Abstract

Memory functions involve three stages: encoding, consolidation, and retrieval. Modulating effects of glucocorticoids (GCs) have been consistently observed for declarative memory with GCs enhancing encoding and impairing retrieval, but surprisingly, little is known on how GCs affect memory consolidation. Studies in rats suggest a beneficial effect of GCs that were administered during postlearning wake periods, whereas in humans, cortisol impaired memory consolidation when administered during postlearning sleep. These inconsistent results raise the question whether effects of GCs critically depend on the brain state during consolidation (sleep vs. wake). Here, we compare for the first time directly the effects of cortisol on memory consolidation during postlearning sleep and wakefulness in different measures of declarative memory. Cortisol (13 mg vs. placebo) was intravenously infused during a postlearning nap or a time-matched period of wakefulness after participants had encoded neutral and emotional text material. Memory for the texts was tested (a) by asking for the contents of the texts (“item” memory) and (b) for the temporal order of the contents within the texts (“relational” memory). Neither postlearning infusion of cortisol during sleep nor during wakefulness affected retention of content words of emotional or neutral texts. Critically, however, the retention of temporal order within the texts, known to rely most specifically on the hippocampus proper within the medial-temporal lobe memory system, was distinctly improved by cortisol infusion during the wake phase but impaired by cortisol during sleep. These results point toward fundamentally different mechanisms of hippocampal memory consolidation, depending on the brain state.

INTRODUCTION

Memory function relies on three subprocesses, that is, (a) the encoding of new information, (b) their subsequent consolidation, and (c) the eventual retrieval of memories. During the process of consolidation, initially labile memory traces are transformed into stable and long-lasting memories (Dudai, 2004; McGaugh, 2000). The reactivation of memory representations during “off-line” periods provides a potential mechanism of memory consolidation (Rasch, Büchel, Gais, & Born, 2007; Sutherland & McNaughton, 2000; Wilson & McNaughton, 1994). Periods of sleep after encoding in comparison with wakefulness have been demonstrated to benefit the consolidation of memories (Diekelmann & Born, 2010; Marshall & Born, 2007; Stickgold, 2005). The three stages of memory formation are differentially affected by multiple neuromodulators. In particular, glucocorticoids (GCs) have been consistently shown to modulate declarative memory that critically relies on medial-temporal lobe structures. Most of the studies in humans in which GC levels were enhanced during encoding of memories reported beneficial effects in a later memory test (e.g., Wolf, 2009; Lupien & Lepage, 2001), although opposite (Rimmele, Domes, Mathiak, & Hautzinger, 2003; Kirschbaum, Wolf, May, Wippich, & Hellhammer, 1996) as well as no effects of GCs have been found as well (Kuhlmann & Wolf, 2006; de Quervain, Roozendaal, Nitsch, McGaugh, & Hock, 2000). In contrast, memory retrieval was consistently shown to be impaired by GCs (Wolf et al., 2001; de Quervain et al., 2000). Effects of GCs on consolidation are less well understood, especially in humans. Studies investigating the effects of postlearning stress on memory consolidation did not help clarifying the picture as stress stimulates, in addition to GCs, a number of other hormones and neuromodulators with well-known effects on memory (e.g., norepinephrine). Accordingly, beneficial effects on the retention of memories observed in these studies cannot be unambiguously attributed to the effects of cortisol (Preuss & Wolf, 2009; Smeets, Otgaar, Candel, & Wolf, 2008; Abercrombie, Speck, & Monticelli, 2006; Beckner, Tucker, Delville, & Mohr, 2006; Cahill, Gorski, & Le, 2003). In rats, GCs improved memory consolidation, but only in the presence of arousal-induced or pharmacologically induced noradrenergic activation (Roozendaal, Okuda, Van der Zee, & McGaugh, 2006; Okuda, Roozendaal, & McGaugh, 2004). The only study, so far, which investigated effects of postlearning administration of cortisol during a wake period on memory consolidation in humans did not reveal any change in the retention of declarative memories (neutral words) after cortisol (de Quervain et al., 2000). In contrast to these results, the infusion of cortisol during postlearning periods of sleep consistently deteriorated the consolidation of word pairs indicating that GCs might state-dependently affect processes of consolidation (Plihal & Born, 1999; Plihal, Pietrowsky, & Born, 1999).

The hippocampus, the central brain structure for declarative memory within the medial-temporal lobe with a particularly dense distribution of GC receptors, has been demonstrated to be a relevant site for GC actions on memory (Roozendaal, McEwen, & Chattarji, 2009). Thus, the task-dependent involvement of the hippocampus critically determines whether memory consolidation is affected by GCs or not. This was supported by studies demonstrating that procedural memories, which are less dependent on hippocampal functioning, are not influenced by GCs (Plihal & Born, 1999). Although declarative memories are often thought to generally depend on the hippocampus, recent studies point toward a critical dependence on specific task characteristics (Tubridy & Davachi, 2010; Qin et al., 2009; Fortin, Agster, & Eichenbaum, 2002; Kesner, Gilbert, & Barua, 2002). In these studies, relational memories (e.g., word pairs or temporal sequence memory) involved the hippocampus to a much greater extent than single item memories.

