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Available online at www.sciencedirect.comScienceDirectStress and memory retrieval: mechanisms andconsequencesOliver T WolfStress impairs memory retrieval. Recent findings illustrate thetemporal dynamics and the underlying mechanisms of thiseffect. The effect appears to occur in multiple memorysystems, ranging from striatal-based stimulus-responsememory to prefrontal-based extinction memory. The effects ofstress on memory retrieval might have long-termconsequences due to their impact on re-encoding and reconsolidation. These properties could be of interest for futureintervention studies.AddressDepartment of Cognitive Psychology, Institute of CognitiveNeuroscience, Faculty of Psychology, Ruhr University Bochum,44801 Bochum, GermanyCorresponding author: Wolf, Oliver T([email protected])Current Opinion in Behavioral Sciences 2017, 14:40–46This review comes from a themed issue on Stress and behaviorEdited by David A Morilak and Carmen 12352-1546/# 2016 Elsevier Ltd. All rights reserved.IntroductionOur memories are influenced by stress and its associatedneuroendocrine responses. A frightening encounter witha robber or an especially poor performance during a jobinterview may be vividly remembered for a life time.These are examples of the enhancing effects stress canhave on memory encoding and consolidation. At thesame time, we might forget our wedding anniversarybecause we are stressed at work, or we might be unableto retrieve the name of a specific brain region during astressful neurobiology exam. The latter two are examples for the impairing effects stress can have on memoryretrieval. This phenomenon in particular is the focusof the present brief and selective review, which willaddress the following main points: the temporal development and underlying mechanisms of retrieval impairment, its occurrence outside of the domain ofhippocampus-based memories, long-term consequencesof this retrieval impairment, and its relevance for mentaldisorders (see Box 1).Current Opinion in Behavioral Sciences 2017, 14:40–46When faced with a real or anticipated threat, the organismresponds with a complex and well-orchestrated neuroendocrine stress response [1 ]. The rapid activation of thesympathetic nervous system (SNS) leads to the release of(nor)adrenalin (NA) from the adrenal medulla. This initial response causes hypervigilance at the expense ofselective attention and other top-down control processes[2,3 ], and, with respect to memory, leads to enhancedencoding of salient and relevant features of the environment [4,5]. In parallel, the hypothalamic–pituitary–adrenal (HPA) axis is activated. Corticotrophin-releasinghormone (CRH), secreted from the paraventricular nucleus of the hypothalamus, stimulates the anterior pituitary to release adrenocorticotrophin (ACTH). Thismessenger, in turn, causes the adrenal cortex to releaseglucocorticoids (GCs; mostly cortisol in humans, andcorticosterone in most laboratory rodents). These stresshormones first increase 5–10 min after stress onset andtypically reach their peak 20–30 min post-onset [6]. Glucocorticoids exert their action via mineralocorticoid(MRs) and glucocorticoid receptors (GRs). These tworeceptor types differ in their localization (MRs are morerestricted to limbic regions, GRs are expressed morewidespread in the brain) and affinity. It was initiallyassumed that these receptors exist exclusively withinthe cell and exert slow but potentially long-lasting actionby directly influencing the genome (genomic GC effects)[7 ]. More recently, however, convincing evidence hasshown rapid, non-genomic GC effects mediated via membrane-bound (as opposed to intracellular) versions ofthese receptors [7 ,8]. Three interacting and partiallyoverlapping stress response signals must thus be considered: (1) The initial arousal response mediated by NA andCRH, (2) the slightly delayed non-genomic GC signalwith mostly excitatory properties, which occurs in interaction with the initial NA signal, and (3) the furtherdelayed genomic GC signal, which, mostly mediatedby intracellular GRs, reduces neuronal excitability andpromotes normalization of the system [1,9,10,11 ]. Thesethree response waves are illustrated in Figure 1. The timeframes mentioned represent rough estimates, as they arelikely to differ depending on the intensity of the stressorand/or the investigated brain region.Stress and episodic memory retrieval:temporal development and underlyingmechanismsInitial findings on the enhancing effects of stress and GCtreatment on memory consolidation were already described in the 1960s (e.g., [12]). Since then researchwww.sciencedirect.com

