Pre-learning stress differentially affects long-term memory for emotional words, depending on temporal proximity to the learning experience

Physiology & Behavior 103 (2011) 467–476

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Physiology & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h b

Pre-learning stress differentially affects long-term memory for emotional words, depending on temporal proximity to the learning experience Phillip R. Zoladz a,⁎, Brianne Clark a, Ashlee Warnecke a, Lindsay Smith a, Jennifer Tabar a, Jeffery N. Talbot b a b

Department of Psychology & Sociology, Ohio Northern University, Ada, Ohio, 45810, USA Department of Pharmaceutical & Biomedical Sciences, Ohio Northern University, Ada, Ohio, 45810, USA

a r t i c l e

i n f o

Article history: Received 17 September 2010 Received in revised form 6 January 2011 Accepted 16 January 2011 Keywords: Cortisol Stress Hippocampus Amygdala Learning Memory

a b s t r a c t Stress exerts a profound, yet complex, influence on learning and memory and can enhance, impair or have no effect on these processes. Here, we have examined how the administration of stress at different times before learning affects long-term (24-hr) memory for neutral and emotional information. Participants submerged their dominant hand into a bath of ice cold water (Stress) or into a bath of warm water (No stress) for 3 min. Either immediately (Exp. 1) or 30 min (Exp. 2) after the water bath manipulation, participants were presented with a list of 30 words varying in emotional valence. The next day, participants' memory for the word list was assessed via free recall and recognition tests. In both experiments, stressed participants exhibited greater blood pressure, salivary cortisol levels, and subjective pain and stress ratings than nonstressed participants in response to the water bath manipulation. Stress applied immediately prior to learning (Exp. 1) enhanced the recognition of positive words, while stress applied 30 min prior to learning (Exp. 2) impaired free recall of negative words. Participants' recognition of positive words in Experiment 1 was positively associated with their heart rate responses to the water bath manipulation, while participants' free recall of negative words in Experiment 2 was negatively associated with their blood pressure and cortisol responses to the water bath manipulation. These findings indicate that the differential effects of pre-learning stress on long-term memory may depend on the temporal proximity of the stressor to the learning experience and the emotional nature of the to-be-learned information. © 2011 Published by Elsevier Inc.

1. Introduction Stress exerts a profound, yet complex, influence on learning and memory. Over the past few decades, a growing body of literature has revealed that stress can enhance, impair or have no effect on learning and memory, depending on several factors related to the stressor, the information being learned and the organism under investigation [1–3]. For instance, the effects of stress on learning and memory appear to depend, at least in part, on the particular stage of learning and memory that is being affected by the stress, as well as the emotional nature of the information that is being tested [4,5]. Research has shown that stress generally exerts deleterious effects on memory retrieval [6–12] (however, see [13], where stress enhanced retrieval), yet when stress is administered after learning, it enhances consolidation [11,14,15], thus boosting performance on subsequent memory assessments. Both of these effects tend to be more pronounced for information that is emotionally arousing in nature [8,9,11,12,14]. The effects of prelearning stress on long-term memory, however, have been less clear; ⁎ Corresponding author at: Ohio Northern University, Department of Psychology & Sociology, 525 S. Main St. Hill 013, Ada, OH, 45810, USA. Tel.: +1 419 772 2142; fax: +1 419 772 2746. E-mail address: [email protected] (P.R. Zoladz). 0031-9384/$ – see front matter © 2011 Published by Elsevier Inc. doi:10.1016/j.physbeh.2011.01.016

studies in humans and rodents have reported that pre-learning stress can enhance, impair or have no effect on the storage of information [6,16–24]. When significant effects of pre-learning stress have been observed, the most common, but not unanimous, finding has been enhanced memory for emotionally arousing information, at the cost of (i.e., impaired memory for) emotionally neutral information. With regards to pre-learning stress, the duration of the stress, in addition to the temporal proximity of the stressor to the learning experience, strongly influences the types of effects that are observed on long-term memory [25]. Research has suggested that pre-learning stress can enhance long-term hippocampus-dependent memory as long as the stress is relatively brief and is in close temporal proximity to the learning experience [1]. Indeed, studies have shown that brief stress administered immediately or shortly before learning enhances long-term memory [20,21,23–25], while the same brief stressor administered 30 min before learning has no effect on subsequent memory [25]. Moreover, if the duration of the stressor applied immediately before learning is extended, to 30 min for instance, then long-term memory can be impaired [6,16,18,19]. To explain how pre-learning stress affects learning, Diamond and colleagues [25] developed a theory in which they speculated that stress produces different temporal activation profiles for different brain regions. A majority of their theory focused on an amygdala-

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induced biphasic response pattern of hippocampal function following the initiation of stress [26,27]. According to this theory, acute stress initially produces a rapid enhancement of hippocampal neuroplasticity, which facilitates the storage of new information; over time, however, the hippocampus is forced into a refractory state, during which learning and memory processes are impaired. Part of the basis for this theory was electrophysiological work indicating that glucocorticoids, as well as electrical stimulation of the amygdala, could exert immediate excitatory, but delayed inhibitory, effects on hippocampal synaptic plasticity [26–31]. According to the theory, stress that is applied immediately before learning should enhance memory storage, while stress that is applied a longer time before learning should impair memory storage. In their manuscript, Diamond and colleagues [25] provided support for the theory by demonstrating that 2 min of cat exposure (i.e., predator stress) applied immediately, but not 30 min, prior to learning enhanced longterm water maze memory in rats. The application of brief stress 30 min prior to learning should have theoretically impaired long-term memory, but the training parameters did not allow for such a memory impairment to be detected. The temporal dynamics model of emotional memory processing is based largely on findings from non-human animal studies. Few human studies have examined the influence of pre-learning stress on long-term memory, and to our knowledge, no studies in humans have specifically examined how stress that is applied at different times before learning differentially affects long-term memory processes. Since the effects of pre-learning stress on memory might differ between humans and non-human animals, the present experiments were designed to extend the temporal dynamics model of emotional memory processing to humans by examining the effects of brief stress, applied immediately or 30 min prior to learning, on long-term memory in people. Our hypothesis was that stress applied immediately prior to learning would enhance long-term memory, while stress applied 30 min prior to learning would impair long-term memory. Since previous work has shown that the emotional nature of the to-be-learned information also mediates the effects of stress on learning, we varied the emotional valence of the information that participants learned and expected that such information may be more affected by the stress manipulations.