Here, we directly compared the effects of postlearning infusion of cortisol on the consolidation of item and relational memories during sleep and wakefulness. Subjects learned neutral and emotional texts and were tested for the retention of the contents (representing “item” memory) as well as for the temporal sequence in the texts. Emotional material was included in addition to the neutral one because GC effects can differ depending on the emotional impact of the learned material (e.g., Wagner, Degirmenci, Drosopoulos, Perras, & Born, 2005; Buchanan & Lovallo, 2001). Because temporal sequence memory refers to the relational aspect between items of an episode, we hypothesized GCs to affect temporal order memory to a greater extent than item memories.

METHODS

Participants

Thirty-two healthy men recruited at the University of Lübeck to participate in the study (mean age = 23.91 years, SEM = 0.66 years) were equally assigned to a “sleep group” and a “wake group.” All participants were nonsmokers, were free of medication, and had no history of neurological, psychiatric, or endocrine disorders. They gave written informed consent and were paid for participation in the study, which was approved by the local ethics committee of the University of Lübeck. The experiments took place in the sleep laboratory of the Department of Neuroendocrinology at the University of Lübeck. Although subjects of the “sleep group” stated to habitually take naps in the afternoon, two of them had to be excluded from analysis because of poor sleep quality (>50% wake time of total sleep time). The subjects included in the wake group, unlike the sleep subjects, did not need to be habitual nappers.

Design and Procedure

Each subject participated in two treatment conditions (cortisol and placebo) according to a double-blind, within-subject crossover design, with the order of conditions balanced across subjects (Figure 1). In each condition, subjects performed during a learning phase and a retrieval phase that were 6 hr apart; during which subjects either remained awake (“wake group,” n = 16) or slept for the first 2 hr (“sleep group,” n = 14). The two treatment conditions for each participant were separated by at least 2 weeks. Each experimental session started at 15:00 hr with placement of two intravenous catheters into the subject's forearms for substance administration and blood sampling, respectively. Electrodes were placed for sleep recording in the “sleep group.” A standard meal was provided to all subjects afterward. Learning (encoding) of the two texts took place between 17:00 and 18:00 hr with the order of neutral and emotional texts balanced across subjects. Please note that the order of texts (i.e., whether emotional or neutral texts were learned first) did not affect retention performance (p > .13). Cortisol (13 mg, Hydrocortison 100, Rotexmedica, Trittau, Germany, dissolved in 100 ml saline) or placebo (100 ml of saline solution, 0.91% sodium chloride) was infused intravenously for 2 hr at a rate of 13 mg/hr during the first 30 min and of 4.3 mg/hr during the remaining time. The dose of cortisol was chosen on the basis of previous experiments (Plihal & Born, 1999). In the 2-hr interval of substance administration, subjects in the “wake group” stayed awake, whereas subjects in the “sleep group” were allowed to sleep. At 19:30 hr, subjects in the “wake group” additionally learned a list of numbers (number list learning task). This task was introduced to assure that cortisol effectively enhanced encoding processes as demonstrated in previous studies (Henckens, Hermans, Pu, Joels, & Fernandez, 2009; Smeets et al., 2009; Abercrombie, Kalin, Thurow, Rosenkranz, & Davidson, 2003; Buchanan & Lovallo, 2001). Retrieval of memory for the texts was tested at 0:00 hr when enhanced cortisol levels after cortisol infusion had returned to normal values. During wake periods of the retention interval, subjects played standardized simple games like “Snood” (www.snood.com) and Backgammon. Blood was sampled every 30 min for determination of cortisol and adrenocorticotropin (ACTH) concentrations, except for the 2 hr of sleep in the “sleep group.” Before learning and retrieval testing, subjects rated their subjective sleepiness, activation, motivation, and concentration on 5-point Likert scales with 1 indicating not at all and 5 indicating very much.

Figure 1. 

Experimental procedure (A) and cortisol concentrations (B) in the “sleep group” and the “wake group.” Emotional and neutral texts were encoded between 17:00 and 17.45 hr, and retention performance was tested at 0:00 hr after a 6-hr retention interval in which subjects slept or were awake. Encoding was tested by the number list learning task performed between 19:30 and 20:00 hr only in the “wake group.” Substances (cortisol vs. placebo) were intravenously infused between 18:00 and 20:00 hr (cortisol condition: 13 mg hydrocortisone dissolved in 100 ml saline, placebo condition: 100 ml saline). Mean ± SEM cortisol concentrations in the cortisol (“wake group”: filled circles, “sleep group”: filled triangle) and placebo condition (“wake group”: open circles, “sleep group”: open triangle).

