Abstract

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.

INTRODUCTION

Networks of semantic knowledge are built from specific episodic experiences (Eichenbaum, Dudchenko, Wood, Shapiro, & Tanila, 1999). These experiences are encoded by the hippocampus as separate representations (Kirwan & Stark, 2007; Leutgeb, Leutgeb, Moser, & Moser, 2007), thus allowing details of a single event to be remembered. However, the content of experiences is often similar, and such overlap provides a basis for generalizing across discrete episodic experiences to create more abstract, semantic representations. The hippocampus is thought to enable memory generalization by integrative encoding of episodes into a linked network of mnemonic nodes (Shohamy & Wagner, 2008) and by creating flexible memory representations that allow associative inference processes (Heckers, Zalesak, Weiss, Ditman, & Titone, 2004; Preston, Shrager, Dudukovic, & Gabrieli, 2004; Eichenbaum, 2000). The capacity to generalize across experiences is critically dependent on this flexibility of hippocampal memory. Other brain areas, such as the dorsal striatum, may support memory performance after hippocampal damage (Packard & McGaugh, 1996; McDonald & White, 1994), yet nonhippocampal memory lacks the flexibility that is required to generalize across discrete events (Myers et al., 2003; Collie, Myers, Schnirman, Wood, & Maruff, 2002).

Stress has a major impact on hippocampal functioning (Kim & Diamond, 2002; Lupien & Lepage, 2001). Although the effects of stress on hippocampal neuroplasticity and encoding are complex (Schwabe, Wolf, & Oitzl, 2010; Joels & Krugers, 2007; Diamond, Park, & Woodson, 2004), several studies reported impaired hippocampal memory processes after stress (Schwabe, Bohringer, & Wolf, 2009; Diamond et al., 2006). Moreover, stress has been shown to promote a shift from hippocampal to dorsal striatal control of memory (Schwabe & Wolf, 2012; Schwabe et al., 2007; Kim, Lee, Han, & Packard, 2001). Both of these effects are mediated by hormones and neurotransmitters that are released in response to stressful encounters, in particular, glucocorticoids (mainly cortisol in humans) and noradrenaline (Schwabe, Tegenthoff, Hoffken, & Wolf, 2010, 2013; Kukolja, Klingmuller, Maier, Fink, & Hurlemann, 2011; Roozendaal, McReynolds, et al., 2009; Roozendaal, Hui, et al., 2006; Roozendaal, Okuda, Van der Zee, & McGaugh, 2006; Packard & Wingard, 2004). These stress mediators may alter hippocampal functioning directly or indirectly via increased amygdala activation (Diamond et al., 2006; Roozendaal, Okuda, Van der Zee, et al., 2006; Kim & Diamond, 2002; McGaugh, Cahill, & Roozendaal, 1996; Joels & De Kloet, 1989). If memory generalization relies on the hippocampus and this area is (directly or indirectly) affected by stress, one may predict that stress can interfere with memory generalization processes. Indeed, very recent evidence from our lab suggests that stress hinders memory generalization (Dandolo & Schwabe, 2016). However, the mechanisms underlying the stress-induced generalization deficit are still largely unknown. In particular, it is unclear whether the concerted activity of glucocorticoids and noradrenaline is required to impair memory generalization or whether the action of one of these stress mediators is sufficient to produce this effect.

Moreover, there is accumulating evidence showing that the influence of stress and major stress mediators such as glucocorticoids and noradrenaline on learning and memory may differ in men and women (Felmingham et al., 2010; Andreano & Cahill, 2006, 2009; Buchanan & Tranel, 2008). For instance, acute stress enhanced hippocampal spine density in male rats but reduced hippocampal spine density in female rats (Shors, Falduto, & Leuner, 2004; Shors, Chua, & Falduto, 2001). Similarly, stress shortly before the acquisition of a hippocampus-dependent spatial task impaired memory in women but not in men (Guenzel, Wolf, & Schwabe, 2014). Given that men and women differ in their prevalence of stress-related mental disorders, in which distorted memory is prominent (McLean, Asnaani, Litz, & Hofmann, 2011; Olff, Langeland, Draijer, & Gersons, 2007; Altemus, 2006), such sex differences in the impact of stress and stress hormones on memory are highly relevant. Whether stress hormones have a differential impact on memory generalization in men and women is unknown.

In this study, we employed pharmacological manipulations to examine the impact of elevated glucocorticoid and noradrenergic activity on memory generalization in men and women. Healthy participants received either a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine leading to increased noradrenergic stimulation, or both drugs before they completed an associative learning task probing memory generalization. In this task, participants first learned associations between antecedent and consequent stimuli and were then required to generalize across the learned associations to respond correctly to new items (Myers et al., 2003). The task design and experimental setup was comparable to our previous study (Dandolo & Schwabe, 2016), except for differences in the treatment testing interval due to the different experimental manipulations. On the basis of evidence showing that both glucocorticoids and noradrenaline may affect hippocampal functioning (Marzo, Bai, & Otani, 2009; Joels, Pu, Wiegert, Oitzl, & Krugers, 2006; Almaguer-Melian et al., 2005; Kim & Diamond, 2002; Katsuki, Izumi, & Zorumski, 1997) and that stress-induced elevations in both autonomic arousal and cortisol were correlated with impaired generalization (Dandolo & Schwabe, 2016), we predicted that both hydrocortisone and yohimbine would be sufficient to disrupt memory generalization. Because stress effects on hippocampal memory appear to be stronger in women than in men (Guenzel et al., 2014; Wolf, Schommer, Hellhammer, McEwen, & Kirschbaum, 2001), we further hypothesized that the impact of hydrocortisone and yohimbine should be particularly pronounced in women.

