Stress and Cognition: the relevance of timing, steroid receptors and sex differences

Abstract

In response to a stressful situation the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis are activated, eventually leading to the release of catecholamines and corticosteroids. These stress hormones bind to different receptors in the brain (in case of corticosteroids, mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs)) and thereby affect many brain areas that play an essential role in cognitive functioning, such as the hippocampus, amygdala and prefrontal cortex (PFC). Accordingly, stress and stress hormones can influence a wide range of cognitive processes, like memory and decision making. However, stress effects reported for these cognitive domains are complex and often contradictory, sometimes impairing and sometimes enhancing cognitive functioning. A possible explanation for these contradictory results may be that the effects of stress and cortisol on cognition are modulated by several factors, such as the delay between the stressful episode and the cognitive task (‘timing’), emotional arousal, context or sex differences. The overall objective of this thesis was to further investigate the effects of stress and cortisol on cognitive processes. More specifically, we aimed to examine the relevance of timing, steroid receptors and sex differences in determining stress and cortisol effects on several cognitive domains, including declarative memory, working memory, fear memory and decision making. The main findings of this thesis show that 1) Memory performance is differentially affected by stress in men versus women, and those effects depend on the emotional value of the learned information. Specifically, psychosocial stress resulted in enhanced recognition memory for emotional versus neutral information and improved working memory only in male subjects; stress did not affect memory performance in women. 2) MRs play a role in the regulation of the HPA axis and in stress effects on cognitive performance. We found that blockade of MRs with an antagonist in combination with psychosocial stress, presumably resulting in a shift from MR towards GR activation, resulted in enhanced long-term memory and impaired working memory in men. 3) The timing of cortisol with respect to the acquisition or encoding of memory critically influences the outcome of those effects. That is, rapid corticosteroid actions impaired the contextualization of emotional memories, but did not influence fear conditioning processes, while delayed effects of cortisol enhanced contextualization of emotional memories and strengthened trace, but not delay conditioning. 4) Performance on an intertemporal choice task was not affected by psychosocial stress, independent of the timing of the stressor. Thus, we indeed demonstrated the importance of timing, steroid receptors, sex differences and additional factors, like emotional arousal and context, in determining stress and cortisol effects on cognitive function. These findings emphasize the complexity of this research field, and can form the starting point for more extensive studies in the future, aimed at unraveling the underlying mechanisms in the human brain.