Post-retrieval stress impairs subsequent memory depending on hippocampal memory trace reinstatement during reactivation.

Upon retrieval, memories can become susceptible to meaningful events, such as stress. Post-retrieval memory changes may be attributed to an alteration of the original memory trace during reactivation-dependent reconsolidation or, alternatively, to the modification of retrieval-related memory traces that impact future remembering. Hence, how post-retrieval memory changes emerge in the human brain is unknown. In a 3-day functional magnetic resonance imaging study, we show that post-retrieval stress impairs subsequent memory depending on the strength of neural reinstatement of the original memory trace during reactivation, driven by the hippocampus and its cross-talk with neocortical representation areas. Comparison of neural patterns during immediate and final memory testing further revealed that successful retrieval was linked to pattern-dissimilarity in controls, suggesting the use of a different trace, whereas stressed participants relied on the original memory representation. These representation changes were again dependent on neocortical reinstatement during reactivation. Our findings show disruptive stress effects on the consolidation of retrieval-related memory traces that support future remembering.

Consistently increased dorsolateral prefrontal cortex activity during the exposure to acute stressors.

Stress has a major impact on our mental health. Nonetheless, it is still not fully understood how the human brain responds to ongoing stressful events. Here, we aimed to determine the cortical dynamics during the exposure to ecologically valid, standardized stressors. To this end, we conducted 3 experiments in which healthy participants underwent the Trier Social Stress Test (experiments 1 and 2) and the Socially Evaluated Cold Pressor Test (experiment 3) or a respective control manipulation, while we measured their cortical activity using functional near-infrared spectroscopy. Increases in salivary cortisol and subjective stress levels confirmed the successful stress induction in all experiments. Results of experiment 1 showed significantly increased cortical activity, in particular in the dorsolateral prefrontal cortex, during the exposure to the Trier Social Stress Test. Experiment 2 replicated this finding and showed further that this stress-related increase in dorsolateral prefrontal cortex activity was transient and limited to the period of the Trier Social Stress Test. Experiment 3 demonstrated the increased dorsolateral prefrontal cortex activity during the Socially Evaluated Cold Pressor Test, suggesting that this increase is generalizable and not specific to the Trier Social Stress Test. Together, these data show consistently that dorsolateral prefrontal cortex activity is not reduced, as commonly assumed, but increased under stress, which may promote coping with the ongoing stressor.

Causal role of the angular gyrus in insight-driven memory reconfiguration.

Maintaining an accurate model of the world relies on our ability to update memory representations in light of new information. Previous research on the integration of new information into memory mainly focused on the hippocampus. Here, we hypothesized that the angular gyrus, known to be involved in episodic memory and imagination, plays a pivotal role in the insight-driven reconfiguration of memory representations. To test this hypothesis, participants received continuous theta burst stimulation (cTBS) over the left angular gyrus or sham stimulation before gaining insight into the relationship between previously separate life-like animated events in a narrative-insight task. During this task, participants also underwent EEG recording and their memory for linked and non-linked events was assessed shortly thereafter. Our results show that cTBS to the angular gyrus decreased memory for the linking events and reduced the memory advantage for linked relative to non-linked events. At the neural level, cTBS targeting the angular gyrus reduced centro-temporal coupling with frontal regions and abolished insight-induced neural representational changes for events linked via imagination, indicating impaired memory reconfiguration. Further, the cTBS group showed representational changes for non-linked events that resembled the patterns observed in the sham group for the linked events, suggesting failed pruning of the narrative in memory. Together, our findings demonstrate a causal role of the left angular gyrus in insight-related memory reconfigurations.

Time-dependent memory transformation in hippocampus and neocortex is semantic in nature.

