Susanne Vogel

Cognitive Adaptation under Stress : A Case for the Mineralocorticoid Receptor

Corticosteroid hormones, released during stressful encounters, have profound and far-reaching effects on cognition. They are often thought to accomplish these effects primarily via glucocorticoid receptors (GR), but recent findings from rodent and human studies argue for an additional, critical role of the mineralocorticoid receptor (MR) in cognitive changes in response to stress. We propose that the MR initiates rapid changes in the recruitment of specific neural systems, inducing a shift towards cognitively less-demanding processing and allowing a quick and adequate response to the situation. In combination with slower and longer-lasting actions mediated by GR, this shift leads to optimal coping with the ongoing stressful event.

Blocking the mineralocorticoid receptor in humans prevents the stress-induced enhancement of centromedial amygdala connectivity with the dorsal striatum

Two research lines argue for rapid stress-induced reallocations of neural network activity involving the amygdala. One focuses on the role of norepinephrine (NE) in mediating a shift towards the salience network and improving vigilance processing, whereas the other focuses on the role of cortisol in enhancing automatic, habitual responses. It has been suggested that the mineralocorticoid receptor (MR) is critical in shifting towards habitual responses, which are supported by the dorsal striatum. However, until now it remained unclear whether these two reallocations of neural recourses might be part of the same phenomenon and develop immediately after stress onset. We combined methods used in both approaches and hypothesized specifically that stress would lead to rapidly enhanced involvement of the striatum as assessed by amygala-striatal connectivity. Furthermore, we tested the hypothesis that this shift depends on cortisol interacting with the MR, by using a randomized, placebo-controlled, full-factorial, between-subjects design with the factors stress and MR-blockade (spironolactone). We investigated 101 young, healthy men using functional magnetic resonance imaging after stress induction, which led to increased negative mood, heart rate, and cortisol levels. We confirmed our hypothesis by revealing a stress-by-MR-blockade interaction on the functional connectivity between the centromedial amygdala (CMA) and the dorsal striatum. Stress rapidly enhanced CMA-striatal connectivity and this effect was correlated with the stress-induced cortisol response, but required MR availability. This finding might suggest that the stress-induced shift described by distinct research lines might capture different aspects of the same phenomenon, ie, a reallocation of neural resources coordinated by both NE and cortisol.

Learning and memory under stress: implications for the classroom

Exams, tight deadlines and interpersonal conflicts are just a few examples of the many events that may result in high levels of stress in both students and teachers. Research over the past two decades identified stress and the hormones and neurotransmitters released during and after a stressful event as major modulators of human learning and memory processes, with critical implications for educational contexts. While stress around the time of learning is thought to enhance memory formation, thus leading to robust memories, stress markedly impairs memory retrieval, bearing, for instance, the risk of underachieving at exams. Recent evidence further indicates that stress may hamper the updating of memories in the light of new information and induce a shift from a flexible, ‘cognitive’ form of learning towards rather rigid, ‘habit’-like behaviour. Together, these stress-induced changes may explain some of the difficulties of learning and remembering under stress in the classroom. Taking these insights from psychology and neuroscience into account could bear the potential to facilitate processes of education for both students and teachers.

A Stress-Induced Shift From Trace to Delay Conditioning Depends on the Mineralocorticoid Receptor

BACKGROUND Fear learning in stressful situations is highly adaptive for survival by steering behavior in subsequent situations, but fear learning can become disproportionate in vulnerable individuals. Despite the potential clinical significance, the mechanism by which stress modulates fear learning is poorly understood. Memory theories state that stress can cause a shift away from more controlled processing depending on the hippocampus toward more reflexive processing supported by the amygdala and striatum. This shift may be mediated by activation of the mineralocorticoid receptor (MR) for cortisol. We investigated how stress shifts processes underlying cognitively demanding learning versus less demanding fear learning using a combined trace and delay fear conditioning paradigm. METHODS In a pharmacological functional magnetic resonance imaging study, we tested 101 healthy men probing the effects of stress (socially evaluated cold pressor vs. control procedure) and MR-availability (400 mg spironolactone vs. placebo) in a randomized, placebo-controlled, full-factorial, between-subjects design. RESULTS Effective stress induction and successful conditioning were confirmed by subjective, physiologic, and somatic data. In line with a stress-induced shift, stress enhanced later recall of delay compared with trace conditioning in the MR-available groups as indexed by skin conductance responses. During learning, this was accompanied by a stress-induced reduction of learning-related hippocampal activity for trace conditioning. The stress-induced shift in fear and neural processing was absent in the MR-blocked groups. CONCLUSIONS Our results are in line with a stress-induced shift in fear learning, mediated by the MR, resulting in a dominance of cognitively less demanding amygdala-based learning, which might be particularly prominent in individuals with high MR sensitivity.