Figure 1. 

Experimental procedure (A) and cortisol concentrations (B) in the “sleep group” and the “wake group.” Emotional and neutral texts were encoded between 17:00 and 17.45 hr, and retention performance was tested at 0:00 hr after a 6-hr retention interval in which subjects slept or were awake. Encoding was tested by the number list learning task performed between 19:30 and 20:00 hr only in the “wake group.” Substances (cortisol vs. placebo) were intravenously infused between 18:00 and 20:00 hr (cortisol condition: 13 mg hydrocortisone dissolved in 100 ml saline, placebo condition: 100 ml saline). Mean ± SEM cortisol concentrations in the cortisol (“wake group”: filled circles, “sleep group”: filled triangle) and placebo condition (“wake group”: open circles, “sleep group”: open triangle).

Tasks

Memory for Texts

To assess consolidation of neutral and emotional memory, validated German text material was used (Schürer-Necker, 1994). The material consists of two texts in each category (neutral: “Bronze” and “Fashion”; emotional: “Paraplegia” and “Murderer”) and is described in detail elsewhere (Wagner, Gais, & Born, 2001; Schürer-Necker, 1994). In the learning phase, each subject learned one neutral and one emotional story. The order of texts within a session and the order of parallel versions used in the subject's two experimental sessions were balanced across subjects. At learning, the subjects were instructed to carefully read the texts that were written on a sheet of paper within 4 mins and to memorize its content as detailed as possible. After reading, subjects rated each text on 7-point scales on the dimensions: comprehensible–incomprehensible, interesting–uninteresting, difficult–easy, neutral–emotional, harmless–startling, important–unimportant, vivid–abstract, amusing–serious, boring–arousing, familiar–unfamiliar, positive–negative. Thereafter, in an immediate free recall test, the participants were asked to write down the previously read text as accurately as possible, without time restriction. This immediate test served to determine how much information was initially encoded, thereby providing an individual baseline value for recall performance assessed at later retrieval testing. Immediately after completion of the learning phase, subjects played the simple, nonarousing but distractive computer game (“Snood”) for 15 min to prevent rehearsal. Delayed free recall after the 6-hr retention interval was performed in the same manner as immediate free recall. Retention performance was calculated as the relative number of content words remembered at delayed recall with reference to the number of content words at immediate recall, which was set to 100%. Additionally, a test was performed that aimed to assess memory for the temporal order (i.e., relational memory) in the texts (Krug, Born, & Rasch, 2006; Swain, Polkey, Bullock, & Morris, 1998). In this test, for each story, 12 pairs of words were presented with one word of the pair representing a content word of the respective text and the other one a synonym. First, as a test of recognition memory, subjects should indicate for each word pair the one that occurred in the text. Then, he should order the selected content words according to the sequential order in which they occurred in the respective text. Recall of sequential order was determined by a deviation score, that is, the distance of the remembered sequence position for a content word from its actual position in the story (Krug et al., 2006; Swain et al., 1998). In this measure, lower scores indicate better memory for the temporal order in the story.

Number List Learning Task

Two parallel versions of the number list learning task (Rasch, Born, & Gais, 2006) were used to compare encoding in the placebo and cortisol session in the wake group. Each list contained 16 two-digit numbers ranging from 12 to 99 that were presented sequentially for 2 sec in randomized order with an ISI of 500 msec. After presenting the list four times and an interval of 1 min, free recall and recognition memory was tested. Recognition was tested by presenting all 16 numbers of the old list interspersed among 16 new numbers. The subject had to decide whether a number belonged to the old list or not. Note that this task differs from classical working memory tasks by testing slightly delayed recall of longer lists of items and, thus, rather gives information on the actual capabilities of encoding.

Hormone Assays

Hormone concentrations were determined in blood samples that were collected every 30 min (except for the 2 hr the subjects of the “sleep group” were allowed to sleep) and stored at −80°C until assay. Serum cortisol concentrations were assessed using the Immulite (DPC Biermann, Bad Nauheim, Germany, intra- and interassay coefficients of variation [CV] < 1%); ACTH was assessed in plasma by Lumitest (Brahms Diagnostica, Hennigsdorf, Germany; interassay CV = 2.8%, intra-assay CV = 1.6%).

Sleep Recordings

Standard polysomnographic recordings were obtained including EEG recordings from electrodes attached at C3 and C4 (according to the international 10–20 system, referenced to an electrode attached to the nose) and electrooculographic and EMG recordings. Signals were amplified (Brain Amp, Brain Products, Germany) and digitized, with the EEG sampled at a rate of 200 Hz and filtered between 0.16 and 70 Hz. Sleep stages were determined off-line for subsequent 30-sec recording epochs following standard criteria (Rechtschaffen & Kales, 1968). Sleep onset (with reference to lights off), total sleep time, and the time of total sleep time spent in the different sleep stages (wake; Stages 1, 2, 3, and 4; and rapid eye movement [REM] sleep) were determined. SWS was defined by the sum of time in Stages 3 and 4 sleep. Latencies of SWS and REM sleep were assessed with reference to sleep onset, that is, the first occurrence of a period of Stage 1 sleep followed by Stage 2 sleep.