Memories undergo a time-dependent neural reorganization, which is assumed to be accompanied by a transformation from detailed to more gist-like memory. However, the nature of this transformation and its underlying neural mechanisms are largely unknown. Here, we report that the time-dependent transformation of memory is semantic in nature, while we find no credible evidence for a perceptual transformation. Model-based MRI analyses reveal time-dependent increases in semantically transformed representations of events in prefrontal and parietal cortices, while specific pattern representations in the anterior hippocampus decline over time. Posterior hippocampal memory reinstatement, in turn, increases over time and is linked to the semantic gist of the original memory, without a statistically significant link to perceptual details. These findings indicate that qualitative changes in memory over time, associated with distinct representational changes in the neocortex and within the hippocampus, reflect a semantic transformation, which may promote the integration of memories into abstract knowledge structures.

Strong but Fragmented Memory of a Stressful Episode.

While it is commonly assumed that stressful events are vividly remembered, it remains largely unknown whether all aspects of memory for a stressful episode are enhanced. In this preregistered study, we tested whether stress enhances later remembering of individual elements of a stressful episode at the cost of impaired processing of the association between these elements. Therefore, male and female participants (N = 122) underwent a stressful (or control) episode during which they encoded a series of stimuli. To investigate stress effects on the memory for individual events and the links between these, we used temporal sequence effects in recognition memory tested 24 h after encoding. Specifically, we tested whether stress would affect the memory enhancement for a target item if this is preceded by another item that also preceded the target during encoding (recognition priming). Our results showed that participants recalled single events encoded under stress better than those encoded under nonstressful conditions, but were less able to leverage the temporal sequence of events encoded under stress to cue memory at delayed recall, reflected in reduced memory for items preceded by the item that preceded them also during encoding. Functional near-infrared spectroscopy further revealed that encoding under stress was accompanied by opposite changes in inferotemporal and dorsolateral prefrontal areas. Together, our data suggest that acute stress induces a mode of memory formation that results in strong but less integrated memories.

Higher subjective socioeconomic status is linked to increased charitable giving and mentalizing-related neural value coding.

Socioeconomic status (SES), a concept related to an individual's economic and social position relative to others, can shape social interactions like altruistic behaviors. However, little is known about the exact neurocognitive mechanisms that link SES with altruism. Our study aimed to provide a comprehensive account of the sociocognitive and neural mechanisms through which SES affects charitable giving - an important variant of human altruism. To this end, participants completed a charitable donation task while their brain activity was measured using functional magnetic resonance imaging (fMRI). We also assessed participants' socio-cognitive ability to infer other people's mental states (i.e., mentalizing) - a driver of prosocial behavior - in an independent social task. Behaviorally, we found that both charitable giving and social cognition were status-dependent, as subjective SES positively predicted donations and mentalizing capacity. Moreover, the link between SES and charitable giving was mediated by individuals' mentalizing capacity. At the neural level, a multivariate pattern analysis of fMRI data revealed that higher subjective SES was associated with stronger value coding in the right temporoparietal junction (rTPJ). The strength of this value representation predicted charitable giving and was linked to mentalizing. Furthermore, we observed an increased negative functional coupling between rTPJ and left putamen with higher SES. Together, increased charitable giving in higher-status individuals could be explained by status-dependent recruitment of mentalizing-related value coding and altered functional connectivity in the brain. Our findings provide insights into the socio- and neurocognitive mechanisms explaining why and when higher SES leads to prosociality, which might ultimately inform targeted interventions to promote prosocial behavior in human societies.

Multiple routes to enhanced memory for emotionally relevant events.

Events associated with aversive or rewarding outcomes are prioritized in memory. This memory boost is commonly attributed to the elicited affective response, closely linked to noradrenergic and dopaminergic modulation of hippocampal plasticity. Herein we review and compare this 'affect' mechanism to an additional, recently discovered, 'prediction' mechanism whereby memories are strengthened by the extent to which outcomes deviate from expectations, that is, by prediction errors (PEs). The mnemonic impact of PEs is separate from the affective outcome itself and has a distinct neural signature. While both routes enhance memory, these mechanisms are linked to different - and sometimes opposing - predictions for memory integration. We discuss new findings that highlight mechanisms by which emotional events strengthen, integrate, and segment memory.

