) or placebo (PLC; n = 15) group. All subjects were administered 80 mg of propranolol 60 minutes prior to exposure to psychosocial stress. Salivary cortisol and alpha amylase (sAA), heart rate, blood pressure and subjective stress responses were assessed throughout the study. We observed significantly reduced sAA levels and heart rate increases in the PROP group in response to stress, with no effects of the drug on systolic or diastolic blood pressure changes. In line with previous studies, a significant increase in cortisol was seen in response to the stress exposure. Importantly, the cortisol increase was significantly higher in the PROP group. A typical increase in subjective stress could be seen in both groups, with no significant group differences emerging. Complementing previous work, this study further demonstrates a significant interaction between the HPA and the SNS during acute stress. The HPA activity was found to be elevated in the presence of a suppressed SNS in reactivity to the TSST.     

Cortisol Response to Repeated Psychosocial Stress

Psychosocial stress plays a major role in the etiology and the course of mental disorders that often show an altered activation of the hypothalamus–pituitary–adrenal (HPA) axis. The Trier Social Stress Test (TSST) reliably activates the HPA axis and reflects real life stress exposure. However, habituation may confound the results of clinical trials that apply TSST. The present study investigates the cortisol response after repeated psychosocial stress induction with short-term and long-term intervals between repeated testing sessions. Forty-one healthy subjects were exposed to the TSST four times with an interval of 24 h between the first and the second testing session (t1 and t2). The 3rd and the 4th testing session (t3 and t4) were also separated by a 24-hour interval whereas there were 10 weeks between t2 and t3. A significant decrease in the salivary cortisol responses was noticed from testing session t1 to t2 as well as from testing session t3 to t4. By contrast, there were no differences in the HPA axis reactivity between testing session t2 and t3. Our results demonstrated the habituation of the HPA axis to a standardized psychosocial stress test when testing was repeated after 24 h. By contrast, a renewed challenge with a ten-week-interval in-between activated the HPA axis in a similar manner as before. It is suggested that studies designed to investigate the HPA axis activity under repeated psychosocial stress conditions should apply the TSST three times in order to separate habituation from intervention effects.     

The association between affective psychopathic traits,time incarcerated,and cortisol response to psychosocial stress

Previous research has demonstrated that psychopathic personality traits are significantly predictive of blunted cortisol reactivity to a performance-based stressor task (Trier Social Stress Test; TSST) in college students. However, the relationship between cortisol reactivity and psychopathy has not been explored in high risk samples such as incarcerated populations. Further, the role of imprisonment in relation to cortisol stress reactivity has not been previously explored, but could have practical and conceptual consequences in regard to rehabilitation and biological sensitivity to context, respectively. The current study tested the hypotheses that both psychopathic personality traits and amount of time incarcerated are related to cortisol blunting in response to stress among incarcerated young adults. A sample of 49 young adult male offenders was recruited to complete the TSST. Salivary hormone samples were taken just prior to and 20 min post-stressor, and participants were interviewed with the Psychopathy Checklist-Youth Version. Variables quantifying the amount of time at the present facility prior to the date of testing and number of commitments in juvenile facilities were also collected. Correlational analyses indicated that only number of incarcerations was related to blunted cortisol. Hierarchical Linear Modeling revealed that time incarcerated and number of commitments were related to a blunted cortisol response among responders and declining cortisol reactivity among nonresponders, respectively. Controlling for time incarcerated, psychopathic traits were significantly related to cortisol decline in response to the stressor among nonresponders, but were not related to blunted cortisol among responders. Results of this project highlight the potential biological effects of prolonged and repeated incarcerations, and extend our understanding about the relationship between psychopathic traits and cortisol reactivity in an incarcerated sample.     

