How the amygdala affects emotional memory by altering brain network properties

Hermans, E.J.; Battaglia, F.P.; Atsak, P.; Voogd, L.D. de; Fernandez, G.S.E.; Roozendaal, B.
2014, Article / Letter to editor (Neurobiology of Learning and Memory, 112, (2014), pp. 2-16)
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 How the amygdala affects emotional memory by altering
brain network properties

Erno J. Hermans1,2
Francesco P. Battaglia1,2,3
Piray Atsak1,2
Lycia D. de Voogd1,2
Guillén Fernández1,2
Benno Roozendaal1,2

1. Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, 6500
HB, The Netherlands
2. Department for Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, 6525 EZ, The
Netherlands
3. Departments for Neuroinformatics and Neurophysiology, Faculty of Science, Radboud University
Nijmegen, Nijmegen, 6525 AJ, The Netherlands

Neurobiology of Learning and Memory 112, 2-16.

DOI: 10.1016/j.nlm.2014.02.005

Corresponding author:
Erno J. Hermans
Donders Institute for Brain, Cognition and Behaviour
Centre for Cognitive Neuroimaging
P.O. Box 9101
6500 HB Nijmegen
The Netherlands
Ph: +31 (0)24 36 68294
Fx: +31 (0)24 36 10989
e-mail: [email protected]

Key words: amygdala, emotional memory, stress hormones, memory consolidation, connectivity
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Abstract
The amygdala has long been known to play a key role in supporting memory for emotionally arousing
experiences. For example, classical fear conditioning depends on neural plasticity within this anterior medial
temporal lobe region. Beneficial effects of emotional arousal on memory, however, are not restricted to
simple associative learning. Our recollection of emotional experiences often includes rich representations of,
e.g., spatiotemporal context, visceral states, and stimulus-response associations. Critically, such memory
features are known to bear heavily on regions elsewhere in the brain. These observations led to the
modulation account of amygdala function, which postulates that amygdala activation enhances memory
consolidation by facilitating neural plasticity and information storage processes in its target regions. Rodent
work in past decades has identified the most important brain regions and neurochemical processes involved
in these modulatory actions, and neuropsychological and neuroimaging work in humans has produced a large
body of convergent data. Importantly, recent methodological developments make it increasingly realistic to
monitor neural interactions underlying such modulatory effects as they unfold. For instance, functional
connectivity network modeling in humans has demonstrated how information exchanges between the
amygdala and specific target regions occur within the context of large-scale neural network interactions.
Furthermore, electrophysiological and optogenetic techniques in rodents are beginning to make it possible to
quantify and even manipulate such interactions with millisecond precision. In this paper we will discuss that
these developments will likely lead to an updated view of the amygdala as a critical nexus within large-scale
networks supporting different aspects of memory processing for emotionally arousing experiences.

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Introduction
Stressful and emotionally arousing experiences are preferentially retained in memory (Joëls, Fernández, &
Roozendaal, 2011; Schacter, 1999). It has long been known that the amygdala, an anterior medial temporal
lobe structure, plays a pivotal role in this usually highly adaptive phenomenon. The notion that the amygdala
is involved in affective processing dates back to the classic report by Klüver and Bucy (1937) on the effects
of temporal lobectomy in rhesus monkeys. Bilateral lesions of this region were shown to result in striking
behavioral changes, including visual agnosia, dietary changes, and hypersexuality, but also profound
alterations in affective behaviors, including tameness and loss of fear. Further investigations into these
effects by Weiskrantz in the 1950s demonstrated that these affective changes were largely due to
anteromedial temporal lobe lesions, particularly to the amygdala (Weiskrantz, 1956). Weiskrantz’ work also
demonstrated that amygdala lesions not only block the expression of conditioned fear, but also impair new
fear learning. This observation set the stage for a line of research into the role of the amygdala in emotional
memory that now spans multiple decades (McGaugh & Roozendaal, 2002; Phelps & LeDoux, 2005;
Roozendaal, McEwen, & Chattarji, 2009a). Initially, this research focused on the amygdala proper as a
storage site for associations underlying fear memory (Davis & Whalen, 2000; LeDoux, 2000). For instance,
it was shown that fear learning depends on the induction of neural plasticity within the basolateral complex
of the amygdala (BLA) (Miserendino, Sananes, Melia, & Davis, 1990; Rogan, Stäubli, & LeDoux, 1997).
These findings led to the view that the BLA might be a crucial site where sensory input converges and
synaptic plasticity can produce lasting changes in emotional responses to environmental stimuli.
However, the beneficial effects of emotional arousal on memory extend well beyond associative fear
learning. Recollection of emotional experiences typically includes not only representations of sensory cues,
but, for example, also of spatial and temporal context in which these have been encountered (Christianson,
1992; Diamond, Campbell, Park, Halonen, & Zoladz, 2007; Phelps, 2004; Sandi & Pinelo-Nava, 2007).
Importantly, such types of declarative memory rely heavily on neural systems elsewhere in the brain (Bird &
Burgess, 2008; Henke, 2010). This notion has been corroborated by an extensive body of evidence
documenting beneficial effects of stress hormones and neurotransmitters released during emotionally
arousing experiences on various types of memory, both in rodents (McGaugh, 1989) and in humans (Lupien,
Maheu, Tu, Fiocco, & Schramek, 2007; Schwabe, Joëls, Roozendaal, Wolf, & Oitzl, 2012). These
developments led to the proposal that the amygdala contributes to enhancement of memory for emotional
events primarily by integrating these neuromodulatory influences and modulating mnemonic activity and
synaptic plasticity in other brain regions (McGaugh & Roozendaal, 2002; Roozendaal, McEwen, &
Chattarji, 2009a). Research into the role of the amygdala in influencing memory consolidation processes in
other memory systems was pioneered by James L. McGaugh and colleagues. However, this modulation
hypothesis of amygdala function can historically be traced back to Ralph W. Gerard, who hypothesized
already many years before the first experiments were performed that amygdalar nuclei could “modify the
ease and completeness of experience fixation even if the nuclei were not themselves the loci of engrams”
(Gerard, 1961).

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 As we will address below, the modulation hypothesis has received wide empirical support over the
years. Rodent studies have utilized pharmacological manipulations, selective lesions and immediate-early
gene activation to delineate the relevant structures, pathways and neurochemical processes. This work has
dovetailed tightly with behavioral, psychopharmacological, neuropsychological, and neuroimaging studies in
humans. However, more recent methodological developments make it increasingly feasible to monitor neural
activity in real-time, and thus to explore how information is processed and exchanged between brain regions.
For instance, the rapid proliferation of techniques for functional connectivity network modeling in humans
using functional magnetic resonance imaging (fMRI) has made it possible to study interactions within large-
scale neural systems in the human brain (Raichle, 2009). Findings gathered using these techniques have
generated novel insights into how brain regions implicated in different types of memory are part of distinct
large-scale connectivity networks (Ranganath & Ritchey, 2012). As explained below, these findings yield
important heuristics for translation back to basic neuroscience, which offers the technology to investigate
these processes more mechanistically and in more spatial and temporal detail. For instance, in vivo
electrophysiological techniques in rodents now make it possible to simultaneously record activity of
neuronal ensembles distributed across different brain regions during different phases of memory processing
(Buzsáki, 2004), while optogenetic techniques allow manipulations of specific neural connections with
millisecond precision (Boyden, Zhang, Bamberg, Nagel, & Deisseroth, 2005; Tye et al., 2011). Future
application of these techniques to the amygdala and its many efferent connections will lead to a sophisticated
understanding of how the amygdala engages stress hormone and neurotransmitter systems to modulate large-
scale network properties and influence distant neural processes underlying the formation and consolidation
of memory for emotionally arousing experiences.