Inferring danger with minimal aversive experience.

Learning about threats is crucial for survival and fundamentally rests upon Pavlovian conditioning. However, Pavlovian threat learning is largely limited to detecting known (or similar) threats and involves first-hand exposure to danger, which inevitably poses a risk of harm. We discuss how individuals leverage a rich repertoire of mnemonic processes that operate largely in safety and significantly expand our ability to recognize danger beyond Pavlovian threat associations. These processes result in complementary memories - acquired individually or through social interactions - that represent potential threats and the relational structure of our environment. The interplay between these memories allows danger to be inferred rather than directly learned, thereby flexibly protecting us from potential harm in novel situations despite minimal prior aversive experience.

Imagining is not seeing: lower insight-driven memory reconfiguration when imagining the link between separate events.

Gaining insight into the relationship between previously separate events allows us to combine these events into coherent episodes. This insight may occur via observation or imagination. Although much of our reasoning occurs in the absence of direct sensory stimuli, how mnemonic integration is accomplished via imagination has remained completely unknown. Here, we combined fMRI with representational similarity analysis and a real-life-like narrative-insight task (NIT) to elucidate the behavioral and neural effects of insight through imagination (vs. observation). Healthy participants performed the NIT in the MRI scanner and underwent memory testing one week later. Crucially, participants in the observation group gained insight through a video, while participants in the imagination group gained insight through an imagination instruction. Although we show that insight via imagination was weaker than insight via direct observation, the imagination group showed better detail memory. Moreover, the imagination group showed no representational change in the anterior hippocampus or increases in frontal and striatal activity for the linked events, as was the case in the observation group. However, the hippocampus and striatum were more activated during linking via imagination, which might indicate that their increased recruitment during imagination impedes concurrent mnemonic integration but may facilitate long-term memory.

Neural Index of Reinforcement Learning Predicts Improved Stimulus-Response Retention under High Working Memory Load.

Human learning and decision-making are supported by multiple systems operating in parallel. Recent studies isolating the contributions of reinforcement learning (RL) and working memory (WM) have revealed a trade-off between the two. An interactive WM/RL computational model predicts that although high WM load slows behavioral acquisition, it also induces larger prediction errors in the RL system that enhance robustness and retention of learned behaviors. Here, we tested this account by parametrically manipulating WM load during RL in conjunction with EEG in both male and female participants and administered two surprise memory tests. We further leveraged single-trial decoding of EEG signatures of RL and WM to determine whether their interaction predicted robust retention. Consistent with the model, behavioral learning was slower for associations acquired under higher load but showed parametrically improved future retention. This paradoxical result was mirrored by EEG indices of RL, which were strengthened under higher WM loads and predictive of more robust future behavioral retention of learned stimulus-response contingencies. We further tested whether stress alters the ability to shift between the two systems strategically to maximize immediate learning versus retention of information and found that induced stress had only a limited effect on this trade-off. The present results offer a deeper understanding of the cooperative interaction between WM and RL and show that relying on WM can benefit the rapid acquisition of choice behavior during learning but impairs retention.SIGNIFICANCE STATEMENT Successful learning is achieved by the joint contribution of the dopaminergic RL system and WM. The cooperative WM/RL model was productive in improving our understanding of the interplay between the two systems during learning, demonstrating that reliance on RL computations is modulated by WM load. However, the role of WM/RL systems in the retention of learned stimulus-response associations remained unestablished. Our results show that increased neural signatures of learning, indicative of greater RL computation, under high WM load also predicted better stimulus-response retention. This result supports a trade-off between the two systems, where degraded WM increases RL processing, which improves retention. Notably, we show that this cooperative interplay remains largely unaffected by acute stress.

Neural correlates of conflict adaptation predict daily stress reactivity.