Spatial ability is impaired and hippocampal mineralocorticoid receptor mRNA expression reduced in zebra finches (Taeniopygia guttata) selected for acute high corticosterone response to stress

In mammals, stress hormones have profound influences on spatial learning and memory. Here, we investigated whether glucocorticoids influence cognitive abilities in birds by testing a line of zebra finches selectively bred to respond to an acute stressor with high plasma corticosterone (CORT) levels. Cognitive performance was assessed by spatial and visual one-trial associative memory tasks. Task performance in the high CORT birds was compared with that of the random-bred birds from a control breeding line. The birds selected for high CORT in response to an acute stressor performed less well than the controls in the spatial task, but there were no significant differences between the lines in performance during the visual task. The birds from the two lines did not differ in their plasma CORT levels immediately after the performance of the memory tasks; nevertheless, there were significant differences in peak plasma CORT between the lines. The high CORT birds also had significantly lower mineralocorticoid receptor mRNA expression in the hippocampus than the control birds. There was no measurable difference between the lines in glucocorticoid receptor mRNA density in either the hippocampus or the paraventricular nucleus. Together, these findings provide evidence to suggest that stress hormones have important regulatory roles in avian spatial cognition.     

No response of plasma substance P, but delayed increase of interleukin-1 receptor antagonist to acute psychosocial stress

Psychosocial stress has been shown to induce inflammatory reactions, followed by the release of immunosuppressive glucocorticoids. This may be mediated by catecholamines or other stress reactive substances such as neuropeptides or cytokines. We here set out to explore the effects of acute psychosocial stress on plasma levels of substance P (SP), a possible mediator of stress-induced inflammatory reactions, and interleukin-1 receptor antagonist (IL-1ra). Twelve healthy male subjects (mean age 27 yrs.) were subjected to the psychosocial stress test "Trier Social Stress Test" (TSST) and a resting control condition. Blood and saliva samples were taken before, as well as 1, 20, 45, and 90 min after TSST or rest, respectively. Salivary cortisol and plasma SP and IL-1ra were measured using immunoassays, salivary alpha-amylase (sAA) was measured by an enzyme kinetic method, and plasma epinephrine (E) and norepinephrine (NE) were measured by HPLC. The TSST induced immediate increases of E, NE, and sAA, and a delayed increase of free cortisol. Plasma IL-1ra showed an even further delayed peak at 90 min after stress. Plasma levels of SP did not respond to stress. No significant associations between changes of stress hormones and IL-1ra or SP were found. We conclude that substance P, epinephrine, and norepinephrine are probably not involved in mediating peripheral inflammation following psychosocial stress, at least with respect to IL-1ra. Further studies have to reveal the mechanisms involved in the stress-induced up regulation of IL-1ra.     

Selective Impact of Early Parental Responsivity on Adolescent Stress Reactivity

Research in animals has shown that early life experience, particularly parenting behaviors, influences later-life stress reactivity. Despite the tremendous relevance of this finding to human development and brain function, it has not been tested prospectively in humans. In this study two aspects of parenting were measured at age 4 in a sample of healthy, low socioeconomic status, African American children, and stress reactivity was measured in the same children 11–14 years later using a modified version of the Trier Social Stress Test (n = 55). Salivary cortisol was measured before, during and after the stressor and data were analyzed using piecewise hierarchical linear modeling. Parental responsivity, independent of the use of physical discipline, was positively related to cortisol reactivity. Effects were independent of subjective appraisals of the stressor and were also independent of other environmental risk factors and current psychosocial functioning. Therefore this study demonstrates in a novel and precise fashion that early childhood parental responsivity prospectively and independently predicts stress reactivity in adolescence.     

The stress-response-dampening effects of placebo

This experiment used both biological and self-report measures to examine how alcohol modifies stress responses, and to test whether the interaction between these two factors alters risk-taking in healthy young adults. Participants were divided into stress or no-stress conditions and then further divided into one of three beverage groups. The alcohol group consumed a binge-drinking level of alcohol; the placebo group consumed soda, but believed they were consuming alcohol; the sober group was aware that they were not consuming alcohol. Following beverage consumption, the stress group was subjected to the Trier Social Stress Test (TSST) while the no-stress group completed crossword puzzles; all participants subsequently completed a computerized risk-taking task. Exposure to the TSST significantly increased salivary levels of the hormone cortisol and the enzyme alpha-amylase, as well as subjective self-ratings of anxiety and tension. In the stress condition, both placebo and intoxicated groups reported less tension and anxiety, and exhibited a smaller increase in cortisol, following the TSST than did the sober group. Thus, the expectation of receiving alcohol altered subjective and physiological responses to the stressor. Neither alcohol nor stress increased risk taking, however the sober group demonstrated lower risk-taking on the computer task on the second session. These findings clearly demonstrate that the expectation of alcohol (placebo) alters subsequent physiological responses to stress.     