METHODS

Participants

We tested 103 healthy, young volunteers (52 women; age (M ± SEM): 24.79 ± 0.36 years) who were screened for the following exclusion criteria: self-reported BMI below 19 or above 27 (M ± SEM: 22.79 ± 0.19 kg/m2), lifetime history of any neurological or mental disorders, medication intake within the 4 weeks before participation, tobacco or drug use or intake of hormonal contraceptives in women. Participants were further screened for hydrocortisone intolerance, cardiovascular disorders, including low and high blood pressure, diabetes, as well as related disorders. Female participants were not invited for participation during their menses. Participants gave written informed consent before testing and received a compensation of €35 after completing the study. This sample is part of a larger project on stress hormones and cognition, which was approved by the ethics committee of the Hamburg Medical Association.

Experimental Design and Procedure

We used a double-blind, fully crossed, placebo-controlled, between-subject design with the factors noradrenergic stimulation (placebo vs. yohimbine) and cortisol (placebo vs. hydrocortisone), resulting in four experimental groups to which participants were randomly assigned (n = 12–13 men and 12–14 women per group). To control for the diurnal rhythm of cortisol, all testing took place in the afternoon, between 12:30 and 19:00.

Physiological and Subjective Measures

After their arrival at the lab, participants completed the Beck Depression Inventory (BDI; Beck, Ward, Mendelson, Mock, & Erbaugh, 1961), the Trier Inventory for Chronic Stress (TICS; Schulz & Schlotz, 1999), and the State-Trait Anxiety Inventory (Spielberger, Sydeman, & Maruish, 1994) to control for depression, chronic stress, as well as state and trait anxiety. Next, measures of subjective mood (German Mood Scale [MDBF]; Steyer, Schwenkmezger, Notz, & Eid, 1994) were taken together with blood pressure measurements, using an Omron blood pressure measuring device (Omron Healthcare Europe BV, Hoofddorp, The Netherlands), as well as salivary cortisol samples. These measures were taken again 45 and 70 min after pill intake as well as after task completion (85 min after medication intake) to validate the action of the drugs. Saliva samples were collected using Salivette collection devices (Sarstedt, Germany). After collection, saliva samples were stored at −18°C. At the end of the experiment, free concentrations of cortisol were analyzed from these saliva samples using a luminescence assay (IBL, Hamburg, Germany; intra- and interassay coefficients of variance were below 10%).

Pharmacological Manipulation

Participants received orally either a placebo, 20 mg hydrocortisone, 20 mg yohimbine (an α2-adrenoceptor-antagonist leading to increased noradrenergic stimulation), or both drugs. The different pills looked identical, and neither the participants nor the experimenter knew about the pill contents (double-blind). Both timing of administration as well as the administered dosages were chosen according to previous studies (Henckens, van Wingen, Joels, & Fernandez, 2010; Schwabe, Tegenthoff, et al., 2010; Buchanan & Lovallo, 2001).

Acquired Equivalence Paradigm

About 70 min after pill intake, participants completed a computerized version of an associative learning task with increasing difficulty, which was adapted from Myers and colleagues (2003) and served to assess memory generalization processes. In this task, participants saw differentially colored fish (consequent stimulus), each paired with a specific individual (antecedent stimulus; Figure 1), differing in age, sex, and hair color. There was a total of eight fish and eight individuals. Participants were requested to learn which fish belongs to which individual. The task consisted of an acquisition phase and a generalization phase. During the acquisition phase, participants saw one individual and two differently colored fish in each trial. They were asked to indicate by button press on a keyboard which fish belonged to the individual presented. Once participants selected a fish, a frame was placed around the fish and feedback was given about the correctness of their answer. The acquisition phase consisted of three stages: “shaping,” “equivalence training,” and “new consequents.” During the shaping stage, participants learned four pairings between individual (antecedent stimulus) and fish (consequent stimulus). In the equivalence training stage, immediately following the shaping stage, four new individuals were presented in addition to the already familiar ones. These four new individuals were paired with the already presented fish, thus forming equivalences between two of the individuals (i.e., these individuals were associated with the same fish), which always shared two features (sex and hair color) to facilitate equivalence learning. The “new consequents” stage comprised again the four individuals shown during the shaping stage as well as the four individuals shown during the equivalence training stage; this time, however, the four individuals from the shaping stage were shown with new consequent stimuli (fish), indicating that each individual can be associated with two different fish. During each stage, a total of 24 new trials was introduced and presented together with the trials from the preceding stage. The acquisition phase was followed by the generalization phase, during which all 72 old trials from the acquisition phase were randomly intermixed with 24 new trials. In these new trials, individuals from the second stage of the acquisition phase were presented each with two of the new fish that were shown during the third acquisition stage. Thus, participants were required to use the equivalences learned in the “equivalence learning” stage to predict correctly which fish belongs to the shown individual. In the generalization phase, no feedback was given to avoid new learning effects. The generalization phase can therefore be utilized to test whether participants were able to generalize the already learned associations to new trials not shown during the acquisition phase (Myers et al., 2003; Collie et al., 2002). To further quantify participants' ability to generalize already learned associations to new stimulus pairs, a generalization score was calculated (Dandolo & Schwabe, 2016). This generalization score was calculated by subtracting the percentage correct of the 24 old trials that were presented in Stage 3 of the acquisition phase from the percentage of correct responses in the 24 new trials plus a constant of 100. The generalization score is an indispensable measure of memory generalization as it takes the interdependence of initial learning and subsequent memory generalization into account and allows us to disentangle participants' memory for the learned associations from their ability to generalize these memories to novel situations.

Figure 1. 

