Dorsolateral Prefrontal Cortex Enables Updating of Established Memories.

Updating established memories in light of new information is fundamental for memory to guide future behavior. However, little is known about the brain mechanisms by which existing memories can be updated. Here, we combined functional magnetic resonance imaging and multivariate representational similarity analysis to elucidate the neural mechanisms underlying the updating of consolidated memories. To this end, participants first learned face-city name pairs. Twenty-four hours later, while lying in the MRI scanner, participants were required to update some of these associations, but not others, and to encode entirely new pairs. Updating success was tested again 24 h later. Our results showed increased activity of the dorsolateral prefrontal cortex (dlPFC) specifically during the updating of existing associations that was significantly stronger than when simple retrieval or new encoding was required. The updating-related activity of the dlPFC and its functional connectivity with the hippocampus were directly linked to updating success. Furthermore, neural similarity for updated items was markedly higher in the dlPFC and this increase in dlPFC neural similarity distinguished individuals with high updating performance from those with low updating performance. Together, these findings suggest a key role of the dlPFC, presumably in interaction with the hippocampus, in the updating of established memories.

Stress affects the neural ensemble for integrating new information and prior knowledge.

Prior knowledge, represented as a schema, facilitates memory encoding. This schema-related learning is assumed to rely on the medial prefrontal cortex (mPFC) that rapidly integrates new information into the schema, whereas schema-incongruent or novel information is encoded by the hippocampus. Stress is a powerful modulator of prefrontal and hippocampal functioning and first studies suggest a stress-induced deficit of schema-related learning. However, the underlying neural mechanism is currently unknown. To investigate the neural basis of a stress-induced schema-related learning impairment, participants first acquired a schema. One day later, they underwent a stress induction or a control procedure before learning schema-related and novel information in the MRI scanner. In line with previous studies, learning schema-related compared to novel information activated the mPFC, angular gyrus, and precuneus. Stress, however, affected the neural ensemble activated during learning. Whereas the control group distinguished between sets of brain regions for related and novel information, stressed individuals engaged the hippocampus even when a relevant schema was present. Additionally, stressed participants displayed aberrant functional connectivity between brain regions involved in schema processing when encoding novel information. The failure to segregate functional connectivity patterns depending on the presence of prior knowledge was linked to impaired performance after stress. Our results show that stress affects the neural ensemble underlying the efficient use of schemas during learning. These findings may have relevant implications for clinical and educational settings.

Stress leads to aberrant hippocampal involvement when processing schema-related information.

Prior knowledge, represented as a mental schema, has critical impact on how we organize, interpret, and process incoming information. Recent findings indicate that the use of an existing schema is coordinated by the medial prefrontal cortex (mPFC), communicating with parietal areas. The hippocampus, however, is crucial for encoding schema-unrelated information but not for schema-related information. A recent study indicated that stress mediators may affect schema-related memory, but the underlying neural mechanisms are currently unknown. Here, we thus tested the impact of acute stress on neural processing of schema-related information. We exposed healthy participants to a stress or control manipulation before they processed, in the MRI scanner, words related or unrelated to a preexisting schema activated by a specific cue. Participants' memory for the presented material was tested 3-5 d after encoding. Overall, the processing of schema-related information activated the mPFC, the precuneus, and the angular gyrus. Stress resulted in aberrant hippocampal activity and connectivity while participants processed schema-related information. This aberrant engagement of the hippocampus was linked to altered subsequent memory. These findings suggest that stress may interfere with the efficient use of prior knowledge during encoding and may have important practical implications, in particular for educational settings.

Cortisol boosts risky decision-making behavior in men but not in women.

Acute stress may escalate risky decision-making in men, while there is no such effect in women. Although first evidence links these gender-specific effects of stress to stress-induced changes in cortisol, whether elevated cortisol is indeed sufficient to boost risk-taking, whether a potential cortisol effect depends on simultaneous noradrenergic activation, and whether cortisol and noradrenergic activation exert distinct effects on risk-taking in men and women is unknown. In this experiment, we therefore set out to elucidate the impact of cortisol and noradrenergic stimulation on risky decision-making in men and women. In a fully-crossed, placebo-controlled, double-blind design, male and female participants received orally either a placebo, hydrocortisone, yohimbine, an alpha-2-adrenoceptor-antagonist leading to increased noradrenergic stimulation, or both drugs before completing the balloon analogue risk task, a validated measure of risk-taking. Overall, participants' choice was risk-sensitive as reflected in reduced responding in high- compared to moderate- and low-risk conditions. Cortisol, however, led to a striking increase in risk-taking in men, whereas it had no effect on risk-taking behavior in women. Yohimbine had no such effect and the gender-specific effect of cortisol was not modulated by yohimbine. Our data show that cortisol boosts risk-taking behavior in men but not in women. This differential effect of cortisol on risk-taking may drive gender differences in risky decision-making under stress.

Noradrenergic Stimulation Impairs Memory Generalization in Women.

Memory generalization is essential for adaptive decision-making and action. Our ability to generalize across past experiences relies on medial-temporal lobe structures, known to be highly sensitive to stress. Recent evidence suggests that stressful events may indeed interfere with memory generalization. Yet, the mechanisms involved in this generalization impairment are unknown. We tested here whether a pharmacological elevation of major stress mediators-noradrenaline and glucocorticoids-is sufficient to disrupt memory generalization. In a double-blind, placebo-controlled design, healthy men and women received orally a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine that leads to increased noradrenergic stimulation, or both drugs, before they completed an associative learning task probing memory generalization. Drugs left learning performance intact. Yohimbine, however, led to a striking generalization impairment in women, but not in men. Hydrocortisone, in turn, had no effect on memory generalization, neither in men nor in women. The present findings indicate that increased noradrenergic activity, but not cortisol, is sufficient to disrupt memory generalization in a sex-specific manner, with relevant implications for stress-related mental disorders characterized by generalization deficits.

Impact of Stress and Glucocorticoids on Schema-Based Learning.

Pre-existing knowledge, a 'schema', facilitates the encoding, consolidation, and retrieval of schema-relevant information. Such schema-based memory is key to every form of education and provides intriguing insights into the integration of new information and prior knowledge. Stress is known to have a critical impact on memory processes, mainly through the action of glucocorticoids and catecholamines. However, whether stress and these major stress mediators affect schema-based learning is completely unknown. To address this question, we performed two experiments, in which participants acquired a schema on day 1 and learned schema-related as well as schema-unrelated information on day 2. In the first experiment, participants underwent a stress or control manipulation either immediately or about 25 min before schema-based memory testing. The second experiment tested whether glucocorticoid and/or noradrenergic activation is sufficient to modulate schema-based memory. To this end, participants received orally a placebo, hydrocortisone, the α2-adrenoceptor-antagonist yohimbine, leading to increased noradrenergic stimulation, or both drugs, before completing the schema-based memory test. Our data indicate that stress, irrespective of the exact timing of the stress exposure, impaired schema-based learning, while leaving learning of schema-unrelated information intact. A very similar effect was obtained after hydrocortisone, but not yohimbine, administration. These data show that stress disrupts participants' ability to benefit from prior knowledge during learning and that glucocorticoid activation is sufficient to produce this effect. Our findings provide novel insights into the impact of stress and stress hormones on the dynamics of human memory and have important practical implications, specifically for educational contexts.