Sandra Cornelisse

Adult hippocampal glucocorticoid receptor expression and dentate synaptic plasticity correlate with maternal care received by individuals early in life

Maternal care in mammals is the prevailing environmental influence during perinatal development. The adult rat offspring of mothers exhibiting increased levels of pup licking/grooming (LG; High LG mothers), compared to those reared by Low LG dams, show increased hippocampal glucocorticoid receptor expression, complex dendritic tree structure, and an enhanced capacity for synaptic potentiation. However, these data were derived from studies using the total amount of maternal care directed toward the entire litter, thus ignoring possible within‐litter variation. We show that the amount of LG received by individual pups within a litter varies considerably. Therefore, we questioned if the amount of LG received by individual pups correlates with and thus putatively predicts later hippocampal structure and function. To this end, LG‐scores were determined during the first postnatal week for all pups in 32 litters and correlated with neuroendocrine and hippocampal parameters in young‐adulthood. Pup LG‐score positively correlated with the glucocorticoid receptor mRNA expression in the adult hippocampus. Moreover, the ability to induce synaptic potentiation in the dentate gyrus in vitro was enhanced in animals with high LG‐scores. Structural plasticity correlated less reliably with LG‐scores early in life and differed between sexes. Male offspring with high LG‐scores displayed fewer newborn neurons, higher brain derived neurotrophic factor expression and tended to have more complex granule cell dendritic trees. We conclude that even moderate variations in early life environment have a major impact on adult hippocampal function. This principle could provide a mechanistic basis for individual differences in susceptibility to psychopathology.

Implications of psychosocial stress on memory formation in a typical male versus female student sample.

Stress is known to differentially modulate memory function. Memory can be impaired or strengthened by stress, depending on e.g. the memory type and phase under study, the emotional value of the learned information and the sex of the subjects. Here, we addressed the latter and investigated the impact of psychosocial stress on long-term memory for neutral and emotional pictures and working memory in typical samples of male versus female students. In total, 77 subjects (54 women of which 39 used oral contraceptives) were exposed to either the Trier Social Stress Test (TSST) or a control condition, and then engaged in a long-term memory task (emotionally arousing and neutral pictures; surprise recall after one week) and a working memory (n-back) task. During the experiment salivary cortisol and alpha-amylase levels as well as subjective affect state were assessed. As expected, stress hormone concentrations as well as subjective negative affect states increased significantly in response to the stress task. Men reacted more to the stressor in terms of cortisol responses than women, probably due to oral contraceptive use of the latter. Results show that, in male as well as in female students, memory for emotional arousing information was better than for neutral information, in both the stress and control condition. Stress enhanced recognition memory for emotional versus neutral pictures only in male subjects. Moreover, stress enhanced working memory, particularly in males, during the first block of a 2-back task. The lack of stress effects on memory in women might be explained by oral contraceptive use, leading to blunted HPA-axis responses and secondary to reduced stress effects on memory. The results emphasize that stress affects both long-term and working memory differentially in male versus female students.

A randomized trial on mineralocorticoid receptor blockade in men: effects on stress responses, selective attention, and memory

Corticosteroids, released in high amounts after stress, exert their effects via two different receptors in the brain: glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). GRs have a role in normalizing stress-induced effects and promoting consolidation, while MRs are thought to be important in determining the threshold for activation of the hypothalamic–pituitary–adrenal (HPA) axis. We investigated the effects of MR blockade on HPA axis responses to stress and stress-induced changes in cognitive function. In a double-blind, placebo-controlled study, 64 healthy young men received 400 mg of the MR antagonist spironolactone or placebo. After 1.5 h, they were exposed to either a Trier Social Stress Test or a non-stressful control task. Responses to stress were evaluated by hormonal, subjective, and physiological measurements. Afterwards, selective attention, working memory, and long-term memory performance were assessed. Spironolactone increased basal salivary cortisol levels as well as cortisol levels in response to stress. Furthermore, spironolactone significantly impaired selective attention, but only in the control group. The stress group receiving spironolactone showed impaired working memory performance. By contrast, long-term memory was enhanced in this group. These data support a role of MRs in the regulation of the HPA axis under basal conditions as well as in response to stress. The increased availability of cortisol after spironolactone treatment implies enhanced GR activation, which, in combination with MR blockade, presumably resulted in a decreased MR/GR activation ratio. This condition influences both selective attention and performance in various memory tasks.