Chronic exposure to daily stress can be harmful to mental health especially when individuals lack adaptive adjustment mechanisms. The present study aimed to investigate how the adaptive capacities in cognition and emotion as well as their neural signatures could moderate the stress reactivity in daily life. Seventy-five healthy participants aged 18-24 years participated in this study. We recorded brain activity using electroencephalography while participants were performing a conflict task and an emotion regulation task in the laboratory. Using the experience sampling method, participants were subsequently instructed to report their daily stress and daily affect on 14 consecutive days. Our results revealed that a larger adaptation effect in reaction times of the conflict task predicted a stronger negative affect in response to the stress of the same day. The adaptation effect in the N2 and P3 components elicited by the conflict task predicted a weaker influence of today's stress level on the next day's stress level, pointing to a better stress adaptation. However, emotion regulation capacities did not predict daily stress reactivity. Our data indicate that conflict adaption predicts two aspects of stress reactivity in daily life: how stress influences the negative affect that day, and how stress that day is related to stress the next day. These findings point to new avenues for early screening of stress-vulnerable populations, with implications for the prevention and intervention of stress-related mental disorders.

Stress disrupts insight-driven mnemonic reconfiguration in the medial temporal lobe.

Memories are not stored in isolation. Insight into the relationship of initially unrelated events may trigger a flexible reconfiguration of the mnemonic representation of these events. Such representational changes allow the integration of events into coherent episodes and help to build up-to-date-models of the world around us. This process is, however, frequently impaired in stress-related mental disorders resulting in symptoms such as fragmented memories in PTSD. Here, we combined a real life-like narrative-insight task, in which participants learned how initially separate events are linked, with fMRI-based representational similarity analysis to test if and how acute stress interferes with the insight-driven reconfiguration of memories. Our results showed that stress reduced the activity of medial temporal and prefrontal areas when participants gained insight into the link between events. Moreover, stress abolished the insight-related increase in representational dissimilarity for linked events in the anterior part of the hippocampus as well as its association with measures of subsequent memory that we observed in non-stressed controls. However, memory performance, as assessed in a forced-choice recognition test, was even enhanced in the stress group. Our findings suggest that acute stress impedes the neural integration of events into coherent episodes but promotes long-term memory for these integrated narratives and may thus have implications for understanding memory distortions in stress-related mental disorders.

Disentangling the roles of dopamine and noradrenaline in the exploration-exploitation tradeoff during human decision-making.

Balancing the exploration of new options and the exploitation of known options is a fundamental challenge in decision-making, yet the mechanisms involved in this balance are not fully understood. Here, we aimed to elucidate the distinct roles of dopamine and noradrenaline in the exploration-exploitation tradeoff during human choice. To this end, we used a double-blind, placebo-controlled design in which participants received either a placebo, 400 mg of the D2/D3 receptor antagonist amisulpride, or 40 mg of the ß-adrenergic receptor antagonist propranolol before they completed a virtual patch-foraging task probing exploration and exploitation. We systematically varied the rewards associated with choice options, the rate by which rewards decreased over time, and the opportunity costs it took to switch to the next option to disentangle the contributions of dopamine and noradrenaline to specific choice aspects. Our data show that amisulpride increased the sensitivity to all of these three critical choice features, whereas propranolol was associated with a reduced tendency to use value information. Our findings provide novel insights into the specific roles of dopamine and noradrenaline in the regulation of human choice behavior, suggesting a critical involvement of dopamine in directed exploration and a role of noradrenaline in more random exploration.

Spatio-temporal theta pattern dissimilarity in the right centro-parietal area during memory generalization.