Role of the amygdala in memory modulation

During an emotionally arousing episode, stress hormones (epinephrine and glucocorticoids) are secreted
from the adrenal glands and several neurotransmitters and neuropeptides are released in the brain (Joëls &
Baram, 2009). The amygdala plays a critical role in integrating these various neuromodulatory influences on
memory (McGaugh, 1989; 2004). The modulation hypothesis proposes that during and shortly after an
emotionally arousing experience, the amygdala engages stress-related hormones and neurotransmitters to
enhance the consolidation and storage of memory within other parts of the brain. Studies performed since the
1970s have produced a wealth of convergent data supporting this notion. Gold and van Buskirk (1975) were
the first to report that systemic post-learning injection of the adrenomedullary hormone epinephrine
enhances long-term retention of inhibitory avoidance training. The epinephrine effect was both dose-
dependent and time-dependent. Memory enhancement was greatest when epinephrine was administered
shortly after training (Gold & Van Buskirk, 1975). Epinephrine-induced memory enhancement has now been
extended to many other types of training in rodents (Costa-Miserachs, Portell-Cortés, Aldavert-Vera, Torras-
García, & Morgado-Bernal, 1994; Introini-Collison & McGaugh, 1986; Sternberg, Isaacs, Gold, &
McGaugh, 1985) as well as declarative memory in humans (Cahill & Alkire, 2003). Similar findings were
obtained, for example, with post-learning elevations of adrenocortical glucocorticoid hormones in both

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rodents (Cottrell & Nakajima, 1977; Hui et al., 2004; Okuda, Roozendaal, & McGaugh, 2004; Roozendaal &
McGaugh, 1996; Zorawski & Killcross, 2002) and humans (van Marle, Hermans, Qin, Overeem, &
Fernández, 2013; Wilhelm, Wagner, & Born, 2011). However, these stress hormones appear to affect
memory consolidation only for emotionally arousing experiences in the presence of arousal-induced
noradrenergic activity (Borrell, de Kloet, & Bohus, 1984; Borrell, de Kloet, Versteeg, & Bohus, 1983; Liang,
Juler, & McGaugh, 1986; Okuda et al., 2004; Roozendaal, Carmi, & McGaugh, 1996; Roozendaal, Okuda,
van der Zee, & McGaugh, 2006b). A similar dependency on concurrent noradrenergic activity was found for
other memory-enhancing compounds such as the opiate receptor antagonist naloxone (Izquierdo &
Graudenz, 1980), corticotropin-releasing factor (CRF) (Lee, Lee, Wang, & Lin, 1993), and cannabinoid
compounds (Atsak, Roozendaal, & Campolongo, 2012). As we will discuss below, extensive evidence
indicates that the effects of various stress-related neurochemical changes converge onto arousal-induced
activation of noradrenergic transmission within the amygdala, which in turn interacts with other brain
regions in regulating the consolidation of different types of memory. Although in this paper we will mainly
focus on the role of the amygdala in regulating the encoding and consolidation of memory, there exists now
compelling evidence that amygdala activity, via its interactions with other brain regions, is also crucially
involved in regulating stress hormone and emotional arousal effects on other aspects of memory processing
such as memory retrieval, memory extinction, and working memory (Roozendaal, Hahn, Nathan, de
Quervain, & McGaugh, 2004a; Roozendaal, McReynolds, & McGaugh, 2004b).

Evidence for a modulatory role of the amygdala in rodents

Findings of experiments by Kesner (Kesner et al., 1983; Ellis et al., 1981) and Gallagher (Gallagher et al.,
1981) were the first to suggest that the noradrenergic system of the amygdala is involved in influencing
memory consolidation. A ß-adrenoceptor antagonist administered into the amygdala post-training was shown
to impair memory, while concurrent infusion of norepinephrine blocked this memory impairment (Gallagher
et al., 1981). Many subsequent studies found that post-training infusions of norepinephrine or ß-adrenoceptor
agonists into the amygdala (or selectively into the BLA) enhance memory consolidation for a wide variety of
training experiences (Bianchin, Mello e Souza, Medina, & Izquierdo, 1999; Ferry & McGaugh, 1999;
Hatfield & McGaugh, 1999; Huff, Wright-Hardesty, Higgins, Matus-Amat, & Rudy, 2005; Introini-Collison,
Dalmaz, & McGaugh, 1996; Introini-Collison, Miyazaki, & McGaugh, 1991; Introini-Collison, Saghafi,
Novack, & McGaugh, 1992; Lalumiere, Buen, & McGaugh, 2003; Lalumiere, Nawar, & McGaugh, 2005;
Liang et al., 1986; Liang, Chen, & Huang, 1995; Liang, McGaugh, & Yao, 1990; Roozendaal, Castello,
Vedana, Barsegyan, & McGaugh, 2008). Experiments investigating the role of amygdala norepinephrine in
modulating memory consolidation have generally used emotionally arousing training conditions that induce
the release of high levels of norepinephrine in the amygdala. However, as is shown in Figure 1, recent
findings indicate that post-training noradrenergic activation of the BLA also enhances memory of a low-
arousing object recognition training experience that otherwise would not induce strong memory (Roozendaal
et al., 2008). Thus, these findings suggest that in the absence of high arousal, noradrenergic activation of the
BLA is sufficient to enhance memory consolidation. Noradrenergic activity within the BLA also plays an

6
important role in mediating the modulatory effects of many other hormones and neurotransmitters on
memory consolidation (Roozendaal, 2007). For example, a ß-adrenoceptor antagonist infused into the BLA
post-learning blocks the memory-modulatory effects of epinephrine, glucocorticoids, cannabinoids, CRF as
well as GABAergic and opioid peptidergic drugs (Atsak et al., 2012; Introini-Collison, Nagahara, &
McGaugh, 1989; Quirarte, Roozendaal, & McGaugh, 1997; Roozendaal et al., 2008; Roozendaal &
McGaugh, 2011).
The extensive evidence that noradrenergic activity within the amygdala modulates memory
consolidation suggests that emotionally arousing learning experiences should induce the release of
norepinephrine within the amygdala. Findings of studies using in vivo microdialysis and high-performance
liquid chromatography (HPLC) to measure ongoing changes in norepinephrine levels in the amygdala
strongly support this implication. Footshock stimulation comparable to that used for inhibitory avoidance
training, the task used in many rodent studies, significantly increases amygdala norepinephrine release
(Galvez, Mesches, & McGaugh, 1996; Quirarte, Galvez, Roozendaal, & McGaugh, 1998). Moreover, drugs
and hormones that enhance memory consolidation augment footshock-induced increases in norepinephrine
levels in the amygdala and drugs that impair consolidation decrease amygdala norepinephrine levels
(Hatfield, Spanis, & McGaugh, 1999; Kawahara, Hesselink, van Scharrenburg, & Westerink, 2004;
McReynolds et al., 2010; Quirarte et al., 1998; Williams, Men, Clayton, & Gold, 1998). McIntyre et al.
(2002) found that norepinephrine levels in the amygdala increased significantly after inhibitory avoidance
training. Additionally, and importantly, the retention performance of individual animals tested the following
day correlated highly with levels of amygdala norepinephrine induced by the training. Thus, there is now
extensive evidence indicating that emotionally arousing experiences induce the release of norepinephrine
into the BLA and that this noradrenergic activity plays an important role in mediating the modulatory
influences of other hormones and neurotransmitters on memory consolidation of these experiences
(Roozendaal & McGaugh, 2011).
As discussed above, many of the experiments investigating BLA involvement in memory
consolidation have used inhibitory avoidance training (Aggleton, 2000; Izquierdo et al., 1997; McGaugh &
Izquierdo, 2000; Parent & McGaugh, 1994; Wilensky, Schafe, & LeDoux, 2000). However, comparable
effects of post-training amygdala treatments have been obtained with many different kinds of training,
including both high-arousing and low-arousing tasks, such as contextual fear conditioning (Lalumiere et al.,
2003; Sacchetti, Lorenzini, Baldi, Tassoni, & Bucherelli, 1999; Vazdarjanova & McGaugh, 1999), cued fear
conditioning (Hui et al., 2004; Roozendaal, Hui, Hui, Berlau, McGaugh, et al., 2006a; Sacchetti et al., 1999;
Schafe & LeDoux, 2000), Y-maze discrimination training (McGaugh, Introini-Collison, & Nagahara, 1988),
change in reward magnitude (Salinas, Introini-Collison, Dalmaz, & McGaugh, 1997), conditioned place
preference (Hsu, Schroeder, & Packard, 2002; Schroeder & Packard, 2003; 2004), radial-arm maze
appetitive training (Packard & Chen, 1999), water-maze spatial and cued training (Packard & Teather, 1998;
Packard, Cahill, & McGaugh, 1994), conditioned taste aversion (Miranda, LaLumiere, Buen, Bermudez-
Rattoni, & McGaugh, 2003; Miranda, Quirarte, Rodriguez-Garcia, McGaugh, & Roozendaal, 2008),
olfactory training (Kilpatrick & Cahill, 2003a), object recognition (Roozendaal, Okuda, van der Zee, &