Associative learning task. The task has been adapted from Myers et al. (2003) and consists of two phases, the Acquisition Phase and the Generalization Phase. The Acquisition Phase comprises three stages during which participants learn the relationships between stimuli as well as equivalences. In the first phase (“shaping”), participants learn four pairings between antecedent (individual) and consequent (fish) stimuli (we show only two examples). In the second stage (“equivalence training”), four new antecedent stimuli were shown in addition to the already familiar ones. The new individuals (antecedent stimuli) were associated with the same fish (consequent stimuli) as one of the already familiar individuals, thereby creating equivalences. In the third stage (“new consequents”), the individuals from the shaping phase were associated with one additional new fish each, thus showing that one individual can be associated with two different fish. In each trial, participants were shown one antecedent stimulus (individual) and two fish and were asked to indicate, by button press, which fish is associated with the individual shown. During the acquisition phase, participants always received feedback after their answer. In the generalization phase, immediately following the third acquisition stage, participants were required to utilize their knowledge about the individual–fish associations from the previous trials and generalize across new trials. During these new trials, individuals that were introduced in the second acquisition phase were shown with two of the fish that were newly presented in the third acquisition stage. Participants were required to utilize the equivalences learned in the second acquisition stage. This time, participants also did not receive feedback after they provided an answer for each trial.

Figure 1. 

Associative learning task. The task has been adapted from Myers et al. (2003) and consists of two phases, the Acquisition Phase and the Generalization Phase. The Acquisition Phase comprises three stages during which participants learn the relationships between stimuli as well as equivalences. In the first phase (“shaping”), participants learn four pairings between antecedent (individual) and consequent (fish) stimuli (we show only two examples). In the second stage (“equivalence training”), four new antecedent stimuli were shown in addition to the already familiar ones. The new individuals (antecedent stimuli) were associated with the same fish (consequent stimuli) as one of the already familiar individuals, thereby creating equivalences. In the third stage (“new consequents”), the individuals from the shaping phase were associated with one additional new fish each, thus showing that one individual can be associated with two different fish. In each trial, participants were shown one antecedent stimulus (individual) and two fish and were asked to indicate, by button press, which fish is associated with the individual shown. During the acquisition phase, participants always received feedback after their answer. In the generalization phase, immediately following the third acquisition stage, participants were required to utilize their knowledge about the individual–fish associations from the previous trials and generalize across new trials. During these new trials, individuals that were introduced in the second acquisition phase were shown with two of the fish that were newly presented in the third acquisition stage. Participants were required to utilize the equivalences learned in the second acquisition stage. This time, participants also did not receive feedback after they provided an answer for each trial.

Statistical Analyses

Physiological and subjective parameters were analyzed using mixed-design ANOVAs with Time point of measurement as within-subject factor and Noradrenergic stimulation (placebo vs. yohimbine), Cortisol (placebo vs. hydrocortisone), and Sex (male vs. female) as between-subject factors. Performance in acquisition trials was analyzed using mixed-design ANOVAs with the Stage of the acquisition phase as within-subject factor and noradrenergic stimulation (placebo vs. yohimbine), Cortisol (placebo vs. hydrocortisone), and Sex (male vs. female) as between-subject factors. Performance in the test trials was analyzed using a univariate ANCOVA with Performance in the new trials as dependent variable and Noradrenergic stimulation (placebo vs. yohimbine), Cortisol (placebo vs. hydrocortisone), and sex (male vs. female) as independent variables. The percentage correct of the 24 old trials that were presented in Stage 3 of the acquisition phase was added as a covariate to account for initial learning performance. Generalization performance was analyzed further, using a univariate ANOVA, with the Generalization score, the critical index of memory generalization, as dependent variable and Noradrenergic stimulation (placebo vs. yohimbine), Cortisol (placebo vs. hydrocortisone), and Sex (male vs. female) as independent variables. Greenhouse–Geisser correction was applied, if required. All reported p values are two-tailed.

RESULTS

Manipulation Check

Before pill intake, systolic blood pressure and cortisol levels were comparable between groups (all F ≤ 1.921, all p ≥ .169; Figure 2). Diastolic blood pressure was slightly increased in the yohimbine groups at baseline (F(1, 95) = 4.003, p = .048, η2 = .040). Subjective measures were not significantly different between groups before pill intake (all F ≤ 3.324, all p ≥ .071; see Table 1).

Figure 2. 

Effectiveness of the pharmacological manipulation in men and women. In response to administration of yohimbine alone or in combination with hydrocortisone a significant increase in (A) systolic blood pressure in women and (C) men was observed, compared with participants who received a placebo treatment or hydrocortisone alone. Hydrocortisone administration alone or in combination with yohimbine led to a significant increase in salivary cortisol levels in (B) women and (D) men, compared with participants who received either a placebo or yohimbine alone. Gray bars show time point of drug administration as well as the timing of the associative learning task. Error bars indicate SEM. Significances indicate the increased blood pressure in both yohimbine groups (A and C) as well as increased cortisol levels in participants that have received hydrocortisone alone or combination (B and D). *p < .05, **p < .001.

Figure 2. 

Effectiveness of the pharmacological manipulation in men and women. In response to administration of yohimbine alone or in combination with hydrocortisone a significant increase in (A) systolic blood pressure in women and (C) men was observed, compared with participants who received a placebo treatment or hydrocortisone alone. Hydrocortisone administration alone or in combination with yohimbine led to a significant increase in salivary cortisol levels in (B) women and (D) men, compared with participants who received either a placebo or yohimbine alone. Gray bars show time point of drug administration as well as the timing of the associative learning task. Error bars indicate SEM. Significances indicate the increased blood pressure in both yohimbine groups (A and C) as well as increased cortisol levels in participants that have received hydrocortisone alone or combination (B and D). *p < .05, **p < .001.

Table 1. 