Stress and memory retrieval Wolf 41Box 1 Summary of key pointsThe effects of stress on memory retrieval last longer than initiallyexpected. They reflect non-genomic and genomic GC effects.The effects of stress on memory retrieval are not restricted tohippocampus-based episodic memory retrieval. Striatum-based SRmemory retrieval as well as PFC-based (fear) extinction memoryretrieval are two examples for this.The impairing effect of stress on retrieval can have long-lastingconsequences through the modification of re-encoding and reconsolidation. This feature could make cortisol a useful add-on totherapeutic interventions (e.g., exposure psychotherapy).Patients with mental disorders (e.g., MDD and PTSD) show differentresponsivities to GC, which are in line with an altered central GCsensitivity in these disorders.has established that the stress-induced activation of theSNS and HPA axis leads to enhanced memories of thestressful episode [13], especially regarding its centralaspects [5]. The two stress mediators achieve this byinteracting in the basolateral amygdala (BLA), therebyboosting memory consolidation in the hippocampus(for recent reviews, see [4,9,14,15]). The impairing effectof stress on memory retrieval was first thoroughly characterized in 1998 by de Quervain and colleagues in rats. Byseparating the initial acquisition phase from the retrievaltest by a day, they were able to show that stress prior tolong-term memory retrieval substantially impaired spatialmemory retrieval [16 ]. Importantly, this effect wasapparent 30 min, but not two minutes or four hours, afterstress induction. This temporal profile is well in line witha presumed non-genomic GC effect on memory retrieval.Follow-up animal studies on this phenomenon revealedthat NA arousal and an intact basolateral amygdala (BLA)are pre-requisites for its occurrence [17]. Similar findingscould be demonstrated in humans: GC administration orexposure to a psychosocial laboratory stressor resulted inimpaired memory retrieval [18,19]. It is to be noted thatonly free recall, but not recognition or cued recall, wasimpaired in these initial studies, a fact which will bepicked up again later in this review. Additional studiesfurther revealed that the impairing effect of cortisol onmemory retrieval depends on testing-induced arousal [20]and can be blocked by the administration of a betaFigure 1NoradrenalinCortisolsresSt12060NAGC nongenomicEnhancedencodingof salientmaterialEnhancedconsolidationbut impairedretrieval180 (time, in minutes)90GC -genomicImpaired retrieval;impaired encodingof novel materialCurrent Opinion in Behavioral SciencesNeuroendocrine stress responses to a brief stressor (e.g., the Trier Social Stress Test) and their transcriptional and cognitive consequences.Stress influences the brain via a rapid increase in noradrenalin (NA). With a slight delay, glucocorticoids (GCs) are released. These hormones canexert rapid non-genomic and delayed genomic effects. Both effects are likely to co-occur around one hour after stress exposure. Genomic andnon-genomic GC effects typically cause impaired memory retrieval. In contrast, initial encoding as well as consolidation of material perceivedaround the time of the stressor is enhanced. Note: The depicted temporal development is based on a broad estimate derived from the literature.For further explanations, see the associated text.www.sciencedirect.comCurrent Opinion in Behavioral Sciences 2017, 14:40–46

42 Stress and behaviorblocker preventing this arousal [21]. Regarding the neuralcorrelates of GC-induced memory retrieval impairments,pharmacological neuroimaging studies were able to showGC-mediated reduced activity in the hippocampus andadjacent cortical structures during memory retrieval[22,23].Stimulated by the mounting evidence for rapid nongenomic GC effects, studies have started to comparerapid and delayed effects of stress or GC treatment inseveral cognitive domains, including memory [1 ,24].While substantial progress has been made, time-dependent variations in the effect of stress on memory retrievalhave received relatively little attention. One relevantpharmacological study was recently able to show that acortisol injection affected memory retrieval within eightminutes, which is strongly suggestive of a non-genomiceffect [25]. Another recent study in humans reported thatmemory retrieval was impaired 25 min (at the time ofpeak cortisol) but also 90 min stress exposure, illustratingthat the impairing effect of stress on memory might lastlonger than initially expected [26 ]. Interestingly, cortisolconcentrations were already back to baseline levels in thegroup tested 90 min after stress exposure, demonstratingthat impairing effects of stress on memory retrieval canoccur even when GC levels are no longer elevated.Together with the initial findings observed in rodents[16 ], this study suggests that the impairing effects ofstress on memory retrieval occur rapidly once cortisolconcentrations are sufficiently elevated, but that theseeffects also persist for at least 90 min. This implies thatboth initial non-genomic effects and later genomic effectslead to impaired memory retrieval (for an in-depth review, see [11 ]). This interpretation is also in line withrecent studies in rodents [27]. Roozendaal postulates thatmembrane-bound GRs in the BLA interact with centralNA signaling in rapidly boosting memory consolidationand