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McGaugh, 2006b), extinction of contextual fear conditioning (Berlau & McGaugh, 2006), and extinction of
conditioned reward (Schroeder & Packard, 2003). As these different training experiences are known to
engage different brain systems (Gold, 2004; Izquierdo & Medina, 1997; McGaugh, 2002; Packard & Cahill,
2001; Packard & Knowlton, 2002; Quillfeldt et al., 1996; Zanatta et al., 1996), the BLA-induced modulation
no doubt involves influences on information processing occurring in these different brain regions. Packard
and colleagues (Packard et al., 1994; Packard & Teather, 1998) were the first to show that the amygdala can
modulate memory processes in both the striatum (caudate nucleus) and hippocampus. Considerable evidence
indicates that the striatum and hippocampus are involved in different aspects of memory (e.g., McDonald &
White, 1993; Packard & Cahill, 2001; Packard & McGaugh, 1992; 1996). These authors found that the
stimulant drug amphetamine infused into the striatum after training on a water-maze task selectively
enhanced memory of visually cued water-maze training, whereas amphetamine administered into the dorsal
hippocampus selectively enhanced memory of spatial water-maze training. In contrast, amphetamine infused
into the amygdala post-training enhanced memory of both cued and spatial training. Moreover, as
inactivation of the amygdala prior to retention testing did not block the amphetamine effect on memory of
either kind of training, these findings indicate that amygdala activation modulates the consolidation of both
striatal-dependent and hippocampus-dependent memory but is not a critical locus of memory for either type
of training.
Studies of the effects of post-training administration of glucocorticoid hormones provide additional
evidence of BLA-hippocampus interactions in memory consolidation. As is shown in Figure 2, unilateral
post-training intra-hippocampal infusions of the specific glucocorticoid receptor (GR) agonist RU 28362
enhance rats’ retention of inhibitory avoidance training and the enhancement is blocked by ipsilateral
infusions of a ß-adrenoceptor antagonist into the BLA. These findings clearly indicate that arousal-associated
noradrenergic activity within the BLA is a co-requirement in enabling glucocorticoid effects on memory
processing in the hippocampus. Noradrenergic stimulation of the BLA that enhances memory consolidation
also increases dorsal hippocampal levels of activity-regulated cytoskeletal protein (Arc) (McIntyre et al.,
2005), an immediate-early gene implicated in hippocampal synaptic plasticity and memory consolidation
processes (Guzowski et al., 2000). Additionally, inactivation of the BLA with post-training infusions of
lidocaine impairs memory consolidation and decreases Arc protein levels in the dorsal hippocampus
(McIntyre et al., 2005). The finding that intra-BLA infusions of muscimol attenuate the increase in Arc
mRNA induced by contextual fear conditioning provides further evidence that the BLA modulates memory
consolidation via regulation of Arc expression in the hippocampus (Huff et al., 2006).
Studies of BLA influences on hippocampal neural plasticity provide additional important evidence
of amygdala-hippocampal interactions (Abe, 2001). Electrical stimulation of the BLA enhances the induction
of long-term potentiation (LTP) in the dentate gyrus of the hippocampus (Akirav & Richter-Levin, 1999;
Almaguer-Melian, Martínez-Martí, Frey, & Bergado, 2003; Frey, Bergado-Rosado, Seidenbecher, Pape, &
Frey, 2001; Ikegaya, Saito, & Abe, 1995; Vouimba & Richter-Levin, 2013), but appear to block LTP in the
CA1 region of the hippocampus (Vouimba & Richter-Levin, 2005; 2013). Also, selective lesions of the BLA
or infusions of a ß-adrenoceptor antagonist into the BLA block the induction of LTP in the dentate gyrus

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(Ikegaya et al., 1995; Ikegaya, Nakanishi, Saito, & Abe, 1997; Ikegaya, Saito, & Abe, 1994). Norepinephrine
and glucocorticoids both influence the effects of BLA stimulation on dentate gyrus LTP (Akirav & Richter-
Levin, 2002; Vouimba, Yaniv, & Richter-Levin, 2007). Recent findings indicate that electrical stimulation
of the BLA also enhances LTP at cortical synapses onto striatal neurons (Popescu, Saghyan, & Paré, 2007)
and that coherent gamma oscillations couple the BLA and striatum during learning (Popescu, Popa, & Paré,
2009). Such findings fit well with the evidence that amygdala activation enhances the consolidation of both
hippocampus and striatal-dependent memory (Packard et al., 1994; Packard & Teather, 1998).
Findings of several studies indicate that the BLA also modulates neocortical functioning involved in
memory consolidation. Neurons within the BLA project directly to the entorhinal cortex (Paré & Gaudreau,
1996; Paré, Dong, & Gaudreau, 1995; Petrovich, Canteras, & Swanson, 2001; Pikkarainen, Rönkkö,
Savander, Insausti, & Pitkänen, 1999). Memory enhancement induced by post-training drug infusions
administered into the entorhinal cortex (Izquierdo & Medina, 1997) requires a functioning BLA, as lesions
of the BLA prevent the memory enhancement induced by 8-bromo-cAMP infused post-training into the
entorhinal cortex (Roesler, Roozendaal, & McGaugh, 2002). BLA lesions or blocking of β-adrenoceptors in
the BLA also prevent the memory-enhancing effects of 8-bromo-cAMP infused post-training into the insular
cortex (Miranda & McGaugh, 2004) and of oxotremorine infused into the rostral anterior cingulate cortex
(Malin, Ibrahim, Tu, & McGaugh, 2007). There is also evidence indicating that the BLA and the medial
prefrontal cortex, a brain region involved in higher cognitive processing, interact in regulating memory
consolidation. Inactivation of the medial prefrontal cortex with an AMPA receptor antagonist impairs
consolidation of inhibitory avoidance memory (Liang, Hu, & Chang, 1996). In contrast, activation of
noradrenergic and dopaminergic mechanisms in the medial prefrontal cortex enhances the consolidation of
inhibitory avoidance training and trace fear conditioning (Liang, 2001; Runyan & Dash, 2004). The GR
agonist RU 28362 infused into the medial prefrontal cortex induces similar memory enhancement
(Barsegyan, Mackenzie, Kurose, McGaugh, & Roozendaal, 2010; Roozendaal, McReynolds, van der Zee,
Lee, et al., 2009b). However, lesions of the BLA block the GR agonist-induced memory enhancement.
Furthermore, consistent with the evidence of functional connectivity between both brain regions (McDonald,
1991; Pérez-Jaranay & Vives, 1991; Rosenkranz & Grace, 2002), the administration of RU 28362 into the
medial prefrontal cortex after inhibitory avoidance training increases BLA activity, as assessed with
phosphorylation of extracellular signal-regulated kinase type 1 and 2 (Erk1/2), a member of the mitogen-
activated protein kinase family (Roozendaal, McReynolds, van der Zee, Lee, et al., 2009b). Blockade of this
increase in phosphorylated Erk1/2 levels in the BLA with a MEK inhibitor prevents the memory
enhancement induced by medial prefrontal cortex GR agonist infusions. Interestingly, infusions of a GR
agonist into the BLA induce a similar increase in phosphorylated Erk1/2 activity in the medial prefrontal
cortex, suggesting bi-directional interactions between both brain regions in regulating memory consolidation.
In conclusion, there is now a wealth of evidence from experiments using primarily local drug
administration supporting the hypothesis that neuromodulatory influences on the amygdala after learning
promote memory processing in regions elsewhere in the brain. These regions include the hippocampus,
entorhinal cortex, striatum, medial prefrontal cortex, anterior cingulate cortex, and insula, and this list is