Linking genetic variants of the mineralocorticoid receptor and negative memory bias: Interaction with prior life adversity

Substantial research has been conducted investigating the association between life adversity and genetic vulnerability for depression, but clear mechanistic links are rarely identified and investigation often focused on single genetic variants. Complex phenotypes like depression, however, are likely determined by multiple variants in interaction with environmental factors. As variations in the mineralocorticoid receptor gene (NR3C2) have been related to a higher risk for depression, we investigated whether NR3C2 variance is related to negative memory bias, an established endophenotype for depression, in healthy participants. Furthermore, we explored the influence of life adversity on this association. We used a set-based analysis to simultaneously test all measured variation in NR3C2 for an association with negative memory bias in 483 participants and an interaction with life adversity. To further specify this interaction, we split the sample into low and high live adversity groups and repeated the analyses in both groups separately. NR3C2 variance was associated with negative memory bias, especially in the high life adversity group. Additionally, we identified a functional polymorphism (rs5534) related to negative memory bias and demonstrating a gene×life adversity interaction. Variations in NR3C2 are associated with negative memory bias and this relationship appears to be influenced by life adversity. As negative memory bias is implicated in the susceptibility to depression, our findings provide mechanistic support for the notion that variations in NR3C2 - which could compromise the proper function of this receptor - are a risk factor for the development of mood disorders.

Stress in the zoo: Tracking the impact of stress on memory formation over time

Although stress is well known to modulate human memory, precisely how memory formation is altered by a stressful encounter remains unclear. Stress effects on cognition are mainly mediated by the rapidly acting sympathetic nervous system, resulting in the release of catecholamines, and the slower acting hypothalamus-pituitary-adrenal axis secreting cortisol, which induces its effects on cognition through fast, non-genomic actions and delayed, genomic actions. Importantly, these different waves of the physiological stress response are thought to dynamically alter neural processing in brain regions important for memory such as the amygdala and the hippocampus. However, the precise time course of stress effects on memory formation is still unclear. To track the development of stress effects on memory over time, we tested individuals who underwent a stressful experience or a control procedure before a 2-h walk through a zoo, while an automatic camera continuously photographed the events they encoded. In a recognition memory test one week later, participants were presented with target photographs of their own zoo tour and lure photographs from an alternate tour. Stressed participants showed better memory for the experimental treatment than control participants, and this memory enhancement for the stressful encounter itself was directly linked to the sympathetic stress response. Moreover, stress enhanced memory for events encoded 41-65min after stressor onset, which was associated with the cortisol stress response, most likely arising from non-genomic cortisol actions. However, memory for events encoded long after the stressor, when genomic cortisol actions had most likely developed, remained unchanged. Our findings provide novel insights into how stress effects on memory formation develop over time, depending on the activity of major physiological stress response systems.

How Administration of the Beta-Blocker Propranolol Before Extinction can Prevent the Return of Fear.

Combining beta-blockers with exposure therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol before extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24 h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by (i) reducing retrieval of fear memory, via the dmPFC and (ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers.

Depressed patients in remission show an interaction between variance in the mineralocorticoid receptor NR3C2 gene and childhood trauma on negative memory bias