Statistical Analysis

Effects of cortisol on memory consolidation and encoding were statistically assessed by ANOVAs with the within-subject factor Cortisol/Placebo and the between-subject factor Sleep/Wake. ANOVA on the recall of texts included an additional within-subject factor “neutral/emotional.” For hormonal measures, two separate ANOVAs for each experimental group (Sleep group and Wake group) including an additional “time” factor was calculated because of the different numbers of time points in both groups (to avoid disturbing subjects' sleep, no blood was sampled during the 2-hr sleep interval). ANOVAs were followed by post hoc t tests. Greenhouse–Geisser correction of degrees of freedom was applied where appropriate. The level of significance was set to p ≤ .05.

RESULTS

Learning of Text Material

Recall performance for the texts is summarized in Table 1. In the learning phase, immediate recall performance did not differ between the cortisol and placebo conditions neither in the Sleep group nor in the Wake group (main effect of Cortisol/Placebo in a 2 (cortisol/placebo) × 2 (sleep/wake) × 2 (neutral/emotional) ANOVA, F(28, 1) = 2.51, p > .13), although overall learning performance was worse in Sleep than Wake subjects (main effect of Sleep/Wake: F(28, 1) = 5.17, p = .03), possibly an effect of anticipated napping. As expected, emotional texts were generally better remembered than neutral texts (main effect of Emotional/Neutral: F(28, 1) = 136.61, p < .001). Ratings confirmed that emotional compared with neutral texts were experienced as more comprehensible, interesting, emotional, startling, important, serious, arousing, and negative (all ps < .01).

Table 1. 

Memory for Emotional and Neutral Texts


Wake
Sleep
Placebo
Cortisol
Placebo
Cortisol
Free Recall 
Learning 
 Emotional 47.38 ± 3.30 50.06 ± 3.16 42.21 ± 3.95 43.57 ± 2.25 
 Neutral 30.25 ± 3.20 33.06 ± 2.58 21.71 ± 2.39 25.21 ± 3.09 
Retrieval 
 Emotional 40.13 ± 3.25 38.75 ± 3.07 35.86 ± 3.86 35.29 ± 2.21 
 Neutral 22.06 ± 3.31 24.31 ± 2.67 16.86 ± 2.25 21.29 ± 3.21 
Retention 
 Emotional (% of learning) 83.77 ± 2.73 77.30 ± 4.04 83.90 ± 4.16 81.01 ± 3.00 
 Neutral (% of learning) 69.79 ± 5.67 72.67 ± 4.27 76.64 ± 4.82 80.82 ± 6.26 
 
Recognition 
Emotional 8.80 ± 0.46 9.13 ± 0.40 8.14 ± 0.35 8.14 ± 0.47 
Neutral 7.80 ± 0.59 8.80 ± 0.40 8.07 ± 0.30 7.93 ± 0.45 
 
Temporal Sequence Memory 
Emotional 26.29 ± 3.14 21.14 ± 2.57 25.93 ± 2.92 27.57 ± 2.51 
Neutral 35.86 ± 3.00 27.21 ± 2.41** 28.29 ± 2.00 34.00 ± 2.26** 

Wake
Sleep
Placebo
Cortisol
Placebo
Cortisol
Free Recall 
Learning 
 Emotional 47.38 ± 3.30 50.06 ± 3.16 42.21 ± 3.95 43.57 ± 2.25 
 Neutral 30.25 ± 3.20 33.06 ± 2.58 21.71 ± 2.39 25.21 ± 3.09 
Retrieval 
 Emotional 40.13 ± 3.25 38.75 ± 3.07 35.86 ± 3.86 35.29 ± 2.21 
 Neutral 22.06 ± 3.31 24.31 ± 2.67 16.86 ± 2.25 21.29 ± 3.21 
Retention 
 Emotional (% of learning) 83.77 ± 2.73 77.30 ± 4.04 83.90 ± 4.16 81.01 ± 3.00 
 Neutral (% of learning) 69.79 ± 5.67 72.67 ± 4.27 76.64 ± 4.82 80.82 ± 6.26 
 
Recognition 
Emotional 8.80 ± 0.46 9.13 ± 0.40 8.14 ± 0.35 8.14 ± 0.47 
Neutral 7.80 ± 0.59 8.80 ± 0.40 8.07 ± 0.30 7.93 ± 0.45 
 
Temporal Sequence Memory 
Emotional 26.29 ± 3.14 21.14 ± 2.57 25.93 ± 2.92 27.57 ± 2.51 
Neutral 35.86 ± 3.00 27.21 ± 2.41** 28.29 ± 2.00 34.00 ± 2.26** 

Indicated is the number of content words recalled in a free recall test at learning and at retrieval. Retention performance is indicated by the number of content words remembered at retrieval relative to the number of content words remembered at learning in percentages. Memory for the contents of the texts was additionally tested in a recognition test. Memory for the temporal order of content words within the texts was measured by a deviation score. Note that the better the memory for the temporal order in the text, the lower is the deviance score. Significant differences between “placebo” and “cortisol” conditions are indicated by asterisks (** p ≤ .01).