impairing memory retrieval [8]. In contrast, work byDorey and colleagues has provided evidence that hippocampal membrane-bound MRs, but not GRs, play a rolein mediating the rapid stress effects on memory retrieval[28]. With respect to genomic effects, Rimmele andcolleagues could demonstrate that blocking the MR impaired memory retrieval, while blocking the GR enhanced retrieval [29]. In this study, the drugs wereadministered several hours before memory retrievalwas tested, which suggests that it was indeed the consequences of genomic GC actions that were being measured. In summary, it seems that both non-genomic andgenomic GC effects induce memory retrieval deficits (seeFigure 1).While an inverted-U-shaped dose–response curve between GCs and memory consolidation is well-established[14], the investigation of dose–response relationships hasreceived little attention with respect to memory retrieval.Stress studies in humans illustrate that even a moderateCurrent Opinion in Behavioral Sciences 2017, 14:40–46increase in cortisol in the late afternoon (when endogenous cortisol concentrations are low) can impair memoryretrieval [30]. In contrast, a recent pharmacological studyusing cortisol injections provided initial evidence foran inverted-U-shaped function instead [25]. The dose–response curve might differ depending on the presence(stress) or absence (pharmacological cortisol administration) of strong prior noradrenergic activation [1 ]. Moreover, there may be differences in dose–responserelationships between non-genomic and genomic effects.If an inverted-U-shaped dose–response curve indeedexists, its peak may lie in the range of basal (stress-free)physiological cortisol concentrations.Conceptually, it has been proposed that the retrievalimpairment is restricted to the ‘memory formation mode’but is no longer present during the ‘memory storagemode’ (during consolidation) [31]. However, the findingsdiscussed above indicate that the effects occur later andlast longer, thus primarily occurring during the consolidation phase.Stress and memory retrieval outside thedomain of hippocampus-based memoriesInitially, it appeared that the effects of stress on memoryretrieval are restricted to hippocampus-based episodic/spatial memory tasks [16 ,19]. This was in line with thenotion that the hippocampus is especially sensitive tostress due to its high number of MRs and GRs [32].Indeed, recognition and cued recall were not influencedby stress in initial studies in humans, further supportingthe notion of a specific effect on hippocampus-basedepisodic recollection [18,19]. More recently, however,several studies have demonstrated stress-induced recognition impairments, evidencing that not only free recall isaffected by stress [33]. Accumulating evidence reviewedbelow has quite convincingly shown that the effects ofstress on memory retrieval are far broader than initiallyconceived.Stimulus-response (SR) memory describes the learnedassociation between a specific cue and a specific response.It has been linked to the basal ganglia [34] and can betested in humans and rodents by using maze tasks with asingle, clearly visible cue [35]. In the first human study onthis topic, participants exposed to stress prior to SRretrieval showed impaired retrieval performance [36].Similar findings were obtained recently in rodents[37 ]. In this study, the authors could additionally demonstrate that the SR retrieval deficit is indeed mediatedby GCs. These findings thus highlight that stress and theassociated release of GCs can also impair the retrieval ofstriatal-based SR memories.Another area of research in which the impairing effects ofstress on memory retrieval have received considerableattention is the field of (fear) extinction. When a neutralwww.sciencedirect.com

Stress and memory retrieval Wolf 43Figure 2 CSCRSuccessful fearextinctionCRstress inducedreturn of fear– CSStress–Current Opinion in Behavioral SciencesImpact of stress on extinction memory retrieval. Top row: After successful extinction, the conditioned stimulus (CS; e.g., a tone) no longer leads toa conditioned response (CR; an increase in heart rate). This is due to the inhibitory action of the extinction memory trace (green arrow). Theoriginal acquisition memory trace (red arrow), however, is not erased but still intact. Bottom row: Stress appears to weaken this inhibitory memorytrace, causing a return of the initial response.stimulus (e.g., a tone; the conditioned stimulus or CS) iscoupled with an aversive event (e.g., a shock; the unconditioned stimulus, or UCS), the organism quickly learns torespond to the CS alone (e.g., by showing freezing behavior; the conditioned response, or CR). During extinction, the CS is no longer coupled with the UCS, and theCR disappears. The majority of current learning modelspostulate that this decreased responding is not caused byan erasure of the original acquisition memory trace, butrather reflects new inhibitory learning [38,39 ]. This isdemonstrated by the occurrence of several recovery phenomena such