study. All of the methods for the experiments were approved by the Institutional Review Board at Ohio Northern University. 2.2. Experimental procedures The experimental timeline for each experiment is presented in Fig. 1. To control for diurnal variations in cortisol levels, all testing was carried out between 1200 and 1800 h. 2.2.1. Socially Evaluated Cold Pressor Test (SECPT) Participants were asked to submerge their dominant hand, up to and including the wrist, in a bath of water for 3 min. Those participants who had been randomly assigned to a stress condition (Experiment 1: N = 15; Experiment 2: N = 16) placed their hand in a bath of ice cold (0–2 °C) water, while participants who had been randomly assigned to a control condition (Experiment 1: N = 21; Experiment 2: N = 20) placed their hand in a bath of warm (35–37 °C) water. The water was maintained at the appropriate temperature by a Lauda Brinkmann RMT6 circulating water bath. To maximize the stress response, participants in each experiment were encouraged to keep their hand in the water bath for the entire 3-min period. However, if a participant found the water bath too painful, he or she was allowed to remove his or her hand from the water and continue with the experiment. From Experiments 1 and 2 combined, there was only one participant who did not keep his or her hand in the water bath for the entire 3 min. Based on previous work [32], a social evaluative component was added to the cold pressor manipulation. Participants in the stress conditions were misleadingly informed that they were being videotaped during the procedure for subsequent evaluation of their facial expressions, and throughout the water bath manipulation, they were asked to keep their eyes on a camera that was located on the wall of the laboratory. Moreover, a confederate member of the opposite sex was in the testing facility and stared at participants in the stress conditions throughout the water bath manipulation.

2.1. Participants

2.2.2. Subjective pain and stress ratings All participants were asked to rate the painfulness and stressfulness of the water bath manipulation at 1-min intervals on 11-point scales ranging from 0 to 10, with 0 indicating a complete lack of pain or stress and 10 indicating unbearable pain or stress. If a participant removed his or her hand from the water before 3 min had elapsed, the remaining data points were automatically scored as 10 s for each measure.

Seventy-two healthy men and women (20 men, 52 women; age: M = 19.68, SD = 2.94; body-mass-index (BMI): M = 23.40, SD = 3.77) from Ohio Northern University volunteered to participate in the experiments. Individuals were excluded from participating if they met any of the following conditions: history of severe head injury; current treatment with psychotropic medications, narcotics, beta-blockers, steroids or any other medication that affects central nervous or endocrine system function; medical illness within the 3 weeks prior to participation; mental or substance use disorder; regular nightshift work. Individuals who smoked were allowed to participate in the study; information regarding individuals' smoking habits was collected prior to the experiments via a short demographic survey. From both experiments combined, there were only 3 participants who reported smoking on a regular basis, and inclusion of the data from these participants in the statistical analyses did not alter the results. Participants were asked to refrain from using recreational drugs (e.g., marijuana) for 3 days prior to the experimental sessions; to refrain from drinking alcohol or exercising extensively for 24 h prior to the experimental sessions; and, to refrain from eating or drinking anything but water for 2 h prior to the experimental sessions. Participants were awarded class credit upon completion of the

2.2.3. Word presentation Either immediately (Experiment 1) or 27 min (Experiment 2) following the water bath manipulation, participants were presented with a list of 30 words, composed of 10 neutral, 10 positive and 10 negative words. The words were chosen from the Affective Norms for English Words [33] and, across emotional valence categories, were balanced for word length and word frequency. As per the methods employed by Schwabe and colleagues [20], participants were instructed to read each word aloud and rate its emotional valence on a scale from − 3 (very negative) to +3 (very positive) on a sheet of paper containing the list of words. This manipulation was performed to promote encoding of the words. Two versions of the word list were used in the experiments. According to the Affective Norms for English Words [33], the mean (±SEM) valence and arousal ratings for the words that made up these lists were as follows: word list 1 (positive words: valence=7.83±0.17, arousal=5.56±0.43; negative words: valence=2.24 ±0.14, arousal =5.75 ±0.39; neutral words: valence=5.12±0.21, arousal=4.28±0.28) and word list 2 (positive words: valence=7.64±0.12, arousal=5.25±0.48; negative words: valence = 2.18 ± 0.15, arousal = 5.59 ± 0.28; neutral words: valence=4.90±0.17, arousal=4.30±0.33).

2. Method

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Fig. 1. Timeline for the methodology employed in Experiments 1 and 2. Participants were exposed to the water bath manipulation at time point 0. Participants in the stress conditions placed their dominant hand in cold (0–2 °C) water while being observed by a confederate of the opposite sex and believing that they were being videotaped; participants in the no stress conditions placed their dominant hand in warm (35–37 °C) water. Either immediately (Experiment 1) or 27 min (Experiment 2) following the water bath manipulation, participants were presented with a list of 30 words (10 positive, 10 negative, 10 neutral). They were asked to read each word aloud and rate its emotional valence. To verify the induction of a stress response, several saliva samples (S in the figure) and cardiovascular measurements (C in the figure) were obtained from participants throughout the first experimental session. Twenty-fours hours later, participants returned to the laboratory to complete free recall and recognition tasks regarding the word list that was studied on the previous day. Recognition memory was assessed 15 min following the free recall assessment.

