Chapter
AMYGDALA-INDUCED MODULATION
OF COGNITIVE BRAIN STRUCTURES
UNDERLIES STRESS-INDUCED
ALTERATIONS OF LEARNING AND
MEMORY: IMPORTANCE OF
STRESSOR TIMING AND
SEX DIFFERENCES
Phillip R. Zoladz, Andrea E. Kalchik,
Chelsea E. Cadle, and Sarah M. Lyle
Department of Psychology, Sociology, and Criminal
Justice, Ohio Northern University, Ada, Ohio, US
ABSTRACT
Stress exerts complex effects on cognition. While stress can enhance
learning and result in powerful memories that last a lifetime, it can also
impair learning and cause us to be forgetful in our everyday lives. Over
the past several years, it has become apparent that the types of effects that

Corresponding author: Phillip R. Zoladz, Ohio Northern University, Department of Psychology,
Sociology, and Criminal Justice, 525 S. Main St. Hill 013, Ada, OH, 45810, US. Phone:
419-772-2142, Fax: 419-772-2746, Email: p-zoladz@onu.edu.
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Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
stress exerts on learning and memory depend critically on several factors
related to the organism being studied, the learning experience, and the
timing of the stressor. For instance, post-learning stress often facilitates
long-term memory, while pre-learning and pre-retrieval stress effects are
more variable and can involve enhancements or impairments of memory.
In addition, stressors that are administered immediately before learning
seem to result in amygdala-induced enhancements of hippocampal
neuroplasticity, which promote learning, whereas stressors that are
temporally separated from the learning experience result in amygdalainduced suppression of hippocampal neuroplasticity, which impairs
learning. In the present review, we provide a comprehensive discussion of
factors that mediate stress-induced alterations of hippocampus-dependent
learning and memory and contend that the neurochemicals released
following stress (e.g., cortisol, norepinephrine, glutamate, etc.) exert
temporally distinct effects on brain areas devoted to processing emotional
and cognitive information, such as the amygdala, hippocampus, and
prefrontal cortex. We also propose that such stress-memory interactions
differ significantly between males and females, which may be
attributable, at least in part, to differences in amygdala activity and
temporal dynamics of the stress response. Collectively, understanding the
neurobiological basis of stress-memory interactions and how sex
mediates such effects will facilitate the scientific community's
understanding of traumatic memory formation and the onset of stressrelated psychological disorders, such as post-traumatic stress disorder.
INTRODUCTION
The effects of stress on cognition are profound, yet complex. For instance,
stress can strengthen learning and produce memories that last a lifetime, but it
can also hinder learning and lead to significant memory impairments. Today,
scientists are faced with the task of understanding when stress enhances versus
impairs learning and memory and what ramifications such phenomena have
for psychological health. We approach this issue with the prediction that
stress-induced changes in learning and memory are adaptive in nature and
have facilitated organisms’ survival over time. Thus, stress-induced
enhancements of learning allow organisms to remember information
pertaining to threatening situations, which later facilitates survival by helping
them avoid similar, potentially dangerous, circumstances. On the other hand,
stress-induced impairments of learning result from brain memory systems
giving priority to the consolidation of stressor-related information, thereby
compromising the storage or retrieval of other, less important, information.
Amygdala-Induced Modulation of Cognitive Brain Structures …
3
Although these types of effects on learning are adaptive, they can also
have serious inadvertent consequences. For instance, the enhancement of
learning that occurs during a stressful event can lead to the production of
traumatic memories that are difficult to extinguish and promote the onset of
psychological disorders, such as post-traumatic stress disorder (PTSD). Thus,
developing a better understanding of stress-induced alterations of learning and
memory could lend important insight into factors governing the development
of stress-related psychological illness.
It has become apparent that stress-induced alterations of learning and
memory depend on several factors related to the stressor (e.g., type, timing,
intensity, duration), the information being learned (e.g., emotional nature of
the information, learning strategy required), and the organism under
investigation (e.g., sex, age, physical health). In recent years, researchers have
made significant progress describing how these factors interact with the
neurobiological stress response to influence cognition. In the present chapter,
we will present a developing comprehensive theory on how stress, primarily of
the acute variety, interacts with these factors to influence learning and
memory, especially in humans.
WHAT IS STRESS?
Stress is an ill-defined term that has come to mean many things. A
common component of stress is arousal. Stress results in significant activation
of two major physiological systems commonly associated with arousalinducing stimuli, the sympathetic nervous system (SNS) and the
hypothalamus-pituitary-adrenal (HPA) axis. Upon SNS activation, there is a
rapid, almost immediate, release of epinephrine and norepinephrine from the
adrenal medulla, which mobilizes metabolic resources that are necessary for
the fight-or-flight response (Gunnar and Quevedo, 2007). This results in a
significant increase in heart rate and blood pressure and prepares an organism
to act. The HPA axis activation is a slower response that eventually, minutes
later, leads to the synthesis and secretion of corticosteroids (de Kloet, Oitzl,
and Joels, 1999; Joels, 2001). Upon activation of the HPA axis, the
hypothalamus releases corticotropin-releasing hormone (CRH), which
stimulates the anterior pituitary gland to release adrenocorticotropin hormone,
which then travels to the adrenal cortex to induce glucocorticoid synthesis and
release (i.e., cortisol in humans, corticosterone in rodents). Similar to
epinephrine and norepinephrine, glucocorticoids are involved in an organism’s
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Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
stress response, but one of their main functions is to act as a homeostatic
mechanism and regulate the stress response by inhibiting SNS activity (Brown
and Fisher, 1986; Komesaroff and Funder, 1994; Kvetnansky et al., 1993). In
laboratory studies of stress, investigators frequently measure SNS and HPA
axis activity to verify the induction of a stress response.
However, it is important to emphasize that although these responses are
characteristic of stress episodes, their occurrence does not necessitate the
presence of stress. Many activities other than stress (e.g., sex, exercise) can
produce significant SNS and/or HPA axis activity. Therefore, arousal, alone, is
not sufficient to define stress. In addition to arousing, a stressful experience
must be aversive, meaning that, if given the opportunity, an organism would
avoid the situation that is leading to the arousing response. This characteristic
of stress introduces the importance of perception in defining stress. As certain
situations are aversive to some people but not others, not every individual will
consider the same situations to be stressful. Public speaking is an example of
this concept. Some individuals would do anything to avoid public speaking,
whereas others thrive in such situations. Therefore, how an organism views the
situation plays an important role in whether or not stress is experienced.
Finally, even situations that are both aversive and arousing, under some
circumstances, can have minimal effects on physiology and behavior. Another
important variable related to the stress concept is controllability (Maier and
Watkins, 2010). Extensive work has shown that uncontrollable, but not
controllable, aversive and arousing experiences exert significant effects on
physiology and behavior. Thus, having the sense of control over a situation
acts as a buffer against the stress response. Ultimately, based on the
framework put forth by Kim and Diamond (2002), we would contend that
stress is a perceived lack of control over an arousing, aversive experience.
NEUROBIOLOGY OF STRESS – USING
CHRONIC STRESS EFFECTS ON BRAIN
STRUCTURE AS AN EXAMPLE
Stress exerts powerful effects on learning and memory, in large part,
because it results in the release of neurochemicals that have dramatic effects
on cognitive brain areas, such as the amygdala, hippocampus, and prefrontal
cortex (PFC). Each of these brain structures contains at least a moderate
density of corticosteroid receptors, making them highly susceptible to the
Amygdala-Induced Modulation of Cognitive Brain Structures …
5
effects of stress (Diorio, Viau, and Meaney, 1993; McEwen, Macewen, and
Weiss, 1970; McEwen, Weiss, and Schwartz, 1968, 1969; McGaugh, 2004).
The hippocampus, which is necessary for the formation of spatial and/or
declarative memories (Broadbent, Squire, and Clark, 2004, 2006; Eichenbaum,
2004; Kaut and Bunsey, 2001; Moser and Moser, 1998; Squire, Stark, and
Clark, 2004), and the PFC, which is important for higher-order cognitive
function and working memory (Bechara, 2005; Muller and Knight, 2006;
Nebel et al., 2005; Rowe, Owen, Johnsrude, and Passingham, 2001), regulate
the stress response cycle through a negative feedback loop that is initiated by
corticosteroid receptor binding. The amygdala, in contrast, is important for
emotion (primarily fear) (McGaugh, 2004; Roozendaal, McEwen, and
Chattarji, 2009) and can exacerbate the HPA axis response to stress through
corticosteroid receptor-mediated positive feedback.
Preclinical animal models have reported a dissociation between the effects
of stress on hippocampal / PFC and amygdala structure and function. For
instance, chronic stress significantly reduces the length, spine density, and
arborization of dendrites on neurons in the hippocampus and PFC (Cerqueira,
Mailliet, Almeida, Jay, and Sousa, 2007; Conrad, LeDoux, Magarinos, and
McEwen, 1999; Cook and Wellman, 2004; Kole, Costoli, Koolhaas, and
Fuchs, 2004; Lambert et al., 1998; Liston et al., 2006; Magarinos and
McEwen, 1995a, 1995b; Magarinos, McEwen, Flugge, and Fuchs, 1996;
Radley et al., 2005; Radley et al., 2006; Radley et al., 2004), while increasing
each of these parameters on neurons in the amygdala (Vyas, Bernal, and
Chattarji, 2003; Vyas, Jadhav, and Chattarji, 2006; Vyas, Mitra,
Shankaranarayana Rao, and Chattarji, 2002). Unsurprisingly, the same chronic
stress regimens have been shown to produce significant impairments on
hippocampus-dependent tasks (e.g., spatial learning) and PFC-dependent tasks
(e.g., attention set-shifting, working memory, reversal learning) (Bodnoff et
al., 1995; Cerqueira et al., 2007; Krugers et al., 1997; Liston et al., 2006;
Luine, Villegas, Martinez, and McEwen, 1994; Park, Campbell, and Diamond,
2001; Sousa, Lukoyanov, Madeira, Almeida, and Paula-Barbosa, 2000;
Zoladz, Conrad, Fleshner, and Diamond, 2008), while enhancing performance
on amygdala-dependent tasks (e.g., fear conditioning) (Conrad, LeDoux et al.,
1999; Sandi, Merino, Cordero, Touyarot, and Venero, 2001). Additionally, the
same chronic stress that leads to hypertrophy of cells in the amygdala
increases the expression of anxiety-like behaviors in rats tested on the elevated
plus maze (Vyas et al., 2003; Vyas et al., 2006; Vyas et al., 2002).