Consolidation of Text Material

At retrieval testing after the 6-hr retention interval, free recall of emotional texts was also distinctly superior to that of neutral texts (main effect of Emotional/Neutral in a 2 × 2 × 2 ANOVA, F(28, 1) = 89.18, p < .001, for the absolute number of recalled content words; F(28, 1) = 4.08, p = .05, for retention performance, i.e., percentage of recalled content words with performance at learning set to 100%; Table 1). Retention of neutral and emotional texts was not consistently influenced by cortisol, neither in the Wake nor in the Sleep group (main effect of Cortisol/Placebo and its interactions, F(28, 1) < 3.09, p > .09; Figure 2). Also, cortisol did not affect recognition of content words from neutral or emotional texts examined after free recall of the texts (main effect of Cortisol/Placebo and its interactions in a 2 × 2 × 2 ANOVA, F(27, 1) > 0.96, p > .33).

Figure 2. 

Retention of the contents (item memory) of neutral and emotional texts following postlearning administration of cortisol (black bars) and placebo (white bars) in the Sleep and Wake group. Retention is expressed as percentage of content words recalled at retrieval testing with performance at learning set to 100%. There were no significant differences in item memory retention between the cortisol and placebo conditions.

Figure 2. 

Retention of the contents (item memory) of neutral and emotional texts following postlearning administration of cortisol (black bars) and placebo (white bars) in the Sleep and Wake group. Retention is expressed as percentage of content words recalled at retrieval testing with performance at learning set to 100%. There were no significant differences in item memory retention between the cortisol and placebo conditions.

Subjects remembered the sequential order of content words in the emotional texts significantly better than in the neutral texts (main effect of Emotional/Neutral in a 2 × 2 × 2 ANOVA, F(1, 26) = 11.66, p < .01). Despite comparable memory for the contents of the texts, cortisol after learning affected memory for the sequence of content words in the texts differentially in the Sleep and the Wake group (interaction Cortisol/Placebo × Sleep/Wake: F(1, 26) = 9.79, p < .01; Figure 3). Whereas sequence memory was enhanced after cortisol infusion during wakefulness, it was deteriorated when cortisol was infused during sleep. Although the three-way interaction between the factors Cortisol/Placebo, Sleep/Wake, and Emotional/Neutral did not reach significance (F(1, 26) = 1.40, p > .24), for exploratory purposes, we calculated post hoc t tests to further characterize the effects of cortisol as a function of emotionality. The memory for sequential order appeared to be more robust for the neutral texts, which is revealed by significant differences between the cortisol and placebo conditions (Wake group: Placebo 35.86 ± 3.00, cortisol 27.21 ± 2.41, p = .012; Sleep group: Placebo 28.29 ± 2.00, cortisol 34.00 ± 2.26, p = .014), whereas no differences were found for the emotional texts (Wake group: Placebo 26.29 ± 3.14, cortisol 21.14 ± 2.57, p = .19; Sleep group: Placebo 25.93 ± 2.92, cortisol 27.57 ± 2.51, p = .71).

Figure 3. 

Temporal sequence memory (relational memory) for the texts following postlearning administration of cortisol (black bars) and placebo (white bars) in the Sleep and Wake group. The deviation of the remembered position of a content word from its actual position in the text is indicated. A sum score (deviation score) across all 12 content words tested for each text is given. Note that the better the memory for the temporal order within a text, the smaller is the deviation score. **p ≤ .01 for pairwise comparisons between the cortisol and placebo condition. Note that although pairwise comparisons revealed significance only for neutral texts, respective ANOVA interactions with the Neutral/Emotional factor were not significant (p > .24).

Figure 3. 

Temporal sequence memory (relational memory) for the texts following postlearning administration of cortisol (black bars) and placebo (white bars) in the Sleep and Wake group. The deviation of the remembered position of a content word from its actual position in the text is indicated. A sum score (deviation score) across all 12 content words tested for each text is given. Note that the better the memory for the temporal order within a text, the smaller is the deviation score. **p ≤ .01 for pairwise comparisons between the cortisol and placebo condition. Note that although pairwise comparisons revealed significance only for neutral texts, respective ANOVA interactions with the Neutral/Emotional factor were not significant (p > .24).