2.2.4. Twenty-four hour free recall and recognition testing One day following the first experimental session, participants returned to the laboratory to have their memory for the list of words assessed. Participants were given 5 min to write down as many words as they could remember from the list of words that they studied on the previous day (i.e., free recall). Then, participants sat quietly and completed school work that they had brought to the laboratory. After 15 min had elapsed, participants were given a recognition test. They were presented with a list of words containing 30 “old” words (i.e., words that were presented on the previous day) and 30 “new” words (i.e., words that were not presented on the previous day) and were instructed to label each word as “old” or “new.” The “new” words were matched to the “old” words on emotional valence, word length and word frequency. To assess participants' ability to discriminate between “old” and “new” words, we calculated a sensitivity index (d' = z[p(hit) − p(false alarm)]) for each category of word (i.e., positive, negative and neutral) to be used for statistical analysis [34]. 2.3. Cardiovascular analysis Heart rate (HR) and blood pressure (BP) measurements were taken 2 min before (baseline), halfway through, 5 min after and 15 min after the water bath manipulation. Cardiovascular activity was measured with the vital signs monitor (Mark of Fitness WS-820 Automatic Wrist Blood Pressure Monitor) placed on the wrist of each participant's non-dominant hand. 2.4. Cortisol analysis Saliva samples were collected from participants 2 min before (baseline), 5 min after, 15 min after and 25 min after the water bath manipulation to analyze salivary cortisol concentrations. The samples were collected in a Salivette saliva collection device (Sarstedt, Inc., Newton, NC). Participants were asked to place a swab of cotton in their mouths and chew on it so that it would easily absorb their saliva. Following 1 min of chewing, the swab was collected and placed in the Salivette conical tube and kept at room temperature until the experimental session was completed. The samples were subsequently stored at −20 °C until assayed for cortisol. Since salivary cortisol levels do not rise immediately following stress onset, we did not assay those samples collected 5 min after the water bath manipulation. Saliva samples were thawed and extracted by low-speed centrifugation, and salivary cortisol levels were assayed by enzyme immuno assay (EIA; Caymen Chemical Co., Ann Arbor, MI) according to the manufacturer's protocol. The minimum detectable concentration of

cortisol was approximately 8 pg/ml, and the average inter- and intraassay percent coefficients of variation were less than 5.2% and 14%, respectively. 2.5. Statistical analyses Mixed-model ANOVAs were used to analyze the data from each experiment. The between-subjects factor utilized in these analyses was stress, and the within-subjects factor was word valence (for recall and recognition analyses) or time (for physiological and subjective ratings analyses). Sex was not included as a between-subjects factor in these analyses because of (1) the uneven distribution of males and females to the stress and no stress conditions in each experiment and (2) the small number of males in some experimental cells. Participants in the stress conditions from each experiment were divided into “Responders” and “Non-Responders” based on their cortisol responses to the SECPT. Those participants exhibiting a cortisol increase of at least 1.5 nmol/l 15 min following the SECPT were considered Responders; all other participants were considered Non-Responders. The cutoff for dividing participants into Responder and Non-Responder groups was based on previous work using a similar criterion [20]. The Responders and Non-Responders were then statistically compared on memory and, when deemed necessary, on physiological measures. Bivariate correlations (Pearson's r) were performed on the data from each experiment to examine the relationship between participants' physiological stress responses and their long-term memory performance. To limit the inflation of Type I error rates, correlations were performed only for memory measures affected by stress. Alpha was set at 0.05 for all analyses, and Bonferroni-corrected post hoc tests were employed when necessary. SPSS (version 18.0; SPSS, Inc.) was used to perform all statistical analyses. 3. Results 3.1. Experiment 1: Stress immediately before learning 3.1.1. Cardiovascular and hormonal activity The stress manipulation had no effect on HR (significant main effect of time: F(3,99) = 4.35, p b 0.01, η2 = 0.12; no significant main effect of stress: F(1,33) = 1.19, p N 0.05, η2 = 0.04; no significant Time × Stress interaction: F(3,99) = 2.50, p N 0.05, η2 = 0.07). However, the stress group exhibited significantly greater systolic (significant main effect of time: F(3,99) = 55.73, p b 0.001, η2 = 0.63; significant Time × Stress interaction: F(3,99) = 10.90, p b 0.001, η2 = 0.25; no

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significant main effect of stress: F(1,33) = 3.14, p N 0.05, η2 = 0.09) and diastolic (significant main effect of time: F(3,99) = 50.98, p b 0.001, η2 = 0.61; significant main effect of stress: F(1,33) = 5.65, p b 0.05, η2 = 0.15; significant Time × Stress interaction: F(3,99) = 15.89, p b 0.001, η2 = 0.33) BP during the water bath manipulation than the control group (Table 1). The stress group also exhibited significantly greater cortisol levels than the control group at 15 and 25 min following the water bath manipulation (significant main effect of time: F(2,36)= 8.92, pb 0.001, η2 =0.33; significant main effect of stress: F(1,18)=7.67, pb 0.01, η2 =0.30; significant Time×Stress interaction: F(2,36)=6.56, pb 0.01, η2 =0.27; Fig. 2). 3.1.2. Subjective ratings of water bath manipulation Relative to the control group, the stress group expressed significantly greater overall pain ratings of the water bath manipulation (significant main effect of stress: F(1,34) = 134.43, p b 0.001, η2 = 0.80), and the ratings observed in the stress group significantly increased over time (significant main effect of time: F(2,68) = 9.41, p b 0.001, η2 = 0.22; significant Time x Stress interaction: F(2,68) = 8.07, p b 0.001, η2 = 0.19; Table 2). The stress group also expressed significantly greater overall stress ratings of the water bath manipulation than the control group (significant main effect of stress: F(1,34) = 62.10, p b 0.001, η2 = 0.65; no significant main effect of time: F(2,68) = 2.53, p N 0.05, η2 = 0.07; no significant Time × Stress interaction: F(2,68) = 1.43, p N 0.05, η2 = 0.04). 3.1.3. Word list ratings and 24-hour memory 3.1.3.1. Word list ratings. The analysis of subjective valence ratings for the different types of words verified that participants rated negative words as negative (M = −2.17, SEM = 0.05), neutral words as neutral (M = −0.08, SEM = 0.06) and positive words as positive (M = 2.10, SEM = 0.06) (significant main effect of word valence: F(2,68) = 599.74, p b 0.001, η2 = 0.95). This effect was not dependent upon group (no significant main effect of stress: F(1,34) = 1.20, p N 0.05, η2 = 0.03; no significant Word Valence × Stress interaction: F(2,68) = 0.45, p N 0.05, η2 = 0.01). 3.1.3.2. Free recall. Participants exhibited significantly better recall performance for emotional words (i.e., positive and negative words) than for neutral words (significant main effect of word valence: F(2,60) = 8.92, p b 0.001, η2 = 0.23). However, stress did not signifiTable 1 Cardiovascular activity before, during and after the water bath manipulation in Experiments 1 and 2. Condition