Importantly, the effects of chronic stress on hippocampal and PFC
morphology have been found to be reversible – that is, the dendrites re-grow
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Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
when the stress is discontinued (Conrad, LeDoux et al., 1999; Radley et al.,
2005; Sousa et al., 2000). This is not the case, however, for the effects of
chronic stress on amygdala morphology or the amygdala-mediated expression
of anxiety-like behavior (Vyas, Pillai, and Chattarji, 2004). Given the
amygdala’s involvement in emotion, particularly fear, these differences have
important implications for understanding how stress can facilitate the onset of
psychological illness.
Most of the aforementioned effects of chronic stress on brain structure and
function have been observed in male rodents. This highlights an important bias
that has been present in the stress literature for some time, and one that we will
address throughout the chapter. Specifically, very few investigators have
attempted to understand the differential effects of stress on males and females,
likely because of the inconvenience and difficulty in dealing with the influence
of the estrus (rodents) or menstrual (humans) cycle on such effects. The few
investigators who have examined the effects of stress on females have often
reported effects opposite to the ones observed in males. For instance, in
preclinical work, chronic stress has been reported to have no effect on or
enhance dendritic arborization in the hippocampus and PFC of female rodents
(Galea et al., 1997; Garrett and Wellman, 2009; McLaughlin, Baran, and
Conrad, 2009) and enhance their spatial learning and memory (Bowman,
Beck, and Luine, 2003; McLaughlin, Baran, Wright, and Conrad, 2005). The
differential effects observed in males and females are likely attributable to the
influence of ovarian hormones in females, as some work has indicated (Garrett
and Wellman, 2009; Luine, Beck, Bowman, Frankfurt, and Maclusky, 2007;
McLaughlin et al., 2009).
The effects of chronic stress on cognitive brain regions, especially the
hippocampus, appear to be mediated by corticosteroid and excitatory amino
acid activity, although most of this work, again, has been conducted in male
rodents. In hippocampal neurons, chronic stress and chronic elevations of
corticosteroids result in excessive glutamatergic activity, in part due to a
reduction of glutamate reuptake and altered GABA signaling (Magarinos and
McEwen, 1995b; Reagan et al., 2004); thus, the dendrites of such neurons
retract to avoid toxic increases in glutamate-induced increases in intracellular
calcium (Conrad, 2006). Accordingly, chronic corticosteroid administration
mimics the effects of chronic stress on hippocampal and PFC morphology
(Magarinos, Orchinik, and McEwen, 1998; Sousa et al., 2000; Watanabe,
Gould, Cameron, Daniels, and McEwen, 1992; Woolley, Gould, and McEwen,
1990), and the stress-induced dendritic retraction in the hippocampus of male
rats can be blocked by steroid synthesis inhibitors, as well as N-methyl-D-
Amygdala-Induced Modulation of Cognitive Brain Structures …
7
aspartate (NMDA) receptor antagonists and agents that significantly reduce
extracellular levels of glutamate (Magarinos and McEwen, 1995b; Magarinos
et al., 1996; Watanabe, Gould, Cameron et al., 1992; Watanabe, Gould,
Daniels, Cameron, and McEwen, 1992).
GENERAL CORRELATES OF ACUTE STRESS
EFFECTS ON LEARNING AND MEMORY
Over the past couple of decades, considerable research has accumulated
indicating that stress can influence many different types of learning (e.g.,
hippocampus-dependent, striatum-dependent, PFC-dependent), oftentimes in
different manners. The majority of this chapter will focus on how acute stress
influences hippocampus-dependent learning and memory, as this seems to be
the most complex and least understood form of stress-memory interaction.
Nonetheless, at the end of the chapter, we will briefly address the influence of
acute stress on multiple memory systems and how alterations of hippocampal
function may be related to this phenomenon.
One important distinction to make when considering how stress affects
learning and memory is to consider how stress affects one’s memory for
events or information that is unrelated to the stressor versus how stress affects
one’s memory for the stress experience itself. In most cases, stress enhances
one’s memory for the stress-inducing stimulus (e.g., terrorist attack, crime that
has taken place), whereas the effects that stress has on one’s memory for
events or information that is unrelated to the stressor are more variable (Wolf,
2008). Thus, when considering the influence of stress on learning and
memory, one must distinguish between intrinsic and extrinsic stressors (Joels,
Pu, Wiegert, Oitzl, and Krugers, 2006). Intrinsic stressors are stressors that are
inherent to the learning experience. In rodents, intrinsic stress has been
manipulated by decreasing the water temperature in a water maze for a spatial
learning task or by increasing the shock intensity in a Pavlovian fear
conditioning experiment (Cordero, Merino, and Sandi, 1998; Sandi,
Loscertales, and Guaza, 1997). In humans, intrinsic stress (or perhaps
“arousal” in this case) has often been manipulated by having participants learn
words or pictures that vary in emotional arousal [i.e., positive (e.g., kiss),
negative (e.g., poison), and neutral (e.g., chair) words or pictures] (Cahill and
McGaugh, 1995; Kuhlmann and Wolf, 2006a). In general, intrinsic stress
enhances learning and long-term memory. Thus, as the water temperature
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Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
decreases in a water maze or the shock intensity increases in a fear
conditioning experiment, the organisms exhibit a greater stress response and
consequentially better learning. In addition, humans exhibit significantly
greater learning and memory for words or pictures that are emotionally
arousing, relative to emotionally neutral information. The enhancing effects of
intrinsic stress on long-term memory have been associated with corticosteroid
and noradrenergic activity in the amygdala (Cahill et al., 1996; Cahill and
McGaugh, 1996; Canli, Zhao, Brewer, Gabrieli, and Cahill, 2000; Strange and
Dolan, 2004; van Stegeren et al., 2005). These mechanisms will be a recurring
theme throughout the chapter, as they explain many of the stress-induced
alterations of learning and memory that have been observed.
Extrinsic stress, on the other hand, includes stressors that are not part of
the learning experience but exert some sort of influence on that experience.
For instance, preclinical investigators have exposed rats to stressors such as
predator stress (e.g., cat), tailshock, or restraint to examine their effects on
learning that takes place in another context (e.g., spatial learning in a water
maze, object recognition learning, etc.) (Campbell et al., 2008; de Quervain,
Roozendaal, and McGaugh, 1998; Diamond et al., 2006; Diamond, Park,
Heman, and Rose, 1999; Kim, Koo, Lee, and Han, 2005; Kim, Lee, Han, and
Packard, 2001; Woodson, Macintosh, Fleshner, and Diamond, 2003). In
humans, investigators have exposed participants to social evaluative stressors
(e.g., Trier Social Stress Test; TSST) or physical stressors (e.g., cold pressor
test – hand placed in ice-cold water) to examine their effects on learning a list
of words or pictures (Cahill, Gorski, and Le, 2003; Schwabe, Bohringer,
Chatterjee, and Schachinger, 2008; Schwabe et al., 2009; Zoladz, Clark et al.,
2011; Zoladz et al., 2013). One of the dogmas in the field of stress-memory
interactions used to be the notion that extrinsic stressors globally impair
hippocampal function; however, over the past decade or so, it has become
apparent that stressors experienced outside of the learning context can either
enhance or impair hippocampus-dependent learning and memory, depending
on numerous factors (Diamond, Campbell, Park, Halonen, and Zoladz, 2007;
Joels, Fernandez, and Roozendaal, 2011; Joels et al., 2006; Schwabe, Joels,
Roozendaal, Wolf, and Oitzl, 2012). Similar to the concept described in the
previous paragraph, some investigators have shown that extrinsic stress can
enhance learning and memory if the information being learned is conceptually
related to the stressor. For instance, Smeets and colleagues exposed
participants to social evaluative stress before learning a list of words that were
either (a) stressor-related or stressor-unrelated and (b) highly arousing or low
arousing (Smeets et al., 2009). The results showed that stress enhanced
Amygdala-Induced Modulation of Cognitive Brain Structures …
9
participants’ long-term memory for stressor-related, high arousing words only,
supporting the idea that extrinsic stress can facilitate the acquisition of
information that is conceptually related to the stressor.
Several studies in both humans and rodents have reported that stressinduced (intrinsic and extrinsic) enhancements and impairments of
hippocampus-dependent learning and memory are associated with endogenous
levels of circulating corticosteroids (Diamond et al., 2007; Wolf, 2009; Zoladz
and Diamond, 2008). Comparable electrophysiological studies have provided
strong evidence for an involvement of corticosteroids in the stress-induced
modulation of long-term potentiation (LTP), a well-studied physiological
model of memory in which an enhancement of synaptic transmission is
produced by high-frequency stimulation of afferent fibers (Diamond et al.,
2007; Kim and Diamond, 2002; Kim, Song, and Kosten, 2006). Studies have
reported that both abnormally low and abnormally high levels of
corticosteroids impair hippocampal synaptic plasticity, suggesting an inverted
U-shaped relationship between corticosteroid levels and hippocampal function
(Diamond, Bennett, Fleshner, and Rose, 1992).