Stress-induced reductions of sensory reactivity in female rats depend on ovarian hormones and the application of a painful stressor

The current experiments occurred in the context of disputes in the literature concerning whether inescapable stress causes differential changes in sensory reactivity, which could lead to differences in many learning procedures. We tested rats for differences in sensitivity and responsivity to acoustic stimuli through the use of the acoustic startle response (ASR) 2 h after stressor exposure and ambulatory activity 24 h later in the open field. Stressed females showed reduced responsivity to acoustic stimuli with no apparent shift in stimulus sensitivity. Males did not show differences in either reactivity index following stressor exposure. Reduced responsivity did not occur if females had been OVX (OVX alone did not effect stimulus responsivity or sensitivity). All groups that experienced tailshock stress also had reduced open field activity 24 h later. Restraint for 2 h did not reduce stimulus responsivity in the ASR or open field activity in female rats. Acute reductions in ASRs after a painful stressor appear to be a feature specific to females, with an apparent role of ovarian hormones as a modulator of the effect. Possible hormone and/or immunological mechanisms of these sex-specific effects are discussed. Understanding the mechanisms of this stressor-induced reduction in sensory reactivity could advance our knowledge of how individual differences in ovarian hormone levels influence the physical and psychological processes by which females acutely respond and later recover from traumatic events.     

Hippocampal damage abolishes the cortisol response to psychosocial stress in humans

The hippocampus (HC) is necessary for learning and memory, but it also plays a role in other behaviors such as those related to stress and anxiety. In support of the latter idea, we show here that bilateral HC damage abolishes the cortisol response to psychosocial stress. We collected salivary cortisol, heart rate, and affective responses to the Trier Social Stress Test (TSST) from 7 participants with bilateral HC lesions, 12 participants with damage outside the HC, and 28 healthy normal comparison participants matched to the HC participants on age and sex. HC participants showed elevated pre-stress cortisol, but no cortisol response to the TSST. Heart rate and affective responses in the HC group were similar to those of the comparison groups. Participants with brain damage outside the HC showed stress responses that were comparable to those of the healthy comparison group. These findings support the idea that the functions of the human HC extend beyond learning and memory, and suggest that the HC is necessary for producing the cortisol response to psychosocial stress.     

Social Stress Increases Cortisol and Hampers Attention in Adolescents with Excess Weight

Objective

To experimentally examine if adolescents with excess weight are more sensitive to social stress and hence more sensitive to harmful effects of stress in cognition.

Design and Methods

We conducted an experimental study in 84 adolescents aged 12 to 18 years old classified in two groups based on age adjusted Body Mass Index percentile: Normal weight (n=42) and Excess weight (n=42). Both groups were exposed to social stress as induced by the virtual reality version of the Trier Social Stress Task --participants were requested to give a public speech about positive and negative aspects of their personalities in front of a virtual audience. The outcome measures were salivary cortisol levels and performance in cognitive tests before and after the social stressor. Cognitive tests included the CANTAB Rapid Visual Processing Test (measuring attention response latency and discriminability) and the Iowa Gambling Task (measuring decision-making).

Results

Adolescents with excess weight compared to healthy weight controls displayed increased cortisol response and less improvement of attentional performance after the social stressor. Decision-making performance decreased after the social stressor in both groups.

Conclusion

Adolescents who are overweight or obese have increased sensitivity to social stress, which detrimentally impacts attentional skills.     

Voluntary locomotor activity mitigates oxidative damage associated with isolation stress in the prairie vole (Microtus ochrogaster)

Organismal performance directly depends on an individual''s ability to cope with a wide array of physiological challenges. For social animals, social isolation is a stressor that has been shown to increase oxidative stress. Another physiological challenge, routine locomotor activity, has been found to decrease oxidative stress levels. Because we currently do not have a good understanding of how diverse physiological systems like stress and locomotion interact to affect oxidative balance, we studied this interaction in the prairie vole (Microtus ochrogaster). Voles were either pair housed or isolated and within the isolation group, voles either had access to a moving wheel or a stationary wheel. We found that chronic periodic isolation caused increased levels of oxidative stress. However, within the vole group that was able to run voluntarily, longer durations of locomotor activity were associated with less oxidative stress. Our work suggests that individuals who demonstrate increased locomotor activity may be better able to cope with the social stressor of isolation.     