Pre

During

Post 1

Experiment 1: Stress immediately before learning Heart rate (bpm) Stress 76.47 (2.75) 75.87 (3.43) 68.27 (3.06) No stress 79.20 (3.77) 77.60 (3.71) 77.20 (3.38) Systolic blood pressure (mm Hg) ⁎ Stress 127.20 (3.33) 151.53 (3.83) 123.27 (5.26) No stress 125.85 (2.24) 131.95 (1.97) 122.25 (1.77) Diastolic blood pressure (mm Hg) Stress 82.47 (3.10) 103.53 (3.09)⁎ 76.67 (4.31) No stress 78.30 (1.85) 83.60 (1.34) 77.15 (1.43)

Post 2

73.27 (3.81) 80.05 (3.31) 118.07 (3.05) 116.95 (1.48) 75.33 (2.06) 74.35 (1.37)

Experiment 2: Stress 30 min before learning Heart rate (bpm) Stress 81.44 (4.76) 85.00 (3.54)⁎ 78.25 (4.54) 77.50 (3.49) No stress 80.80 (3.83) 77.40 (3.30) 80.95 (3.26) 78.45 (3.03) Systolic blood pressure (mm Hg) Stress 128.88 (3.54) 153.56 (5.54)⁎ 127.69 (3.34)⁎ 119.19 (3.30) No stress 123.10 (1.79) 129.85 (2.28) 119.15 (1.97) 113.95 (1.97) Diastolic blood pressure (mm Hg) Stress 84.13 (2.62)⁎ 104.38 (3.63)⁎ 80.94 (4.01) 76.31 (2.17) No stress 77.40 (1.71) 83.65 (2.02) 75.75 (1.63) 71.95 (1.60) Data are presented as means ± SEM. ⁎ p b 0.05 relative to the no stress group.

Fig. 2. Cortisol levels before and after the water bath manipulation in Experiments 1 (top) and 2 (bottom). In both experiments, exposure to the SECPT (Stress) led to significantly greater salivary cortisol levels than those observed in the control group (No stress). Data are presented as means± SEM; * = p b 0.05 relative to the no stress group.

cantly affect the recall of any type of word (no significant main effect of stress: F(1,30) = 0.16, p N 0.05, η2 = 0.01; no significant Word Valence × Stress interaction: F(2,60) = 1.00, p N 0.05, η2 = 0.03). 3.1.4. Recognition Participants exhibited significantly better recognition of positive and neutral words, relative to negative words (significant main effect of word valence: F(2,64) = 5.02, p b 0.01, η2 = 0.14). In addition, the stress group exhibited significantly better recognition of positive words than the control group (significant Word Valence × Stress interaction: F(2,64) = 4.69, p b 0.05, η2 = 0.13; Fig. 3). There was no significant main effect of stress, F(1,32) = 0.34, p N 0.05, η2 = 0.01. Table 2 Subjective ratings of the water bath manipulation in Experiments 1 and 2. Condition

Minute 1

Minute 2

Minute 3

6.27 (0.60)⁎ 0.05 (0.05)

6.67 (0.65)⁎ 0.05 (0.05)

4.80 (0.67)⁎ 0.29 (0.14)

5.07 (0.69)⁎ 0.33 (0.13)

(0.62)⁎ (0.12)

5.38 (0.60)⁎ 0.40 (0.22)

6.06 (0.56)⁎ 0.40 (0.22)

(0.59)⁎ (0.15)

4.69 (0.69)⁎ 0.50 (0.17)

4.75 (0.62)⁎ 0.45 (0.20)

Experiment 1: Stress immediately before learning Painfulness ratings (scale of 0–10) Stress 5.33 (0.72)⁎ No stress 0.00 (0.00) Stressfulness ratings (scale of 0–10) Stress 4.40 (0.69)⁎ No stress 0.24 (0.17) Experiment 2: Stress 30 min before learning Painfulness ratings (scale of 0–10) Stress 5.88 No stress 0.20 Stressfulness ratings (scale of 0–10) Stress 4.19 No stress 0.30 Data are presented as means ± SEM. ⁎ p b 0.05 relative to the no stress group.

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pb 0.01, η2 =0.23, significant Time×Stress interaction: F(3,102)=12.28, pb 0.001, η2 =0.27). Lastly, the stress group demonstrated significantly greater overall levels of salivary cortisol, relative to the control group (significant main effect of stress: F(1,24)=6.86, pb 0.05, η2 =0.22). Despite there being no significant main effect of time, F(2,48) = 2.15, pN 0.05, η2 =0.08, and no significant Time×Stress interaction, F(2,48)=2.32, pN 0.05, η2 =0.09, inspection of the data suggested that the observed significant main effect of stress was driven by greater salivary cortisol levels in the stress group, relative to the no stress group, at 15 and 25 min post-water bath manipulation, which was confirmed via separate one-way ANOVAs for each time point (p'sb 0.05; Fig. 2).

