Brain and Cognition 85 (2014) 277–285
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Brain and Cognition
journal homepage: www.elsevier.com/locate/b&c
Brief, pre-retrieval stress differentially influences long-term memory
depending on sex and corticosteroid response
Phillip R. Zoladz a,⇑, Andrea E. Kalchik a, Mackenzie M. Hoffman a, Rachael L. Aufdenkampe a,
Hanna M. Burke a, Sarah A. Woelke a, Julia M. Pisansky a, Jeffery N. Talbot b,c
a
b
c
Department of Psychology, Sociology, & Criminal Justice, Ohio Northern University, Ada, OH 45810, USA
Department of Pharmaceutical & Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810, USA
College of Pharmacy and Program for Novel Therapeutics in Neurological and Psychiatric Disorders, Roseman University of Health Sciences, Henderson, NV 89014, USA
a r t i c l e
i n f o
Article history:
Accepted 13 January 2014
Keywords:
Amygdala
Cortisol
Emotion
Hippocampus
Memory
Stress
a b s t r a c t
Previous work has indicated that stress generally impairs memory retrieval. However, little research has
addressed discrepancies that exist in this line of work and the factors that could explain why stress can
exert differential effects on retrieval processes. Therefore, we examined the influence of brief, preretrieval stress that was administered immediately before testing on long-term memory in males and
females. Participants learned a list of 42 words varying in emotional valence and arousal. Following
the learning phase, participants were given an immediate free recall test. Twenty-four hours later, participants submerged their non-dominant hand in a bath of ice cold (Stress) or warm (No Stress) water
for 3 min. Immediately following this manipulation, participants’ memory for the word list was assessed
via free recall and recognition tests. We observed no group differences on short-term memory. However,
male participants who showed a robust cortisol response to the stress exhibited enhanced long-term recognition memory, while male participants who demonstrated a blunted cortisol response to the stress
exhibited impaired long-term recall and recognition memory. These findings suggest that the effects of
brief, pre-retrieval stress on long-term memory are sex-specific and mediated by corticosteroid
mechanisms.
Ó 2014 Elsevier Inc. All rights reserved.
1. Introduction
The effects of stress on learning and memory are complex.
Depending on several factors related to the stressor, the type of
learning being examined and the organism under investigation,
stress can enhance, impair or have no effect on such processes.
One factor that mediates the relationship between stress and
learning is the stage of learning that is affected by the stress. Perhaps the most consistent finding in this area of work is that stress
administered after learning facilitates consolidation (Beckner,
Tucker, Delville, & Mohr, 2006; Cahill, Gorski, & Le, 2003; Preuss
& Wolf, 2009; Smeets, Otgaar, Candel, & Wolf, 2008). The effects
of pre-learning stress, in contrast, have been inconsistent, as studies have reported that such stress enhances, impairs or has no
effect on memory (Duncko, Johnson, Merikangas, & Grillon, 2009;
Elzinga, Bakker, & Bremner, 2005; Jelicic, Geraerts, Merckelbach,
& Guerrieri, 2004; Nater et al., 2007; Payne et al., 2006; Payne
et al., 2007; Schwabe, Bohringer, Chatterjee, & Schachinger, 2008;
⇑ Corresponding author. Address: Department of Psychology, Sociology, &
Criminal Justice, Ohio Northern University, 525 S. Main St. Hill 013, Ada, OH
45810, USA. Fax: +1 419 772 2746.
E-mail address: p-zoladz@onu.edu (P.R. Zoladz).
0278-2626/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.bandc.2014.01.010
Smeets et al., 2008; Zoladz, Clark, et al., 2011; Zoladz et al.,
2013). Research examining the effects of pre-retrieval stress on
cognition has generally reported deleterious effects on memory
(Buchanan & Tranel, 2008; Buchanan, Tranel, & Adolphs, 2006;
Kuhlmann, Piel, & Wolf, 2005; Smeets et al., 2008; Tollenaar,
Elzinga, Spinhoven, & Everaerd, 2008). This has led to an implicit
understanding that stress globally impairs retrieval. However,
there are inconsistencies in this literature, with other studies
reporting that stress enhances or has no effect on retrieval (e.g.,
Beckner et al., 2006; Schwabe et al., 2009). Up to this point, little
attention has been devoted to factors that could result in such
differential effects of stress on retrieval performance.
The neurobiological mechanisms underlying stress effects on
learning and memory involve a dynamic interaction among several
neurotransmitter systems in brain areas devoted to cognitive processing (e.g., prefrontal cortex (PFC), hippocampus, amygdala)
(Diamond, Campbell, Park, Halonen, & Zoladz, 2007; Joels,
Fernandez, & Roozendaal, 2011; Schwabe, Joels, Roozendaal, Wolf,
& Oitzl, 2012). A relatively consistent finding in this area of work is
that stress effects on learning and memory are due to corticosteroids exerting influence on hippocampal and PFC function by
interacting with noradrenergic mechanisms in the basolateral
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P.R. Zoladz et al. / Brain and Cognition 85 (2014) 277–285
amygdala (BLA) (Joels et al., 2011; Roozendaal, Barsegyan, & Lee,
2008). Indeed, investigators have shown that lesions or inactivation of the BLA prevent stress-induced alterations of learning and
memory (Kim, Koo, Lee, & Han, 2005; Kim, Lee, Han, & Packard,
2001; Zoladz, Park, & Diamond, 2011), and the administration of
noradrenergic antagonists blocks stress- and corticosteroidinduced effects on cognition (Roozendaal, Hahn, Nathan, de
Quervain, & McGaugh, 2004; Schwabe et al., 2009). Further
supporting the importance of amygdala activity in stress effects
on learning are the findings that stress often exerts greater effects
on memory for emotional information (Schwabe, Wolf, & Oitzl,
2010; Schwabe et al., 2012; Wolf, 2009) and that the effects of
glucocorticoids on learning and memory are eliminated when a
non-arousing testing environment is employed in laboratory
investigations (Kuhlmann & Wolf, 2006).