Introducing the Maastricht Acute Stress Test (MAST): a quick and non-invasive approach to elicit robust autonomic and glucocorticoid stress responses

Stress-related research has employed several procedures to activate the human stress system. Two of the most commonly used laboratory paradigms are the Trier Social Stress Test (TSST) and the Cold Pressor Test (CPT). We combined their most stressful features to create a simple laboratory stress test capable of eliciting strong autonomic and glucocorticoid stress responses. In comparison with the CPT and its variations, our stress tool (labeled the Maastricht Acute Stress Test; MAST) was found to yield superior salivary cortisol responses, while being equally effective in eliciting subjective stress reactions and (systolic and diastolic) blood pressure increases (study 1; N=80). In study 2 (N=20), we directly compared the effectiveness of the MAST and TSST and found that both methods elicited similar subjective, salivary alpha-amylase, and salivary cortisol stress responses. Finally, we developed and evaluated an appropriate no-stress control version of the MAST that was similar to the stress version, although it did not comprise stressful components (study 3; N=40). Collectively, our results confirm the effectiveness of the MAST in terms of subjective, autonomic, and--most importantly--glucocorticoid stress responses. Thus, as a brief and simple stress protocol, the MAST holds considerable promise for future research.

Time-dependent effects of cortisol on the contextualization of emotional memories

BACKGROUND The inability to store fearful memories into their original encoding context is considered to be an important vulnerability factor for the development of anxiety disorders like posttraumatic stress disorder. Altered memory contextualization most likely involves effects of the stress hormone cortisol, acting via receptors located in the memory neurocircuitry. Cortisol via these receptors induces rapid nongenomic effects followed by slower genomic effects, which are thought to modulate cognitive function in opposite, complementary ways. Here, we targeted these time-dependent effects of cortisol during memory encoding and tested subsequent contextualization of emotional and neutral memories. METHODS In a double-blind, placebo-controlled design, 64 men were randomly assigned to one of three groups: 1) received 10 mg hydrocortisone 30 minutes (rapid cortisol effects) before a memory encoding task; 2) received 10 mg hydrocortisone 210 minutes (slow cortisol) before a memory encoding task; or 3) received placebo at both times. During encoding, participants were presented with neutral and emotional words in unique background pictures. Approximately 24 hours later, context dependency of their memories was assessed. RESULTS Recognition data revealed that cortisols rapid effects impair emotional memory contextualization, while cortisols slow effects enhance it. Neutral memory contextualization remained unaltered by cortisol, irrespective of the timing of the drug. CONCLUSIONS This study shows distinct time-dependent effects of cortisol on the contextualization of specifically emotional memories. The results suggest that rapid effects of cortisol may lead to impaired emotional memory contextualization, while slow effects of cortisol may confer protection against emotional memory generalization.

Time-dependent changes in altruistic punishment following stress

Decisions are rarely made in social isolation. One phenomenon often observed in social interactions is altruistic punishment, i.e. the punishment of unfair behavior by others at a personal cost. The tendency for altruistic punishment is altered by affective states including those induced by stress exposure. Stress is thought to exert bi-directional effects on behavior: immediately after stress, reflex-like and habitual behavior is promoted while later on more far-sighted, flexible and goal-directed behavior is enhanced. We hypothesized that such time-dependent effects of stress would also be present in the context of altruistic punishment behavior. Healthy male participants (N=80) were exposed to either a grouped stress test or a control condition. Participants were tested in prosocial decision making tasks either directly after stress or 75 min later. Altruistic punishment was assessed using the Ultimatum Game. General altruism was assessed with a one-shot version of the Dictator Game in which an anonymous donation could be offered to a charitable organization. We found that stress caused a bi-directional effect on altruistic punishment, with decreased rejection rates in the late aftermath of stress in response to ambiguous 30% offers. In the Dictator Game, stressed participants were less generous than controls, but no time-dependent effect was observed, indicating that the general reward sensitivity remained unchanged at various time-points after stress. Overall, during the late aftermath after acute stress exposure (i.e. 75 min later), participants acted more consistent with their own material self-interest, and had a lower propensity for altruistic punishment, possibly through upregulation of cognitive self-control mechanisms. Thus, our findings underscore the importance of time as a factor in simple, real-life economic decisions in a stressful social context.

No effects of psychosocial stress on intertemporal choice.

Intertemporal choices - involving decisions which trade off instant and delayed outcomes - are often made under stress. It remains unknown, however, whether and how stress affects intertemporal choice. We subjected 142 healthy male subjects to a laboratory stress or control protocol, and asked them to make a series of intertemporal choices either directly after stress, or 20 minutes later (resulting in four experimental groups). Based on theory and evidence from behavioral economics and cellular neuroscience, we predicted a bidirectional effect of stress on intertemporal choice, with increases in impatience or present bias immediately after stress, but decreases in present bias or impatience when subjects are tested 20 minutes later. However, our results show no effects of stress on intertemporal choice at either time point, and individual differences in stress reactivity (changes in stress hormone levels over time) are not related to individual differences in intertemporal choice. Together, we did not find support for the hypothesis that psychosocial laboratory stressors affect intertemporal choice.