Corticosteroids exert their effects by acting on mineralocorticoid (MR,
Type I) and glucocorticoid (GR, Type II) receptors (Joels, 2001; Joels, Karst,
DeRijk, and de Kloet, 2008). MRs exhibit a much higher affinity for
corticosteroids than GRs and are nearly saturated at baseline. In contrast, GRs
have a much lower affinity for corticosteroids and become extensively
occupied only during times of corticosteroid elevation (e.g., stress). This led
early investigators in the field to formulate the opposing receptor hypothesis,
which suggested that MR activity is responsible for maintaining optimal
hippocampal function, while GR activity is responsible for stress- and
corticosteroid-induced impairments of hippocampal function (Conrad, Lupien,
and McEwen, 1999). This hypothesis was initially supported by replacement
studies reporting that, in adrenalectomized rats, the administration of the MR
agonist aldosterone enhanced hippocampal LTP and rescued spatial memory
impairment induced by corticosteroid depletion, while the administration of
GR agonists impaired hippocampal LTP and enhanced hippocampal long-term
depression (LTD), a decrease in synaptic transmission that is produced by lowfrequency stimulation of afferent fibers (Conrad, Lupien, Thanasoulis, and
McEwen, 1997; Pavlides, Kimura, Magarinos, and McEwen, 1995; Pavlides,
Watanabe, Magarinos, and McEwen, 1995). However, other work did not
support such a simple dichotomy between MR and GR activity and suggested
that some GR occupancy is necessary for optimal hippocampal function. In a
series of experiments, Conrad and colleagues found that, when GRs were
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Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
either completely blocked or highly occupied, rats exhibited impaired spatial
memory in the Y-maze, an effect that was independent of the level of MR
activation (Conrad, Lupien et al., 1999). In other words, only when there was a
moderate level of GR occupancy did rats exhibit intact spatial memory.
Collectively, these findings indicated that both MR and GR activity are
necessary for hippocampus-dependent learning and memory. MR activity
seems to be more involved in encoding / acquisition of hippocampusdependent information (e.g., context), while GR activity seems to be involved
in consolidating (i.e., storing) hippocampus-dependent information for
subsequent retrieval (de Kloet et al., 1999; Oitzl and de Kloet, 1992).
Although corticosteroids are typically considered “stress” hormones, they
circulate throughout the body on a regular basis according to a circadian
rhythm. In humans, corticosteroids are the highest in the morning (i.e.,
awakening) hours, but decrease throughout the day and reach their nadir
sometime during the late evening hours. Thus, in the morning, MRs are
saturated, while GRs tend to be approximately 70% occupied. In the afternoon
/ evening, MRs are approximately 90% occupied, while GRs are only around
10% occupied.
Given these circadian-based differences in corticosteroid receptor activity,
researchers speculated that stress or the administration of corticosteroids might
have different effects on hippocampus-dependent learning and memory in the
morning versus the afternoon / evening. Specifically, investigators predicted
that significant elevations of corticosteroids would result in impairment
primarily in the morning (as GRs would likely be close to saturation as a
result) but may enhance learning and memory in the afternoon (as GRs would
likely be only moderately activated). Two preliminary studies provided
support for this prediction. Lupien and colleagues found that afternoon
administration of hydrocortisone resulted in faster recognition of previously
studied words during a delayed free recall assessment (Lupien et al., 2002),
and Maheu and colleagues reported that social evaluative stress prior to
learning a series of pictures impaired memory for the emotional pictures when
administered in the morning, but had no effect on memory when administered
in the afternoon (Maheu, Collicutt, Kornik, Moszkowski, and Lupien, 2005).
In contrast to these studies, however, Smeets recently found that socially
evaluated cold pressor stress impaired memory retrieval for emotional and
neutral words independent of the time of day (i.e., morning or afternoon)
(Smeets, 2011). This latter finding suggested that stress (and corticosteroid
elevation) could impair memory regardless of when it occurred. However,
there were some important differences between these studies that warrant
Amygdala-Induced Modulation of Cognitive Brain Structures …
11
attention. For instance, both Lupien et al. (2002) and Maheu et al. (2005)
examined males only, while Smeets (2011) included males and females in his
study. In addition, Lupien et al. (2002) employed a within-day design, and
Maheu et al. (2005) studied the effects of pre-learning stress on long-term
memory. Smeets (2011), in contrast, assessed the effects of pre-retrieval stress
on long-term memory. Thus, when considering the disparate findings of
Smeets (2011), the differences between the three studies suggest that the
effects of corticosteroid elevations at different times of the day may depend on
sex and the stage of learning and memory that is influenced by such
elevations. Additional work is necessary, however, to validate such
speculation.
Despite the well-established involvement of corticosteroids in the stressinduced modulation of hippocampus-dependent learning and synaptic
plasticity, it is important to note that an increase in corticosteroid levels, alone,
is not sufficient to significantly alter hippocampal processes and often depends
on concurrent activation of β-adrenergic mechanisms in the amygdala. The
necessary involvement of the amygdala in the stress- and corticosteroidinduced modulation of hippocampal function has been addressed in studies
revealing that inactivating or lesioning the basolateral amygdala (BLA), as
well as administering β-adrenergic receptor antagonists directly into the BLA,
despite leaving corticosteroid levels unaffected, prevents the effects of stress
and corticosteroids on hippocampus-dependent learning and synaptic plasticity
(Kim et al., 2005; Kim et al., 2001; Roozendaal, 2003; Roozendaal, Hahn,
Nathan, de Quervain, and McGaugh, 2004; Zoladz, Park, and Diamond, 2011).
EFFECTS OF STRESS DEPEND ON STAGE OF LEARNING
The process of learning and memory can generally be divided into three
major stages: encoding, consolidation, and retrieval. Encoding involves the
acquisition phase, during which information is initially learned (e.g., studying
a list words, associating a tone with a shock). Consolidation is when the
learned information is stored, or consolidated, in order to be successfully
retrieved (the third stage) at a later point in time. Most of the early studies on
stress-memory interactions did not allow investigators to determine which
stage was affected by the stress. For instance, many studies involved withinday stress manipulations, which hindered the ability to know whether the
effects of stress were due to its effects on encoding, consolidation, or retrieval.
As research in this area progressed, most investigators switched to the use of
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Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
two (or more)-day paradigms, in which participants were stressed before (prelearning stress; encoding / consolidation effects) or after (post-learning stress;
consolidation effects) learning and then tested 24 hr (or more) later, sometimes
following stress (pre-retrieval stress; retrieval effects), for their memory of the
learned information. This methodology has enabled investigators to show that
stress exerts differential effects on learning and memory depending on the
stage that is directly influenced.
Pre-Retrieval Stress (Retrieval Effects)
Most research, in both humans and rodents, has reported deleterious
effects of pre-retrieval stress or corticosteroid administration on memory
(Buchanan and Tranel, 2008; Buchanan, Tranel, and Adolphs, 2006; Buss,
Wolf, Witt, and Hellhammer, 2004; de Quervain et al., 1998; Diamond et al.,
2006; Kuhlmann, Kirschbaum, and Wolf, 2005; Kuhlmann, Piel, and Wolf,
2005; Park, Zoladz, Conrad, Fleshner, and Diamond, 2008; Smeets, Otgaar,
Candel, and Wolf, 2008; Tollenaar, Elzinga, Spinhoven, and Everaerd, 2008).
The memory-impairing effects of pre-retrieval stress have been positively
associated with endogenous corticosteroid levels, and administration of
corticosteroid antagonists can prevent the deleterious effects of pre-retrieval
stress on testing (de Quervain et al., 1998). Pre-retrieval stress or
corticosteroid effects on hippocampus-dependent memory appear to depend on
an interaction of corticosteroids and noradrenergic mechanisms in the
amygdala. Indeed, lesions of the BLA or systemic / intra-BLA administration
of β-adrenergic receptor antagonists, such as propranolol, eliminates the
impairing effects of stress or corticosteroids on memory (Roozendaal, 2003;
Roozendaal et al., 2004). In addition, the effects of pre-retrieval stress or
corticosteroids on memory are often selective for emotionally arousing (i.e.,
amygdala-activating) information (Buchanan et al., 2006; Kuhlmann,
Kirschbaum et al., 2005; Kuhlmann, Piel et al., 2005; Smeets et al., 2008;
Tollenaar et al., 2008), and testing subjects under non-arousing conditions
abolishes the adverse effects of stress on memory testing (Kuhlmann and
Wolf, 2006b). For instance, testing participants in the same context as that
which was utilized during encoding (supposedly reducing novelty stress
induced by participating in an experiment) eliminates pre-retrieval stress
effects on memory (Schwabe and Wolf, 2009a). These findings suggest that
arousal, and more specifically noradrenergic activity in the BLA, is a corequisite for stress or corticosteroid-induced alterations of retrieval.