as contextual renewal, reinstatement orspontaneous recovery [40]. When it comes to the impactof stress, the fascinating question arises whether stressprior to extinction retrieval will impair the original acquisition memory trace or the inhibitory extinction memorytrace formed later on. Evidence is accumulating thatstress exposure prior to retrieval typically impairs extinction retrieval, leading to a return of fear in human participants [41] as well as in patients with anxiety disorders[42]. We have demonstrated similar findings using apredictive learning task. Stress induction in the laboratorycaused impaired extinction retrieval, manifested as enhanced conditioned responding in the acquisition context(i.e., an enhanced renewal effect) [43]. In a pharmacological fMRI study with the same predictive learning task,cortisol administration prior to extinction retrieval led towww.sciencedirect.comimpaired extinction retrieval, as evidenced by an enhanced renewal effect. This was associated with reducedneural activity in the ventromedial prefrontal cortex(vmPFC) [44], a key region in the extinction network(e.g., [45]). The available data supports the notion thatGCs impair the extinction memory trace. The reason forthis selective impairment might be the younger age ofthis memory trace, its context dependency, or its relianceon the vmPFC for retrieval. By impairing the extinctionmemory trace, GCs thus cause a return of the initiallyacquired response (see Figure 2). However, enhancedretrieval of the original memory trace could still be cooccurring — an explanation in need of empirical assessment. A mechanistic understanding of the impact of stresson extinction retrieval will pave the way toward better,targeted relapse prevention.Long-term consequences of retrievalimpairmentAnother important issue concerns the long-term consequences of the stress-induced retrieval failure. Is this atemporal blockage which completely disappears oncestress has ceased, or does the impaired retrieval haveconsequences beyond the stressful episode, for example,due to an effect on (re)consolidation? A pharmacologicalstudy using cortisol administration before memory retrieval observed that the cortisol group showed a memoryCurrent Opinion in Behavioral Sciences 2017, 14:40–46

44 Stress and behaviorimpairment as long as one week after the retrieval underthe influence of cortisol had taken place [46]. In addition,another recent study found impaired memory retrieval atvery low cortisol levels, induced by the cortisol-synthesisinhibitor metyrapone [47 ]. Again, this impairment wasstill detectable a week later. Conceptually, the poorretrieval at times of high (or very low) GC concentrationscould lead to impaired re-encoding and/or impaired reconsolidation [48]. Taken together, these findings illustrate that impaired retrieval under stress can have longlasting consequences for the specific memory.Beneficial effects of the long-term consequences of cortisol administration on human memory have been observed in the context of extinction-based (i.e., exposure)psychotherapy. Cortisol administered before exposuretreatment enhanced the long-term success of therapyin patients with fear of heights and in patients with spiderphobia [49 ,50]. The combination of impaired retrievalof the initial fear memory with enhanced consolidation ofthe newly acquired extinction (safety) memory could bethe underlying mechanism of this therapeutic effect ofthe stress hormone [51].Box 2 Open questionsHow does activation of membrane-bound MRs and GRs influencememory retrieval?How do non-genomic and genomic GC effects interact in influencingmemory retrieval?What is the dose–response relationship between GCs and memoryretrieval?Are there memory systems which are resistant to the impairing effectof stress on retrieval?Are the effects of stress modulated by genetic and epigeneticfactors?Do the GC alterations observed in several mental disorders (e.g.,MDD, PTSD) reflect predispositions or consequences of thedisorders?Can the beneficial effects of GCs observed in clinical interventionstudies be translated into the clinical praxis?future research. Some of the most central are summarizedin the Box 2.Conflict of interest statementThe author declares no conflict of interest.Alterations in patients with mental disordersThere is increasing evidence that the effects of stress onmemory retrieval are altered in patients with mentaldisorders. Dysfunctions in the hypothalamic–pituitary–adrenal (HPA) axis have been reported for several mentaldisorders. While major depressive disorder (MDD) seemsto be characterized by enhanced cortisol release in concert with a reduced feedback sensitivity of the HPA axis[52], the opposite pattern has been reported in posttraumatic stress disorder (PTSD) [53]. In a series ofstudies, we investigated the effects of cortisol on memoryretrieval in MDD and PTSD. While cortisol administration failed to affect memory retrieval in MDD patients,patients with PTSD showed enhanced, rather than impaired, memory retrieval