Initially, investigators speculated that stress-induced amygdala
and corticosteroid activity would primarily exert deleterious
effects on learning and memory. However, it has now been wellestablished that the timing of stress and its neurobiological correlates plays a major role in determining how stress affects cognition
(Diamond et al., 2007; Joels, Pu, Wiegert, Oitzl, & Krugers, 2006;
Joels et al., 2011). For instance, extensive work has shown that
glucocorticoids, as well as electrical stimulation of the amygdala,
exert immediate excitatory, but delayed inhibitory, effects on
learning-related synaptic plasticity (Akirav & Richter-Levin, 1999;
Frey, Bergado-Rosado, Seidenbecher, Pape, & Frey, 2001; Karst
et al., 2005; Wiegert, Joels, & Krugers, 2006). This has led to a general consensus among investigators that if a brief stressor is
administered in relatively close proximity to learning, then longterm memory should be enhanced. Based on these ideas, Diamond
and colleagues developed a theory about the temporal dynamics of
emotional memory (Diamond et al., 2007). According to these
investigators, stress rapidly activates the amygdala and results in
rapid, non-genomic effects of glucocorticoids on synaptic plasticity; this leads to enhanced neuroplasticity and improved learning
and memory. However, as times passes, the stressor causes important cognitive brain areas, such as the hippocampus, to enter a
refractory period, during which synaptic plasticity and learning
are impaired. This temporal dynamics model of emotional memory
processing has now received support in human (e.g., Zoladz, Clark,
et al., 2011; Zoladz et al., 2013) and non-human (e.g., Diamond
et al., 2007) laboratory studies.
Although the temporal dynamics model has been used to
understand pre-learning stress effects on long-term memory, little
work has addressed how the timing of a stressor is involved in
stress effects on retrieval. One of the prevailing views of how stress
affects retrieval is that a stressor induces learning-related neuroplasticity, which is accompanied by a significant increase in a host
of neurotransmitters/neuromodulators (e.g., norepinephrine, corticosteroids, glutamate, etc.), that allows the organism to store and
remember the stressful event but results in the overwriting of
and failed access to neural networks responsible for retrieval of
the memory being tested (Diamond, Park, Campbell, & Woodson,
2005; Diamond, Park, & Woodson, 2004; Kim & Diamond, 2002).
However, if stress has rapid excitatory effects on hippocampal
neuroplasticity, it is possible that rather than exerting deleterious
effects on retrieval, a brief stressor administered immediately
before testing could enhance memory. Indeed, recent work by
Schilling and colleagues revealed that intravenous cortisol administration 8 min prior to testing led to an inverted U-shaped relationship between cortisol and memory, where moderate doses of
cortisol resulted in greater memory (Schilling et al., 2013). Importantly, the rapid nature of the cortisol-induced modulation of
memory suggested that the effects were due to rapid, non-genomic
mechanisms, likely resulting from the activation of membranebound corticosteroid receptors. To our knowledge, the influence
of brief stress administered immediately prior to testing on
long-term retrieval has been addressed only in non-human animal
research. These studies have shown, in general, that stress has no
effect on hippocampus-dependent memory. It has been reasoned
that such a manipulation has no effect on memory because corticosteroid levels do not significantly increase until 20–30 min after
stress onset. Indeed, de Quervain and colleagues showed that
stress administered 30 min, but not 2 min, prior to memory testing
impaired retrieval, an effect that was blocked by the administration of metyrapone, a corticosteroid synthesis inhibitor (de
Quervain, Roozendaal, & McGaugh, 1998). Most studies examining
the effects of pre-retrieval stress on memory in humans have
employed stressors of a longer duration, administered brief stress
at a time point that was separated from retrieval testing or examined short-term rather than long-term (i.e., P24-h) memory. These
studies have generally reported deleterious effects on retrieval,
effects that, similar to preclinical studies, have been associated
with corticosteroid levels. On the other hand, Schwabe and
colleagues recently reported that pre-retrieval stress administered
30 min prior to testing enhanced memory for emotionally arousing
information; this enhancement was associated with participants’
corticosteroid levels and required concurrent elevations of norepinephrine (Schwabe et al., 2009). Thus, the notion that stress-induced increases in corticosteroids unequivocally impair retrieval
would seem to be an incomplete perspective on stress-memory
interactions. Moreover, the finding that stress can impair memory
in adrenalectomized rats that cannot manifest stress-induced increases in corticosterone levels suggests that an increase in corticosterone is not even necessary for stress to influence retention
(Zoladz, Park, Munoz, Fleshner, & Diamond, 2008). Ultimately,
the findings that stress can enhance or have no effect on retrieval
(Beckner et al., 2006; Schwabe et al., 2009) warrant an examination of factors that could mediate differential effects of stress on
such processes. Thus, in the present study, we examined the influence of brief stress administered immediately prior to long-term
(24-h) retrieval on memory performance in male and female
participants.