Background Genetic, environmental, and cognitive factors play a role in the development and recurrence of depression. More specifically, cognitive biases have been associated with depression risk genes and life events. Recently, the mineralocorticoid receptor NR3C2 gene, and in particular the rs5534 polymorphism, has been associated with negative memory bias, at least in healthy individuals who experienced severe life adversity. The current study examined the interaction between the rs5534 genotype and different types of adverse life events in a sample of depressed patients in remission. Materials and methods A total of 298 depressed patients in remission performed an incidental emotional memory task (negative and positive words). Life adversity, childhood trauma, and recent adversity were measured using a self-report questionnaire. NR3C2 rs5534 by life adversity, as well as childhood trauma and recent adversity interactions were analyzed for negative and positive memory bias using analyses of covariance. Results The significant interaction between rs5534 and childhood trauma on negative memory bias (P=0.046) indicated that risk ‘A’ allele carriers with childhood trauma tended to show more negative memory bias compared to individuals homozygous for the G allele who had experienced childhood trauma and A allele carriers without childhood trauma. No interaction effects with life adversity or recent adversity were found. Also, no main effect of rs5534 on memory bias was found, although we had insufficient power for this analysis. Conclusion An association of the NR3C2 gene and childhood trauma with negative memory bias was found in depressed patients in remission, which extends previous findings in a healthy population.

Tell me what to do: Stress facilitates stimulus-response learning by instruction

HighlightsInstruction is a highly efficient means to teach new behavioral rules.Despite its relevance for education, factors altering instruction efficacy are unknown.Acute stress boosts the beneficial effect of an instruction on stimulus‐response learning.This enhancement was correlated with the individual cortisol and blood pressure response to stress.High trait anxiety reduces the benefit of an instruction on learning. ABSTRACT Learning by explicit instruction is a highly efficient way to instantaneously learn new behaviors and to overcome potentially harmful learning by trial‐and‐error. Despite the importance of instructed learning for education, influences on the efficacy of an instruction are currently unknown. Decades of research, however, showed that stress is a powerful modulator of learning and memory, including the acquisition of stimulus‐response (S‐R) associations. Moreover, brain areas critical for instructed learning are a major target of hormones and neurotransmitters released during stress. Thus, we investigated here whether acute stress affects instructed S‐R learning and whether this effect differs for trial‐and‐error learning. To this end, healthy participants underwent a stressor (Socially Evaluated Cold Pressor Test) or a control manipulation before learning arbitrary S‐R associations. For half of the stimuli, participants were explicitly instructed about the correct association, whereas the remaining associations had to be learned by trial‐and‐error. As expected, the instruction resulted in better performance and enhanced explicit rule knowledge compared to trial‐and‐error learning. Stress further boosted the beneficial effect of an explicit instruction on learning performance, while leaving trial‐and‐error learning unchanged. These beneficial effects of stress were directly correlated with the activity of the autonomic nervous system and the concentration of cortisol. Moreover, acute stress could override the detrimental effect of high trait anxiety levels on instructed S‐R learning performance. Our findings indicate that acute stress may facilitate learning from instruction, which may represent a highly efficient way to learn how to act, without the necessity of own experience, that helps to save cognitive resources during a stressful encounter.

How acute stress may enhance subsequent memory for threat stimuli outside the focus of attention: DLPFC-amygdala decoupling

&NA; Stress‐related disorders, e.g., anxiety and depression, are characterized by decreased top‐down control for distracting information, as well as a memory bias for threatening information. However, it is unclear how acute stress biases mnemonic encoding and leads to prioritized storage of threat‐related information even if outside the focus of attention. In the current study, healthy adults (N = 53, all male) were randomly assigned to stress induction using the socially evaluated cold‐pressor test (SECPT) or a control condition. Participants performed a task in which they were required to identify a target letter within a string of letters that were either identical to the target and thereby facilitating detection (low distractor load) or mixed with other letters to complicate the search (high load). Either a fearful or neutral face was presented on the background, outside the focus of attention. Twenty‐four hours later, participants were asked to perform a surprise recognition memory test for those background faces. Stress induction resulted in increased cortisol and negative subjective mood ratings. Stress did not affect visual search performance, however, participants in the stress group showed stronger memory compared to the control group for fearful faces in the low attentional load condition. Critically, the stress induced memory bias was accompanied by decoupling between amygdala and DLFPC during encoding, which may represent a mechanism for decreased ability to filter task‐irrelevant threatening background information. The current study provides a potential neural account for how stress can produce a negative memory bias for threatening information even if presented outside the focus of attention. Despite of an adaptive advantage for survival, such tendencies may ultimately also lead to generalized fear, a possibility requiring additional investigation. HighlightsMemory for threatening distracters under acute stress was measured.Acute stress leads to selectively enhanced memory for threatening distracters.This memory enhancement depends on current perceptual load.The memory enhancement appears to be driven by decoupling between amygdala and DLPFC.