Subjective Measures of Stress in All Groups

 Men Women 
Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine 
Mood Questionnaire 
Subjective mood 
 Before pill intake 34.15 (1.31) 32.83 (1.04) 35.08 (0.76) 36.15 (0.85) 34.93 (0.87) 33.62 (1.28) 34.92 (1.13) 34.00 (1.94) 
 45 min after pill intake 34.08 (1.21) 33.25 (1.02) 35.31 (1.02) 34.08 (1.53) 35.36 (0.67) 33.62 (1.35) 31.42 (1.91) 32.92 (1.96) 
 70 min after pill intake 33.54 (1.35) 32.92 (1.09) 34.92 (0.91) 33.00 (1.67) 32.93 (1.38) 33.31 (1.36) 31.50 (1.64) 32.00 (2.10) 
 85 min after pill intake 33.15 (1.55) 33.08 (1.24) 34.23 (0.91) 33.62 (1.30) 33.00 (1.70) 33.46 (1.10) 32.42 (1.87) 32.15 (2.41) 
Wakefulness 
 Before pill intake 32.15 (1.74) 30.00 (1.35) 31.92 (1.22) 32.85 (1.63) 30.07 (1.29) 28.62 (1.67) 32.50 (1.32) 31.15 (1.41) 
 45 min after pill intake 32.69 (1.74) 28.50 (1.66) 30.69 (1.21) 30.69 (1.32) 28.50 (0.96) 26.85 (1.81) 28.00 (1.71) 29.77 (1.82) 
 70 min after pill intake 32.46 (2.07) 29.75 (1.69) 29.77 (1.71) 30.92 (1.50) 25.21 (1.22) 26.08 (1.86) 27.58 (1.59) 25.92 (2.03) 
 85 min after pill intake 33.38 (1.69) 29.00 (1.58) 28.77 (1.70) 30.62 (1.62) 26.57 (1.11) 27.46 (1.65) 27.83 (1.47) 27.62 (2.32) 
Restlessness 
 Before pill intake 33.08 (0.96) 29.33 (1.34) 35.08 (0.72) 34.92 (1.03) 32.71 (1.16) 31.69 (1.04) 31.67 (1.47) 31.46 (1.90) 
 45 min after pill intake 34.00 (1.08) 32.75 (0.95) 34.15 (1.80) 32.08 (2.06) 32.71 (1.02) 31.69 (1.29) 28.08 (2.63) 26.85 (2.55) 
 70 min after pill intake 33.69 (1.18) 31.58 (1.20) 33.38 (1.21) 32.08 (1.97) 31.71 (1.72) 32.00 (1.03) 28.75 (2.29) 28.69 (2.36) 
 85 min after pill intake 33.08 (1.25) 30.25 (1.39) 32.85 (1.42) 33.31 (1.38) 30.93 (1.47) 31.00 (0.93) 29.75 (2.73) 29.38 (2.05) 
 Men Women 
Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine 
Mood Questionnaire 
Subjective mood 
 Before pill intake 34.15 (1.31) 32.83 (1.04) 35.08 (0.76) 36.15 (0.85) 34.93 (0.87) 33.62 (1.28) 34.92 (1.13) 34.00 (1.94) 
 45 min after pill intake 34.08 (1.21) 33.25 (1.02) 35.31 (1.02) 34.08 (1.53) 35.36 (0.67) 33.62 (1.35) 31.42 (1.91) 32.92 (1.96) 
 70 min after pill intake 33.54 (1.35) 32.92 (1.09) 34.92 (0.91) 33.00 (1.67) 32.93 (1.38) 33.31 (1.36) 31.50 (1.64) 32.00 (2.10) 
 85 min after pill intake 33.15 (1.55) 33.08 (1.24) 34.23 (0.91) 33.62 (1.30) 33.00 (1.70) 33.46 (1.10) 32.42 (1.87) 32.15 (2.41) 
Wakefulness 
 Before pill intake 32.15 (1.74) 30.00 (1.35) 31.92 (1.22) 32.85 (1.63) 30.07 (1.29) 28.62 (1.67) 32.50 (1.32) 31.15 (1.41) 
 45 min after pill intake 32.69 (1.74) 28.50 (1.66) 30.69 (1.21) 30.69 (1.32) 28.50 (0.96) 26.85 (1.81) 28.00 (1.71) 29.77 (1.82) 
 70 min after pill intake 32.46 (2.07) 29.75 (1.69) 29.77 (1.71) 30.92 (1.50) 25.21 (1.22) 26.08 (1.86) 27.58 (1.59) 25.92 (2.03) 
 85 min after pill intake 33.38 (1.69) 29.00 (1.58) 28.77 (1.70) 30.62 (1.62) 26.57 (1.11) 27.46 (1.65) 27.83 (1.47) 27.62 (2.32) 
Restlessness 
 Before pill intake 33.08 (0.96) 29.33 (1.34) 35.08 (0.72) 34.92 (1.03) 32.71 (1.16) 31.69 (1.04) 31.67 (1.47) 31.46 (1.90) 
 45 min after pill intake 34.00 (1.08) 32.75 (0.95) 34.15 (1.80) 32.08 (2.06) 32.71 (1.02) 31.69 (1.29) 28.08 (2.63) 26.85 (2.55) 
 70 min after pill intake 33.69 (1.18) 31.58 (1.20) 33.38 (1.21) 32.08 (1.97) 31.71 (1.72) 32.00 (1.03) 28.75 (2.29) 28.69 (2.36) 
 85 min after pill intake 33.08 (1.25) 30.25 (1.39) 32.85 (1.42) 33.31 (1.38) 30.93 (1.47) 31.00 (0.93) 29.75 (2.73) 29.38 (2.05) 

Data represent mean scores in each category (SE). Higher values in subjective mood represent elevated mood, wakefulness, and reduced restlessness.