Encoding of Numbers

We introduced the number list learning task during the retention interval to discriminate effects of cortisol on encoding in the Wake group. Compared with the placebo condition, during infusion of cortisol, encoding of number lists was distinctly improved, that is, in a recognition test immediately following presentation of the number lists, subjects in the cortisol condition correctly identified significantly more list numbers than in the placebo condition (placebo 25.87 ± 1.10, cortisol 28.07 ± 0.77, t(14) = 3.09, p < .01; Figure 4A). Free recall of numbers (examined before recognition testing) also tended to be enhanced during cortisol infusion (placebo 12.13 ± 0.63, hydrocortisone 13.20 ± 0.64, t(14) = 1.98, p < .10; Figure 4B).

Figure 4. 

Encoding performance (assessed at 19:30 hr only in the Wake group) in the number list learning task during cortisol (black bars) and placebo (white bars) infusion as measured by (A) recognition (correctly recognized “old” numbers) and (B) immediate free recall (i.e., absolute number of recalled numbers). **p ≤ .01, #p ≤ .1, for pairwise comparisons between the cortisol and placebo condition.

Figure 4. 

Encoding performance (assessed at 19:30 hr only in the Wake group) in the number list learning task during cortisol (black bars) and placebo (white bars) infusion as measured by (A) recognition (correctly recognized “old” numbers) and (B) immediate free recall (i.e., absolute number of recalled numbers). **p ≤ .01, #p ≤ .1, for pairwise comparisons between the cortisol and placebo condition.

Hormones, Subjective Ratings, and Sleep

Plasma cortisol concentrations were as expected strongly enhanced during and after infusion of the hormone (Wake group: main effect of Cortisol/Placebo in a 2 × 16 (Time) ANOVA, F(1, 13) = 220.94; Sleep group: main effect of Cortisol/Placebo in a 2 × 13 (Time) ANOVA, F(1, 13) = 28.19, both ps < .001; Figure 1). Concentrations during infusion reached maximum values between 16 and 19 μg/dl, which are well comparable with levels observed during moderate stress and upon morning awakening. Importantly, cortisol concentrations during retrieval testing after the retention interval (at 0:00 hr), like those during the learning phase before the retention interval (at 17:45 hr), were practically identical in the cortisol and placebo conditions (at 0:00 hr: Wake group t(15) = 0.39, p > .70, Sleep group t(13) = 0.36, p > .72; at 17:45 hr: Wake group t(15) = 0.63, p = .54, Sleep group t(13) = −1.27, p > .23). Cortisol infusion, as expected, suppressed ACTH secretion (Wake group: F(1, 13) = 35.22, Sleep group: F(1, 12) = 40.27; both ps < .001) with this effect continuing at retrieval (at 0:00 hr: Wake group cortisol 3.89 ± 0.51, placebo condition 11.74 ± 2.38, t(15) = − 3.36, p < .01; Sleep group cortisol, 5.81 ± 0.48, placebo condition, 10.29 ± 0.82, t(12) = −6.26, p < .001).

Subjective ratings revealed an increase in Tiredness and a decrease in Concentration across the 6-hr retention interval (main effect of TIME in a 2 (learning/recall) × 2 (sleep/wake) × 2 (cortisol/placebo) ANOVA for Tiredness: F(1, 26) = 20.96, p < .01; for Concentration: F(1, 26) = 122.48, p < .001). Importantly, neither in the learning phase nor at retrieval testing, subjective ratings differed between the placebo and cortisol conditions (all main effects and interactions with the factor Cortisol/Placebo: F(1, 26) > 2.51, p > .13), although during the learning phase, Sleep subjects felt somewhat more tired and less able to concentrate than Wake subjects (interaction between Sleep/Wake and TIME for Tiredness: F(1, 26) = 11.95, p < .01; Concentration: F(1, 26) = 10.32, p < .01).

Sleep EEG data of both experimental conditions is presented in Table 2. There were no differences between the conditions for all sleep parameters (all ps > .27).

Table 2. 

Sleep Data


Placebo
Cortisol
p
Total sleep time (min) 89.08 ± 7.00 95.23 ± 4.15 .58 
Sleep onset latency (min) 13.46 ± 2.90 11.15 ± 2.53 .62 
Wake (%) 14.34 ± 5.59 9.83 ± 2.95 .66 
Stage 1 (%) 11.82 ± 2.35 17.12 ± 5.16 .27 
Stage 2 (%) 49.35 ± 3.98 50.09 ± 5.55 .66 
SWS (%) 20.49 ± 4.92 19.55 ± 4.72 .52 
REM (%) 3.71 ± 2.17 3.13 ± 1.43 .43 
SWS latency (min) 22.42 ± 5.27 22.69 ± 3.88 .78 
REM latency (min) 85.29 ± 6.24 88.96 ± 5.86 .54 