Modulatory mechanisms of cortisol effects on emotional learning and memory: Novel perspectives

It has long been known that cortisol affects learning and memory processes. Despite a wealth of research dedicated to cortisol effects on learning and memory, the strength or even directionality of the effects often vary. A number of the factors that alter cortisols effects on learning and memory are well-known. For instance, effects of cortisol can be modulated by emotional arousal and the memory phase under study. Despite great advances in understanding factors that explain variability in cortisols effects, additional modulators of cortisol effects on memory exist that are less widely acknowledged in current basic experimental research. The goal of the current review is to disseminate knowledge regarding less well-known modulators of cortisol effects on learning and memory. Since several models for the etiology of anxiety, such as post-traumatic stress disorder (PTSD), incorporate stress and the concomitant release of cortisol as important vulnerability factors, enhanced understanding of mechanisms by which cortisol exerts beneficial as opposed to detrimental effects on memory is very important. Further elucidation of the factors that modulate (or alter) cortisols effects on memory will allow reconciliation of seemingly inconsistent findings in the basic and clinical literatures. The present review is based on a symposium as part of the 42nd International Society of Psychoneuroendocrinology Conference, New York, USA, that highlighted some of those modulators and their underlying mechanisms.

Cortisol mediates the effects of stress on the contextual dependency of memories

Stress is known to exert considerable impact on learning and memory processes. Typically, human studies have investigated memory for single items (e.g., pictures, words), but it remains unresolved how exactly stress may alter the storage of memories into their original encoding context (i.e., memory contextualization). Since neurocircuitry underlying memory contextualization processes is sensitive to the well-known stress hormone cortisol, we here investigated whether cortisol mediates stress effects on memory contextualization. Forty healthy young men were randomly assigned to a psychosocial stress or control group. Ten minutes after stress manipulation offset, participants were instructed to learn and remember neutral and negative words, each of which was depicted against a unique background picture. Approximately 24h later, memory was tested by means of cued retrieval and recognition tasks. To assess memory contextualization half of the words were tested in intact item-contexts pairs, and half in rearranged item-context combinations. Recognition data showed that cortisol, but no other indices of stress such as heart rate or subjective stress, mediated the effects of stress on contextualization of neutral and negative memories. The mediation analysis further showed that stress resulted in increases in cortisol and that cortisol was positively related to memory contextualization, but unrelated to other measures of memory. Thus, there seems to be a specific role for cortisol in the integration of a central memory into its surrounding context.

The Effect of Dexamethasone on Symptoms of Posttraumatic Stress Disorder and Depression after Cardiac Surgery and Intensive Care Admission : Longitudinal Follow-Up of a Randomized Controlled Trial

Objective:Cardiac surgery and postoperative admission to the ICU may lead to posttraumatic stress disorder and depression. Perioperatively administered corticosteroids potentially alter the risk of development of these psychiatric conditions, by affecting the hypothalamic-pituitary-adrenal axis. However, findings of previous studies are inconsistent. We aimed to assess the effect of a single dose of dexamethasone compared with placebo on symptoms of posttraumatic stress disorder and depression and health-related quality of life after cardiac surgery and ICU admission. Design:Follow-up study of a randomized clinical trial. Setting:Five Dutch heart centers. Patients:Cardiac surgery patients (n = 1,244) who participated in the Dexamethasone for Cardiac Surgery trial. Interventions:A single intraoperative IV dose of dexamethasone or placebo was administered in a randomized, double-blind way. Measurements and Main Results:Symptoms of posttraumatic stress disorder, depression, and health-related quality of life were assessed with validated questionnaires 1.5 years after randomization. Data were available for 1,125 patients (90.4%); of which 561 patients received dexamethasone and 564 patients received placebo. Overall, the prevalence of psychopathology was not influenced by dexamethasone. Posttraumatic stress disorder and depression were present in, respectively, 52 patients (9.3%) and 69 patients (12.3%) who received dexamethasone and in 66 patients (11.7%) and 78 patients (13.8%) who received placebo (posttraumatic stress disorder: odds ratio, 0.82; 95% CI, 0.55–1.20; p = 0.30; depression: odds ratio, 0.92; 95% CI, 0.64–1.31; p = 0.63). Subgroup analysis revealed a lower prevalence of posttraumatic stress disorder (odds ratio, 0.23; 95% CI, 0.07–0.72; p < 0.01) and depression (odds ratio, 0.29; 95% CI, 0.11–0.77; p < 0.01) in female patients after dexamethasone administration. Health-related quality of life did not differ between groups and was not associated with psychopathology. Conclusions:Overall, our findings suggest that exogenous administration of the glucocorticoid receptor agonist dexamethasone—compared with placebo—during cardiac surgery does not positively or negatively affect the prevalence of posttraumatic stress disorder and depression. However, in female patients, beneficial effects on the occurrence of posttraumatic stress disorder and depression may be present.