2. Materials and methods
2.1. Participants
Ninety-three healthy men and women (38 men, 55 women;
age: M = 19.45, SD = 1.56) from Ohio Northern University volunteered to participate in the present experiment. Individuals were
excluded from participating if they met any of the following conditions: diagnosis of Raynaud’s disease or peripheral vascular disease; presence of skin diseases, such as severe psoriasis, eczema
or scleroderma; history of syncope or vasovagal response to stress;
history of severe head injury; current treatment with psychotropic
medications, narcotics, beta-blockers, steroids or any other medication that was deemed to significantly affect central nervous or
endocrine system function; 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. There were only two 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.
Females who took birth control on a regular basis were also
allowed to participate in the study; prior to participation, we asked
female participants if they took birth control via a short demographic survey. Females who reportedly took birth control were
not significantly different from naturally cycling females on any
physiological or behavioral measure, nor did stress significantly
interact with birth control in these analyses. Therefore, we treated
P.R. Zoladz et al. / Brain and Cognition 85 (2014) 277–285
all females as a single group in the statistical analyses for this
study. 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 study. All of the methods for the experiment were
approved by the Institutional Review Board at Ohio Northern
University.
2.2. Experimental procedures
To control for diurnal variations in cortisol levels, all testing was
carried out between 1200 and 1800 h.
2.2.1. Word presentation
Participants were presented with a list of 42 words, which were
selected from the Affective Norms for English Words (Bradley & Lang,
1999). Based on standardized valence and arousal ratings, we
chose 14 neutral (7 arousing, 7 non-arousing), 14 positive (7 arousing, 7 non-arousing) and 14 negative (7 arousing, 7 non-arousing)
words, which, across emotional valence and arousal categories,
were balanced for word length and word frequency. As per the
methods employed by Schwabe and colleagues (Schwabe et al.,
2008), participants were instructed to read each word aloud and
rate its emotional valence on a scale from 4 (very negative) to
+4 (very positive) and its arousal level on a scale of 0 (not arousing)
to 8 (very highly arousing) on a sheet of paper containing the list of
words. These manipulations were performed to promote encoding
of the words, and they allowed us to analyze the final memory data
based on participants’ own ratings of the words (see Section 2.3).
According to the Affective Norms for English Words (Bradley &
Lang, 1999), the mean (±SEM) valence and arousal ratings for the
words that made up the list were as follows: positive arousing
words (e.g., ecstasy): valence = 7.79 ± 0.12, arousal = 6.62 ± 0.25;
positive non-arousing words (e.g., butterfly): valence = 7.50 ± 0.12,
arousal = 3.46 ± 0.16; negative arousing words (e.g., burn): valence = 2.21 ± 0.16, arousal = 6.56 ± 0.27; negative non-arousing
words (e.g., unhappy): valence = 2.40 ± 0.20, arousal = 3.89 ± 0.19;
neutral arousing words (e.g., lightning): valence = 4.93 ± 0.27,
arousal = 6.26 ± 0.20; neutral non-arousing words (e.g., poster):
valence = 4.90 ± 0.14, arousal = 3.40 ± 0.13.
2.2.2. Immediate memory testing
Immediately following word list encoding, participants were
given 5 min to write down as many words as they could remember
from the list of words they just studied. This immediate free recall
test was performed to verify that there were no group differences
regarding short-term memory performance and to avoid a potential floor effect during long-term memory assessment (e.g., Zoladz,
Clark, et al., 2011).
2.2.3. Cold pressor test (CPT)
Twenty-four hours following exposure to the word list, participants returned to the laboratory. Participants were asked to submerge their non-dominant hand, up to and including the wrist,
in a bath of water for 3 min. Those participants who had been
randomly assigned to the stress condition (N = 48; 18 males, 30
females) placed their hand in a bath of ice cold (0–2 °C) water,
while participants who had been randomly assigned to the control
condition (N = 45; 20 males, 25 females) placed their hand in a
bath of warm (35–37 °C) water. The water was maintained at the
appropriate temperature by a VWR 1160S circulating water bath.
To maximize the stress response, participants in each experiment
were encouraged to keep their hand in the water bath for the
279
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. Only five participants
from the stress condition removed their hand from the water prior
to 3 min elapsing (M water time = 168.06 s, SD = 37.23), and all
participants from the no stress condition kept their hand in the
water for the entire 3-min period. Inclusion of the data from
stressed participants who removed their hand from the water early
had no significant effect on the observed results.
2.2.4. 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 11point scales ranging from 0–10, 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 10s for each measure.
2.2.5. Delayed memory testing
Immediately following the water bath manipulation, participants were again 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., delayed free recall). Then, participants sat quietly for 7.5 min, after which they were given a recognition test.
Participants were presented with a list of words containing 42
‘‘old’’ words (i.e., words that were presented on the previous day)
and 42 ‘‘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, according to the
ratings obtained from the Affective Norms for English Words
(Bradley & Lang, 1999). To assess participants’ ability to discriminate between ‘‘old’’ and ‘‘new’’ words, we calculated a sensitivity
index (d0 = z[p(hit)] z[p(false alarm)]) for each category of word
(i.e., positive arousing words, positive non-arousing words, negative arousing words, etc.) to be used for statistical analysis.