Over time, there was a significant increase in systolic and diastolic blood pressure in participants who had received yohimbine (Time point of measurement × Noradrenergic stimulation: both F ≥ 7.392, both p ≤ .001). Forty-five minutes after pill intake as well as before the start of the associative learning task, participants who had received yohimbine showed significantly increased systolic and diastolic blood pressure, compared with those who had not received yohimbine (all F ≥ 18.166, all p ≤ .001). There was, however, no effect of hydrocortisone on blood pressure (Time point of measurement × Cortisol: all F ≤ 2.341, all p ≥ .084; see Figure 2).

Conversely, hydrocortisone intake led to a significant increase in salivary cortisol (Time point of measurement × Cortisol: F(1.532, 145,539) = 47.842, p < .001, η2 = .335), whereas there was no effect of yohimbine intake (all F ≤ 2.301, all p ≥ .117). Forty-five minutes as well as 70 min after pill intake, participants that had received hydrocortisone showed significantly increased cortisol levels, compared with those who had not received hydrocortisone (both F ≥ 72.131, both p ≤ .001).

Subjective measures showed increases in negative mood as well as restlessness over time for participants who had received yohimbine (all F ≥ 2.779, all p ≤ .050; see Table 1), whereas there was no effect of hydrocortisone on participants' subjective assessments, neither alone nor in combination with yohimbine (all F ≤ 1.537, all p ≥ .211).

Overall, men showed higher systolic blood pressure, wakefulness, and restlessness but lower cortisol levels compared with women (all F ≥ 5.440, all p ≤ .022). Importantly, however, the pattern of the physiological responses to hydrocortisone and yohimbine was very similar in men and women. Both men and women showed significant increases in systolic blood pressure and cortisol levels over time after intake of yohimbine and hydrocortisone, respectively (all F ≥ 3.554, all p ≤ .026; Figure 2).

Intact Acquisition Performance after Yohimbine and Hydrocortisone Intake

Participants learned the antecedent–consequent pairs very well, as reflected in an average performance of about 87% correct responses. We did not obtain a significant main effect of Acquisition stage, as participants' performance was high in all three acquisition stages (F(1.724, 163.748) = 2.055, p = .138, η2 = .021). Acquisition performance was unaffected by drug treatment and comparable in men and women (all F < 1.411, all p ≥ .247; see Table 2), which may, however, also be related to the fact that performance levels were overall relatively high.

Table 2. 

Percentage Correct Responses in the Acquisition Stages and Generalization Phase in All Groups

 Men Women 
Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine 
Acquisition Stage 
“Shaping phase” 81.73 (3.48) 88.89 (2.63) 88.14 (2.05) 86.22 (2.23) 86.61 (3.33) 82.37 (4.84) 87.50 (3.48) 88.46 (2.80) 
“Equivalence training” 90.39 (1.77) 85.42 (2.10) 90.22 (2.76) 87.50 (2.34) 89.88 (1.60) 85.74 (4.74) 88.37 (1.98) 88.46 (2.28) 
“New consequents” 85.79 (2.44) 86.34 (1.71) 88.03 (2.07) 87.82 (1.30) 88.49 (1.67) 83.65 (3.21) 87.15 (2.55) 87.8 (1.50) 
 
Generalization Phase 
Old “shaping phase” 95.51 (1.45) 94.79 (2.18) 91.99 (3.82) 94.55 (1.97) 95.24 (1.68) 91.99 (3.04) 93.06 (2.20) 93.91 (1.86) 
Old “equivalence training” 94.23 (2.14) 94.10 (2.26) 94.87 (1.58) 93.59 (1.30) 93.75 (2.04) 91.35 (3.73) 92.71 (1.55) 95.19 (1.69) 
Old “new consequents” 88.46 (3.41) 87.85 (2.78) 86.22 (4.41) 88.78 (2.61) 83.93 (3.68) 80.13 (6.45) 88.19 (3.87) 85.90 (3.00) 
New trials 70.83 (4.62) 72.92 (3.86) 77.24 (5.65) 78.53 (4.37) 83.93 (3.80) 76.92 (5.22) 77.43 (5.22) 73.08 (4.57) 
 Men Women 
Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine 
Acquisition Stage 
“Shaping phase” 81.73 (3.48) 88.89 (2.63) 88.14 (2.05) 86.22 (2.23) 86.61 (3.33) 82.37 (4.84) 87.50 (3.48) 88.46 (2.80) 
“Equivalence training” 90.39 (1.77) 85.42 (2.10) 90.22 (2.76) 87.50 (2.34) 89.88 (1.60) 85.74 (4.74) 88.37 (1.98) 88.46 (2.28) 
“New consequents” 85.79 (2.44) 86.34 (1.71) 88.03 (2.07) 87.82 (1.30) 88.49 (1.67) 83.65 (3.21) 87.15 (2.55) 87.8 (1.50) 
 
Generalization Phase 
Old “shaping phase” 95.51 (1.45) 94.79 (2.18) 91.99 (3.82) 94.55 (1.97) 95.24 (1.68) 91.99 (3.04) 93.06 (2.20) 93.91 (1.86) 
Old “equivalence training” 94.23 (2.14) 94.10 (2.26) 94.87 (1.58) 93.59 (1.30) 93.75 (2.04) 91.35 (3.73) 92.71 (1.55) 95.19 (1.69) 
Old “new consequents” 88.46 (3.41) 87.85 (2.78) 86.22 (4.41) 88.78 (2.61) 83.93 (3.68) 80.13 (6.45) 88.19 (3.87) 85.90 (3.00) 
New trials 70.83 (4.62) 72.92 (3.86) 77.24 (5.65) 78.53 (4.37) 83.93 (3.80) 76.92 (5.22) 77.43 (5.22) 73.08 (4.57) 

Data represent mean percent correct responses (SE).