Amygdala-Induced Modulation of Cognitive Brain Structures …
13
The effects of stress or corticosteroid administration on retrieval, however,
are not unequivocal. Some studies have reported that stress can impair
retrieval without a concurrent increase in corticosteroid levels; others have
shown that pre-retrieval stress has no effect on memory; and, still others have
shown that pre-retrieval stress can enhance memory. In preclinical work,
Diamond and colleagues found that systemic administration of stress-level
corticosterone prior to water maze testing had no effect on spatial memory in
rats. These investigators also reported that stress impaired spatial memory
retrieval in adrenalectomized rats that were not able to manifest a stressinduced increase in corticosteroids, suggesting that corticosteroid elevation is
not even necessary for stress-induced retrieval deficits (Zoladz, Park, Munoz,
Fleshner, and Diamond, 2008). In humans, Beckner and colleagues reported
that exposing participants to social evaluative stress (TSST) had no effect on
recall 48 hr later (Beckner, Tucker, Delville, and Mohr, 2006). Schwabe and
colleagues even found that exposing participants to a brief stressor 30 min
prior to testing enhanced 24-hr recall of emotionally arousing words, an effect
that was prevented by administration of a β-adrenergic receptor antagonist
(Schwabe et al., 2009). Recently, Schilling et al. (2013) reported that
intravenous administration of cortisone prior to retrieval dose-dependently
enhanced memory in participants. These findings resonate with previous work
demonstrating an inverted, U-shaped relationship between corticosteroids and
memory retrieval (Domes, Rothfischer, Reichwald, and Hautzinger, 2005;
Wolf, 2009; Zoladz and Diamond, 2008). In fact, recent work by our group
has revealed that brief stress immediately before memory testing can enhance
declarative memory (Zoladz, Kalchik et al., submitted, unpublished findings).
This is consistent with the work from Schwabe and colleagues (Schonfeld,
Ackermann, and Schwabe, 2014), who found that stress near the time of
retrieval enhanced memory, an effect that was associated with increased
autonomic arousal. The enhancing effects of pre-retrieval stress on memory
may also be related to rapid, non-genomic effects of corticosteroids, which
have been associated with enhanced hippocampus-dependent learning and
synaptic plasticity, rather than classic delayed, gene-dependent corticosteroid
signaling, which often results in impairments of hippocampal function.
As with most of the stress-memory literature, much of the research
examining stress effects on retrieval has been conducted in males. In those
studies that have examined the possibility of sex differences in these effects,
some have revealed that pre-retrieval stress exerts similar effects on males and
females, whereas others have shown that pre-retrieval stress can have
differential effects on males and females, especially when considering
14
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
hormone levels in females. Kuhlmann and Wolf (2005) reported that cortisol
administration impaired retrieval in naturally cycling women (mensis and
luteal phases), but had no effect on memory in women using oral
contraceptives. Schoofs and Wolf (2009) later found that stress had no effect
on females during the luteal phase of the menstrual cycle. Finally, Wolf et al.
(2001) showed that pre-retrieval stress led to a negative correlation between
corticosteroids and memory in men, but not women. Collectively, these studies
show that pre-retrieval stress effects on memory can depend on sex and
circulating hormone levels.
Theoretical views on how stress impairs memory retrieval have focused
on the idea of metaplasticity. Researchers have shown that stress activates
mechanisms in common with models of synaptic potentiation, such as LTP
(Diamond, Park, Campbell, and Woodson, 2005; Diamond, Park, and
Woodson, 2004). One might suggest that stress results in such activity because
a memory of the stress must be formed. Therefore, investigators have
contended that stress activates endogenous plasticity, which leads to an
increased threshold for subsequent plasticity to occur (i.e., metaplasticity);
there may even be a shift toward a suppression of synaptic potentiation
following stress, thus facilitating plasticity such as LTD (Kim and Yoon,
1998; Schmidt, Abraham, Maroun, Stork, and Richter-Levin, 2013).
According to this view, pre-retrieval stress prevents access to stored
information by saturating the neural synapses that are necessary for retrieving
the memory. In other words, stress impairs memory by forming a new
memory, and it is the formation of this new memory that results in retrieval
failure. While some research has supported this view (Diamond et al., 2004),
such a perspective fails to account for pre-retrieval stress-induced
enhancements of memory, even though they have rarely been reported.
Post-Learning Stress (Consolidation Effects)
Most of the research examining the effects of post-learning stress on
consolidation has reported enhancements of long-term memory, and these
enhancements have frequently been associated with an organism’s corticosteroid response to the stressor (Beckner et al., 2006; Cahill et al., 2003;
Hui, Hui, Roozendaal, McGaugh, and Weinberger, 2006; Preuss and Wolf,
2009; Smeets et al., 2008). Indeed, the administration of corticosteroids can
mimic the post-learning stress-induced enhancement of long-term memory
(Roozendaal, Barsegyan, and Lee, 2008). Much evidence indicates that
Amygdala-Induced Modulation of Cognitive Brain Structures …
15
noradrenergic activity in the BLA, along with subsequent activation of GRs by
cortisol, plays a central role in this effect, as GR antagonists, BLA lesions, or
β-adrenergic receptor antagonists block the effect (Roozendaal, 2003;
Roozendaal, Okuda, Van der Zee, and McGaugh, 2006). In human work, the
importance of amygdala activity in the enhancement of memory consolidation
has been demonstrated by studies showing that endogenous elevations of
cortisol are associated with enhanced memory only in participants exhibiting
heightened arousal (Abercrombie, Speck, and Monticelli, 2006). In addition,
Cahill and colleagues found that participants exposed to cold pressor stress
immediately following learning recalled more arousing slides and more details
from arousing slides than control participants (Cahill et al., 2003). These
findings support the notion that stress or corticosteroids result in an amygdalainduced enhancement, or emotional tagging, of recently learned information.
The ability of post-learning stress to enhance long-term memory appears
to be time- and sex-dependent. The enhancement has been observed when
stress is administered up to 30 min following learning, but subsides when
longer time intervals are employed (Nielson and Powless, 2007). Thus, for
memory enhancement to occur, there needs to be a convergence in time
between the learned information and the stress experience. It is likely that the
neurochemicals released during stress must converge on brain areas (i.e.,
convergence in space) engaged during learning at the right time (i.e.,
convergence in time) to promote storage of the information (Joels et al., 2006).
Studies examining sex differences in post-learning stress effects on long-term
memory have been mixed. Felmingham and colleagues reported that postlearning cold pressor stress enhanced memory for negative images in females,
but not males (Felmingham, Tran, Fong, and Bryant, 2012). However, others
have reported similar effects of post-learning stress in males and females
(Beckner et al., 2006; Trammell and Clore, in press) or greater effects in males
(Preuss and Wolf, 2009). If females were more sensitive to stress-induced
enhancements of long-term memory, it may explain why females are more
likely to develop stress-related psychological disorders, such as PTSD (Tolin
and Foa, 2006). More research is warranted to explore how sex and hormonal
differences influence post-learning stress effects on consolidation.
Not all studies examining post-learning stress effects on long-term
memory have reported enhancements. Indeed, a paper recently published by
Trammell and Clore (in press) challenged the well-accepted notion that stress
administered after learning enhances long-term recall. These investigators
found that cold pressor stress administered shortly after learning led to
impaired 48-hr recall. Importantly, this effect was independent of the type of
16
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
information being learned (i.e., words or pictures), the valence / arousal of the
learned information, the duration of the stressor (1- or 3-min stressor), and the
sex of the participant. These findings suggest that the enhancement of
consolidation by stress may be more restricted than once thought and requires
additional work to disentangle.
Pre-Learning Stress (Encoding / Consolidation Effects)
In studies examining the effects of pre-learning stress on long-term
memory, one cannot determine the specific stage of learning that is affected by
the stressor. That is to say, pre-learning stress could influence encoding or the
consolidation of information. In an attempt to verify that stress has influenced
the consolidation rather than the encoding of information, some investigators
show that the pre-learning stress has no effect on memory testing during day 1
(i.e., short-term memory) of an experiment and selectively influences memory
testing during day 2 (i.e., long-term memory). However, even in such studies,
it is impossible to conclusively verify that the information has not been
encoding differentially as a result of stress exposure.
Pre-learning stress effects on encoding or consolidation, regardless of
which stage is actually being influenced, are still meaningful. However,
studies examining pre-learning stress effects on long-term memory have been
more inconsistent than studies examining the effects of post-learning or preretrieval stress on memory, which were discussed above. Studies have shown
that pre-learning stress can enhance, impair, or have no effect on long-term
memory, and this inconsistency appears to depend on several factors
(Diamond et al., 2006; Duncko, Johnson, Merikangas, and Grillon, 2009;
Elzinga, Bakker, and Bremner, 2005; Jelicic, Geraerts, Merckelbach, and
Guerrieri, 2004; Kim et al., 2005; Kim et al., 2001; Nater et al., 2007; Park et
al., 2008; Payne et al., 2007; Payne et al., 2006; Schwabe et al., 2008; Zoladz,
Clark et al., 2011; Zoladz et al., 2013). One factor is the emotional nature of
the learned information. Some work has shown that pre-learning stress, or
corticosteroid administration, can enhance long-term memory for emotionally
arousing information, at the cost of (i.e., impairing) memory for emotionally
neutral information (Jelicic et al., 2004; Payne et al., 2007; Payne et al., 2006).
This phenomenon has been referred to as the “emotional trade-off” effect and
does seem to be adaptive in that exposure to stress would intuitively result in
an individual focusing on emotionally arousing, potentially threatening
information, rather than emotionally neutral, innocuous information. That pre-
Amygdala-Induced Modulation of Cognitive Brain Structures …
17
learning stress can exert selective effects on emotionally arousing information
further supports the involvement of amygdala-induced modulation of cognitive
brain structures in stress effects on learning. However, not everyone has
replicated the effect. In fact, some have shown that pre-learning stress can
enhance long-term memory for emotionally neutral information, while
exerting little to no effect on memory for emotionally arousing information
(e.g., Schwabe et al., 2008).
