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.

Neural signature of delayed fear generalization under stress.

Although the generalization of fear to stimuli resembling a threatening stimulus is an adaptive mechanism, fear overgeneralization is maladaptive and thought to play a key role in anxiety-related disorders. Since there is typically a delay between an initial fear experience and a situation in which fear (over)generalization may occur, we assessed delayed fear generalization and its neural signature. Moreover, as stress is known to affect fear learning, we further tested whether acute stress modulates fear generalization. Therefore, we conducted a two-day fear generalization study, with initial fear acquisition on Day 1 and a fear generalization test after a 24-hr delay in the MRI scanner. Prior to fear generalization testing, participants were exposed to a stressor or a control manipulation. Our behavioral data showed the expected generalization of fear. At a neural level, fear generalization was accompanied by increased fear-signaling for stimuli that resembled the conditioned stimulus in the bilateral insula and frontal operculum, whereas activity declined in frontal, hippocampal, and temporal regions, including the ventromedial prefrontal cortex, as stimuli became more similar to the conditioned stimulus. Importantly, stress did not modulate fear generalization, neither on a behavioral nor on a neural level. Interestingly, in an explorative comparison to two other studies that used the same paradigm but tested generalization immediately after acquisition, we observed increased fear generalization in the delayed relative to the immediate generalization test. In sum, our results suggest that stress leaves fear generalization and its neural signature unaffected but that a temporal delay might increase the extent to which fear responses are generalized to stimuli resembling the threatening stimulus.

Stress-induced bias of multiple memory systems during retrieval depends on training intensity.

Stressful events promote a shift from hippocampus-dependent 'cognitive' learning towards dorsal striatum-dependent 'habit' learning. Beyond modulating the recruitment of multiple memory systems during learning, recent evidence suggests that stress may also affect which of these memory systems is employed during retrieval, thereby affecting the nature of remembering. However, while some studies reported increased reliance on 'habit' memory retrieval after stress, other studies suggested even a bias towards 'cognitive' memory retrieval after stress. In the present experiment, we tested the hypothesis that the nature of the stress effect on the control of memory retrieval depends on the extent of initial training. To this end, participants completed a probabilistic classification learning (PCL) task that can be solved by both the 'cognitive' and the 'habit' memory systems, which is reflected in the engagement of specific behavioral strategies. Critically, participants received either moderate (100 trials) or intensive (200 trials) training in the PCL task. Participants then underwent a stress protocol or a non-stressful control procedure, before they completed a retrieval version of the PCL task. The effectiveness of the stress manipulation was verified by increases in salivary cortisol and autonomic arousal. Our results further revealed that participants who received moderate training showed, during retrieval, a stress-induced shift towards strategies indicative of the dorsal striatal 'habit' memory system. After prolonged training, however, stress did not affect which memory system guided retrieval. The present results indicate that the effect of stress on the engagement of multiple memory systems during retrieval is critically dependent on the extent of initial training and, by inference, on the strength of the multiple memory traces established during learning.

How representative are neuroimaging samples? Large-scale evidence for trait anxiety differences between fMRI and behaviour-only research participants.

Over the past three decades, functional magnetic resonance imaging (fMRI) has become crucial to study how cognitive processes are implemented in the human brain. However, the question of whether participants recruited into fMRI studies differ from participants recruited into other study contexts has received little to no attention. This is particularly pertinent when effects fail to generalize across study contexts: for example, a behavioural effect discovered in a non-imaging context not replicating in a neuroimaging environment. Here, we tested the hypothesis, motivated by preliminary findings (N = 272), that fMRI participants differ from behaviour-only participants on one fundamental individual difference variable: trait anxiety. Analysing trait anxiety scores and possible confounding variables from healthy volunteers across multiple institutions (N = 3317), we found robust support for lower trait anxiety in fMRI study participants, consistent with a sampling or self-selection bias. The bias was larger in studies that relied on phone screening (compared with full in-person psychiatric screening), recruited at least partly from convenience samples (compared with community samples), and in pharmacology studies. Our findings highlight the need for surveying trait anxiety at recruitment and for appropriate screening procedures or sampling strategies to mitigate this bias.

Acute stress leaves fear generalization in healthy individuals intact.

Because threatening situations often occur in a similar manner, the generalization of fear to similar situations is adaptive and can avoid harm to the organism. However, the overgeneralization of fear to harmless stimuli is maladaptive and assumed to contribute to anxiety disorders. Thus, elucidating factors that may modulate fear (over)generalization is important. Based on the known effects of acute stress on learning, which are at least partly due to noradrenergic arousal, we investigated whether stress may promote fear overgeneralization and whether we could counteract this effect by reducing noradrenergic arousal. In a placebo-controlled, double-blind, between-subjects design, 120 healthy participants underwent a fear-conditioning procedure on Day 1. Approximately 24 hours later, participants received orally either a placebo or the beta-adrenergic receptor antagonist propranolol and were exposed to a stress or control manipulation before they completed a test of fear generalization. Skin conductance responses as well as explicit rating data showed a successful acquisition of conditioned fear on Day 1 and a pronounced fear generalization 24 hours later. Although physiological data confirmed the successful stress manipulation and reduction of noradrenergic arousal, the extent of fear generalization remained unaffected by stress and propranolol. The absence of a stress effect on fear generalization was confirmed by a second study and a Bayesian analysis across both data sets. Our findings suggest that acute stress leaves fear generalization processes intact, at least in a sample of healthy, young individuals.