3.1.5. Cortisol responders versus non-responders The analyses revealed no significant differences between cortisol Responders and Non-Responders on any memory measure (all p'sN 0.05); therefore, no analyses were performed to compare these groups on physiological measures. 3.1.6. Correlations between physiological stress response and long-term memory There was a significant positive correlation between participants' recognition of positive words and their HR during the water bath manipulation, r(34) = 0.38, p b 0.05 (Fig. 3).

3.2.2. Subjective ratings of water bath manipulation Relative to the control group, the stress group expressed significantly greater overall pain ratings of the water bath manipulation (significant main effect of stress: F(1,34)=126.56, pb 0.001, η2 =0.79; no significant main effect of time: F(2,68)=0.86, pN 0.05, η2 =0.03; no significant Time×Stress interaction: F(2,68)=1.16, pN 0.05, η2 =0.03; Table 2). The stress group also expressed significantly greater overall stress ratings of the water bath manipulation than the control group (significant main effect of stress: F(1,34)=59.68, pb 0.001, η2 =0.64; no significant main effect of time: F(2,68) = 1.51, p N 0.05, η2 = 0.04; no significant Time×Stress interaction: F(2,68)=0.41, pN 0.05, η2 =0.01).

3.2. Experiment 2: Stress 30 min before learning 3.2.1. Cardiovascular and hormonal activity The stress group exhibited significantly greater HR than the control group during the water bath manipulation (significant Time × Stress interaction: F(3,102) = 4.43, p b 0.01, η2 = 0.12; no significant main effect of time, F(3,102) = 2.02, p N 0.05, η2 = 0.06, or no significant main effect of stress: F(1,34) = 0.05, p N 0.05, η2 = 0.00; Table 1). The stress group also displayed significantly greater systolic BP than the control group during and 5 min after the water bath manipulation (significant main effect of time: F(3,102) = 90.78, pb 0.001, η2 =0.73; significant main effect of stress: F(1,34)=8.19, p b 0.01, η2 = 0.19; significant Time× Stress interaction: F(3,102) = 15.27, pb 0.001, η2 =0.31). The stress group demonstrated significantly greater diastolic BP than the control group before and during the water bath manipulation (significant main effect of time: F(3,102)=60.88, pb 0.001, η2 =0.64; significant main effect of stress: F(1,34)=10.31,

3.2.3. Word list ratings and 24-hour memory 3.2.3.1. Word list ratings. Analysis of the subjective valence ratings for the different word types verified that participants rated negative words as negative (M=−2.17, SEM=0.05), neutral words as neutral (M=−0.12,

Experiment 1: Stress Immediately Before Learning Free Recall 3.0

No Stress

Discrimination Index (d')

% of Words Recalled

25

Recognition

Stress

20 15 10 5 0

Neutral

Positive

No Stress

2.5

1.5 1.0 0.5

Neutral

Word Type Positive Word Recognition (d')

*

2.0

0.0

Negative

Stress

Positive

Negative

Word Type

3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

40

60

80

r = 0.38, p < 0.05 100 120 140

Heart Rate (bpm) during Water Bath Fig. 3. Long-term (24-hr) memory for positive, negative and neutral words (top) and the relationship between positive word recognition and HR during the water bath manipulation (bottom) in Experiment 1. Exposure to the SECPT (Stress) immediately before learning had no significant effect on free recall but led to a significant enhancement of positive word recognition 24 h later. There was also a significant positive correlation between participants' recognition of positive words and their HR during the water bath manipulation. In the scatter plot, the black circles represent the Stress group, while the gray circles represent the No stress group. The memory data (top) are presented as means ± SEM; * = p b 0.05 relative to the no stress group.

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SEM=0.06) and positive words as positive (M=2.21, SEM=0.06) (significant main effect of word valence: F(2,68)=509.31, pb 0.001, η2 =0.94). This effect was not dependent upon group (no significant main effect of stress: F(1,34)=0.93, pN 0.05, η2 =0.03; no significant Word Valence×Stress interaction: F(2,68)=0.93, pN 0.05, η2 =0.03).

3.2.3.2. Free recall. Participants exhibited significantly better recall performance for emotional words (i.e., positive and negative words) than for neutral words (significant main effect of word valence: F(2,62)= 13.63, pb 0.001, η2 =0.31). The stress group recalled significantly fewer negative words than the control group (significant Word Valence x Stress interaction: F(2,62)=6.52, pb 0.01, η2 =0.17; Fig. 4). The stress group also tended to recall more positive words than the control group, although

this effect did not attain statistical significance (p=0.07). There was no significant main effect of stress, F(1,31)=0.36, pN 0.05, η2 =0.01. 3.2.3.3. Recognition. Participants exhibited significantly better recognition of positive words than of negative and neutral words (significant main effect of word valence: F(2,68)=3.11, p=0.05, η2 =0.08). However, stress had no effect on the recognition of any type of word (no significant main effect of stress: F(1,34)=1.21, pN 0.05, η2 =0.03; no significant Word Valence x Stress interaction: F(2,68)=0.15, pN 0.05, η2 =0.00). 3.2.4. Cortisol responders versus non-responders When comparing the performance of cortisol Responders and NonResponders on long-term memory, we found that there was a significant Word Valence×Group interaction for 24-hr free recall, F(4,54)=3.50,

Experiment 2: Stress 30 Minutes Before Learning Free Recall

Recognition

Stress

Stress

No Stress

3.0

β

Discrimination Index (d')