Two other factors that appear to mediate pre-learning stress effects on
long-term memory are the timing of the stressor relative to learning and the
sex of the individual being examined. As will be described more thoroughly
below, investigators have proposed that stress exerts time-dependent,
multiphasic effects on several brain regions involved in cognition. According
to this view, stress that occurs in close temporal proximity to a learning
experience will result in an enhancement of long-term memory, while stress
that is temporally separated from learning will result in an impairment of longterm memory. Some investigations have corroborated this speculation, but it is
apparent that the sex of the individual under study is important as well. For
instance, we recently reported that brief stress administered 30 min prior to
learning impaired long-term memory in males who exhibited a robust cortisol
response to the stressor, while having no effect on females (Zoladz et al.,
2013).
TEMPORAL DYNAMICS OF ACUTE
STRESS EFFECTS ON LEARNING
Much of the early research on stress and cognition led scientists to
conclude that stress exerted global deleterious effects on hippocampal
function. However, a shift in thought has occurred over the past couple of
decades with the realization that stress, even when occurring outside the
context of the learning experience, can enhance or impair hippocampusdependent learning and memory. Although numerous studies have shown that
acute stress impairs synaptic plasticity in the hippocampus, most of these
studies did not deliver tetanizing (i.e., high-frequency) stimulation to the
neural fibers until long after (e.g., > 20 min) the onset of stress (see Diamond
et al., 2007 for a review). Indeed, a closer examination of the literature, as
indicated by Diamond and colleagues, reveals that when high-frequency
stimulation is delivered shortly after a stressful or arousing event, hippocampal
18
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
synaptic plasticity is actually enhanced (Ahmed, Frey, and Korz, 2006;
Almaguer-Melian et al., 2005; Davis, Jones, and Derrick, 2004; Frey, 2001;
Li, Cullen, Anwyl, and Rowan, 2003; Seidenbecher, Balschun, and Reymann,
1995; Seidenbecher, Reymann, and Balschun, 1997; Straube, Korz, and Frey,
2003; Uzakov, Frey, and Korz, 2005). Because the induction of synaptic
plasticity, such as LTP, is considered to be a well-established physiological
model of learning, one might reason that stress effects on learning might also
be time-dependent.
As a result of their thorough examination of the research literature,
Diamond and colleagues (Diamond et al., 2007) developed the temporal
dynamics model of emotional memory processing to address how the timing
of a stressor might influence the effects of stress on learning. The temporal
dynamics model was inspired by research demonstrating an amygdala-induced
biphasic response pattern of hippocampal function. Specifically, Akirav and
Richter-Levin found that electrical stimulation of the BLA immediately prior
to high-frequency stimulation of the perforant pathway enhanced LTP in the
dorsal dentate gyrus (DG) of the hippocampus, while stimulating the BLA 1 hr
before high-frequency stimulation impaired dorsal DG LTP (Akirav and
Richter-Levin, 1999). Subsequent work revealed that both the enhancement
and impairment of dorsal DG LTP that was induced by BLA stimulation
depended on corticosteroids and norepinephrine, most likely interacting in the
amygdala (Akirav and Richter-Levin, 2002). Also, these investigators showed
that basal, but not lateral or central, amygdala stimulation was responsible for
the effects on hippocampal plasticity (Akirav and Richter-Levin, 1999, 2002).
Interestingly, Richter-Levin and colleagues found that the same BLA priming
stimulation that enhanced DG LTP impaired LTP induction in the CA1 region
of the hippocampus, a region known to be involved in spatial learning and
memory, and that this effect was independent of corticosteroid and
norepinephrine activity (Vouimba and Richter-Levin, 2005; Vouimba, Yaniv,
and Richter-Levin, 2007). Importantly, however, the investigators in these
studies examined the effects of BLA stimulation on plasticity in the ventral
part of the CA1 region, and because extensive work has reported a dissociation
between the functions of the dorsal and ventral hippocampus (Maggio and
Segal, 2012; Segal, Richter-Levin, and Maggio, 2010), the finding may be less
related to memory and more associated with emotional functions of the
structure.
The amygdala-induced biphasic effects on hippocampal plasticity
resonated with the relatively recent discovery that corticosteroids could induce
biphasic effects on hippocampal plasticity as well (de Kloet, Karst, and Joels,
Amygdala-Induced Modulation of Cognitive Brain Structures …
19
2008; Karst et al., 2005; Morsink et al., 2006). The traditional view of
corticosteroid action was that it exerts effects on cells in a delayed manner by
binding to intracellular receptors which enter the nucleus and act as
transcription factors to modulate gene expression. However, it was discovered
that corticosteroids could also bind to membrane-bound receptors and exert
rapid, non-genomic effects on neuronal transmission, effects that were
dependent on MR-induced increases in glutamatergic transmission.
Thus, according to Diamond and colleagues (Diamond et al., 2007), stress
induces two phases of hippocampal function: an excitatory phase (Phase 1)
and an inhibitory phase (Phase 2). At the onset of a stress experience, the
amygdala is rapidly activated, which, in addition to activating the SNS and
HPA axis, would stimulate and enhance hippocampal function (excitatory
Phase 1). Enhanced hippocampal function would be fueled by a dramatic
increase in the levels of numerous excitatory neurochemicals (e.g., glutamate,
acetylcholine, CRH, norepinephrine, dopamine), all of which have been shown
to enhance hippocampal LTP (Ahmed et al., 2006; Blank, Nijholt, Eckart, and
Spiess, 2002; Gray and Johnston, 1987; Hopkins and Johnston, 1988; Li et al.,
2003; Ovsepian, Anwyl, and Rowan, 2004; Wang, Tsai, and Lee, 2000; Wang,
Wayner, Chai, and Lee, 1998; Ye, Qi, and Qiao, 2001) and would, hypothetically, activate endogenous forms of hippocampal neuroplasticity and
facilitate memory storage. Corticosteroid-mediated effects on the hippocampus
would not be observed immediately, as there is a several minute delay from
the onset of stress to the release of corticosteroids from the adrenal cortex
(Cook, 2001). Nevertheless, when the newly synthesized corticosteroids
reached the hippocampus, they would exert immediate, non-genomic
excitatory effects on synaptic plasticity by enhancing glutamate transmission
and facilitating NMDA receptor-dependent synaptic plasticity (Joels et al.,
2011; Joels et al., 2008). Learning that occurred during this phase would
theoretically be enhanced. This would explain why individuals exhibit very
strong memories for stressful experiences by forming so-called “flashbulb
memories” (Brown, 1977). It would also potentially explain how intensely
stressful events can lead to traumatic memory formation and, as a result,
psychological disorders such as PTSD.
As the time from stress onset increased, corticosteroid levels would
significantly rise, resulting in extensive GR activation. In addition, there
would be a buildup of glutamate and calcium, promoting the desensitization of
NMDA receptors (Alford, Frenguelli, Schofield, and Collingridge, 1993;
Nakamichi and Yoneda, 2005; Price, Rintoul, Baimbridge, and Raymond,
1999; Rosenmund and Westbrook, 1993; Zorumski and Thio, 1992). These
20
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
events would result in an inhibition of hippocampal function (Phase 2), which
would lead to impaired learning and memory. Despite the seemingly negative
effects of Phase 2, they would theoretically have adaptive consequences. For
instance, Diamond and colleagues (Diamond et al., 2007) suggested that an
inhibition of hippocampal function following stress would allow for the region
to properly consolidate the information that had been acquired around the time
of the stressor, information that would hypothetically be more important for an
organism’s survival. In addition, Phase 2 would occur to protect hippocampal
cells from the threat of excitotoxicity. As glutamate levels steadily rose, the
increase in intracellular calcium levels would endanger cell survival. Thus,
desensitization of NMDA receptors could be viewed as a compensatory
mechanism to counter this threat. Finally, as a foreshadowing of a subsequent
section, it is during Phase 2 that one might predict an organism to switch
learning strategies from a hippocampus-dependent to a hippocampusindependent strategy (Packard, 2009). This type of adaptive mechanism would
allow an organism to still learn during stress-induced hippocampal impairment
by utilizing a different style of learning.
Although the focus of the temporal dynamics model is how stress
influences hippocampal function, it also includes the prediction that stress
exerts differential effects on amygdala and PFC function. As discussed by
Diamond and colleagues, stress would exert biphasic effects on amygdala
activity, rapidly activating the amygdala shortly after stress but eventually
inhibiting amygdala function over time. Support for this prediction comes
mainly from preclinical research demonstrating time-dependent effects of
stress on amygdala plasticity (Kavushansky and Richter-Levin, 2006;
Schroeder and Shinnick-Gallagher, 2005; Tsvetkov, Carlezon, Benes, Kandel,
and Bolshakov, 2002); however, there is also some evidence that
corticosteroids result in decreased amygdala activity in humans (Henckens,
van Wingen, Joels, and Fernandez, 2010, 2012). It is not clear how the
timeline of amygdala activity would vary following stress onset, and it is
likely, as the authors of the model suggest, that the amygdala would undergo a
longer excitatory phase than that of the hippocampus before entering its
refractory state (Diamond et al., 2007). Nevertheless, the prediction that the
amygdala undergoes a biphasic response pattern following stress relates well
with human studies in which stress administered immediately before fear
conditioning enhanced fear memory, while stress administered more than 30
min before fear conditioning impaired fear memory (Antov, Wolk, and
Stockhorst, 2013). In terms of stress effects on PFC function, Diamond and
colleagues predicted that stress turns the PFC “offline” and impairs PFC
Amygdala-Induced Modulation of Cognitive Brain Structures …
21
function from the onset of the stressor. This prediction is consistent with
extensive work revealing that acute stress impairs PFC-dependent working
memory in both humans and rodents and blocks LTP induction in the PFC
(Maroun and Richter-Levin, 2003; Moghaddam and Jackson, 2004).