Placebo
Cortisol
p
Total sleep time (min) 89.08 ± 7.00 95.23 ± 4.15 .58 
Sleep onset latency (min) 13.46 ± 2.90 11.15 ± 2.53 .62 
Wake (%) 14.34 ± 5.59 9.83 ± 2.95 .66 
Stage 1 (%) 11.82 ± 2.35 17.12 ± 5.16 .27 
Stage 2 (%) 49.35 ± 3.98 50.09 ± 5.55 .66 
SWS (%) 20.49 ± 4.92 19.55 ± 4.72 .52 
REM (%) 3.71 ± 2.17 3.13 ± 1.43 .43 
SWS latency (min) 22.42 ± 5.27 22.69 ± 3.88 .78 
REM latency (min) 85.29 ± 6.24 88.96 ± 5.86 .54 

Data are in mean ± SEM for total sleep time, time spent awake, Stage 1 sleep, Stage 2 sleep, Stage 3 sleep, Stage 4 sleep, SWS (the sum of Stages 3 and 4 sleep) and REM sleep given in percentage of total sleep time, and latency of the first period of SWS and REM sleep (with reference to sleep onset). The rightmost column indicates p values from pairwise comparisons between the treatment conditions. None of the parameters differed between cortisol and placebo conditions.

DISCUSSION

On the basis of previous data suggesting that GCs affect consolidation of memories depending on the brain state (sleep vs. wake), the present study directly compared, for the first time, the effects of postlearning administration of a GC (cortisol) on memory consolidation between retention periods of sleep and wakefulness. There are two main findings: First, consolidation of temporal sequence memory was improved by postlearning infusion of cortisol when infused during waking but was deteriorated by cortisol when infused during sleep, indicating a clear brain state dependency of cortisol effects. Second, unlike temporal sequence memory, memories for the content of texts were not consistently affected by cortisol neither in the wake state nor in the sleep state.

Apart from the effects of cortisol on memory consolidation, we confirmed an enhancing effect of cortisol on the encoding of neutral memories (for numbers) during wakefulness. This finding is consistent with numerous previous studies indicating a robust enhancing effect of GCs when their levels are acutely elevated during encoding (Henckens et al., 2009; Smeets et al., 2009; Abercrombie et al., 2003; Lupien et al., 2002; Buchanan & Lovallo, 2001). Improvements in encoding were particularly prominent when GCs were given during the evening hour in the presence of low endogenous cortisol release. As the behavioral assessment of encoding necessarily relies on an immediate free recall, it could be argued that the improved encoding of numbers in our study reflects a benefiting effect of cortisol on retrieval rather than encoding per se. However, this possibility can be excluded on the basis of a compelling set of studies showing that GCs impair rather than improve retrieval (de Quervain et al., 2003; Roozendaal et al., 2001; Wolf et al., 2001). Only subjects in both wake groups were asked to perform on the number learning task. Adding an encoding task to the wake group could have confounded the effect of cortisol on processes of memory consolidation primarily by retroactive interference. However, such mediation is unlikely because cortisol enhanced encoding, which should have resulted in stronger retroactive interference and, in turn, impaired (rather than improved) consolidation in the wake group after cortisol administration.

To investigate specifically the process of consolidation, endogenous cortisol was enhanced during the 6-hr postlearning retention interval of a memory task (remembering text material). At learning (encoding) and retrieval of the task, cortisol levels were closely comparable between both treatment conditions, indicating that the observed differences in memory performance can be safely attributed to cortisol actions during the consolidation period. There were also no differences between the conditions in self-reported tiredness and concentration, making it unlikely that cortisol exerted influences on retrieval via unspecific changes in central nervous arousal. However, cortisol administration suppressed the release of ACTH because of feedback inhibition, which persisted at the time of retrieval testing. Probably, this feedback inhibition also extended to the hypothalamic releasing factors of the hypothalamo–pituitary–adrenal axis, specifically to the release of corticotropin-releasing hormone. However, changes in memory performance being in opposite direction depending on whether cortisol was infused during waking or sleep cannot be explained by a contaminating influence of lacking ACTH and central nervous corticotropin-releasing hormone during retrieval.

We included only men for reasons of feasibility, although this is a clear limitation of our study. Investigating women requires a more complex study protocol to take into account the modulating impact of hormones of the menstrual cycle (like estrogen and progesterone) on memory function (Krug et al., 2006). Basically, effects of cortisol in women could be the same as in men, although the absolute levels of memory performance likely varies, depending on the menstrual phase (e.g., Rosenberg & Park, 2002; Drake et al., 2000). Future studies need to be conducted that test women with an analogous study protocol.