Noradrenergic stimulation increases fear memory expression.

Fear responses are typically not limited to the actual threatening stimulus but generalize to other stimuli resembling the threatening stimulus. Although this fear generalization is generally adaptive, fear overgeneralization is maladaptive and assumed to contribute to anxiety disorders. Despite the clinical relevance of fear (over)generalization, how the extent of fear generalization is modulated remains not well understood. Based on the known effects of stress on learning and memory, we tested here the impact of major stress mediators, glucocorticoids and noradrenergic arousal, on fear generalization. In a laboratory-based, placebo-controlled, double-blind, between-subject design, 125 healthy participants first underwent a fear conditioning procedure. About 24 h later, participants received orally either a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine, leading to increased noradrenergic stimulation, or both drugs before a test of fear generalization. Skin conductance responses as well as explicit rating data revealed that yohimbine intake led to enhanced fear memory expression, i.e. an enhanced responding to the CS+ but not to stimuli resembling the CS+. Moreover, neither enhanced safety learning nor a mere enhancement of perceptual discrimination ability could explain this result. In contrast to yohimbine, hydrocortisone had no significant effect on fear memory. These findings suggest that noradrenergic arousal strengthens fear memory expression and have important implications for mental disorders in which the overgeneralization of conditioned fear is prominent.

Stress-induced modulation of multiple memory systems during retrieval requires noradrenergic arousal.

Stress has been shown to favor dorsal striatum-dependent 'habit' memory over hippocampus-dependent 'cognitive' memory during learning. Here, we investigated whether stress may modulate the engagement of these 'cognitive' and 'habit' systems also during memory retrieval and if so, whether such a stress-induced shift in the control of memory retrieval depends on noradrenergic activation. To this end, participants acquired a probabilistic classification learning (PCL) task that can be solved by both the 'cognitive' and the 'habit' system, reflected in the distinct behavioral strategies. Twenty-four hours later, participants received either the beta-adrenergic receptor antagonist propranolol or a placebo before they underwent a psychosocial stressor or a non-stressful control manipulation, followed by a retrieval version of the PCL task. Overall, participants showed a practice-dependent shift from 'cognitive' to 'habit' memory. Stressed participants that had received a placebo fell back to a 'cognitive' strategy during retrieval, which was linked to an impairment in retrieval performance. Propranolol blocked this stress-induced shift towards the less efficient strategy. Moreover, our results showed that salivary cortisol was related to the retrieval strategy only when paralleled by increased autonomic arousal. Together, these results indicate that stress effects on the modulation of multiple memory system during retrieval necessitate noradrenergic arousal, with relevant implications for retrieval performance under stress.

Across time and space: spatial-temporal binding under stress.

Successful episodic memory requires binding of event details across spatial and temporal gaps. The neural processes underlying mnemonic binding, however, are not fully understood. Moreover, although acute stress is known to modulate memory, if and how stress changes mnemonic integration across time and space is unknown. To elucidate these issues, we exposed participants to a stressor or a control manipulation shortly before they completed, while electroencephalography was recorded, an encoding task that systematically varied the demands for spatial and temporal integration. Associative memory was tested 24 h later. While early event-related potentials, including the P300 and Late Positive Component, distinguished different levels of spatiotemporal discontinuity, only later Slow Waves were linked to subsequent remembering. Furthermore, theta oscillations were specifically associated with successful mnemonic binding. Although acute stress per se left mnemonic integration largely unaffected, autonomic activity facilitated object memory and glucocorticoids enhanced detail memory, indicative for mnemonic integration. At the neural level, stress amplified the effects of spatiotemporal discontinuity on early information processing. Together, our results indicate that temporal and spatial gaps recruit early neural processes, providing attentional resources. The actual binding success, however, appears to depend on later processes as well as theta power and may be shaped by major stress response systems.

Glucocorticoids, Noradrenergic Arousal, and the Control of Memory Retrieval.

Glucocorticoids and noradrenaline can enhance memory consolidation but impair memory retrieval. Beyond their effects on quantitative memory performance, these major stress mediators bias the engagement of multiple memory systems toward "habitual" control during learning. However, if and how glucocorticoids and noradrenaline may also affect which memory system is recruited during recall, thereby affecting the control of retrieval, remain largely unknown. To address these questions, we trained healthy participants in a probabilistic classification learning task, which can be supported both by cognitive and habitual strategies. Approximately 24 hr later, participants received a placebo, hydrocortisone, yohimbine (an α2-adrenoceptor antagonist increasing noradrenergic stimulation), or both drugs before they completed a recall test for the probabilistic classification learning task. During training, all groups showed a practice-dependent shift toward more habitual strategies, reflecting an "automatization" of behavior. In the recall test, after a night of sleep, this automatization was even more pronounced in the placebo group, most likely due to offline consolidation processes and with beneficial effects on recall performance. Hydrocortisone or yohimbine intake abolished this further automatization, preventing the shift to a more efficient memory system and leading, in particular in the hydrocortisone group, to impaired recall performance. Our results suggest that glucocorticoids and noradrenergic stimulation may modulate the engagement of different strategies at recall and link the well-known stress hormone-induced retrieval deficit to a change in the system controlling memory retrieval.