Moreover, BLA stimulation 30 sec or 1 hr prior to high-frequency stimulation
impairs LTP in the medial PFC (Richter-Levin and Maroun, 2010).
Most of the support for the temporal dynamics model has come from
preclinical work in non-human animals examining hippocampal synaptic
plasticity or hippocampus-dependent learning and memory in males. As
described above, in electrophysiological studies, an enhancement of the
magnitude and duration of hippocampal LTP has resulted only when tetanizing
electrical stimulation occurred in conjunction with the onset of the arousing
experience. In contrast, when tetanizing stimulation was delivered 30 min or
more after the onset of stress or corticosteroid administration, then LTP has
primarily been inhibited. Behaviorally, investigators have shown that brief
stress applied immediately, but not 30 min, prior to learning enhanced water
maze memory and novel object recognition in male rats (Bullard, Park, and
Diamond, 2013; Diamond et al., 2007). Subsequent work revealed that these
pre-learning stress-induced enhancements of long-term memory were
dependent on β-adrenergic receptor activity, as the administration of
propranolol blocked the effects (Bullard et al., 2013; Halonen, Zoladz, Park,
and Diamond, 2007). More recently, some investigators have shown that
stimulating the BLA immediately after rats learn a novel object recognition
task enhances long-term recognition memory, an effect that is dependent on an
intact hippocampus (Bass, Nizam, Partain, Wang, and Manns, 2013; Bass,
Partain, and Manns, 2012). These latter findings provide perhaps some of the
most conclusive evidence for amygdala-induced modulation of hippocampal
function as a pre-requisite for stress-induced enhancements of memory.
In general, human work in which the timing of stress has been
experimentally manipulated is limited. Our laboratory was the first to
experimentally manipulate the timing of stress before learning to examine its
effects on long-term memory in humans (Zoladz, Clark et al., 2011). We found
that when participants were exposed to brief (i.e., 3-min) socially evaluated
cold pressor stress immediately before learning, they exhibited enhanced
memory for positive words 24 hr later, an effect that was positively associated
with their heart rate response to the stressor. In contrast, when participants
were exposed to the same stressor 30 min prior to learning, they exhibited
impaired memory for negative words 24 hr later, an effect that was negatively
associated with their corticosteroid and blood pressure responses to the
22
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
stressor. That the effects were present only for emotionally arousing
information again implicates an involvement of amygdala activity in the
findings. Overall, the findings of this study suggested that the rapid
enhancement of hippocampus-dependent learning is associated with stressinduced increases in autonomic activity (likely noradrenergic signaling), while
the delayed impairing effects are associated with stress-induced increases in
both corticosteroids and autonomic activity.
Our laboratory recently provided additional support for the temporal
dynamics model by showing that brief (i.e., 3-min) cold pressor stress
administered 30 min before learning impaired overall long-term memory 24 hr
later (Zoladz et al., 2013). Additional work in humans, though limited, has
further supported these findings. For instance, Quaedflieg et al. (2013) found
that stress administered immediately or 30 min prior to learning a series of
images, overall, impaired long-term memory. However, they reported that
stress-induced cortisol responses were positively associated with memory
when stress was administered immediately before learning and negatively
associated with memory when stress was administered 30 min before learning,
suggesting that rapid versus delayed corticosteroid actions could be associated
with different effects on learning. Wolf and colleagues (Pabst, Brand, and
Wolf, 2013) also reported that stress administered 5 or 18 min prior to a
decision-making task led to an improvement of decision-making, while stress
administered 28 min prior to the task led to more risky decisions. As decisionmaking is often dependent on PFC function, these findings suggest that stress
could exert biphasic effects on PFC-dependent, in addition to hippocampusand amygdala-dependent, tasks. Additional work is necessary, however, to
corroborate such speculation.
In addition to the aforementioned studies, much human work related to the
temporal dynamics model has focused on time-dependent effects of
corticosteroids, as opposed to stress, on physiology and behavior. For instance,
Henckens and colleagues have conducted several studies on the rapid (i.e.,
non-genomic) versus delayed (i.e., genomic) effects of corticosteroids on
learning and brain activity in male participants. These investigators found that
rapid corticosteroid activity led to decreased functioning of the amygdala
toward both positive and negative stimuli, while delayed corticosteroid activity
only continued to block amygdala response to positive stimuli, as the response
to negative stimuli returned to baseline levels (Henckens et al., 2010). These
researchers also found that working memory and PFC activity increased as a
result of delayed corticosteroid action (Henckens, van Wingen, Joels, and
Fernandez, 2011). In addition, delayed corticosteroid activity led to decreased
Amygdala-Induced Modulation of Cognitive Brain Structures …
23
activity in the hippocampus when compared to a placebo condition, but not
when compared to rapid corticosteroid effects (Henckens et al., 2012).
Some of these findings concerning time-dependent effects of corticosteroids on brain function seem contrary to what one would predict based on
the temporal dynamics model. However, it is important to emphasize that
studies examining the influence of corticosteroids on physiology and behavior,
though useful for understanding basic stress processes, are not synonymous
with the effects of stress. Indeed, as mentioned above, stress induces the
release of an overabundance of neurochemicals that likely interact with each
other in a complex manner. Therefore, the effects of corticosteroids on
learning, memory, and brain activity do not allow for a full picture of the
consequences that stress can have on the very same processes. It is also
important to note that Henckens and colleagues did not consistently use the
same dosage of corticosteroids across their studies. As described above,
Schilling et al. (2013) demonstrated that, when administering cortisol before
retrieval, the non-genomic effects of cortisol follow a dose-dependent,
inverted U-shaped function. Participants who received a moderate amount of
cortisol, equivalent to what would be experienced during moderate stress,
showed the greatest cued-recall performance. Participants who received either
more or less cortisol recalled fewer items. Therefore, it is possible that
different effects could be seen in the brain regions examined by Henckens and
colleagues if participants are given different amounts of cortisol.
NUANCES OF THE TEMPORAL DYNAMICS MODEL
The temporal dynamics model is a general approach to understanding how
stress can influence cognitive brain areas, which then influence learning and
memory capabilities. It is important to emphasize that, depending on several
factors, the timing and duration of Phase 1 and Phase 2 of the model could
vary considerably. For instance, as illustrated in Figure 1, a very intense
stressor could result in a more short-lived excitatory phase of hippocampal
function and a faster onset of its inhibitory phase. In fact, it is possible that
traumatic stressors could force the hippocampus into a refractory phase
immediately following the onset of stress, which may explain the phenomenon
of traumatic amnesia (Bryant et al., 2009; Layton, Krikorian, Dori, Martin, and
Wardi, 2006). In addition, individual differences, such as different
physiological responses to stress, different perceptions of the stressor, or
different perceived controllability over the stress, could also influence the
24
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
model. Thus, in most cases, stress results in an immediate excitatory phase of
hippocampal function that is followed by a delayed inhibitory phase; however,
the specifics of these phases are likely guided by several factors related to the
stressor and the organism under investigation.
The temporal dynamics model of emotional memory formation is clearly
applicable to how pre-learning stress influences the acquisition and
consolidation of information, but is it relevant to post-learning or pre-retrieval
stress effects on long-term memory? With regards to post-learning stress, we
have already described the requirement of a convergence in time between the
learning experience and the stressor for an enhancement of long-term memory
to be observed. Thus, in this respect, the temporal dynamics model does
appear applicable. That is to say, following learning, the application of a
stressor would enhance amygdala and hippocampal function and facilitate
memory storage. One major difference between the temporal dynamics of preversus post-learning stress may relate to the time window for enhancement. In
other words, post-learning stress may result in an excitatory phase of
hippocampal function that is more prolonged than the excitatory phase time
window observed following pre-learning stress. Of course, the recent finding
that post-learning stress impairs memory consolidation by Trammell and Clore
(in press) suggests that the typical temporal dynamics model, with an
excitatory and inhibitory phase, could apply. More work regarding how postlearning stress affects consolidation processes is needed to further test this
possibility.
Figure 1. Figure 1A (left) illustrates the general model for the temporal dynamics of
acute stress effects on hippocampal function. Shortly following stress onset, amygdala
activity coupled with the rapid actions of several stress-related neurochemicals [e.g.,
norepinephrine (NE), glutamate (Glu)] would enhance hippocampal function and,
consequentially, result in enhanced learning during this time frame. As the time from
Amygdala-Induced Modulation of Cognitive Brain Structures …
25
stress onset increased, the hippocampus would eventually enter a refractory phase,
during which learning would be impaired. The refractory phase would result from
delayed effects of corticosteroids (CORT), as well as NMDA receptor desensitization.
Figure 1B (right) illustrates how the general temporal dynamics model may differ if a
very intense stressor is experienced. In this case, the stress-induced enhancement of
hippocampal function may be more short-lived, and the refractory phase may have a
more rapid onset. Of course, a similar pattern of stress-induced alterations of
hippocampal function could result from other factors, such as individual differences
(e.g., sex, genetic variation).