2.2.6. Cardiovascular analysis
Heart rate (HR) and blood pressure (BP) measurements were
taken 2 min before (baseline), halfway through and 5 min after
cessation of the water bath manipulation. Cardiovascular activity
was measured with a vital signs monitor (Mark of Fitness WS820 Automatic Wrist Blood Pressure Monitor) placed on the wrist
of each participant’s dominant hand.
2.2.7. Cortisol analysis
Saliva samples were collected from participants 2 min before
(baseline) and 22 min following exposure to 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. We
did not collect a saliva sample immediately following stress exposure because we wanted to conduct memory testing as soon as the
stressor ended and because we did not want to adversely impact
participants’ behavioral performance.
Saliva samples were thawed and extracted by low-speed
centrifugation. Salivary cortisol levels were determined by enzyme
immunoassay (EIA; Cayman Chemical Co., Ann Arbor, MI) according to the manufacturer’s protocol. The minimum detectable
concentration of cortisol was approximately 8 pg/ml, and the
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P.R. Zoladz et al. / Brain and Cognition 85 (2014) 277–285
average inter- and intra-assay percent coefficients of variation
were less than 6.9% and 6.8%, respectively.
2.3. Statistical analyses
Based on previous stress-memory research from our own
laboratory and from that of others, we initially analyzed the data
after dividing stressed participants into ‘‘responders’’ and
‘‘non-responders’’ based on their cortisol responses to the CPT.
The findings of Schilling et al. (2013) also led us to perform such
a manipulation, as we believed that it could have lent insight into
which participants were more susceptible to rapid, non-genomic
corticosteroid effects on memory performance. Those participants
exhibiting a cortisol increase of at least 2.5 nmol/l following the
CPT were considered Responders; all other participants were considered Non-Responders. This cutoff criterion corresponds to an
elevation of approximately 1 lg/dL of serum or plasma cortisol
and is thought to reflect a cortisol secretory episode that would
occur following a stressor. Following this data manipulation,
mixed-model ANOVAs were used to analyze all physiological and
behavioral data; the between-subjects factors utilized in these
analyses were stress (levels = cortisol responder, cortisol nonresponder, no stress) and sex, and the within-subjects factors were
word valence and arousal (for recall and recognition analyses) or
time (for physiological and subjective ratings analyses). The analyses of participants’ valence and arousal ratings and memory for the
words (i.e., immediate free recall, delayed free recall, and recognition) were performed based on categorizing the words (i.e., distributing the words to positive arousing, positive non-arousing,
negative arousing, etc. groups) according to participants’ subjective
valence and arousal ratings that were obtained during the study
(see Section 2.2.1).
We also conducted bivariate correlations (Pearson’s r) to
explore possible relationships between participants’ physiological
responses to stress and cognitive performance. To limit the inflation of Type I error rates, these 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.
F(2, 164) = 2.97, p = 0.054). No other significant effects were
observed.
3.1.3. Diastolic blood pressure (see Table 1)
Stressed participants, independent of cortisol response to the
stressor, exhibited greater diastolic BP than non-stressed participants during the water bath manipulation (significant effect of
time: F(2, 162) = 115.55, p < 0.001; significant effect of condition:
F(2, 81) = 5.67, p < 0.01; significant Condition Time interaction:
F(4, 162) = 10.67, p < 0.001). Male participants also exhibited greater diastolic BP than female participants (significant effect of sex:
F(1, 81) = 4.23, p < 0.05). No other significant effects were observed.
3.1.4. Salivary cortisol (see Fig. 1)
Based on the criteria employed to divide participants into
cortisol responders and cortisol non-responders, we ended up with
the following sample sizes for each group: 27 cortisol responders
(12 male, 15 female) and 21 cortisol non-responders (6 male, 15
female). As expected, cortisol responders exhibited greater salivary
cortisol levels than cortisol non-responders and non-stressed
participants after the water bath manipulation (significant effect
of time: F(1, 86) = 45.05, p < 0.001; significant effect of condition:
F(2, 86) = 10.92, p < 0.001; significant Condition Time interaction: F(2, 86) = 50.73, p < 0.001). Females also exhibited greater
cortisol levels than males (significant effect of sex: F(1, 86) = 5.43,
p < 0.05). As depicted in Fig. 1C, similar effects were observed when
analyzing the effects of stress, overall, on cortisol levels (significant
effect of time: F(1, 88) = 23.97, p < 0.001; significant effect of
condition: F(1, 88) = 8.83, p < 0.01; significant effect of sex:
F(1, 88) = 4.98, p < 0.05; significant Condition Time interaction:
F(1, 88) = 22.46, p < 0.001). No other significant effects were
observed.
Table 1
Cardiovascular activity before, during and after the water bath manipulation.
DV/condition
Heart rate (bpm)
Cortisol responders
Male
75.67
Female
81.57
Cortisol non-responders
Male
83.67
Female
82.27
No stress
Male
75.80
Female
83.75
3. Results
3.1. Physiological responses
3.1.1. Heart rate (see Table 1)
The stress manipulation had no effect on HR (no significant effect of condition: F(2, 82) = 0.41, p > 0.05). However, participants’
HR did decrease after the water bath manipulation, particularly
in cortisol responders and non-responders (significant effect of
time: F(2, 164) = 11.27, p < 0.001; significant Condition Time
interaction: F(4, 164) = 4.56, p < 0.01). No other significant effects
were observed.