Generalization across past events may guide our action in novel situations. Although generalization is a fundamental memory process, its neural underpinnings are not fully understood yet. In the present experiment, we combinedElectroencephalography(EEG) with multivariate representational similarity analysis (RSA) to examine in particular the role of spatio-temporal patterns of theta oscillations known to be important for associative memory processes, in memory generalization. We recorded EEG while healthy participants (n = 56) performed an acquired equivalence task. In this task, participants first acquired multiple associations among antecedent and consequent stimuli before they were required to transfer the acquired knowledge to novel stimulus pairs, thus probing memory generalization. Our behavioural data indicated that participants learned the initial associations well and transferred these associations successfully to novel test stimuli, demonstrating successful memory generalization. Our neural data revealed that, compared to mere memory retrieval, generalization was associated with significantly increased pattern dissimilarity of theta activity in the right centro-parietal area (electrodes P4 and P6). This pattern was specific to theta oscillations and not observed in other frequency bands. Our findings suggest an important role of theta oscillations in memory generalization, potentially serving the reactivation and integration of distinct events that enable the generalization across experiences.

Reappraisal enhances memory formation for a stressful episode.

Emotion regulation strategies have been shown to modify the physiological response to stress, yet whether these strategies can modulate also cognitive responses to stress is largely unknown. A prominent cognitive response to stress is the enhanced memory formation for the stressful event, which is an adaptive mechanism to prepare for similar events in the future. Thus, the present study aimed to investigate whether emotion regulation strategies impact the memory formation for a stressful episode. In a two-day study, participants (n = 124) underwent an enriched stressful episode or a control episode. Critically, before the exposure to the stressor, they were instructed to use a suppression or reappraisal strategy during the stressful episode. One week later, participants completed a memory test for central and peripheral details of this episode. Our results show that reappraisal enhanced not only the cortisol response to the stressor but also the memory formation for central features of the stressful episode. This reappraisal-related boost of memory for the stressor was particularly pronounced in participants' with high working memory capacity. These findings show that reappraisal may not only impact the physiological response to a stressful event but also the cognitive representation of this event in memory.

Stress diminishes outcome but enhances response representations during instrumental learning.

Stress may shift behavioural control from a goal-directed system that encodes action-outcome relationships to a habitual system that learns stimulus-response associations. Although this shift to habits is highly relevant for stress-related psychopathologies, limitations of existing behavioural paradigms hinder research from answering the fundamental question of whether the stress-induced bias to habits is due to reduced outcome processing or enhanced response processing at the time of stimulus presentation, or both. Here, we used EEG-based multivariate pattern analysis to decode neural outcome representations crucial for goal-directed control, as well as response representations during instrumental learning. We show that stress reduced outcome representations but enhanced response representations. Both were directly associated with a behavioural index of habitual responding. Furthermore, changes in outcome and response representations were uncorrelated, suggesting that these may reflect distinct processes. Our findings indicate that habitual behaviour under stress may be the result of both enhanced stimulus-response processing and diminished outcome processing.

Mechanisms of memory under stress.

It is well established that stress has a major impact on memory, driven by the concerted action of various stress mediators on the brain. Recent years, however, have seen considerable advances in our understanding of the cellular, neural network, and cognitive mechanisms through which stress alters memory. These novel insights highlight the intricate interplay of multiple stress mediators, including-beyond corticosteroids, catecholamines, and peptides-for instance, endocannabinoids, which results in time-dependent shifts in large-scale neural networks. Such stress-induced network shifts enable highly specific memories of the stressful experience in the long run at the cost of transient impairments in mnemonic flexibility during and shortly after a stressful event. Based on these recent discoveries, we provide a new integrative framework that links the cellular, systems, and cognitive mechanisms underlying acute stress effects on memory processes and points to potential targets for treating aberrant memory in stress-related mental disorders.

Altruism under Stress: Cortisol Negatively Predicts Charitable Giving and Neural Value Representations Depending on Mentalizing Capacity.