The traditional view has been that stress influences retrieval in a timedependent manner, but any effect that occurs is likely to be impairment. For
instance, researchers have shown that stress shortly before retrieval has no
effect on memory, but when the stress occurs approximately 30 min before
retrieval, providing enough time for endogenous corticosteroid levels to rise,
impairment results (de Quervain et al., 1998). However, recent work from our
laboratory and from that of others has suggested that this is an issue requiring
further examination. Schilling and colleagues reported that intravenous
cortisol administration shortly before retrieval dose-dependently enhanced
recall (Schilling et al., 2013). This enhancement is likely a result of rapid, nongenomic effects of corticosteroids exerting a facilitative effect on cognitive
brain function. In addition, our laboratory recently found that exposing
participants to brief (i.e., 3-min), cold pressor stress immediately prior to 24-hr
retrieval enhanced memory in males who exhibited a robust cortisol response
to the stressor, thus suggesting a role of rapid, non-genomic corticosteroid
actions in this enhancement (Zoladz, Kalchik et al., submitted, unpublished
findings). These findings, though preliminary, do indicate that pre-retrieval
stress or corticosteroid administration can enhance memory. Of course, preretrieval stress effects on memory might not follow the exact same temporal
dynamics that have been put forth for pre-learning stress, as such a model does
not necessarily fit with the finding that brief stress administered 30 min before
retrieval enhances memory (Schwabe et al., 2009). Future work must delineate
the timeline for pre-retrieval stress effects on human memory and the
mechanisms or factors that could mediate different directions of the effects
observed.
26
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
SEX DIFFERENCES IN ACUTE
STRESS EFFECTS ON LEARNING
Throughout the stress-memory literature, there has been a clear bias
toward studying male, as opposed to female, subjects. This has likely resulted
from the inconvenience and difficulty in controlling for the influence of the
estrus / menstrual cycle on any observed effects. Those investigators who have
explored the influence of sex in stress-memory interactions have shown that
stress exerts sex-specific effects on learning and memory; however, the
differences observed in these studies have been inconsistent and difficult to
unravel. Preclinical work has shown that acute stress enhances classical
eyeblink conditioning in male rats, while impairing such conditioning in
female rats (Wood and Shors, 1998). These effects may be related to baseline
differences that have been observed between males and females in eyeblink
conditioning paradigms, as females tend to exhibit greater performance than
males under such conditions. Neurobiologically, researchers have shown that
the differential effects of stress on eyeblink conditioning in males and females
require an intact BLA (Waddell, Bangasser, and Shors, 2008). Moreover,
acute stress has been reported to exert differential effects on hippocampal
spine density in male and female rodents (Shors, Chua, and Falduto, 2001;
Shors, Falduto, and Leuner, 2004). While such stress increases CA1 spine
density in males, it decreases this spine density in females. Research
examining sex differences in mediating stress-induced alterations of other
types of learning has been less conclusive. For instance, some investigators
have shown that acute stress impairs spatial learning and memory in males,
while enhancing it in females (Conrad et al., 2004); others have shown that
acute stress exerts comparable effects on both sexes or that females are less
severely affected than males, yet not enhanced (Park et al., 2008). Many of the
differences observed in the stress-induced alterations of learning and memory
in male and female rodents has been attributed to the influence of ovarian
hormones (Shors, Lewczyk, Pacynski, Mathew, and Pickett, 1998; Wood,
Beylin, and Shors, 2001).
Like preclinical work, research in humans has also been biased against the
inclusion of females in stress-memory investigations, perhaps even to a greater
degree. Nevertheless, several studies have reported greater stress-induced
alterations of learning and memory in males, relative to females. Investigators
have frequently reported negative or curvilinear relationships between stressinduced cortisol and memory in males, while observing no relationship
Amygdala-Induced Modulation of Cognitive Brain Structures …
27
between these variables in females (Andreano and Cahill, 2006; Wolf et al.,
2001). On the other hand, females tend to recall emotional information better
than males, an effect that has been associated with greater noradrenergic
activity in females (Felmingham, Tran et al., 2012; Schwabe, Hoffken,
Tegenthoff, and Wolf, 2013). Similar to preclinical work, ovarian hormones
may play a role in mediating these effects. Cahill and colleagues observed a
positive correlation between stress-induced cortisol and memory only when
female participants were in the mid-luteal phase of the menstrual cycle, a time
when progesterone levels are elevated (Andreano, Arjomandi, and Cahill,
2008). Later work substantiated these findings by reporting that females
exhibiting high levels of progesterone demonstrate better memory for
emotional information, greater stress-induced elevations of salivary cortisol,
and stronger stress-induced enhancements of memory than women with low
levels of progesterone (Ertman, Andreano, and Cahill, 2011; Felmingham,
Fong, and Bryant, 2012). Females also exhibit stronger responses of the
amygdala-hippocampus neural network to emotional stimuli when they are in
the luteal phase (Andreano and Cahill, 2010). These findings may collectively
explain why females are more susceptible to stress-related psychological
disorders such as PTSD (Tolin and Foa, 2006).
It is also possible that the female brain does not respond to emotion in the
same manner that the male brain does. Some research has shown that the brain
responses of males and females to emotional stimuli are hemisphere-specific.
For instance, Cahill and others have reported that, when presented with
emotional stimuli, males tend to exhibit greater activity in the right amygdala,
while females tend to exhibit greater activity in the left amygdala (Cahill et al.,
2001; Cahill, Uncapher, Kilpatrick, Alkire, and Turner, 2004; Canli, Desmond,
Zhao, and Gabrieli, 2002; Mackiewicz, Sarinopoulos, Cleven, and Nitschke,
2006). Interestingly, the right amygdala has been associated with one’s
memory for gist, while the left amygdala has been associated with one’s
memory for details (Fink et al., 1996; Fink, Marshall, Halligan, and Dolan,
1999). Thus, it may not be surprising to note that, under emotionally arousing
conditions, males exhibit greater memory for the central aspects of a scene,
while females exhibit greater memory for the details (Cahill and van Stegeren,
2003). This differential activation of brain areas in response to emotional
stimuli could play an important role in sex influences on stress-memory
interactions.
We have recently observed sex differences in pre-learning stress-induced
alterations of hippocampus-dependent memory. In one study, we were
interested in testing the time-dependent influences of stress on false memory
28
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
production (Zoladz, Peters et al., submitted, unpublished findings). Based on
the temporal dynamics model, we hypothesized that stressing participants
immediately before encoding would reduce false memory production, as
opposed to increasing it (Payne, Nadel, Allen, Thomas, and Jacobs, 2002). We
exposed participants to brief cold pressor stress immediately before having
them perform the Deese-Roediger-McDermott (DRM) false memory paradigm
(Deese, 1959; Roediger and McDermott, 1995). In this paradigm, participants
are exposed to several lists of semantically-related words (e.g., candy, sour,
sugar, bitter, chocolate, cake) and subsequently given free recall and
recognition tests for the word lists. Experiments employing this paradigm have
reported that many participants falsely recall / recognize semantically-related,
non-presented “critical lures” (e.g., sweet) as being a part of the original word
list. In the study, participants were stressed, given 10 of the DRM word lists to
learn (one at a time) and tested for their memory after the presentation of each
list. As predicted, we found that stress, overall, reduced false memory. We
then analyzed the data in a slightly different manner, by comparing the effects
of stress on false memory for critical lures from the first half of the word lists
studied, relative to the second half of the word lists studied. Hypothetically, if
the temporal dynamics model is accurate, one would expect stress to enhance
learning for the first five word lists that were presented, as they would be
temporally more proximal to the stress experience. We found that stressed
males recalled fewer critical lures from the first five word lists, while stressed
females recalled fewer critical lures from the second five word lists. This
suggested to us that the temporal dynamics of acute stress, and its
neurobiological consequences, could differ between the sexes.
For instance, as illustrated in Figure 2, it is possible that while males
exhibit a temporal pattern that more closely aligns with the traditional
temporal dynamics timeline described above, females might demonstrate a
temporal pattern in which stress-induced enhancements of hippocampal
function are delayed, relative to males, or simply last longer than those of
males. This hypothesis is supported by other work from our laboratory in
which we found that brief cold pressor stress administered 30 min prior to
learning led to impaired long-term memory in males, but not females. In this
case, the hippocampal function of females may not have yet entered the
predicted refractory phase, which is why their long-term memory was not
influenced. Further research is necessary to address this speculation and to
ascertain the influence of menstrual cycle activity on such effects.
Amygdala-Induced Modulation of Cognitive Brain Structures …
29
Figure 2. Figure 2A (top left) illustrates how genetic variation might influence the
temporal dynamics of stress effects on hippocampal function. The deletion variant of
the ADRA2B gene, for instance, could enhance the excitatory phase as a result of
greater amygdala and noradrenergic activity and promote even greater stress-induced
enhancements of learning. Other genetic polymorphisms could lead to alterations of
the refractory phase as well. Importantly, depending on the type of genetic variation,
the alterations in each phase could be facilitative or inhibitory. Figures 2B (top right)
and 2C (bottom) provide additional examples of how individual differences, such as
genetic variation or sex, could influence the dynamics of stress effects on hippocampal
function. As an example, following stress onset, females might display either a longerlasting excitatory phase with a delayed-onset inhibitory phase (Figure 2B) or simply a
delayed-onset excitatory phase (Figure 2C), relative to males.