3.1.2. Systolic blood pressure (see Table 1)
Stressed participants, independent of cortisol response to the
stressor, exhibited greater systolic BP than non-stressed participants during the water bath manipulation (significant effect of
time: F(2, 164) = 141.91, p < 0.001; significant effect of condition:
F(2, 82) = 4.64, p < 0.05; significant Condition Time interaction:
F(4, 164) = 9.98, p < 0.001). Male participants also exhibited greater
systolic BP than female participants, particularly during the water
bath manipulation (significant effect of sex: F(1, 82) = 28.18,
p < 0.001; Sex Time interaction approaching significance:
Pre
During
Post
(4.43)
(3.92)
79.92 (4.52)
80.77 (4.04)
73.91 (4.16)
77.71 (2.88)
(7.03)
(4.78)
80.60 (8.78)
83.27 (4.63)
75.50 (4.92)
75.87 (3.41)
(3.21)
(2.83)
74.20 (2.49)
76.72 (2.22)
74.35 (2.32)
78.16 (2.18)
163.67 (6.72)*
144.46 (3.34)*
132.09 (3.02)
118.46 (1.94)
167.60 (8.26)*
152.27 (3.96)*
134.17 (5.15)
123.27 (2.90)
149.55 (3.13)
129.32 (1.54)
128.20 (2.52)
113.72 (4.67)
107.42 (4.89)*
98.62 (3.14)*
82.73 (2.43)
76.08 (1.75)
106.00 (6.12)*
104.73 (4.20)*
77.17 (2.06)
76.87 (1.71)
91.79 (2.25)
83.04 (1.41)
77.35 (1.82)
74.84 (1.62)
Systolic blood pressure (mm Hg)
Cortisol responders
Male
134.17 (3.30)
Female
121.92 (2.78)
Cortisol non-responders
Male
142.33 (2.63)
Female
128.13 (3.14)
No stress
Male
138.10 (3.28)
Female
125.08 (2.06)
Diastolic blood pressure (mm Hg)
Cortisol responders
Male
83.33 (3.06)
Female
76.85 (1.85)
Cortisol non-responders
Male
84.67 (1.17)
Female
80.20 (1.91)
No stress
Male
84.00 (3.04)
Female
79.42 (1.79)
Data are presented as means ± SEM.
p < 0.05 relative to the no stress group.
*
P.R. Zoladz et al. / Brain and Cognition 85 (2014) 277–285
3.2. Subjective ratings of water bath manipulation
3.2.1. Pain ratings
Stressed participants (cortisol responders: M = 7.00, SEM = 0.30;
cortisol non-responders: M = 6.14, SEM = 0.38), independent of
cortisol response to the stressor, reported greater pain ratings than
non-stressed participants (M = 0.32, SEM = 0.23) throughout the
water bath manipulation (significant effect of condition:
F(2, 87) = 186.19, p < 0.001). No other significant effects were
observed.
3.2.2. Stress ratings
Stressed participants (cortisol responders: M = 5.97, SEM = 0.41;
cortisol non-responders: M = 4.75, SEM = 0.52), independent of
cortisol response to the stressor, reported greater stress ratings
than non-stressed participants (M = 0.68, SEM = 0.32) throughout
the water bath manipulation (significant effect of condition:
F(2, 87) = 57.79, p < 0.001). No other significant effects were
observed.
3.3. Word list ratings
3.3.1. Valence ratings
Positive words were given more positive ratings than neutral
words, which were given more positive ratings than negative
words (significant effect of valence: F(2, 174) = 567.25, p < 0.001).
In addition, neutral arousing words were given more negative ratings than neutral non-arousing words, while positive arousing
words were given more positive ratings than positive non-arousing
words (significant Valence Arousal interaction: F(2, 174) = 8.08,
p < 0.001). Males also rated non-arousing words as more negative
than did females (significant Sex Arousal interaction:
F(1, 87) = 4.54, p < 0.05). No other significant effects were observed.
3.3.2. Arousal ratings
Arousing words were rated as more arousing than non-arousing
words (significant effect of arousal: F(1, 87) = 131.95, p < 0.001).
Positive words were rated as more arousing than negative words,
which were rated as more arousing than neutral words (significant
effect of valence: F(2, 174) = 83.38, p < 0.001). Males also gave
greater arousal ratings for the words than did females (significant
effect of sex: F(1, 87) = 4.87, p < 0.05). This effect was driven largely
by male cortisol responders rating negative and neutral arousing
words as more arousing than females (significant Sex Arousal
interaction: F(1, 87) = 8.33, p < 0.05; significant Valence Arousal
interaction: F(2, 174) = 15.83, p < 0.001; significant Condition Sex Arousal interaction: F(2, 87) = 3.22, p < 0.05). No other
significant effects were observed.
3.4. Memory testing
3.4.1. Immediate free recall (see Fig. 2)
There were no significant differences between stressed and
non-stressed participants (no significant effect of condition:
F(1, 83) = 0.95, p > 0.05). However, participants recalled more positive words than negative words, which were recalled better than
neutral words (significant effect of valence: F(2, 166) = 23.22,
p < 0.001). Participants also recalled more arousing words than
non-arousing words, but only when they were positive or negative
in valence (significant effect of arousal: F(1, 83) = 66.36, p < 0.001;
significant
Valence Arousal
interaction:
F(2, 166) = 19.50,
p < 0.001). No other significant effects were observed.