The retention interval in our study covered the period between 18:00 and 0:00 hr, which was accompanied by a higher level of tiredness and less concentration at the time of retrieval compared with the time of encoding. Because our subjects' performance at retrieval was roughly comparable to previous studies in which we tested retrieval performance on the same task in the morning or earlier in the evening (Groch et al., 2011; Wagner, Gais, & Born, 2001), any disturbing effect of late night testing, if present at all, was probably rather small. Importantly, it is very unlikely that the time of retrieval testing confounded our main finding because this factor equally affected the placebo and the cortisol condition (in both the sleep and wake groups). We chose this schedule for two reasons: First, effects of cortisol elevation are assumed to be most pronounced around the time of the circadian nadir of cortisol release, which is in the late evening hour (Het, Ramlow, & Wolf, 2005; Lupien et al., 2002). Second, this interval roughly corresponds to the retention interval of early nocturnal sleep that we used in previous studies to examine effects of GCs on sleep-dependent processes of consolidation (Plihal & Born, 1999; Plihal et al., 1999). Those studies indicated that enhanced GC levels during early nocturnal sleep, which is dominated by SWS, impair the consolidation of hippocampus-dependent declarative memories (for word paired associates). In line with these studies, the elevation of cortisol also decreased the consolidation of temporal sequence memories in our sleeping subjects. In contrast, cortisol administration during a wake period enhanced temporal sequence memories.

Unlike temporal sequence memories, retention of the story contents (item memory) was not influenced by cortisol neither in the wake nor the sleep state. In a previous study by de Quervain et al. (2000), cortisol during a wake retention interval also failed to affect the consolidation of word lists. Taken together, these data indicate that effects of cortisol on memory consolidation clearly do not only depend on the brain state during consolidation (sleep vs. wake) but also on the type of memory that is tested. Temporal sequence memory as well as the word paired associates used by Plihal and colleagues (1999) depend on the relational binding between items, which has been shown to depend to a greater extent on hippocampal activation (Lehn et al., 2009; Dragoi & Buzsaki, 2006; Fortin et al., 2002) whereas the recall of single items of a word list or a story possibly involves preferentially the perirhinal cortex (Staresina & Davachi, 2009; Davachi, 2006; Aggleton & Brown, 2005). Numerous studies indicated that cortisol binding to hippocampal GC receptors mediates the effects on memory formation, which might explain why cortisol preferentially impacts the consolidation of hippocampus-dependent tasks (Joels, 2008; de Kloet, Joels, & Holsboer, 2005; Sousa & Almeida, 2002). Thus, our data suggest that, even within declarative memory generally relying on medial-temporal lobe structures, different tasks display different sensitivity to changes in GC levels, depending on the extent to which the hippocampus proper is involved. To further enlighten the role of the hippocampus in mediating GC effects on memory, such effects need to be examined in future fMRI studies comparing tasks that are more or less hippocampus-dependent (i.e., comparing item and source memory).

Previous studies indicated that late-night REM sleep benefits the consolidation of emotional material (Walker, 2009; Wagner et al., 2001), although the rise in cortisol levels accompanying late nocturnal sleep was revealed to dampen consolidation of emotional memories (Wagner & Born, 2008; Wagner et al., 2005). In contrast to late-night sleep, a midday nap typically includes high amounts of non-REM sleep, whereas the proportion of REM sleep is rather low (i.e., in our study: 2–3% vs. 18–25% during the night). The lacking REM sleep in our sleep group might explain why we did not find any effect of cortisol administration on emotional memories.

The opposing effects of GCs during wake and sleep retention intervals indicate that processes of consolidation must be based on fundamentally different mechanisms during both brain states. Although the exact nature of these mechanisms is obscure, recent studies have provided some clues that they may be linked to the “off-line” reactivation of neuronal memory representations that is assumed to underlie the consolidation process (for a review, see O'Neill, Pleydell-Bouverie, Dupret, & Csicsvari, 2010). Such reactivations can occur during sleep but also during waking (Karlsson & Frank, 2009; Hoffman & McNaughton, 2002). Interestingly, reactivations occurring during waking lead to a temporary labilization of the memory representation to interfering inputs, which possibly allows for an immediate updating of the memory but requires reconsolidation to restabilize the representation (Nader & Hardt, 2009; Sara, 2000). By contrast, reactivations occurring during sleep exert an immediate stabilizing effect on memory representations without undergoing labilization (Diekelmann, Büchel, Born, & Rasch, 2011; Rasch et al., 2007). High levels of GCs likely suppress the frequency of hippocampal memory reactivation, as they were found to distinctly diminish sharp wave/ripple events that normally accompany such reactivations (Weiss, Krupka, Bahner, Both, & Draguhn, 2008). On this background, the beneficial effects of cortisol in our waking subjects might reflect that reduced memory reactivations during waking lead to a diminished labilization of respective memory traces, which are thus less vulnerable to nonspecific interference. In contrast, during sleep, the GC induced reduction in memory reactivations would be expected to exert an immediate impairing influence on the consolidation of respective memory representations.

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (SFB 654). The authors thank Susanne Diekelmann and Sabine Groch for fruitful discussion of data and Johannes Schneeweiss and Christian Tiburtius for skillful technical assistance.

Reprint requests should be sent to Jan Born, Department of Medical Psychology and Behavioral Neurobiology, Gartenstrasse 29, 74072 Tübingen, Germany, or via e-mail: born@kfg.uni-luebeck.de.

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