9
likely to expand in the future. We will now turn to human neuropsychological and neuroimaging work on the
involvement of the amygdala in modulating distinct types of memory.

Evidence for a modulatory role of the amygdala in humans

The first studies investigating the role of the amygdala in memory modulation in humans were performed in
patients with damage to this brain region. In agreement with rodent findings, epilepsy patients who
underwent unilateral anteromedial temporal lobe resection exhibited impaired acquisition of conditioned fear
(LaBar, LeDoux, Spencer, & Phelps, 1995; Peper, Karcher, Wohlfarth, Reinshagen, & LeDoux, 2001). A
similar deficit was observed in a patient with Urbach-Wiethe disease (also known as lipoid proteinosis)
(Bechara et al., 1995), a rare congenital disorder that causes a progressive and selective calcification of the
amygdala, particularly in the BLA region (Terburg et al., 2012). Critically, in line with the modulation
hypothesis, effects of amygdala lesions were not confined to fear learning. Urbach-Wiethe patients exhibited
broader memory deficits that extend into the domain of declarative memory (Markowitsch et al., 1994;
Thornton et al., 2008). Urbach-Wiethe patients, for example, fail to show enhancement of episodic memory
for emotional events within a story (Adolphs, Cahill, Schul, & Babinsky, 1997; Cahill, Babinsky,
Markowitsch, & McGaugh, 1995), a finding that closely resembles the effects of ß-adrenoceptor blockade in
healthy volunteers (Cahill, Prins, Weber, & McGaugh, 1994). A larger group of Urbach-Wiethe patients
exhibited impaired recognition memory for emotionally arousing photographs (Siebert, Markowitsch, &
Bartel, 2003). Amygdala damage also results in a loss of the benefit of gist over detail memory for emotional
episodes (Adolphs, Denburg, & Tranel, 2001; Adolphs, Tranel, & Buchanan, 2005), suggesting that the
amygdala modulates sensory processes (Henckens, Hermans, Pu, Joëls, & Fernández, 2009; Vuilleumier,
Richardson, Armony, Driver, & Dolan, 2004) as well as prefrontal regions involved in extracting and
representing gist (Qin, Hermans, van Marle, & Fernández, 2012; Qin, van Marle, Hermans, & Fernández,
2011) already at the time of encoding. Unilateral anteromedial temporal lobe resection patients furthermore
show impaired consolidation of emotional information. Unlike control participants, patients did not exhibit
an increase in memory for emotionally arousing words over a 1-hour period of consolidation (LaBar &
Phelps, 1998).
A critical development in human research on the amygdala was the arrival of non-invasive
techniques for functional neuroimaging. Initial studies used positron emission tomography (PET) to
demonstrate amygdala activity in response to socially salient stimuli such as facial expressions (Breiter et al.,
1996; Morris et al., 1996), but also during fear conditioning (Fredrikson, Wik, Fischer, & Andersson, 1995;
Hugdahl et al., 1995; Morris, Friston, & Dolan, 1998). The temporal resolution of PET, however, is
insufficient to detect transient responses evoked by discrete events such as conditioned stimuli. This
possibility came with blood oxygenation level-dependent fMRI (BOLD-fMRI). A wave of BOLD-fMRI
studies confirmed the hypothesis that the amygdala responds to conditioned stimuli (Buchel, Dolan, Armony,
& Friston, 1999; Büchel, Morris, Dolan, & Friston, 1998; Cheng, Knight, Smith, Stein, & Helmstetter, 2003;
LaBar, Gatenby, Gore, LeDoux, & Phelps, 1998; Schiller et al., 2008). A number of studies also reported
hippocampal coactivation during trace conditioning (Buchel et al., 1999; Cheng, Disterhoft, Power, Ellis, &

10
Desmond, 2008) and contextual conditioning (Kalisch et al., 2006; Marschner, Kalisch, Vervliet,
Vansteenwegen, & Büchel, 2008).
Functional MRI has furthermore been used to demonstrate that noradrenergic activity increases
excitability of the human amygdala already at the time of encoding. Induction of acute stress unselectively
increased amygdala responses to presentations of emotional facial expressions, stimuli that robustly elicit
amygdala activation (van Marle, Hermans, Qin, & Fernández, 2009). Although exposure to acute stress
likely causes a surge of norepinephrine from the locus coeruleus (Valentino & van Bockstaele, 2008), this
finding may be explained by neuromodulatory mechanisms other than norepinephrine. Subsequent studies,
however, showed that amygdala responses to emotional stimuli are enhanced in carriers of a deletion variant
of ADRA2B (the gene encoding the a2b-adrenoceptor), who have increased noradrenergic tone (Rasch et al.,
2009). Stress induction was also shown to cause a stronger increase in amygdala responses in ADRA2B
deletion carriers (Cousijn et al., 2010). Furthermore, pharmacological studies showed that ß-adrenoceptor
blockade with propranolol reduces the amygdala response to emotional material (Hurlemann et al., 2010;
Strange & Dolan, 2004; van Stegeren et al., 2005), whereas the selective norepinephrine-reuptake inhibitor
reboxetine has an opposite effect (Onur et al., 2009). Thus, ample evidence supports the involvement of
norepinephrine in modulating amygdala activity in humans.
In line with rodent findings of adrenergic-glucocorticoid interactions (McGaugh & Roozendaal,
2002), one study showed that the effects of propranolol on amygdala responses to emotional stimuli interact
with endogenous cortisol (van Stegeren et al., 2007). A pharmacological experiment involving both
reboxetine and hydrocortisone administration observed the largest amygdala responses when both drugs
were administered simultaneously (Kukolja et al., 2008), although studies combining yohimbine, a
noradrenergic stimulant, and hydrocortisone administration have produced less clear results (Schwabe,
Hoffken, Tegenthoff, & Wolf, 2013a; van Stegeren, Roozendaal, Kindt, Wolf, & Joëls, 2010). A study in
which only hydrocortisone was administered, without manipulation of noradrenergic activity, found a
decreased amygdala responsiveness at both 75 and 285 min after administration, suggesting that such slow
effects of glucocorticoids might be involved in the recovery from stress (Henckens, van Wingen, Joëls, &
Fernández, 2010). Consistent with the findings from animal studies, glucocorticoids therefore appear to
potentiate amygdala responses in humans primarily during the time window of elevated noradrenergic
activity.
In further agreement with the modulation view, a number of studies have found that amygdala
activation during learning influences mnemonic processes that depend on other brain regions. Early studies
using PET found that amygdala activity during encoding is associated with interindividual differences in
hippocampal-dependent declarative memory for emotionally arousing experiences (Cahill et al., 1996; 2001;
Hamann, Ely, Grafton, & Kilts, 1999). With BOLD-fMRI, such findings were extended to trial-by-trial
variation in success of memory formation (Cahill, Uncapher, Kilpatrick, Alkire, & Turner, 2004; Canli,
Zhao, Brewer, Gabrieli, & Cahill, 2000; Kensinger & Corkin, 2004). One such study showed that encoding-
related activation of the amygdala and hippocampus was more strongly correlated for emotionally arousing

