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Study III: Noradrenergic Stimulation Impairs Memory
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sensitive to stress effects specifically when considering hippocampal memory (Guenzel et al., 2014;
Wolf, Schommer, Hellhammer, McEwen, & Kirschbaum, 2001), it is tempting to speculate that effects observed will be stronger in women.
Methods
Procedure
We tested 103 healthy participants (52 female) in a double blind, fully-crossed, placebo-controlled between-subjects design. Depending on the group, participants received either a placebo, the alpha-2-adrenoceptor antagonist yohimbine (20 mg), hydrocortisone (20 mg) or both drugs. About 70 minutes after pill intake, participants completed a memory generalization task.
Task
More specifically, participants completed the acquired equivalence task by Myers et al (2003). The task comprised two phases, namely the acquisition phase and the generalization phase. Participants first completed the acquisition phase during which pictures of specific individuals were paired with differentially colored fish (eight fish and eight individuals in total). Individuals differed in age, gender and hair color. Participants were asked to learn the specific associations between fish and individual by trial and error. In the first of three stages of the acquisition phase (shaping), participants learned four pairings between individual and fish. To do so participants saw a picture of an individual on a computer screen and the images of two fish below the individual. Participants were then asked to indicate by button press, to which fish the individual belonged. Participants received feedback about the correctness of their choice. The equivalence stage immediately followed the shaping stage and comprised four additional individuals that were also paired with the already shown fish.
Hence, participants were required to form equivalences between the individuals that were associated with the same fish and comprehend that these individuals always shared the same features (gender and hair color). In the third stage, new consequents, the eight individuals from the previous two stages were shown again, however, the four individuals from the shaping stage were now associated with an additional, completely new and differently colored fish. Participants were required to learn that each individual can be associated with two fish. Then the generalization phase followed. During the generalization phase, all trials from the acquisition phase were shown as
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well as new trials during which the individuals from the equivalence training stage were paired with new fish. In the generalization phase however, participants were not given feedback. Hence, the generalization phase can be used well to test whether participants were able to generalize the associations they had learned in the previous phase to the new trials (Collie, Myers, Schnirman, Wood, & Maruff, 2002; Myers et al., 2003; figure 7). To assess participants’ generalization ability, a generalization score was calculated. This score was calculated by subtracting the percentage
correct of the trials during the new consequents stage from the percentage correct of the new trials from the generalization phase with an added constant of 100, to avoid negative scores. This score specifically allows to separate the ability to generalize across associations and initial memory (Dandolo & Schwabe, 2016).
Results
Manipulation Check
Intake of yohimbine alone or in combination led to a significant increase in blood pressure.
Hydrocortisone intake, alone or in combination caused a significant increase in salivary cortisol, in comparison to participants receiving a placebo.
Generalization Performance
Results showed that participants learned very well and that the intake of yohimbine and/or hydrocortisone did not hamper initial learning in the acquisition phase, i.e. performance was comparable between the treatment groups as well as between men and women. The ability to generalize across new pairs in the acquired equivalence task however, was impacted by the intake of yohimbine and this impact was different in men and women. More specifically, yohimbine alone or in combination with hydrocortisone led to a decrease in generalization performance in women, while the effect was almost opposite in men (although this did not reach statistical significance).
Yohimbine intake also had a significant impact on the generalization score in women. Cortisol on the other hand did not affect the ability to generalize in the current task (figure 8).
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Figure 7 – Acquired Equivalence Task
The acquired equivalence task has been adapted from Myers et al (2003). The task comprises two phases, the acquisition phase consisting of three stages and the generalization phase. During the acquisition phase, the participant learns the associations between an individual and a specifically colored fish. In the first stage (shaping), participants learn four pairings between individual and fish. In the second stage (equivalence training) four additional individuals are associated with the four fish from the shaping stage, so that each fish is associated with two individuals, based on a specific characteristic (gender and hair color). During the third stage (new consequents), the individuals from the shaping stage are associated with an additional fish each. During the acquisition stage, participants always received immediate feedback. During the generalization phase, participants were required to indicate to which of the newly introduced fish during the new consequents stage, the individuals from the equivalence training stage belonged to. This time participants did not receive feedback, but were required to generalize across new items.
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Figure 8 – Noradrenaline is Detrimental to Generalization Performance in Women
The generalization score indicates participants’ generalization performance with respect to initial learning. A score of 100 represents an equal performance between old and new trials in the generalization phase, while a score below 100 indicates a generalization impairment as it reflects a better performance in old compared to new trials. There was a significant decrease in generalization performance in women that received yohimbine alone or in combination with hydrocortisone, while women that received a placebo or hydrocortisone performed well and were able to generalize across discreet experiences. In men, there was no significant difference between generalization performance in the individual treatment groups. Women receiving a placebo showed a significantly better performance compared to men that received a placebo. Error bars represent standard error of the mean. * p < .05.
Discussion
The aim of the current study was to elucidate the specific effects of the major stress mediators on our ability to utilize previous knowledge and generalize across experiences, an ability crucial for our everyday life, decision-making and survival (Shohamy & Wagner, 2008). Recent evidence indicates that stress has an impact on generalization ability (Dandolo & Schwabe, 2016) and our results show that elevated noradrenergic stimulation, triggered by the alpha-2-adrenoceptor-antagonist
yohimbine disrupts memory generalization in women exclusively, while this result could not be found in men. Cortisol on the other hand, did not affect performance, neither in men nor in women.
Current results seem to pinpoint a modulatory effect of specifically noradrenaline on generalization performance. Previous reports have also indicated the importance of noradrenaline in mediating the effect of stress on memory, showing direct effects of noradrenaline on memory processes as well as an absence of effects when noradrenergic activity is blocked (Packard & Wingard, 2004;
Roozendaal, Okuda, Van der Zee, & McGaugh, 2006; Schwabe, Hoffken, Tegenthoff, & Wolf, 2013;
Schwabe et al., 2009; Williams, Men, Clayton, & Gold, 1998). While this can only be speculated, it is possible that noradrenaline acts on the hippocampus via the amygdala, impacting generalization performance (McGaugh, Cahill, & Roozendaal, 1996). This mode of action may also explain the
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observed gender effects, as previous studies have reported structural and functional differences in the amygdala of men and women (Cahill, 2006). Hence noradrenergic arousal plays an important role when considering the impact of stress on memory processes and seemingly also on memory generalization. While the current data showed a strong impact of noradrenaline on memory generalization, there was no impact of increased cortisol levels. However, Dandolo and Schwabe (2016) showed a negative association between cortisol and generalization performance. It can be speculated that the effect of cortisol requires concurrent noradrenergic activity, despite the fact that current results did not indicate any interaction effects. It may however still be possible that, while not sufficient, effects of cortisol are necessary to induce generalization impairments, as the concurrent activity of noradrenaline and cortisol is frequently reported and emphasized
(Roozendaal et al., 2004; Roozendaal, Okuda, de Quervain, et al., 2006; Roozendaal, Okuda, Van der Zee, et al., 2006). Hence, the current study provides direct evidence for a specific impact of
noradrenaline on memory generalization in women and that noradrenaline may be sufficient to exert this disruptive effect.
Furthermore, current results also extend our knowledge on how stress, but specifically stress mediators impact the use of prior knowledge during learning, beyond its influence on schema-based learning described above. Additionally, we may present a different mechanism by which our ability to use prior knowledge may be impacted by stress. In the following I will discuss and
integrate the present findings to allow for a better understanding of the underlying mechanisms that may impact our ability to use and benefit from prior knowledge.