% of Words Recalled

25 20 15

*

10 5 0

Neutral

Positive

No Stress

2.5 2.0 1.5 1.0 0.5 0.0

Negative

Neutral

Positive

35 30 r = -0.36, p < 0.05 25 20 15 10 5 0 100

120

140

160

180

200

220

35 30

r = -0.47, p < 0.01

25 20 15 10 5 0 60

70

80

90

100 110 120 130 140

Diastolic Blood Pressure (mmHg) during Water Bath

Systolic Blood Pressure (mmHg) during Water Bath % of Negative Words Recalled

Negative

Word Type % of Negative Words Recalled

% of Negative Words Recalled

Word Type

35 30

r = -0.38, p < 0.05

25 20 15 10 5 0 -20

-10

0

10

20

30

40

Change in Cortisol after Water Bath (nmol/l) Fig. 4. Long-term (24-hr) memory for positive, negative and neutral words (top) and the relationship between negative word free recall and cardiovascular (middle)/cortisol (bottom) activity during or after the water bath manipulation in Experiment 2. Exposure to the SECPT (Stress) 30 min prior to learning significantly impaired free recall of negative words and marginally enhanced free recall of positive words 24 h later. However, exposure to the SECPT had no effect on recognition memory. There were significant negative correlations between participants' free recall of negative words and their systolic BP during the water bath manipulation, their diastolic BP during the water bath manipulation and their change in cortisol levels after the water bath manipulation. In the scatter plots, the black circles represent the Stress group, while the gray circles represent the No stress group. The memory data (top) are presented as means ± SEM; * = p b 0.05 relative to the no stress group; β = p = 0.07 relative to the no stress group.

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pb 0.05, η2 =0.21. Post hoc tests indicated that Responders, but not NonResponders, recalled significantly fewer negative words than the control group (Fig. 4). We also found significant Time x Group interactions for systolic, F(3,87) = 10.49, η2 = 0.42, and diastolic, F(3,87) = 7.20, η2 =0.33, BP (p'sb 0.001). These effects revealed that, during the SECPT, the Responders exhibited significantly greater systolic and diastolic BP than the Non-Responders, who in both cases exhibited statistically equivalent BP to the control group. 3.2.5. Correlations between physiological stress response and long-term memory There were significant negative correlations between participants' free recall of negative words and their systolic BP during the water bath manipulation, r(34) = −0.36, their diastolic BP during the water bath manipulation, r(34) = − 0.47, and their change in cortisol levels after the water bath manipulation, r(28) = −0.38 (p's b 0.05; Fig. 4). 4. Discussion The purpose of the present experiments was to determine whether acute stress applied immediately versus 30 min prior to learning would exert differential effects on long-term (24-hr) memory. Based on the available experimental evidence from rodent and human studies [20,21,23–25], we hypothesized that stress applied immediately prior to learning would enhance long-term memory, while stress applied 30 min prior to learning would impair long-term memory. From a general standpoint, the present data supported our hypotheses. However, the observed effects were scattered across free recall and recognition testing of words differing in emotional valence, and there were several drawbacks of the experimental design of the present studies that limit the conclusions one can make about the general nature of pre-learning stress effects on long-term memory. Nonetheless, the present studies do provide a wellneeded extension to humans of the assessments of the temporal dynamics model of emotional memory processing that have previously been performed in rodents. They also provide insight, however preliminary, into the nature of pre-learning stress effects on long-term memory that could be useful for future investigators developing studies to further advance our knowledge in this area of scientific inquiry. When participants in the present experiments were stressed immediately prior to learning, they exhibited enhanced recognition of positive words 24 h later; yet, when participants were stressed 30 min prior to learning, they exhibited impaired free recall of negative words 24 h later. Interestingly, participants' recognition of positive words in Experiment 1 was positively correlated with their HR during the water bath manipulation, while participants' free recall of negative words in Experiment 2 was negatively correlated with their systolic and diastolic BP during the water bath manipulation, as well as with their increase in salivary cortisol levels following the water bath manipulation. Although these correlations do not afford one to make causal inferences, they could be suggestive of an involvement of different mechanisms in the differential effects of prelearning stress on long-term memory. Previous work has provided some support for this view, showing that the pre-learning stress-induced enhancement, but not impairment, of long-term (24-hr) memory is dependent upon β-adrenergic receptor activity [17]. In this particular study, rats were exposed to a cat (i.e., predator stress) for 2 or 30 min prior to being trained in a water maze. As the authors had shown previously [25], 2 min of cat exposure enhanced, while 30 min of cat exposure impaired, 24-hr memory retrieval. More importantly, however, peripheral administration of the β-adrenergic receptor antagonist propranolol blocked the effects of 2 min, but not 30 min, of cat exposure on long-term memory. These findings suggested that while blockade of βadrenergic receptor activity was sufficient to prevent the prelearning stress-induced enhancement of long-term memory, other mechanisms, such as the delayed genomic effects of glucocorticoids,