11
than for neutral stimuli (Dolcos, Labar, & Cabeza, 2004). Structural equation modeling of PET data indicates
that the amygdala modulates activity of the parahippocampal gyrus and ventrolateral prefrontal cortex during
encoding of emotional memory (Kilpatrick & Cahill, 2003b). ß-adrenoceptor blockade with propranolol
during memory encoding was shown to diminish the enhancement of hippocampal activity for emotional
items at retention testing 10 hours later, when propranolol was no longer active (Strange & Dolan, 2004).
Amygdala modulation of hippocampal-dependent encoding processes was demonstrated more directly in an
fMRI study involving patients with variable lesions in the hippocampus and amygdala (Richardson, Strange,
& Dolan, 2004). While hippocampal lesions blocked declarative memory for both emotional and neutral
stimuli, amygdala lesions selectively impaired memory for emotional items. Hippocampal activity associated
with successful memory formation for emotional items was negatively associated with the extent of
amygdala lesions. Thus, emotional enhancement of encoding efficiency within the hippocampus depends on
the integrity of the amygdala.
Emotional modulation of memory is not restricted to amygdala influences on the hippocampus. As
described above, the hippocampus and striatum comprise functionally distinct memory systems (McDonald
& White, 1993; Packard et al., 1994). While the hippocampal memory system in humans is commonly
thought to support spatial and episodic aspects of memory (Henke, 2010), the striatum is a critical region for
stimulus-response learning and habit formation (Ashby, Turner, & Horvitz, 2010; Schwabe & Wolf, 2013).
Recent findings in humans have shown that this latter system is particularly augmented during acute stress.
In navigation learning, for instance, stress induction caused a shift from spatial towards stimulus-response
learning strategies (Schwabe et al., 2007). In line with the notion that stress causes relapse in addiction
(Arnsten, 2009), stress induction causes a persistence of habitual behavior despite devaluation of its
outcomes (Schwabe & Wolf, 2009). Neuroimaging work has confirmed that neural activity during a
probabilistic category learning task shifts from hippocampus to striatum under stress (Schwabe & Wolf,
2012). A recent study has shown that this effect is accompanied by a shift in connectivity of the amygdala
from hippocampus to striatum, thus providing direct human evidence supporting the view that the amygdala
plays a critical role in inducing this shift between memory systems during emotionally arousing situations
(Schwabe, Tegenthoff, Hoffken, & Wolf, 2013b).
In conclusion, findings of neuropsychological and neuroimaging studies in humans are in general
agreement with those of animal experiments, and confirm the critical role of arousal-associated
noradrenergic activation of the amygdala in modulating memory processes that take place elsewhere in the
brain. One notable difference between animal and human work is that human studies have focused more
strongly on memory encoding than on consolidation, while the opposite is true for animal work. By showing
that the amygdala also modulates encoding-related activity, human data have provided an important
extension of rodent work. In the following section, we will turn to studies into the architecture of
connectivity networks involving the amygdala and other brain regions involved in memory processing of
emotionally arousing experiences.

12
Human neuroimaging work on network interactions involving the amygdala
Guided by animal research, human neuroimaging studies initially employed targeted region-of-interest
analyses to focus exclusively on the role of the amygdala. However, numerous limitations aside, BOLD-
fMRI in humans has one critical advantage over animal work using selective lesions and targeted
pharmacological interventions. This advantage is that magnetic resonance imaging protocols used for fMRI
easily reach full-brain coverage without compromising temporal resolution beyond the minimum
requirements to sample event-related hemodynamic responses, and thus allow for simultaneous investigation
of activity across the entire brain. Consequently, even though fMRI studies into the amygdala often focus on
findings from this area only, the same analyses are performed throughout the brain. Findings observed in
unexpected regions, however, are usually only reported in tables and often remain uninterpreted due to lack
of space, interest, or prior knowledge about those regions.
Ironically, in the broader field of human functional neuroimaging, it were the findings that ended up
in such tables that led to some of the field’s most influential discoveries. It turned out that particular sets of
distributed brain regions systematically co- or deactivate in response to widely different cognitive tasks
(Corbetta & Shulman, 2002; Raichle et al., 2001). Meta-analyses across large numbers of functional imaging
studies furthermore revealed that regions that exhibit similar evoked activity also show correlated intrinsic
BOLD signal fluctuations (<.1 Hz) during rest (Greicius, Krasnow, Reiss, & Menon, 2003; Raichle et al.,
2001; Smith et al., 2009), suggesting that such regions form large-scale neural networks. The topography of
such networks moreover corresponds with structural connectivity data (van den Heuvel, Mandl, Kahn, &
Hulshoff Pol, 2009). Recent years has seen a rapid progress in mapping the anatomy of a variety of such
networks (Damoiseaux et al., 2006; Raichle, 2009; Raichle & Snyder, 2007).
The first large-scale neural system that was identified using these techniques was a set of brain
regions that consistently deactivates in response to tasks requiring goal-directed attention and is referred to
as the default mode network (Raichle et al., 2001). This network most prominently includes the
(ventro)medial prefrontal cortex, inferior parietal lobule, and posterior cingulate and retrosplenial cortex
(Buckner, Andrews-Hanna, & Schacter, 2008). Notably, these brain regions also exhibit substantial resting
functional connectivity with medial temporal lobe structures, including the hippocampus and amygdala
(Buckner et al., 2008). Robust default mode network activation during waking rest has led to the suggestion
that this network supports “offline” associative processing (Bar, 2007) and prospection (Buckner & Carroll,
2007). Such a notion concurs with rodent findings of coupling between the hippocampus and prefrontal
cortex (Ji & Wilson, 2007; Qin, McNaughton, Skaggs, & Barnes, 1997; Wierzynski, Lubenov, Gu, & Siapas,
2009), in particular the (ventro)medial prefrontal cortex (Takehara-Nishiuchi & McNaughton, 2008), during
waking rest. Resting hippocampal-neocortical connectivity, or default mode network activity, has therefore
been proposed to support systems consolidation, in particular the integration of newly encoded information
into pre-existing associative networks (e.g., Ranganath & Ritchey, 2012) or schemas (Preston &
Eichenbaum, 2013; van Kesteren, Fernández, Norris, & Hermans, 2010; van Kesteren, Ruiter, Fernández, &
Henson, 2012). The limited temporal resolution of BOLD-fMRI, however, makes it difficult to investigate
the precise timing and directionality of these interactions.