Stressors, Including Social Conflict, Decrease Plasma Prolactin in Male Golden Hamsters

Following exposure to a stressor, plasma prolactin (PRL) rises in most species. The purpose of the present study was to examine the effect of social conflict or of footshock stress on PRL responsiveness in male Syrian hamsters. Contrary to expectations, PRL was significantly lower in subordinate hamsters than in their dominant opponents or in controls following one, five, or nine exposures to social conflict. Similarly, PRL was reduced in hamsters subjected to a mild footshock stressor. By contrast, adrenocorticotropin, another stress-responsive hormone, was elevated following exposure to each of these stressors. We also demonstrate that PRL release is inhibited by dopamine as it is in other species by showing that there is a dose-dependent increase in PRL release following treatment with the dopamine receptor blocker, domperidone.     

The Reaction to Social Stress in Social Phobia: Discordance between Physiological and Subjective Parameters

Background

Research on the biopsychological background of social phobia (SP) is scarce and inconsistent. We investigated endocrine and autonomic markers along with subjective responses to a standardized stress situation (Trier Social Stress Test, TSST) in SP patients and healthy controls (HC).

Methods

We examined 88 patients with the primary diagnosis of SP as well as 78 age and sex comparable HCs with the TSST. Blood and saliva samples were obtained before and after the TSST for the assessment of salivary cortisol, plasma cortisol, salivary alpha-amylase (sAA), and prolactin. Heart rate (HR) and heart rate variability (HRV) were recorded continuously. Scalp-near hair samples were collected for the assessment of long-term cortisol secretion. The self-reported stress response was measured with different state and trait scales.

Results

While self-reported anxiety was elevated in SP before, during, immediately after, and one week after the TSST, no significant differences in biological stress responses were observed between SP and HC. There was a trend for SP to show higher baseline stress markers. Also long-term cortisol deposition in hair remained unaltered.

Conclusions

Our results suggest that the excessive self-reported stress in SP is not reflected by a respective biological stress response. Patients with SP apparently show neither an extreme form of focused fear reactivity nor excessive defensive impairment.     

Differences in Salivary Alpha-Amylase and Cortisol Responsiveness following Exposure to Electrical Stimulation versus the Trier Social Stress Tests

Background

Cortisol is an essential hormone in the regulation of the stress response along the HPA axis, and salivary cortisol has been used as a measure of free circulating cortisol levels. Recently, salivary alpha-amylase (sAA) has also emerged as a novel biomarker for psychosocial stress responsiveness within the sympathetic adrenomedullary (SAM) system.

Principal Findings

We measured sAA and salivary cortisol in healthy volunteers after exposure to the Trier Social Stress Test (TSST) and electric stimulation stress. One hundred forty-nine healthy volunteers participated in this study. All subjects were exposed to both the TSST and electric stimulation stress on separate days. We measured sAA and salivary cortisol levels three times immediately before, immediately after, and 20 min after the stress challenge. The State (STAI-S) and Trait (STAI-T) versions of the Spielberger Anxiety Inventory test and the Profile of Mood State (POMS) tests were administered to participants before the electrical stimulation and TSST protocols. We also measured HF, LF and LF/HF Heart Rate Variability ratio immediately after electrical stimulation and TSST exposure. Following TSST exposure or electrical stimulation, sAA levels displayed a rapid increase and recovery, returning to baseline levels 20 min after the stress challenge. Salivary cortisol responses showed a delayed increase, which remained significantly elevated from baseline levels 20 min after the stress challenge. Analyses revealed no differences between men and women with regard to their sAA response to the challenges (TSST or electric stimulations), while we found significantly higher salivary cortisol responses to the TSST in females. We also found that younger subjects tended to display higher sAA activity. Salivary cortisol levels were significantly correlated with the strength of the applied electrical stimulation.

Conclusions

These preliminary results suggest that the HPA axis (but not the SAM system) may show differential response patterns to distinct kinds of stressors.