3.4.2. Delayed free recall (see Fig. 3)
Male cortisol non-responders recalled fewer words than all
other groups (significant effect of condition: F(2, 84) = 5.31,
281
p < 0.01; significant Condition Sex interaction: F(2, 84) = 3.95,
p < 0.05). Participants recalled more positive words than negative
or neutral words, especially when they were non-arousing
(significant effect of valence: F(2, 168) = 17.95, p < 0.001; significant Valence Arousal interaction: F(2, 168) = 6.40, p < 0.01). Also,
participants recalled more arousing words than non-arousing
words (significant effect of arousal: F(1, 84) = 55.46, p < 0.001). No
other significant effects were observed.
3.4.3. Delayed recognition (see Fig. 4)
Male cortisol responders recognized more words than male
cortisol non-responders and non-stressed males, and male cortisol
non-responders tended to recognize fewer words than nonstressed males, although the latter effect was only approaching significance (p = 0.09) (effect of condition approaching significance:
F(2, 83) = 2.86, p = 0.063; significant effect of sex: F(1, 83) = 5.25,
p < 0.05; significant Condition Sex interaction: F(2, 83) = 4.40,
p < 0.05). Positive words were also better recognized than negative
words, especially if they were arousing (significant effect of
valence: F(2, 166) = 3.73, p < 0.05; significant effect of arousal:
F(1, 83) = 10.16, p < 0.01; significant Valence Arousal interaction:
F(2, 166) = 3.53, p < 0.05). No other significant effects were
observed.
3.5. Associations between physiological stress response and memory
We performed bivariate correlations (Pearson’s r) between
long-term memory and cortisol (time point 2) and cardiovascular
activity (during the water bath manipulation). These analyses revealed a significant negative correlation between HR and total
long-term free recall, r(15) = 0.54, p < 0.05. Importantly, this correlation was evident only in stressed males.
4. Discussion
Previous work has generally reported that pre-retrieval stress
impairs memory. However, in light of discrepant findings in this
area, we hypothesized that brief stress administered immediately
before retrieval could possibly enhance memory. In support of this
hypothesis, we found that stress enhanced long-term recognition
memory in male cortisol responders. A majority of our findings,
however, emphasized that the same stress impaired long-term
recall and recognition in male cortisol non-responders. Interestingly, memory performance in stressed males was negatively associated with the HR response to the CPT. These findings suggest that
the effects of pre-retrieval stress on memory may be sex-specific,
as female memory was not significantly affected by the stress
manipulation. They also indicate that brief stress administered
immediately before testing can enhance or impair memory
depending on the type of corticosteroid response to the stressor.
4.1. Neurobiological mechanisms of pre-retrieval stress
We have shown that a brief stressor administered immediately
before retrieval enhanced memory in male cortisol responders and
impaired memory in male cortisol non-responders. Thus, our
observations, at first glance, appear to contradict work in the
stress-memory literature reporting that cortisol elevations impair
retrieval. We would contend that the apparent contradictory nature of our findings in stressed male participants emphasizes the
consideration of certain variables in stress-memory interactions,
such as the timing of the stressor relative to testing and the nature
of corticosteroid activity following stress. It is possible that, at least
in males, when brief stress is administered immediately before
testing and subsequently produces a significant increase in
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P.R. Zoladz et al. / Brain and Cognition 85 (2014) 277–285
Males
Cortisol Responders
Cortisol Non-Responders
No Stress
14
*
10
8
6
5
10
15
12
10
8
6
4
2
0
20
25
-5
0
5
Time (min)
C
10
15
20
25
Time (min)
18
Males - Stress
Males - No Stress
Females - Stress
Females - No Stress
16
14
12
*
*
10
8
6
2
0
-5
0
Recognition
4
Free Recall
Water Bath
Cortisol (nmol/l)
Recognition
0
14
Free Recall
-5
*
Cortisol Responders
Cortisol Non-Responders
No Stress
Water Bath
0
Recognition
2
Free Recall
4
18
16
12
Water Bath
Cortisol (nmol/l)
16
Females
B
18
Cortisol (nmol/l)
A
5
10
15
20
25
Time (min)
Fig. 1. Salivary cortisol concentrations before and after the water bath manipulation in males and females. The top two graphs (i.e., A and B) depict the salivary cortisol
responses after stressed participants had been divided into cortisol responders and non-responders. In both sexes, cortisol responders were the only participants to exhibit
significantly increased cortisol concentrations following the water bath manipulation. The bottom graph (C) depicts the salivary cortisol responses in all stressed participants
(i.e., cortisol responders and non-responders) relative to controls. Data are presented as means ± SEM; * = p < 0.05 relative to the cortisol non-responder and/or no stress
groups.
Males
50
40
30
20
10
0
Cortisol Responders
Cortisol Non-Responders
No Stress
70
Free Recall (% of total)
60
Free Recall (% of total)
Females
Cortisol Responders
Cortisol Non-Responders
No Stress
60
50
40
30
20
10
0
Arousing
NonArousing
Positive
Arousing
NonArousing
Arousing
Negative
NonArousing
Neutral
Arousing
Total
NonArousing
Positive
Arousing
NonArousing
Arousing
Negative
NonArousing
Neutral
Total
Fig. 2. Immediate free recall performance for males (left) and females (right). No statistically significant group differences were observed. Data are presented as means ± SEM.
cortisol, rapid, non-genomic effects of the increasing corticosteroids enhance memory. This is consistent with the recent finding
by Schilling et al. (2013), whereby intravenous corticosteroid
administration 8 min prior to testing led to an inverted, U-shaped
relationship between corticosteroid levels and retrieval. In their
study, moderate levels of circulating corticosteroids were associated with enhanced memory, presumably a result of non-genomic
corticosteroid activity. Our findings thus emphasize that preretrieval stress does not unequivocally impair long-term memory;
rather, depending on the sex of the organism and the timing of the
stressor and its neurobiological correlates, such stress can have
facilitative effects on such processes.