13
 Studies into amygdala function likewise led to a number of serendipitous observations. Emotionally
arousing tasks that activate the amygdala were shown to lead to a consistent and robust coactivation of a
specific set of other brain regions. This set includes the dorsal anterior cingulate cortex and medial prefrontal
cortex, and the anterior portion of the insula (often extending into the inferior frontal gyrus). These regions
are associated with autonomic control and visceral perception (Critchley, 2005). Furthermore, coactivated
brain regions include areas involved in attentional regulation (thalamus and inferotemporal and
temporoparietal regions) (Corbetta, Patel, & Shulman, 2008), stimulus-response learning and habitual
behavior (striatum), catecholaminergic signaling (brainstem and midbrain nuclei), and regulation of
peripheral stress effector systems (hypothalamus) (Ulrich-Lai & Herman, 2009). Meta-analyses of human
functional neuroimaging studies have indicated that these brain regions respond consistently to a variety of
salient stimuli, including unconditioned stimuli, conditioned stimuli, pain, and empathy for pain (Kober et
al., 2008). An important observation was that these brain regions also exhibit coordinated activity in the
resting brain, and thus form a distinct intrinsic connectivity network (Menon, 2011; Menon & Uddin, 2010;
Seeley et al., 2007). Although the exact topology of the salience network remains subject to debate, there is
wide agreement regarding its core components, namely the dorsal anterior cingulate cortex and anterior
insula (Dosenbach, Fair, Cohen, Schlaggar, & Petersen, 2008; Hermans et al., 2011; Menon, 2011).
An influential hypothesis is that this network integrates various neurocognitive functions relevant to
processing salient stimuli (Seeley et al., 2007), including attentional vigilance, interoceptive representation,
and homeostatic regulation. Attentional functions of the salience network are understood as a system for
exogenous attention or reorienting (Corbetta et al., 2008). For instance, spontaneous activity in the salience
network is associated with electroencephalographic signatures of alertness (Sadaghiani et al., 2010).
Activation of the salience network is thought to facilitate switches of task sets within a more dorsal executive
control system that regulates endogenous attention (Corbetta et al., 2008). Notably, theories of noradrenergic
function propose a similar circuit-breaking or network switching function for noradrenergic projections
towards the neocortex (Aston-Jones & Cohen, 2005; Sara & Bouret, 2012). Because noradrenergic neurons
in the locus coeruleus exhibit tonically increased firing rates under stress (Aston-Jones & Cohen, 2005;
Valentino & van Bockstaele, 2008), it was proposed that stress or emotional arousal causes a prolonged
increase in neural excitability within brain regions comprising the salience network (Corbetta et al., 2008;
Sara & Bouret, 2012).
A recent study directly tested this hypothesis by quantifying functional connectivity within the
salience network during exposure to a fear-related stressor, i.e., a movie fragment depicting extreme violence
(Hermans et al., 2011). The strength of functional connectivity within the salience network increased in
response to this stressor and was found to correlate positively with salivary levels of a-amylase, a peripheral
measure of adrenergic activity (Nater & Rohleder, 2009). Network connectivity also correlated with levels of
salivary cortisol and subjective ratings of negative affect induced by the movie clips. As shown in Figure 3, a
follow-up experiment demonstrated that ß-adrenoceptor blockade with propranolol, but not the cortisol-
synthesis inhibitor metyrapone, blocked the stress-induced increase in functional connectivity within this

14
salience network (Hermans et al., 2011). Furthermore, resting connectivity within the salience network
remained elevated during awake rest immediately following exposure to this stressor (van Marle, Hermans,
Qin, & Fernández, 2010). A critical suggestion of these theoretical accounts is that salience network activity
is involved in the formation of an interoceptive representation of the physiological state evoked by prior
salient events, and thus contributes to long-term memory and adaptation (Craig, 2008; Damasio & Carvalho,
2013). The brain regions comprising the salience network indeed map remarkable well onto the regions
modulated by the amygdala through noradrenergic mechanisms listed in the previous sections (e.g., dorsal
anterior cingulate cortex, insula, and striatum). However, while attentional and homeostatic functions of the
salience network have been explored quite extensively, mnemonic functions, and the role the amygdala in
these, have up to now received little attention.
In sum, brain regions shown in rodent work to be modulated by the amygdala appear to exhibit well-
orchestrated interactions as part of distinct large-scale networks. Prominently among these are the
hippocampal complex and medial prefrontal cortex, which are part of the midline-centered default mode
network, and insular, anterior cingulate, and striatal structures that are part of the salience network. A
network understanding of these interactions and how they contribute to memory encoding and consolidation
is just beginning to develop. In the following section, we will outline how these observations generate novel
questions for future research, some of which can be addressed through back-translation to basic
neuroscience.

Rodent and primate electrophysiology work on network interactions and its extension to the amygdala
Lesions, pharmacological interventions, and immediate early gene activation techniques in rodents have led
to an identification of brain regions, pathways, and neurochemical processes involved in the consolidation of
memory of emotionally arousing experiences. Human work has corroborated these findings, and has
moreover offered an initial window onto the organization of neural interactions within large-scale neural
ensembles, suggesting that the consolidation of emotional memories is a network process in which the
amygdala plays a central role. However, to gain a true understanding of how information is processed,
stored, and passed between brain regions, it is necessary to capture and manipulate transient and oscillatory
phenomena that typically take place within a time window of milliseconds. This requires a temporal
resolution that far exceeds what is possible with BOLD-fMRI. Sufficient temporal resolution can be
achieved with novel technology for rodent studies such as high-density neural ensemble recordings (Buzsáki,
2004), which can be used to simultaneously record activity from ensembles distributed across different brain
regions, and across longer periods of time. The study of memory processes in brain networks with such fine-
grained techniques has been pursued with great intensity in the past 20 years. However, as we will explain
below, the role of the amygdala and stress-related neuromodulators in modulating these processes remains
unclear. Nonetheless, this work fosters many new directions for exploration, and a picture complementary to
that offered by behavioral, pharmacological, and imaging methods is beginning to emerge.

15
Electrophysiological recordings in the amygdala
Only recently, researchers have started using electrophysiological techniques to directly record activity from
neuronal ensembles within the amygdala. A substantial hurdle in this development has been the difficulty to
selectively target subnuclei of the amygdala, which play different roles in the neural circuitry and have
distinct functional correlates. Knowledge of the dynamics of amygdala networks and interactions with
structures that support memory therefore remains relatively scarce.
In line with lesion work in rodents (Davis & Whalen, 2000), electrophysiological studies revealed
profound functional differentiations between centromedial and basolateral nuclei of the monkey amygdala
(Mosher, Zimmerman, & Gothard, 2010). In a task involving attentional orienting and viewing a variety of
emotional images, centromedial neurons correlated more with the different phases of the task, whereas
basolateral activity was more informative about the content of the stimuli. There was, however, considerable
overlap between these response types across basolateral and centromedial nuclei, suggesting distributed
information processing. Processing of complex visual stimuli in the BLA was analyzed in detail by Gothard
et al. (2007). In agreement with BOLD-fMRI work in humans described above (Adolphs, 2003; Whalen,
2007), these authors found robust neural responses in the amygdala to socially salient stimuli (e.g., facial
expressions and identity), but also to other stimulus properties (e.g., novel vs. familiar). The complexity of
these responses suggests that the amygdala is involved in higher-order stimulus processing, and contributes
to the extraction of the behavioral significance of stimuli, including emotional salience and valence.
Even within a single subregion such as the BLA, electrophysiological recordings show considerable
variability in responses. Distinct populations of neurons in this region were found to respond to fear
conditioning (correlating with fear expression) and fear extinction (correlating with extinction performance),
respectively (Herry et al., 2008). These two populations furthermore have very different connectivity
patterns. ‘Fear’ neurons receive inputs from the ventral hippocampus, whereas ‘extinction’ neurons are
mainly innervated by medial prefrontal afferents. Although both cell classes project strongly to the medial
prefrontal cortex, neurons activated during fear expression predominantly target the prelimbic subregion of
the medial prefrontal cortex, while those activated during extinction selectively target the infralimbic
subregion (Senn et al., 2014). Note that prelimbic and infralimbic subregions of the medial prefrontal cortex
are seen as the rodent homologs of the human dorsal anterior cingulate cortex and ventromedial prefrontal
cortex, respectively (Milad & Quirk, 2012). Direct evidence from network electrophysiology for a role of the
amygdala in memory consolidation, however, remains scarce. In the following sections, we will summarize
current knowledge about network activity patterns that correlate with memory consolidation and outline the
potential role of the amygdala and noradrenergic modulation in these processes.