Noradrenergic Arousal Disrupts Memory Generalization in Women

In the generalization phase, participants were required to generalize trained equivalences from the acquisition phase to new stimulus pairs. Increased noradrenergic arousal after yohimbine intake had a significant impact on memory generalization, when initial acquisition performance was controlled for, and this impact differed significantly between men and women (Noradrenergic stimulation × Sex interaction: F(1, 94): 7.630, p = .007, η2 = .075). Yohimbine, irrespective of whether administered alone or in combination with hydrocortisone, reduced performance in the new (i.e., generalization) trials in women (F(1, 47) = 4.551, p = .038, η2 = .088; see Table 2). In men, however, yohimbine tended even to increase generalization performance, yet this effect did not reach statistical significance (F(1, 46) = 2.874, p = .097, η2 = .059). Cortisol on the other hand did not have an effect on generalization performance (no main effect or any relevant interactions, all F ≤ .223, all p ≥ .638), and neither did we obtain an interaction effect of cortisol and noradrenaline in combination with sex or without (both F ≤ .180, p ≥ .673).

The critical behavioral index of memory generalization was the generalization score that explicitly takes the performance for the items from the “new consequents” stage into account (see Methods). Also for this generalization score, we obtained different effects of yohimbine in men and women (Noradrenergic stimulation × Sex interaction: F(1, 95) = 8.802, p = .004, η2 = .085). As shown in Figure 3, generalization performance was reduced in women who had received yohimbine alone or in combination with hydrocortisone (F(1, 48) = 6.019, p = .018, η2 = .111). In men, there was again a trend for increased memory generalization after yohimbine intake (F(1, 47) = 2.966, p = .092, η2 = .059). Cortisol did not have any significant effects on generalization performance, and we did not obtain any interactive effects between cortisol and noradrenergic stimulation, nor was there an interaction with sex (all F ≤ .345, p ≥ .558). Furthermore, placebo-treated women showed significantly better generalization performance than placebo-treated men (t(25) = −3.528, p = .002).

Figure 3. 

Impact of cortisol and noradrenaline on generalization performance. The generalization score quantifies participants' ability to generalize the acquired stimulus associations to new stimuli, with respect to their initial learning performance. A score of 100 describes an equal performance in old and new trials during the generalization phase, whereas a score below 100 illustrates a lower performance in new trials compared with old trials, pointing toward an impairment in memory generalization. Women who have received yohimbine either alone or in combination with hydrocortisone show impaired generalization performance, compared with women that have received either a placebo or hydrocortisone alone. In men, no such effect was observed. In the placebo groups, women outperformed men. Furthermore, cortisol did not affect generalization performance, neither in men nor in women. Error bars reflect SEMs. *p < .05.

Figure 3. 

Impact of cortisol and noradrenaline on generalization performance. The generalization score quantifies participants' ability to generalize the acquired stimulus associations to new stimuli, with respect to their initial learning performance. A score of 100 describes an equal performance in old and new trials during the generalization phase, whereas a score below 100 illustrates a lower performance in new trials compared with old trials, pointing toward an impairment in memory generalization. Women who have received yohimbine either alone or in combination with hydrocortisone show impaired generalization performance, compared with women that have received either a placebo or hydrocortisone alone. In men, no such effect was observed. In the placebo groups, women outperformed men. Furthermore, cortisol did not affect generalization performance, neither in men nor in women. Error bars reflect SEMs. *p < .05.

Control Variables

To control for chronic stress, depressive mood, as well as state and trait anxiety, participants completed the TICS (Schulz & Schlotz, 1999), the BDI (Beck et al., 1961), and the State/Trait Anxiety Inventory (Spielberger et al., 1994) before pill intake. We did not obtain any significant group differences in these control variables (all F < 1.787, p > .185). However, overall women had a higher BDI score (F(1, 95) = 5.752, p = .018, η2 = .057) and tended to have a higher chronic stress level (F(1, 95) = 3.133, p = .080, η2 = .032, see Table 3). To test whether these sex differences could explain the differential responses of men and women to noradrenergic stimulation by yohimbine, we repeated our analyses with BDI or TICS scores as covariates. Our pattern of results, however, remained unaffected by these covariates, suggesting that the obtained sex differences were not due to differences in depressive mood or chronic stress level. In particular, the interaction between sex and yohimbine intake remained significant after controlling for differences in depressive mood (F(1, 94) = 9.014, p = .003, η2 = .087) or chronic stress (F(1, 94) = 8.201, p = .005, η2 = .080).

Table 3. 

Control Variables in All Groups

 Men Women 
Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine 
Chronic Stress 
TICS Screening Score 13.15 (2.86) 15.92 (2.22) 12.23 (2.68) 13.00 (1.66) 15.71 (2.12) 15.38 (2.10) 18.17 (2.52) 16.54 (1.99) 
 
Depression Index 
BDI Score 5.15 (1.27) 4.42 (0.69) 4.62 (0.96) 4.08 (1.12) 6.14 (1.53) 8.08 (1.11) 5.92 (1.31) 6.00 (0.96) 
 
State and Trait Anxiety 
State 36.08 (2.00) 36.90 (1.84) 33.08 (1.15) 32.75 (1.71) 34.62 (2.60) 33.92 (1.06) 35.55 (2.09) 35.54 (2.41) 
Trait 37.23 (2.62) 38.92 (2.59) 33.62 (2.32) 32.85 (1.55) 36.64 (2.75) 39.77 (2.04) 36.64 (2.39) 33.38 (2.10) 
 Men Women 
Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine Placebo Hydrocortisone Yohimbine Hydrocortisone + Yohimbine 
Chronic Stress 
TICS Screening Score 13.15 (2.86) 15.92 (2.22) 12.23 (2.68) 13.00 (1.66) 15.71 (2.12) 15.38 (2.10) 18.17 (2.52) 16.54 (1.99) 
 
Depression Index 
BDI Score 5.15 (1.27) 4.42 (0.69) 4.62 (0.96) 4.08 (1.12) 6.14 (1.53) 8.08 (1.11) 5.92 (1.31) 6.00 (0.96) 
 
State and Trait Anxiety 
State 36.08 (2.00) 36.90 (1.84) 33.08 (1.15) 32.75 (1.71) 34.62 (2.60) 33.92 (1.06) 35.55 (2.09) 35.54 (2.41) 
Trait 37.23 (2.62) 38.92 (2.59) 33.62 (2.32) 32.85 (1.55) 36.64 (2.75) 39.77 (2.04) 36.64 (2.39) 33.38 (2.10) 

Data represent mean scores in each category (SE).