Other researchers, particularly those conducting non-human
animal research, have also reported relatively rapid effects of stress
and corticosteroids on memory retrieval, albeit effects that have
usually been in the opposite direction of those reported here. For
instance, Beracochea and colleagues (Chauveau et al., 2009; Dorey
et al., 2011) found that stress or corticosteroids administered
15 min before testing led to a reversal of serial memory retrieval
pattern and impaired spontaneous alternation in male mice. These
effects appeared to be a result of membrane-bound mineralocorticoid receptor (MR) activity, as they were blocked by MR, but not
glucocorticoid receptor (GR), antagonists. It is possible that preretrieval stress impaired memory in these studies because the stress
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P.R. Zoladz et al. / Brain and Cognition 85 (2014) 277–285
Males
50
40
30
20
*
10
Cortisol Responders
Cortisol Non-Responders
No Stress
60
Free Recall (% of total)
Cortisol Responders
Cortisol Non-Responders
No Stress
60
Free Recall (% of total)
Females
0
50
40
30
20
10
0
Arousing
NonArousing
Positive
Arousing
NonArousing
Arousing
Negative
NonArousing
Neutral
Arousing
NonArousing
Positive
Total
Arousing
NonArousing
Arousing
Negative
NonArousing
Neutral
Total
Fig. 3. Long-term (24-h) free recall performance for males (left) and females (right). Male cortisol non-responders recalled significantly fewer words than all other groups.
Data are presented as means ± SEM; * = p < 0.05 relative to the cortisol responder and no stress groups.
Males
*
2.5
β
2.0
1.5
1.0
0.5
0.0
Arousing
NonArousing
Positive
Arousing
NonArousing
Arousing
Negative
2.5
2.0
1.5
1.0
0.5
0.0
NonArousing
Neutral
Cortisol Responders
Cortisol Non-Responders
No Stress
3.0
Discrimination Index (d' )
3.0
Discrimination Index (d' )
Females
Cortisol Responders
Cortisol Non-Responders
No Stress
Arousing
Total
NonArousing
Positive
Arousing
NonArousing
Arousing
Negative
NonArousing
Neutral
Total
Fig. 4. Long-term (24-h) recognition performance for males (left) and females (right). Male cortisol responders recognized more words, overall, than all other groups. Male
cortisol non-responders tended to recognize fewer words than all other groups; however, this effect only approached statistical significance. Data are presented as
means ± SEM; * = p < 0.05 relative to the cortisol responder and no stress groups; b = p = 0.09 relative to the no stress group.
was administered 15 min prior to testing and/or because the tasks
performed were not emotionally arousing. Of course, timing may
not be a reasonable factor used to explain the findings, as Schwabe
et al. (2009) found that stress administered even 30 min before
testing enhanced the retrieval of emotional information in human
subjects. In the present study, corticosteroid levels were likely just
beginning to rise in stressed participants when memory performance was being assessed, as retrieval testing occurred immediately following CPT exposure (i.e., 3–4 min after the onset of
stress). It is therefore unlikely that any of the stressed participants
exhibited a significant elevation of corticosteroid levels at this time
point. What would be expected, however, is a significant increase
in sympathetic-adrenomedullary (SAM) output, resulting in a rapid
increase in cardiovascular and noradrenergic activity. Thus, the
non-genomic activity of slowly rising corticosteroid levels coupled
with the concurrent increase in arousal-induced SAM activity
could have fostered enhanced memory, which is consistent with
previous work emphasizing the need for both corticosteroid and
noradrenergic activity for the stress-induced modulation of learning and memory (Roozendaal, McEwen, & Chattarji, 2009).
In addition to the stress-induced enhancement of memory that
we observed in male cortisol responders, we also observed an
impairment of long-term memory in male cortisol non-responders.
This finding suggests that without a concurrent rise in cortisol,
enhanced SAM activity immediately before testing can result in
impaired memory. This was supported, at least in part, by the
observation of an inverse relationship between stressed males’
HR during the CPT and their subsequent memory performance. In
other words, as stressed males’ HR during the CPT increased, their
recall performance decreased. At least one other study has reported impaired memory in cortisol non-responders (Meyer,
Smeets, Giesbrecht, Quaedflieg, & Merckelbach, 2013), which is
similar to the present findings, but overall, little work has
addressed the role of enhanced noradrenergic activity, alone, in
memory retrieval. Even more interesting is the finding that the
type of corticosteroid response to the CPT led to polar opposite
effects on male memory; that is, cortisol responders exhibited
enhanced memory, and cortisol non-responders exhibited impaired
memory. Together, these ideas suggest that when stress occurs
immediately before retrieval, the non-genomic effects of cortisol
could work as a buffer against memory impairment induced by
noradrenergic activity, again, particularly in males. Of course,
additional research is necessary to corroborate such speculation.