Altruism, defined as costly other-regarding behavior, varies considerably across people and contexts. One prominent context in which people frequently must decide on how to socially act is under stress. How does stress affect altruistic decision-making and through which neurocognitive mechanisms? To address these questions, we assessed neural activity associated with charitable giving under stress. Human participants (males and females) completed a charitable donation task before and after they underwent either a psychosocial stressor or a control manipulation, while their brain activity was measured using functional magnetic resonance imaging. As the ability to infer other people's mental states (i.e., mentalizing) predicts prosocial giving and may be susceptible to stress, we examined whether stress effects on altruism depend on participants' general capacity to mentalize, as assessed in an independent task. Although our stress manipulation per se had no influence on charitable giving, increases in the stress hormone cortisol were associated with reductions in donations in participants with high mentalizing capacity, but not in low mentalizers. Multivariate neural response patterns in the right dorsolateral prefrontal cortex (DLPFC) were less predictive of postmanipulation donations in high mentalizers with increased cortisol, indicating decreased value coding, and this effect mediated the (moderated) association between cortisol increases and reduced donations. Our findings provide novel insights into the modulation of altruistic decision-making by suggesting an impact of the stress hormone cortisol on mentalizing-related neurocognitive processes, which in turn results in decreased altruism. The DLPFC appears to play a key role in mediating this cortisol-related shift in altruism.SIGNIFICANCE STATEMENT Altruism is a fundamental building block of our society. Emerging evidence indicates a major role of acute stress and stress-related neuromodulators in social behavior and decision-making. How and through which mechanisms stress may impact altruism remains elusive. We observed that the stress hormone cortisol was linked to diminished altruistic behavior. This effect was mediated by reduced value representations in the right dorsolateral prefrontal cortex and critically depended on the individual capacity to infer mental states of others. Our findings provide novel insights into the modulation of human altruism linked to stress-hormone dynamics and into the involved sociocognitive and neural mechanisms, with important implications for future developments of more targeted interventions for stress-related decrements in social behavior and social cognition.

Prediction Errors for Aversive Events Shape Long-Term Memory Formation through a Distinct Neural Mechanism.

Prediction errors (PEs) have been known for decades to guide associative learning, but their role in episodic memory formation has been discovered only recently. To identify the neural mechanisms underlying the impact of aversive PEs on long-term memory formation, we used functional magnetic resonance imaging, while participants saw a series of unique stimuli and estimated the probability that an aversive shock would follow. Our behavioral data showed that negative PEs (i.e., omission of an expected outcome) were associated with superior recognition of the predictive stimuli, whereas positive PEs (i.e., presentation of an unexpected outcome) impaired subsequent memory. While medial temporal lobe (MTL) activity during stimulus encoding was overall associated with enhanced memory, memory-enhancing effects of negative PEs were linked to even decreased MTL activation. Additional large-scale network analyses showed PE-related increases in crosstalk between the "salience network" and a frontoparietal network commonly implicated in memory formation for expectancy-congruent events. These effects could not be explained by mere changes in physiological arousal or the prediction itself. Our results suggest that the superior memory for events associated with negative aversive PEs is driven by a potentially distinct neural mechanism that might serve to set these memories apart from those with expected outcomes.

Stress-induced cortisol modulates the control of memory retrieval towards the dorsal striatum.

Stress can modulate the recruitment of multiple memory systems during learning, favouring dorsal striatal "habit" learning over hippocampal "cognitive" learning. Here, we tested whether stress may also bias the engagement of "cognitive" and "habit" systems during retrieval and thereby affect the nature of remembering. To this end, participants first performed a probabilistic classification learning task that can be solved by both the "cognitive" and the "habit" system. Twenty-four hours later, participants underwent either a stress manipulation or a non-stressful control procedure before they completed a retention test for the previously learned task in the MRI scanner. During this retention test, stress-induced cortisol levels were linked to a relative bias towards behavioural strategies indicative for the "habit" system. At the neural level, stress led to increased dorsal striatal activity during retrieval. Elevated cortisol levels were directly correlated with increased activity in the dorsal striatum and further linked to reduced functional connectivity between the hippocampus and the amygdala, which is assumed to orchestrate the stress-related shift from "cognitive" to "habitual" control. Together, our data suggest that stress may bias the contributions of multiple memory systems also at retrieval, in a manner that promotes dorsal striatal "habit" processes and most likely driven by cortisol.