after cortisol [54]. These resultsindicate an altered sensitivity to cortisol in these disorders, which not only influences the HPA axis and itsnegative feedback, but extends to an altered sensitivity ofbrain functions involved in episodic memory retrieval(presumably the hippocampus [55]). Future studies arerequired in order to determine whether these alterationsare reversed after successful treatment, thereby elucidating whether they reflect pre-morbid risk factors or reversible disease consequences.AcknowledgementsThe author’s work was supported by grants from the German ResearchFoundation (DFG). I thank Shira Meir Drexler for most helpful commentson an earlier version of this manuscript. In addition I thank Eve Hessas forlanguage editing and Melinda Baranyai for support regarding the creation ofFigure 1.References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as: of special interest of outstanding interest1. Joels M, Fernandez G, Roozendaal B: Stress and emotional memory: a matter of timing. Trends Cogn Sci 2011, 15:280-288.Important review describing the time-dependent interaction of the SNSand the HPA in influencing emotional memories.2.3. Hermans EJ, Henckens MJ, Joels M, Fernandez G: Dynamicadaptation of large-scale brain networks in response to acutestressors. Trends Neurosci 2014, 37:304-314.Important review illustrating the acute effects of stress on neuronalnetworks.4.Joels M, Pu Z, Wiegert O, Oitzl MS, Krugers HJ: Learning understress: how does it work? Trends Cogn Sci 2006, 10:152-158.5.Wiemers US, Sauvage MM, Schoofs D, Hamacher-Dang TC,Wolf OT: What we remember from a stressful episode.Psychoneuroendocrinology 2013, 38:2268-2277.6.Dickerson SS, Kemeny ME: Acute stressors and cortisolresponses: a theoretical integration and synthesis oflaboratory research. Psychol Bull 2004, 130:355-391.ConclusionTaken together, empirical evidence obtained in recentyears has changed the way we look at the impact of stresson memory retrieval. The impairing effects of stress lastlonger, concern a broader range of memory systems, havelasting consequences and are altered in several mentaldisorders. These novel findings raise new questions forCurrent Opinion in Behavioral Sciences 2017, 14:40–46Arnsten AF: Stress signalling pathways that impair prefrontalcortex structure and function. Nat Rev Neurosci 2009,10:410-422.7. Joels M, Karst H, DeRijk R, De Kloet ER: The coming out of thebrain mineralocorticoid receptor. Trends Neurosci. 2008,31:1-7.Benchmark summary on the membrane version of the MR.www.sciencedirect.com

Stress and memory retrieval Wolf 458.9.Roozendaal B, Hernandez A, Cabrera SM, Hagewoud R,Malvaez M, Stefanko DP, Haettig J, Wood MA: Membraneassociated glucocorticoid activity is necessary for modulationof long-term memory via chromatin modification. J Neurosci2010, 30:5037-5046.Diamond DM, Campbell AM, Park CR, Halonen J, Zoladz PR: Thetemporal dynamics model of emotional memory processing: asynthesis on the neurobiological basis of stress-inducedamnesia, flashbulb and traumatic memories, and the YerkesDodson law. Neural Plast 2007:60803.Human study demonstrating an impairing effect of stress even 90 minafter stress exposure.27. Dorey R, Pierard C, Chauveau F, David V, Beracochea D: Stressinduced memory retrieval impairments: different time-courseinvolvement of corticosterone and glucocorticoid receptors indorsal and ventral hippocampus. Neuropsychopharmacology2012, 37:2870-2880.10. De Kloet ER, Joels M, Holsboer F: Stress and the brain: fromadaptation to disease. 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Oei NY, Elzinga BM, Wolf OT, de Ruiter MB, Damoiseaux JS,Kuijer JP, Veltman DJ, Scheltens P, Rombouts SA:Glucocorticoids decrease hippocampal and prefrontalactivation during declarative memory retrieval in young men.Brain Imaging Behav 2007, 1:31-41.24. Henckens MJ, Pu Z, Hermans EJ, van Wingen GA, Joels M,Fernandez G: Dynamically changing effects of corticosteroidson human hippocampal and prefrontal processing. Hum BrainMapp 2012, 33:2885-2897.25. Schilling TM, Kolsch M, Larra MF, Zech CM, Blumenthal TD,Frings C, Schachinger H: For whom the bell (curve) tolls: cortisolrapidly affects memory retrieval by an inverted U-shapeddose–response relationship. Psychoneuroendocrinology 2013,38:1565-1572.26. Schwabe L, Wolf OT: Timing matters: temporal dynamics of stress effects on memory retrieval. Cogn Affect Behav Neurosci2014, 14:1041-1048.www.sciencedirect.com30. Smeets T: Acute stress impairs memory retrieval independentof time of day. Psychoneuroendocrinology 2011, 36:495-501.31. 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46 Stress and behavior46. Tollenaar MS, Elzinga BM, Spinhoven P, Everaerd W: Immediateand prolonged effects of cortisol, but not propran

GC non-genomic GC -genomic Enhanced encoding of salient material Enhanced consolidation but impaired retrieval Impaired retrieval; impaired encoding of novel material Current Opinion in Behavioral Sciences Neuroendocrine stress responses to a brief stressor (e.g., the Trier Social