The temporal dynamics model of emotional memory processing
suggests that when stress is administered in close proximity to a
learning experience, long-term memory will be enhanced, and
when a stressor is temporally separated from a learning experience, long-term memory will be impaired (Akirav & Richter-Levin,
1999; Diamond et al., 2007; Groeneweg, Karst, de Kloet, & Joels,
2011). This theory is based on the idea that stress-induced amygdala, corticosteroid and noradrenergic activity exert biphasic
effects on hippocampal plasticity, thereby resulting in rapid excitatory, but delayed inhibitory, effects on learning. We attempted to
extend this idea to pre-retrieval stress, as most of the previous
work testing this notion had done so with pre-learning stress
manipulations. What we discovered is that such an idea may hold
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P.R. Zoladz et al. / Brain and Cognition 85 (2014) 277–285
true, but predominantly for males exhibiting a robust corticosteroid response to the stress. This is not surprising, considering that
the temporal dynamics theory is based largely on research
conducted in males, whether it be humans or rodents. It is also
important to point out that in previous studies reporting discrepant pre-retrieval stress or corticosteroid findings, the investigators
were either unable to statistically address sex differences (Schilling
et al., 2013) or only studied male participants (Schwabe et al.,
2009). Thus, our current and previous (Zoladz et al., 2013) findings
related to the experimental assessment of this theory challenge
researchers to extend the theory’s ideas to females. They also
emphasize the need for a more comprehensive theory of how
stress and its underlying neurobiological processes time-dependently affect retrieval, in addition to acquisition and consolidation.
4.2. Sex differences in stress effects on retrieval
Thus far in the stress-memory literature, a clear agreement on
how sex mediates stress effects on cognition, especially in humans,
has not been reached. Several studies have reported cortisol- or
stress-induced alterations of learning and memory in males, while
finding no effect or an opposite effect in females (Andreano &
Cahill, 2006; Cornelisse, van Stegeren, & Joels, 2011; Payne et al.,
2006; Wolf, Schommer, Hellhammer, McEwen, & Kirschbaum,
2001; Zoladz et al., 2013). For instance, Andreano and Cahill
(2006) reported the existence of a curvilinear relationship between
CPT-induced cortisol release and memory in males, but not
females. Wolf et al. (2001) and our laboratory (Zoladz et al., 2013),
in contrast, reported that pre-learning stress-induced increases in
cortisol were associated with impaired memory in males, but not
females. The present findings compare well with these studies, as
all our pre-retrieval stress effects on memory were observed in
males.
It is likely that sex differences in hormones and brain activity
play a large role in the differential effects of stress on cognition
in males and females. Studies have shown that differences in the
menstrual cycle play an important role in the stress-induced alteration of cognition. Andreano, Arjomandi, and Cahill (2008) observed a positive correlation between stress-induced cortisol
levels and memory only when female participants were in the
mid-luteal phase of the menstrual cycle, a time when progesterone
levels are significantly elevated. Along the same lines, studies have
found that females in the luteal phase and exhibiting high levels of
progesterone demonstrate better memory for emotional information, greater stress-induced elevations of salivary cortisol, stronger
stress-induced enhancements of emotional memory, and altered
glucocorticoid sensitivity, relative to women with low levels of
progesterone (Ertman, Andreano, & Cahill, 2011; Felmingham,
Fong, & Bryant, 2012; Rohleder, Schommer, Hellhammer, Engel, &
Kirschbaum, 2001; Rohleder, Wolf, Kirschbaum, & Wolf, 2009). Cahill postulated that under stress, the differential effects observed
between sexes could be due to an enlarged amygdala observed in
males (Cahill, 2006). Supporting this, several studies have shown
a sex difference in amygdala response to emotional stimuli and
associations with subsequent memory for emotional stimuli, and
females do exhibit stronger responses of the amygdala-hippocampus neural network to emotional stimuli when they are in the luteal phase (Andreano & Cahill, 2010). Consequently, differential
amygdala activity, coupled with existing hormonal differences,
could explain why stress exerts much different effects on males
than females.
4.3. Limitations and caveats
There are some limitations of the present study that warrant
consideration. The samples size that we ended up with for male
cortisol non-responders (N = 6) was particularly low. This likely
resulted from an already biased student population with a female
majority, combined with a post hoc split of males into cortisol
responders and non-responders after the study. Thus, the results
for cortisol non-responders, which were a large part of the present
findings, should be interpreted cautiously. In addition, some of our
findings appeared to be associated with mechanisms independent
of corticosteroids, such as an increase in noradrenergic activity.
However, we did not assess noradrenergic activity in participants,
which could have been performed by measuring salivary alphaamylase. Such an assessment could have provided greater support
for our argument that the observed impairment in male cortisol
non-responders was associated with norepinephrine levels and
should be considered in the future. Finally, we did not control for
the menstrual cycle or measure hormone levels in female participants. Given the known influence of these factors in stress-memory interactions, more attention should be paid to these variables
in future work on pre-retrieval stress.
5. Conclusions
In the present study, we have shown that brief, pre-retrieval
stress administered immediately prior to testing enhanced longterm recognition memory in males exhibiting a significant increase
in cortisol levels and impaired long-term recall and recognition
memory in males exhibiting minimal change in cortisol levels.
These findings suggest that, at least in males, an isolated increase
in SAM activity immediately before retrieval could have deleterious effects on memory and that non-genomic corticosteroid activity could be protective against such effects. The findings also
emphasize, again, that males seem to be more susceptible than females to stress-induced alterations of learning and memory. Future
work will need to be conducted to disentangle the neurobiological
mechanisms underlying our observed effects and sex differences.
Acknowledgment
The present study was funded by a faculty research advisor
Grant from Psi Chi to PRZ.
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