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could have been more important for the pre-learning stress-induced impairment of long-term memory. Fittingly, we found that the impairment of negative word free recall in Experiment 2 was observed only in participants who demonstrated a significant increase in salivary cortisol levels following the SECPT; however, such a relationship was not observed for the memory effects observed in Experiment 1. This suggests that there was potentially a greater involvement of cortisol in the observed pre-learning stress-induced impairment of memory, relative to the pre-learning stress-induced enhancement of memory. On the other hand, that cortisol Responders and Non-Responders in Experiment 2 also differed on measures of BP during the SECPT could imply that concomitant actions of glucocorticoids and sympathetic nervous system activity are necessary for the memory impairment that was observed. Future work will be needed to explore this possibility, particularly in the context of the present experiments' methodologies. It would be useful, for instance, to include additional measures of central sympathetic nervous system activity (e.g., salivary alpha-amylase) to correlate with memory performance or to administer pharmacological agents that block β-adrenergic and/or glucocorticoid receptor activity prior to the pre-learning stress manipulations to ascertain the importance of these mechanisms in the observed effects. Independent of condition, participants in the present experiments demonstrated greater long-term memory for emotional words, as compared to neutral words. Moreover, stress exerted greater effects on long-term memory for information that was emotional in nature, as it enhanced the recognition of positive words in Experiment 1 and impaired the recall of negative words in Experiment 2. As indicated above, when previous work has reported significant effects of prelearning stress on long-term memory, the most common, but not unanimous, finding has been enhanced memory for emotionally arousing information, at the cost of (i.e., impaired memory for) emotionally neutral information. Indeed, Payne and colleagues [23,24] reported that exposing participants to the Trier Social Stress Test (TSST) immediately prior to learning enhanced long-term memory for emotional information while impairing long-term memory for neutral information. On the other hand, Schwabe et al. [20] found that exposing participants to the SECPT 10 min prior to learning a list of words led to enhanced long-term recall of neutral words but had no effect on the recall of emotional words. It is likely that differences in methodology explain why we, as well as Schwabe et al., did not observe effects similar to the ones reported by Payne and colleagues. For instance, Payne and colleagues examined the influence of a different stressor (i.e., the TSST), which lasted significantly longer (i.e., approximately 20 min) than the stressor employed in the present experiments and that of Schwabe et al., on learning. In addition, Payne and colleagues examined the effects of stress on participants' learning of complex auditory and visual slideshows, as opposed to a list of words, which were employed here and in the study by Schwabe et al. Why we did not observe effects in the present studies that were similar to those of Schwabe et al. could be explained by the different number of words used in each study (30 words per list here vs. 85 words per list in Schwabe et al.) and/or by the difference in temporal proximity of the stressor to the learning experience in each study (immediately or 30 min before learning here vs. 10 min before learning in Schwabe et al.). One important implication of the differences between these three studies might be that pre-learning stress does not straightforwardly enhance long-term memory for emotional information, while impairing long-term memory for neutral information; rather, the effects of pre-learning stress on long-term memory may be much more complex and depend on several factors including the type and duration of stress, the temporal proximity of the stressor to the learning experience and the type of information (e.g., words vs. pictures, emotional vs. neutral) that is being acquired by the individual/ organism. That the memory effects detected in the present studies were greater for emotional words than neutral words is consistent with

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much of the research literature and implicates an involvement of amygdala activity in the observed modulation of long-term memory [35–40]. Previous work has shown that an intact amygdala is essential for enhanced memory of emotional information, as well as for the stress-induced effects on hippocampus-dependent learning and synaptic plasticity [18,19,41–43]. The differential effects of stress on long-term memory that were observed in the present experiments could possibly be explained by a biphasic modulatory effect of amygdala activation on hippocampal function. Electrophysiological studies have reported that when electrical stimulation of the amygdala immediately precedes attempts to induce synaptic plasticity in the hippocampus, such plasticity is significantly enhanced [26,27]. However, when there is a substantial delay between electrical stimulation of the amygdala and attempts to induce synaptic plasticity in the hippocampus, such plasticity is impaired (however, see [44] for a description of how these effects may depend on hippocampal subregion). Since the presentation of the word list in Experiment 1 immediately followed cessation of the stressor, the biological mechanisms responsible for learning the word list would theoretically be enhanced due to an amygdala-induced enhancement of hippocampal plasticity. Likewise, since the presentation of the word list in Experiment 2 did not occur until 30 min following cessation of the stressor, the biological mechanisms responsible for learning the word list would theoretically be impaired due to an amygdala-induced impairment of hippocampal plasticity. Exactly why the observed memory enhancement and impairment depended on the emotional valence (i.e., positive vs. negative) of the words will need to be explored in future research. The amygdala-induced modulation of hippocampal function appears to be associated with concurrent time-dependent actions of specific neurochemical substances that are released following the onset of stress. Early neurochemical responses to stress, such as rapid glucocorticoid actions and the massive increase in levels of corticotropin-releasing hormone (CRH), norepinephrine and glutamate, seem to favor hippocampal plasticity and the storage of new information [29,30,45–58]. Indeed, recent electrophysiological work has shown that glucocorticoids exert rapid non-genomic enhancing effects on hippocampal synaptic plasticity that involve a mineralocorticoid receptor-dependent increase in glutamate transmission. The delayed effects of stress, however, involve a suppression of hippocampal plasticity and an impairment of information storage, primarily as a result of genomic glucocorticoid activity and NMDA receptor desensitization [59–65]. When learning immediately follows stress, the massive presence of plasticity-enhancing neurochemicals (e.g., glucocorticoids, CRH, norepinephrine, glutamate), combined with amygdala-induced stimulation of hippocampal function, would theoretically facilitate the storage of new information. However, when there is a substantial delay between stress and learning, the presence of the aforementioned neurochemicals would be ineffective in enhancing hippocampal plasticity due to the genomic actions of glucocorticoids suppressing hippocampal function and rendering the storage of new information much more difficult. The above interpretations of the present data should be considered with caution. Although the observed statistically significant effects in the present study (i.e., stress applied immediately before learning enhanced recognition of positive words, while stress applied 30 min prior to learning impaired free recall of negative words) did support our general hypotheses associated with the temporal dynamics model of emotional memory processing, they were scattered across different types of memory assessments (i.e., free recall vs. recognition) for words in different emotional valence categories (i.e., positive vs. negative words). Moreover, in Experiment 2, we observed a trend suggesting that stress applied 30 min prior to learning marginally enhanced 24-hr free recall of positive words. The differential effects of stress applied 30 min prior to learning on the free recall of positive (marginally enhancing) and negative (significantly impairing) words