Furthermore, because men tended to have higher (overall) blood pressure but lower cortisol than women, we ran our analyses again controlling for these variables. Notably, the obtained interactive influence of Noradrenergic stimulation and sex remained significant after controlling for systolic blood pressure (Noradrenergic stimulation × Sex: F(1, 94) = 8.597, p = .004, η2 = .084), diastolic blood pressure (Noradrenergic stimulation × Sex: F(1, 94) = 8.837, p = .004, η2 = .086), and cortisol (Noradrenergic stimulation × Sex: F(1, 94) = 8.710, p = .004, η2 = .085). Finally, we ran our analyses again with subjective mood and restlessness as covariates. These analyses showed that these subjective changes could also not explain the differential effect of noradrenergic stimulation in men and women, that is, the Noradrenergic stimulation × Sex interaction remained (all F ≥ 7.420, all p ≤ .008).

DISCUSSION

Our ability to generalize across multiple discrete experiences allows us to adapt rapidly to constantly changing environments. We showed recently that this ability to generalize may be disrupted by acute stress (Dandolo & Schwabe, 2016). Here, we aimed to elucidate the role of major stress mediators (glucocorticoids and noradrenaline) in memory generalization. Our results indicate that elevated noradrenergic stimulation induced by the α2-adrenoceptor antagonist yohimbine impaired memory generalization in women, but not in men. Increased cortisol concentrations, however, did not modulate generalization performance.

Stressful events are known to be a powerful modulator of memory processes (Schwabe, Joels, Roozendaal, Wolf, & Oitzl, 2012; Sandi & Pinelo-Nava, 2007; Joels et al., 2006) and noradrenaline plays a crucial role in stress-induced changes of memory. For instance, pharmacological elevations of noradrenaline levels can directly modulate memory processes (Packard & Wingard, 2004; Williams, Men, Clayton, & Gold, 1998) and a blockade of noradrenergic activation may prevent stress effects on memory (Schwabe, Hoffken, Tegenthoff, & Wolf, 2011; Schwabe, Romer, et al., 2009; Roozendaal, Okuda, Van der Zee, et al., 2006; McGaugh & Roozendaal, 2002). Our previous study showed negative correlations between autonomic nervous system activation and memory generalization performance, suggesting that (nor)adrenergic activity is also relevant for the stress-induced generalization deficit (Dandolo & Schwabe, 2016). Here, we provide direct evidence that increased noradrenergic stimulation is sufficient to disrupt memory generalization (in women). As memory generalization is thought to rely on the hippocampus (Kumaran & McClelland, 2012; Shohamy & Wagner, 2008), it might be tempting to speculate that the observed impact of yohimbine reflects a direct effect on hippocampal processing. However, we consider this interpretation relatively unlikely because there is evidence that noradrenaline rather enhances hippocampal functioning (Gray & Johnston, 1987; Stanton & Sarvey, 1985). Instead, we assume that the influence of increased noradrenergic activation was mediated by the amygdala, which then modulated hippocampal functioning (McGaugh et al., 1996). The amygdala is a primary target of noradrenergic inputs (Bouret & Sara, 2005; Jones & Moore, 1977) that is known to modulate other memory systems, including the hippocampus (Roozendaal, McEwen, & Chattarji, 2009; Roozendaal, Hui, et al., 2006; McGaugh, 2004). At the same time, recent evidence suggests that stress promotes the recruitment of a salience network, including the amygdala (Hermans, Henckens, Joels, & Fernandez, 2014), and that this recruitment of the salience network is mainly due to the action of noradrenaline (Hermans et al., 2011).

Taking the role of the amygdala into account could also provide an explanation for the observed sex differences, that is, the finding that yohimbine impaired memory generalization in women but not in men. Overall, there is substantial evidence for differences between men and women in amygdala structure and functioning (reviewed in Cahill, 2006). In particular, however, it was previously reported that the same dosage of yohimbine that we used here led to increased amygdala activation in women but to decreased amygdala activation in men (Schwabe, Hoffken, Tegenthoff, & Wolf, 2013). These differences in amygdala activation in men and women may well have resulted in a differential modulation of hippocampal functioning, translating into sex-specific effects of yohimbine on memory generalization. Such sex differences are most likely due to the action of sex hormones such as estrogen and testosterone. These hormones are known to affect limbic areas such as the hippocampus and the amygdala (Barth, Villringer, & Sacher, 2015; Matsumoto, 1991). More specifically, estrogen has been suggested to increase amygdala activity (Schiess, Joels, & Shinnick-Gallagher, 1988), and further evidence indicated that the concerted action of estrogen and noradrenaline may increase amygdala activity (McEwen & Alves, 1999; Matsumoto, 1991). Testosterone, on the other hand, has been suggested to decrease amygdala activity (Flügge, Kramer, & Fuchs, 2001). Future studies that combine pharmacological manipulations of noradrenergic and sex hormone activity are needed to test the proposed interactive influence of noradrenaline and sex hormones on memory generalization as a basis of the reported sex differences.