Replay and the potential role of the amygdala

Spontaneous reactivation of activity configurations that occurred during prior learning experiences, or
replay, is widely seen as a prime candidate for the mechanistic underpinning of memory consolidation (for a
review, see O'Neill, Pleydell-Bouverie, Dupret, & Csicsvari, 2010). Pavlides and Winson (1989) first

16
demonstrated that hippocampal ‘place’ cells (cells that exhibit spatially constrained firing) that had been
active during awake exploration showed increased firing rates during subsequent phases of Non-Rapid Eye-
Movement (NREM) sleep. Such reactivations are coordinated across cell pairs that fired together during
recent experiences (Wilson & McNaughton, 1994), and these pairs were shown to maintain their temporal
ordering of activation (Skaggs & McNaughton, 1996). Lee and Wilson (2002) furthermore showed that
hippocampal place cells could replay sequences of firing mirroring the ordered activation that took place as
the rat repeatedly traversed place fields of different cells in succession. Simultaneous or sequential ensemble
reactivations have also been shown in multiple cortical regions (Euston, Tatsuno, & McNaughton, 2007;
Hoffman & McNaughton, 2002; Ji & Wilson, 2007), suggesting that this phenomenon could be a
manifestation of the activation of cortex-wide cell assemblies, and in the ventral striatum, a key area for the
processing of emotional and reward-related information (Pennartz et al., 2004).
Most studies report sleep replay during NREM sleep (but see, e.g., Louie & Wilson, 2001),
suggesting that the synchronized patterns in that sleep phase are more suited for spontaneous replay.
However, simultaneous and sequential assembly activation correlated to previous experience is also present
during active behavior, and may subserve memory encoding and online processing of information. This
‘awake replay’ (Carr, Jadhav, & Frank, 2011; Karlsson & Frank, 2009) presents features very similar to
sleep replay. Interestingly, in awake replay, sequences may recur both in the original order and in a
temporally reversed order (Diba & Buzsáki, 2007; Foster & Wilson, 2006), which, based on computational
models of reinforcement learning, may be important for learning the relationship between a sequence of
actions and the obtained reward. In line with this interpretation, awake replay is enhanced following salient
(Cheng & Frank, 2008) and reward-related (Singer & Frank, 2009) experiences.
What role could the amygdala play in these processes? One possibility is that amygdala activation
during emotionally arousing experiences or at the beginning of a replay sweep contributes to ‘gating’ and
determines which of a number of possible assemblies will reactivate. This way, the amygdala could select
behaviorally significant sequences and determine which information is preferentially consolidated, based on
salience and valence computations. An alternative scenario is that the amygdala may be recruited as a
consequence of inputs from other brain regions or towards the end of a replay sequence, at the point that
corresponds to the outcome of the replayed action. This would indicate that amygdala involvement in replay
provides information about the valence of a certain outcome. Which of these two possible directions of
information flow is predominant (or whether a bi-directional exchange takes place) is not known.
Interestingly, it was recently shown that activation of a dentate gyrus cell assembly related to a fear memory
is sufficient to cause robust amygdala activation (Ramirez et al., 2013). While this finding is consistent with
the second scenario, more research is needed to reach a definite conclusion.

Hippocampal-neocortical communication and the potential role of the amygdala

Models of systems consolidation propose that the function of spontaneous reactivations of hippocampal cell
assemblies during ‘offline’ states is not merely to strengthen local synaptic modifications. Rather, it is
thought that coordinated reactivation across hippocampal-neocortical networks leads to a gradual integration

17
of newly acquired information into neocortical networks, which is accompanied by a decrease in
hippocampal involvement (Frankland & Bontempi, 2005; Rasch & Born, 2007). In offline states, the
neocortex and hippocampus are indeed engaged in an intense dialogue, with cortical up and down states and
hippocampal sharp waves as the main, inter-dependent components. This dialogue affects how spontaneous
cell assembly activations, which embody replay, can interact across the brain. Recent data showed how
replay of assembly sequences in the visual cortex and the hippocampus takes place in a coordinated fashion
(Ji & Wilson, 2007), and how replay in the prefrontal cortex takes place with increased probability at the
times of occurrence of hippocampal sharp waves (Peyrache, Khamassi, Benchenane, Wiener, & Battaglia,
2009), demonstrating the influence this hippocampal pattern exerts on cortical activity. In fact, cortical
replay also correlates with cortical up states: the average intensity replay covaries with the frequency of
up/down state transitions, generating the ‘slow waves’ of slow wave sleep (Johnson, Euston, Tatsuno, &
McNaughton, 2010). Furthermore, up states appear to act as ‘frames’ delimiting sequential replay events in
visual cortex (Ji & Wilson, 2007). In the prefrontal cortex during early NREM stages, replay tends to peak at
the beginning, and especially at the end of an up-state (Peyrache et al., 2009).
What can be the role of the amygdala in this hippocampal-neocortical exchange? A critical insight
about the possible ‘enabling’ role of the amygdala comes from the work of Paz and Paré (2006), which
shows that amygdala activation facilitates the transmission of information from the entorhinal to perirhinal
cortex, two areas in the medial temporal lobe that are important for memory formation and mediate
communication between the hippocampus and the neocortex (Bauer, Paz, & Paré, 2007). This
communication is normally impeded by strong feedforward inhibition, but simultaneous stimulation of the
amygdala and entorhinal cortex relieves this inhibition and permits the activation of perirhinal neurons. This
suggests that, by acting on the strategic entorhinal-perirhinal pathway, the amygdala may determine which
information passes from the hippocampus to the neocortex.
Additional evidence for the participation of the amygdala in hippocampal-neocortical networks is
available from the analysis of oscillatory coherence and synchronization. These are important phenomena
because they may determine the structure of the effective network of communication between brain regions:
the basic assumption is that when two regions are effectively communicating, they will oscillate at a constant
phase lag, which is optimal to favor coherence (Fries, 2005). Incoherent oscillations or suboptimal phase lags
will greatly reduce the effect of inputs from one region on another. Most relevant for memory encoding
seems to be coherence at the theta range (6-10 Hz), which has been demonstrated between hippocampus and
prefrontal cortex (Adhikari, Topiwala, & Gordon, 2010; Benchenane et al., 2010; Siapas, Lubenov, &
Wilson, 2005), and between hippocampus and ventral striatum (Lansink, Goltstein, Lankelma, McNaughton,
& Pennartz, 2009). Theta coherence between hippocampus and amygdala has also been demonstrated, in
particular during the expression of conditioned fear (Pape, Narayanan, Smid, Stork, & Seidenbecher, 2005;
Seidenbecher, Laxmi, Stork, & Pape, 2003). Furthermore, increased theta activity between amygdala,
hippocampus, and medial prefrontal cortex is observed during Rapid Eye-Movement sleep following the
acquisition of a fear memory, and this increase predicts the later expression of the fear memory (Popa,
Duvarci, Popescu, Léna, & Paré, 2010). Coherence in the higher-frequency gamma band (30-100 Hz) has

18
also been examined. For instance, interactions within the entorhinal-perirhinal pathway described above
were shown to be coordinated by gamma oscillations in a BLA-rhinal network (Bauer et al., 2007). These
findings converge with functional connectivity studies in humans described above, which have shown that
the amygdala, hippocampus, (ventro)medial prefrontal cortex, and dorsal anterior cingulate cortex are part of
large-scale networks (Buckner et al., 2008; Seeley et al., 2007) that are thought to play a role in ‘offline’
processing and consolidation (Ranganath & Ritchey, 2012; van Kesteren et al., 2010).
Despite recent progress described in this section, our understanding of the dynamics of amygdala
ensembles and their role in memory encoding and consolidation, particularly of learning experiences that are
emotionally arousing and associated with noradrenergic activation, remains limited. An important
development that may make it possible to disentangle the internal amygdala circuitry is the new tool of
optogenetics, which allows for specific manipulation of cell types, nuclei, and connections on a millisecond
timescale. While recent studies using this technique concentrate on the modulation of anxiety and motivation
(Jennings et al., 2013; Kim et al., 2013), it will be enticing to test the importance of the same connections for
the joint modulation of memory by the amygdala (see, e.g., Huff, Miller, Deisseroth, Moorman, &
Lalumiere, 2013) and neuromodulatory structures such as the locus coeruleus (Carter et al., 2010). In line
with the modulation hypothesis that has been the starting point of this literature review, the amygdala may
engage stress hormone and neurotransmitter systems to achieve the increase in cortical excitability and
plasticity necessary to promote memory consolidation across widespread cell assemblies. A promising result
in this sense is that noradrenergic neurons in the locus coeruleus continue to fire during NREM sleep, in a
pattern that is phase locked to the cortical slow oscillations (Eschenko, Magri, Panzeri, & Sara, 2012), which
is also known to modulate memory replay, and possibly consolidation. Whether this spontaneous activity of
the locus coeruleus is at the basis of the noradrenergic control on memory consolidation and how this
influences the role of the amygdala in these processes is a question that will need to be explored in future
work.