could be attributable to different levels of arousal generated by the words [20], which we did not assess in participants. It could also imply that the effects of pre-learning stress on long-term memory depend on a much more complex interaction between the temporal proximity of the stressor to the learning experience and the emotional nature of the to-be-learned information. On the other hand, that the effect of pre-learning stress on positive word free recall in Experiment 2 did not attain statistical significance could mean that our speculation is unwarranted. Nevertheless, we are currently studying how arousal level of positive and negative words mediates the effects of prelearning stress on long-term memory. That stress applied immediately prior to learning significantly affected recognition memory, while stress applied 30 min prior to learning significantly affected free recall might seem to imply that pre-learning stress exerts differential effects on brain regions involved in recall versus recognition, depending upon the temporal proximity of the stress to the learning experience. Some investigators have contended that recall is dependent primarily on the hippocampus, while recognition is more reliant on the perirhinal cortex (although, this depends on whether recollection or familiarity is being assessed) [66–69]. However, this dissociation is not agreed upon by the entire scientific community [70,71]. A number of investigators have proposed that, even if the perirhinal cortex is involved in and primarily responsible for recognition memory, the hippocampus is still necessary for the task. Thus, it is difficult to speculate as to why stress exerted differential effects on recall versus recognition in the present experiments. It is possible that stress applied immediately prior to learning affected different brain regions than stress applied 30 min prior to learning; however, it is also possible that the observed effects on 24 h memory were simply different manifestations of similar stress-induced alterations of encoding and/or memory consolidation. An additional concern with regards to the present studies is the poor free recall performance exhibited by participants in each experiment. The maximum average percent of recalled words, which was observed in Experiment 2, was just below 20% (or approximately 2 words out of a possible 10 words per valence category). To inform the reader of the memory patterns demonstrated by participants in each experiment, we have included the raw number of words recalled, in addition to the raw number of hits and false alarms exhibited during recognition testing, in Table 3. Based on these numbers, it is clear that we may not have observed any group differences on some free recall measures because of floor effects, which could have resulted from not informing participants that their memory for the list of words would subsequently be tested (i.e., we examined incidental learning) and/or not including a measure of immediate free recall, which could have strengthened participants' storage of the information. The possibility that we encountered floor effects in the present studies certainly limits, at least to some degree, the confidence that can be placed in any conclusions drawn from the present data set, and future studies, perhaps those assessing explicit learning and utilizing immediate free recall tests for word lists containing more or less words than the number used here, will need to be employed to corroborate the effects observed in the present experiments. Lastly, the sample sizes utilized in each of the present studies were relatively small. This could have led to insufficient statistical power to detect significant effects in some places. On the other hand, given a relatively modest sample size, it is encouraging that we still observed significant effects of pre-learning stress on the aforementioned measures of long-term memory. There were also more females who participated in the study than males, and there was an uneven distribution of males and females to the stress and no stress conditions in each experiment. This problem was most likely a consequence of the significantly skewed gender distribution at the university from which the sample was acquired. It is well known that sex is a factor that mediates the effects of stress on learning. Moreover, various stages of the female menstrual cycle, which were not

P.R. Zoladz et al. / Physiology & Behavior 103 (2011) 467–476 Table 3 Free recall and recognition raw data from Experiments 1 and 2. Condition

Neutral words

Experiment 1: Stress immediately before learning Free recall Stress 0.93 (0.25) No stress 0.90 (0.18) Recognition — hits Stress 8.60 (0.29) No stress 8.76 (0.24) Recognition — false alarms Stress 2.00 (0.31)⁎ No stress 1.24 (0.23) Experiment 2: Stress 30 min before learning Free recall Stress 0.50 (0.13) No stress 0.65 (0.17) Recognition — hits Stress 7.63 (0.45) No stress 7.80 (0.35) Recognition — false alarms Stress 1.38 (0.20) No stress 1.95 (0.34)

Positive words

Negative words

1.47 (0.22) 1.60 (0.23)

1.40 (0.25) 1.55 (0.20)

8.67 (0.29) 8.33 (0.28)

7.87 (0.41) 8.19 (0.25)

1.07 (0.30) 1.48 (0.29)

2.00 (0.32) 1.90 (0.37)

1.88 (0.31)a 1.16 (0.23)

1.00 (0.22)⁎ 1.84 (0.18)

8.31 (0.33) 8.25 (0.30)

8.06 (0.42) 8.10 (0.16)

1.25 (0.31) 1.65 (0.26)

1.75 (0.39) 2.40 (0.36)

Data are presented as means ± SEM. ⁎ p ≤ 0.05 relative to the no stress group. a p = 0.07 relative to the no stress group.

controlled for in these experiments, also differentially affect stressinduced alterations of learning. Therefore, it is not known whether or not these variables played a role in the observed results. 5. Conclusions In summary, we have shown that pre-learning stress exerts effects on long-term (24-hr) memory that depend, at least in part, on the temporal proximity of the stressor to the learning experience and the emotional nature of the to-be-learned information. Specifically, in the present studies, stress applied immediately prior to learning enhanced recognition of positive words, while stress applied 30 min prior to learning impaired free recall of negative words. Correlational analyses revealed that participants' recognition of positive words in Experiment 1 was associated with their HR responses to the water bath manipulation, while participants' recall of negative words in Experiment 2 was associated with their BP and cortisol responses to the water bath manipulation. These data, though preliminary in nature, are in general agreement with the recently proposed temporal dynamics model of emotional memory formation and suggest the possibility of different biological mechanisms contributing to the differential effects of pre-learning stress on memory. However, since the observed effects were scattered across different types of memory assessments for words differing in emotional valence and were potentially limited by the presence of floor effects, additional research will need to be performed in order to validate the findings reported here. Acknowledgements The authors would like to thank Dan Chido and Brandon Pritchard for their assistance in the social evaluative component of the stress procedure. References [1] Joels M, Pu Z, Wiegert O, Oitzl MS, Krugers HJ. Learning under stress: how does it work? Trends Cogn Sci 2006;10:152–8. [2] Sandi C, Pinelo-Nava MT. Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast 2007;2007:78970.

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