GENETIC VARIATION AND STRESS-INDUCED
ALTERATIONS OF LEARNING AND MEMORY
One of the reasons why generating conclusions about stress-memory
interactions is so difficult is because different individuals are often affected
30
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
differently by the same stressor. Thus, a topic of increasing importance in the
field of stress-memory interactions is that of genetic variation and its influence
on such effects. Over the past several years, researchers have established a
clear association between certain genetic polymorphisms, emotional memory,
and the onset of stress-related psychological disorders, such as PTSD
(Amstadter, Nugent, and Koenen, 2009; Skelton, Ressler, Norrholm,
Jovanovic, and Bradley-Davino, 2012; Wilker, Elbert, and Kolassa, in press).
While it is beyond the scope of this review to elaborate extensively on how
such polymorphisms might be involved in stress-induced alterations of
learning and memory, it is potentially an important avenue for future research
in terms of discerning why different individuals respond differently to stress.
There are several examples of associations between genetic polymorphisms, emotional memory, and PTSD in the literature. For instance, a
deletion variant of the ADRA2B gene, which affects ADRA2B (α2Badrenergic) receptor function in a way that leads to greater norepinephrine
availability, results in enhanced emotional memory (de Quervain et al., 2007),
greater amygdala reactivity to stress (Cousijn et al., 2010) and emotional
stimuli (Rasch et al., 2009), and greater intrusiveness of traumatic memories in
people with PTSD (de Quervain et al., 2007). Polymorphisms of the gene that
codes for FK506 binding protein 5 (FKBP5), a co-chaperone of the GR that
interacts with heat shock protein 90 to influence GR sensitivity (Binder, 2009),
have been associated with altered baseline cortisol levels (Mahon, Zandi,
Potash, Nestadt, and Wand, 2013), prolonged physiological responses to stress
(Ising et al., 2008), increased amygdala reactivity (White et al., 2012), and
greater risk for PTSD (Binder et al., 2008; Boscarino, Erlich, Hoffman,
Rukstalis, and Stewart, 2011; Boscarino, Erlich, Hoffman, and Zhang, 2012;
Levy-Gigi, Szabo, Kelemen, and Keri, in press; Mehta et al., 2011; Xie et al.,
2010). As a final example, a single nucleotide polymorphism (SNP)
(Val66Met) in the gene coding for brain-derived neurotrophic factor (BDNF),
a protein involved in neurogenesis and synaptic plasticity, is associated with
greater amygdala activity and impaired extinction learning (Felmingham,
Dobson-Stone, Schofield, Quirk, and Bryant, 2013; Lonsdorf et al., 2010;
Soliman et al., 2010). Despite the clear association of these genetic
polymorphisms with emotional memory and the onset of PTSD, very little
work has addressed the role of such genetic variation in the stress-induced
alteration of learning and memory. Those studies that have investigated
genetic predictors of stress-memory interactions have assessed the
involvement of such genetic variation in the effects of pre-retrieval stress on
memory (Li, Weerda, Guenzel, Wolf, and Thiel, 2013) or have measured PFC-
Amygdala-Induced Modulation of Cognitive Brain Structures …
31
dependent working memory (Buckert, Kudielka, Reuter, and Fiebach, 2012),
as opposed to hippocampus- or amygdala-dependent memory. We would
contend that an examination of how such polymorphisms interact with prelearning stress effects on learning would provide more relevant information
with regards to the formation of traumatic memories and therefore be more
applicable to understanding the onset of stress-related disorder like PTSD.
However, as of yet, there has been no research in this area.
It is our speculation that some of the aforementioned polymorphisms may
increase the risk for PTSD by influencing stress effects on learning and
facilitating traumatic memory formation. For instance, the deletion variant of
ADRA2B may, through its effects on norepinephrine availability, interact with
the temporal dynamics model outlined above to augment the excitatory phase
of amygdala and hippocampal function, thereby facilitating the formation of a
powerful emotional memory following stress (see Figure 2). Other
polymorphisms related to the stress response, such as those for FKBP5, could
influence stress-memory interactions in such a way that exacerbates stressinduced impairments of hippocampal function and learning. Variants of stress
response genes could increase and/or prolong the excitatory and/or inhibitory
phases of hippocampal function that theoretically follow stress onset. Of
course, these effects could result from alterations of physiological mechanisms
underlying the stress response, which thereby influences amygdala-induced
modulation of hippocampal plasticity.
STRESS AND MULTIPLE MEMORY SYSTEMS
The presence of multiple brain memory systems is well supported by
research in both humans and non-human animals (Packard, 2009; Schwabe,
Wolf, and Oitzl, 2010). These memory systems often support different types of
learning (e.g., explicit vs. implicit), yet can interact and are thus not
completely independent of one another. For instance, researchers have
frequently differentiated between a hippocampus-based learning system,
which is a “cognitive” system that supports declarative or spatial learning
strategies, and a striatum-based learning system, which is a “habit” system that
supports response- and cue-based learning strategies. Using clever
experimental apparatus and methodologies, investigators have been able to
examine subjects’ performance on tasks that can be acquired via either of these
strategies. Early studies employing such techniques revealed that organisms
32
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
begin training by adopting a hippocampus-based spatial strategy, but over
time, shift to a hippocampus-independent, striatum-based response strategy.
Research has demonstrated that the amygdala, a brain area heavily
implicated in the stress response, can influence each of these memory systems.
For instance, Packard and colleagues found that amphetamine infusions into
the amygdala enhanced rat performance on cue- (i.e., striatum-dependent) or
spatially- (i.e., hippocampus-dependent) based water maze tasks (Packard,
Cahill, and McGaugh, 1994). Thus, investigators speculated that stress, due to
its association with amygdala activity, might influence the type of learning
strategy that an organism adopts for a task that can be learned in one of
multiple ways. Such studies have generally shown that stress administered
prior to learning or retrieval biases organisms toward a striatum-based
response strategy, as opposed to a hippocampus-based spatial strategy. For
instance, Kim et al. (2001) exposed rats to restraint stress combined with
tailshock for 1 hr prior to water maze learning. When the water maze task
could be solved only by employing a hippocampus-dependent spatial strategy,
stressed rats exhibited an impairment of long-term memory, an effect that was
prevented by lesioning the amygdala. In contrast, pre-learning stress enhanced
long-term memory in the water maze when the task could be solved by
adopting a striatum-dependent cue strategy, suggesting that stress shifted rats’
learning strategy from a hippocampus-based to a striatum-based strategy.
Packard and colleagues observed similar effects in a T-maze when an
anxiogenic pharmacological agent, an α2-adrenergic receptor antagonist, was
injected in the animals systemically or directly into their BLA (Elliott and
Packard, 2008). In addition, inactivation of the BLA prevented the shift from a
hippocampus-dependent spatial strategy to a striatum-dependent response
strategy that resulted from the anxiogenic agent (Packard and Gabriele, 2009).
Collectively, these findings suggest that acute episodes of stress induce
amygdala activity that, when resulting in an impairment of hippocampusdependent learning, shifts organisms’ learning strategy to one that involves
striatum-dependent response learning.
Recent work in humans has reported similar effects. In these studies, acute
stress administered before learning led to a shift from spatial strategies to
response-based strategies (Schwabe and Wolf, 2012). Interestingly,
investigators found that administration of an MR antagonist blocked the stressinduced shift from hippocampus-dependent to striatum-dependent learning
(Schwabe, Tegenthoff, Hoffken, and Wolf, 2013), suggesting an involvement
of corticosteroids in the effects. Other work also revealed that stress impaired
goal-directed (i.e., PFC-dependent) learning and favored habit-based learning
Amygdala-Induced Modulation of Cognitive Brain Structures …
33
(Schwabe and Wolf, 2009b, 2010), which was associated with concurrent
corticosteroid and β-adrenergic receptor activity (Schwabe, Hoffken,
Tegenthoff, and Wolf, 2011; Schwabe, Tegenthoff, Hoffken, and Wolf, 2010).
These results in humans corroborate the abovementioned findings in rodents
and indicate that stress impairs hippocampus- and PFC-dependent learning,
while promoting striatum-dependent strategies.
With regards to the temporal dynamics model of emotional memory, the
shift in learning strategy that occurs following stress would likely take place
during Phase 2. That is, once stress forced hippocampal or PFC function into a
refractory state, organisms might switch to a striatum-based strategy as a
compensatory and adaptive response to the stressor, which would still allow
the organism to acquire important information during hippocampal or PFC
impairment. As discussed above, the switch in learning strategy that occurs is
likely due to amygdala-induced modulation of hippocampal, PFC, and
striatum function and reveals that stress not only can affect how much an
organism learns (i.e., quantity), but also the way in which an organism learns
(i.e., quality) (Schwabe, Wolf et al., 2010).
CONCLUSION
Stress-induced alterations of learning and memory are complex, and
although research over the past couple of decades has allowed us to make
great strides in our understanding of such effects, there is still a great deal
about stress-memory interactions that is as of yet unknown. In the present
chapter, we have reviewed the literature on acute stress effects on
hippocampus-dependent learning and memory in an attempt to provide a
developing theory on factors that mediate such effects. Clearly, there are some
common elements underlying most stress-induced alterations of learning and
memory, including corticosteroid and noradrenergic interactions in the
amygdala. However, it is our speculation that the timing of stress relative to
learning or testing results in differential effects on long-term memory due to
differential time courses of neurochemical-induced effects on amygdala
interaction with cognitive brain structures. These effects may also be shaped
by individual differences (e.g., genetic variation) and the sex of the organism.
Additional work is essential in order to elucidate how the timing of stress
interacts with factors related to the individual to influence learning and
memory.
34
Phillip R. Zoladz, Andrea E. Kalchik, Chelsea E. Cadle et al.
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