Whereas noradrenergic stimulation impaired memory generalization (in women), there was no effect of increased cortisol concentrations. The dose of cortisol that we administered here did also not affect amygdala processing in our previous study (Schwabe, Hoffken, et al., 2013; but see Lovallo, Robinson, Glahn, & Fox, 2010, for time-dependent effects of cortisol on amygdala resting activity), neither in men nor in women. However, glucocorticoid effects on hippocampal plasticity and activity are well documented (Henckens et al., 2010; Lovallo et al., 2010; Kim & Diamond, 2002). Moreover, we obtained previously negative correlations between stress-induced cortisol elevations and participants' capacity to generalize (Dandolo & Schwabe, 2016), although this association may have been dependent on the parallel autonomic activation as there is strong evidence that stress effects on memory processes require concurrent glucocorticoid and noradrenergic activation (Roozendaal, Okuda, de Quervain, & McGaugh, 2006; Roozendaal, Hahn, Nathan, de Quervain, & McGaugh, 2004). Yet, our present data showed also no evidence for an interactive influence of cortisol and noradrenaline. Although our results indicate that elevated glucocorticoid concentrations were not sufficient to affect memory generalization, it cannot be ruled out that they are necessary for stress-induced generalization deficits. Glucocorticoid synthesis inhibitors or pharmacological blockade of receptors for glucocorticoids could help to address this issue.

Another potential explanation for the lack of a hydrocortisone effect in the current study takes the different modes of glucocorticoid action into account. Classically, glucocorticoids were thought to exert delayed, gene-mediated effects through intracellular receptors. More recently, however, it was discovered that glucocorticoids may also act through membrane-associated receptors, inducing rapid, nongenomic effects (Joels, Sarabdjitsingh, & Karst, 2012; Karst et al., 2005). Interestingly, the rapid and delayed glucocorticoid actions have been shown to have different, perhaps even opposite, effects on hippocampal and amygdala functioning (Henckens et al., 2010, 2012; Joels et al., 2012). Although it is not fully understood yet, when exactly genomic glucocorticoid actions develop, it might well be that they are already present at about 80–100 min after hydrocortisone intake, that is, when participants performed the task. It is therefore tempting to speculate that nongenomic and genomic glucocorticoid actions might have cancelled each other out, preventing the detection of any hydrocortisone effect.

The capacity to generalize across discrete experiences may be due to an integrative encoding process that enables later retrieval of knowledge about relations between discrete events (Shohamy & Wagner, 2008) or to an inference process during retrieval (Preston et al., 2004; Dusek & Eichenbaum, 1997). The hippocampus appears to be important for both integrative encoding and the flexible expression of memories on which inferences are based (Shohamy & Wagner, 2008; Eichenbaum, 2000). Because we administered drugs before encoding and the drugs were still active during the generalization phase, we cannot conclude whether yohimbine affected (in women) primarily encoding processes or the expression of memories (or both). The fact that we did not observe any drug effects on performance in the acquisition phase or on the retrieval of items from the acquisition phase that were tested in the generalization phase might be taken as evidence that yohimbine affected neither encoding nor simple retrieval processes but specifically the flexible expression of memories (inference) that is required for memory generalization. This conclusion, however, may be premature as there is accumulating evidence showing that, although performance may seem to be unaffected by stress or stress hormones, it is actually controlled by other, more rigid systems, the effect of which can only be seen when the flexibility of the acquired memories is probed (Schwabe & Wolf, 2009, 2012, 2013; Schwabe et al., 2007; Kim et al., 2001). Interestingly, this stress- and stress hormone-induced shift toward more rigid systems, at the expense of the hippocampus, is also mediated by the amygdala (Vogel, Fernandez, Joels, & Schwabe, 2016; Schwabe, Tegenthoff, et al., 2013; Packard & Wingard, 2004).

Stress and stress hormone effects on memory generalization processes have been reported in other studies as well. Specifically, it has been shown that stress or hydrocortisone affects the contextualization of episodic or conditioned fear memories (van Ast, Cornelisse, Meeter, Joels, & Kindt, 2013; Kaouane et al., 2012; Qin, Hermans, van Marle, & Fernandez, 2012). The conceptualization of memory generalization as reduced contextualization, however, is clearly distinct from the generalization processes examined in this study, which required participants to generalize across past experiences. Thus, although these lines of research both refer (rightfully) to memory generalization processes, the concepts differ and the findings cannot directly be related to one another. The impact of stress hormones of memory generalization or transfer processes of the individual have, to the best of our knowledge, not been tested before. The sample size of this first study examining the impact of different stress hormones on individuals' capacity to generalize across past experiences was rather moderate and future studies should test larger samples. Furthermore, future studies should include different dosages of hydrocortisone and yohimbine to test for potential dose dependencies. Including different dosages would also allow for testing whether the dosages required to modulate memory generalization capacities differ in men and women.

In summary, the present findings show that increased noradrenergic stimulation is sufficient to disrupt memory generalization in women but not in men. Memory generalization is a fundamental process that bridges discrete episodes and allows individuals to draw on past experiences to guide behavior. In addition, dysfunctional memory generalization is characteristic for several stress-related mental disorders, including schizophrenia or major depression (Gotlib & Joormann, 2010; Shohamy et al., 2010). Given that some of these disorders are much more common in women than in men, the sex differences reported here might be of particular interest. If noradrenergic activation turns out to be not only sufficient to impair memory generalization but also necessary for stress-induced generalization deficits, manipulations of noradrenergic activity, for example, by beta blockers, might be used as a tool to alleviate aberrant memory generalization in stress-related psychopathologies.

Acknowledgments

We gratefully acknowledge the assistance of Sonja Timmerman, Olivia Bendlin, and Mewes Muhs during data collection. This study was supported by grants from the German Research Foundation (DFG, SCHW1357/5-3 and SCHW1357/14-1).

Reprint requests should be sent to Prof. Dr. Lars Schwabe, Department of Cognitive Psychology, University of Hamburg, Von-Melle-Park 5, 20146 Hamburg, Germany, or via e-mail: lars.schwabe@uni-hamburg.de.

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