Concluding remarks
In conclusion, the three research lines reviewed here are just starting to interact closely in a way allowing
hypotheses that are jointly tested in a truly interdisciplinary fashion. Aligning pharmacological
manipulations, behavioral paradigms, anatomical systems, and analytical tools for assessing neural activity
and connectivity across research lines and exploiting specific advantages of each line will help us
understanding the neural mechanisms underlying the mnemonic consequences of emotional experiences.
This research agenda can be started from a solid set of evidence showing that the amygdala is a critical nexus
in large-scale networks underlying emotional memory encoding and consolidation, rather than merely being
a storage site. The amygdala modulates neuroplastic processes in widespread neural systems by changing
network properties of large-scale neural systems mainly through noradrenergic mechanisms. Analysis of
intrinsic connectivity within such networks has identified the hippocampus, the (ventro)medial prefrontal
cortex, the anterior cingulate cortex, insula, and striatum as critical constituents of this amygdala-centered
circuit. Despite this recent progress several open questions await to be tackled. For example, invasive

19
electrophysiology in rodents combined with highly specific interventions, as offered by optogenetic
techniques, will enable outlining how the amygdala interacts with these other regions, the directionality of
their coupling, and how this coupling reactivates memory representations. Investigating homeostatic and
attentional processes at encoding will tell us what the mnemonic function of the salience network is as well
as whether and how the default mode network contributes to emotional memory consolidation. Despite the
overlap in insight between research lines there are also critical omissions. For instance, human neuroimaging
studies have largely ignored consolidation processes until recently (but see Deuker et al., 2013; Staresina,
Alink, Kriegeskorte, & Henson, 2013; Tambini & Davachi, 2013; Tambini, Ketz, & Davachi, 2010; van
Kesteren et al., 2010), while animal studies often ignored encoding processes. Furthermore, it appears
essential to go beyond general processes underlying emotional memory and to understand individual
differences explaining why certain individuals are more vulnerable or resilient when confronted with
emotional or even traumatic experiences. However, combining insight in general processes and individual
differences might one day provide a mechanistic account of mental disorders linked via mnemonic traces to
stressful life events that enables mechanistic and individualized treatment.

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Figures

Figure 1. Noradrenergic activation of the basolateral amygdala modulates consolidation of object

recognition memory. (A) Enhancing effects of posttraining intrabasolateral amygdala infusions of
norepinephrine on 24-hr object recognition memory. Saline-infused controls displayed no evidence of
memory of 3 min of training. The retention performance of groups given norepinephrine (0.3 or 1.0 µg in 0.2
µl) after training was significantly better than that of saline controls. Data presented as discrimination index
(mean ± SEM) in percentage on the 24-hr retention trial. The discrimination index was calculated as the
difference in time spent exploring the two objects, expressed as the ratio of the total time spent exploring
both objects. (B) Impairing effects of posttraining intrabasolateral amygdala infusions of the ß-adrenoceptor
antagonist propranolol on 24-hr object recognition memory. All groups received 10 minutes of training.
Saline-infused controls displayed significant memory and propranolol (0.1, 0.3 or 1.0 µg in 0.2 µl) produced
dose-dependent impairment of memory. The performance of all three propranolol groups differed
significantly from that of the corresponding saline controls. *, p < .05; **, p < .01 compared with the
corresponding saline controls. From “Noradrenergic Activation of the Basolateral Amygdala Modulates
Consolidation of Object Recognition Memory,” by B. Roozendaal, N. Castello, G. Vedana, A. Barsegyan,
and J. L. McGaugh, 2008, Neurobiology of Learning and Memory, 90, p. 578. Copyright 2008 by Elsevier.

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Figure 2. Glucocorticoid effects in the hippocampus on memory consolidation require noradrenergic activity
of the basolateral amygdala. Immediate posttraining unilateral infusions of the glucocorticoid receptor
agonist RU 28362 (3, 10, or 30 ng in 0.5 µl) into the hippocampus induced dose-dependent enhancement of
48-hr inhibitory avoidance retention latencies in rats given saline infusions into the basolateral amygdala
concurrently. Ipsilateral infusions of the ß-adrenoceptor antagonist atenolol (0.5 µg in 0.2 µl) into the
basolateral amygdala blocked the memory enhancement induced by the glucocorticoid receptor agonist.
Results represent retention latencies (mean ± SEM) in seconds. *, p < .05; **, p < .01 compared with the
corresponding vehicle group. **, p < .01 compared with the corresponding saline group. From “Basolateral
Amygdala Noradrenergic Influence Enables Enhancement of Memory Consolidation Induced by
Hippocampal Glucocorticoid Receptor Activation,” by B. Roozendaal, B. T. Nguyen, A. Power, and J. L.
McGaugh, 1999, Proceedings of the National Academy of Sciences of the USA, 96, p. 11645. Copyright
1999 by the National Academy of Sciences.

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 Selected IC map (salience network) C Experiment 1 Experiment 2
ISC contrast map (aversive>control)
Salience network ICs Visual network ICs
A

IC maps from both experiments

dACC dACC

Th
FI Mb Hy

Y=19 X=-7

B D
dlPFC dlPFC 3.5 3.5

IC subject modes experiment 2 (a.u.)

FI FI 3 3
dACC
FI IFG
St St
IFG 2.5 2.5
Am Hy Am
PCG PCG
2 2
Th Th
TPJ Mb TPJ 1.5 1.5
1 1
IT
IT IT 0.5 0.5
0 0
Z=-4 Placebo Propranolol Metyrapone

Figure 3. (A) Regions comprising the salience network overlaid onto a canonical T1-weighted MRI scan.
(B) Schematic overview of suprathreshold clusters and relative sizes within the salience network. In
experiment 1, salience network connectivity correlated with multiple measures of stress. (C) Overlap
between the salience work and visual (control) networks in correlational (1) and pharmacological (2)
experiments. (D) Drug effects on functional connectivity strength (+- SEM) within salience and visual
networks in experiment 2. Beta-adrenoceptor blockade lowered functional connectivity within the salience
network but not within the control network. FI, frontoinsular cortex; dACC, dorsal anterior cingulate cortex;
Mb, midbrain; Hy, hypothalamus; Th, thalamus; IT, inferotemporal cortex; TPJ, temporoparietal junction;
Am, amygdala; IFG, inferior frontal gyrus; PCG, precentral gyrus; dlPFC, dorsolateral prefrontal cortex; St,
striatum (caudate/pallidum). From “Stress-related noradrenergic activity prompts large-scale neural network
reconfiguration.,” by E.J. Hermans et al., 2011, Science, 334, p. 1151. Reprinted with permission from
AAAS.

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