Norepinephrine effects on the encoding and consolidation of emotional memory: improving synergy between animal and human studies

doi:10.1016/j.cobeha.2017.02.001

Current Opinion in Behavioral Sciences

Volume 14, April 2017, Pages 115-122

https://doi.org/10.1016/j.cobeha.2017.02.001 Get rights and content

Highlights

•
Noradrenergic activity is important for emotional enhancement of memory.
•
Animal studies examined post-learning norepinephrine effects on memory consolidation.
•
Human studies mostly investigated norepinephrine effects on the encoding of memory.
•
These phasic and more sustained norepinephrine effects might be interdependent.
•
We discuss the importance of improving synergy between animal and human studies.

Noradrenergic activity is important for emotional enhancement of memory. Although findings from both animal and human research provide extensive support for this general conclusion, there are some important, but often ignored, differences between these research lines. Whereas animal experiments mostly employ pharmacological manipulations in the post-learning phase to investigate the effects of sustained noradrenergic activation on the consolidation of long-term memory, neuroimaging studies in humans typically focus on much more dynamic changes in noradrenergic activity during the actual encoding of information. In this paper we discuss the possibility that these two types of noradrenergic effects interact in enhancing memory for emotionally arousing experiences, and explain how elucidating this mechanism might improve synergy between animal and human research.

Introduction

Extensive evidence indicates that noradrenergic activity is enhanced by emotionally arousing training conditions [1]. The hypothesis that norepinephrine plays a role in learning and memory emerged more than four decades ago when Kety [2] suggested that adrenergic catecholamines, such as epinephrine or norepinephrine, released by certain emotional states may serve ‘to reinforce and consolidate new and significant sensory patterns in the neocortex.’ The initial experiments investigating this general hypothesis examined the effects of systemic administration of adrenergic drugs on learning and memory [3]. The findings of Gold and van Buskirk [4] were among the first to suggest the involvement of central norepinephrine in memory. Many subsequent studies in rodents provided extensive support for the hypothesis that norepinephrine or a β-adrenoceptor agonist infused into the basolateral amygdala (BLA) or other brain regions such as the hippocampus or prefrontal cortex enhances long-term memory of emotionally arousing training experiences [1, 5, 6]. Human research generally supports the conclusions of animal studies indicating that an activation of the noradrenergic system is associated with better memory and that this influence involves the amygdala [7••, 8].

There are, however, some important but frequently overlooked methodological differences between the animal and human studies. Whereas most animal research has used post-learning pharmacological manipulations to induce sustained changes in noradrenergic activity during the consolidation phase of memory, human neuroimaging studies typically focus on much more dynamic, that is, phasic, changes in noradrenergic activity during the actual encoding of emotional experiences into memory. While phasic noradrenergic signaling is centrally mediated through rapid increases in firing rates of locus coeruleus neurons [9^•], sustained noradrenergic activity after encoding, at least partially, involves activation of peripheral adrenal stress hormone release: Both epinephrine [10] and glucocorticoids [11] trigger a tonic increase in noradrenergic activity in the amygdala. Such peripheral stress hormone effects on sustained noradrenergic activity might not only be produced as a result of tonic activation of noradrenergic neurons in the locus coeruleus [12] but also involve the activation of noradrenergic cell groups in the nucleus of the solitary tract [10] or an indirect stimulation of norepinephrine levels by inhibiting norepinephrine-reuptake mechanisms [13]. In this paper, we will argue that these phasic and sustained increases in noradrenergic activity might interact in enhancing memory for emotionally arousing experiences. The specific and phasic noradrenergic activation during memory encoding might make these memory traces amenable to the memory-enhancing effects of a more sustained noradrenergic activation in the post-learning consolidation phase. Notably, this sustained post-learning noradrenergic activity may also have no, or even opposite, effects when not preceded by phasic noradrenergic signaling during encoding.

Section snippets

Norepinephrine actions on memory consolidation

Animal studies have provided extensive evidence that noradrenergic activation, arising from catecholaminergic cell bodies in the locus coeruleus and the nucleus of the solitary tract, is critically involved in memory consolidation [14^••]. For example, norepinephrine or β-adrenoceptor agonists administered into the BLA immediately after an emotionally arousing training experience induce dose-dependent enhancement of memory consolidation [15, 16, 17, 18, 19, 21]. Similar norepinephrine infusions

Norepinephrine actions on memory encoding

While pharmacological work in rodents mainly focused on the role of norepinephrine in enhancing the consolidation of memories, it is evident that norepinephrine must also play an important role during memory encoding. A large body of research implicates noradrenergic activation by the locus coeruleus in regulating attention, and thus in regulating sensory intake that is to be encoded. Work in monkeys has shown that locus coeruleus neurons exhibit two distinct modes of activity [9^•]. Tonic

Interactions between noradrenergic actions during encoding and consolidation

Up until recently, encoding and consolidation processes have been studied in relative isolation, largely along the lines of human versus animal research, respectively. The reason for this is that research in animals has often relied on targeted pharmacological manipulations in the post-learning consolidation phase which are too invasive to employ in humans. Contrariwise, the non-invasive techniques available in humans are more suited to study mnemonic processes during encoding, because most

Conclusions and future directions

In conclusion, a critical analysis of the extant literature on the effects of norepinephrine on memory shows a divide between animal research, which has mainly investigated the consolidation phase, and human research, which has traditionally focused on encoding processes. As we outlined, a synergy of these two research lines is beginning to emerge. This is important particularly because noradrenergic effects on encoding and consolidation are not additive but interactive: Noradrenergic signaling

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

BR is supported by a Topfund grant from Radboud University and EJH is supported by a grant from the European Research Council (ERC-2015-CoG 682591).

References (86)

P.E. Gold et al.
Effects of alpha- and beta-adrenergic receptor antagonists on post-trial epinephrine modulation of memory: relationship to post-training brain norepinephrine concentrations
Behav Biol
(1978)
J.L. McGaugh et al.
Role of adrenal stress hormones in forming lasting memories in the brain
Curr Opin Neurobiol
(2002)
D. Gründemann et al.
Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter
Nat Neurosci
(1998)
B. Roozendaal et al.
Memory modulation
Behav Neurosci
(2011)
N.C. Huff et al.
Context pre-exposure obscures amygdala modulation of contextual-fear conditioning
Learn Mem
(2005)
B. Roozendaal et al.
Noradrenergic activation of the basolateral amygdala modulates consolidation of object recognition memory
Neurobiol Learn Mem
(2008)
A. Barsegyan et al.
Noradrenergic activation of the basolateral amygdala modulates the consolidation of object-in-context recognition memory
Front Behav Neurosci
(2014)
P. Ardenghi et al.
Late and prolonged post-training memory modulation in entorhinal and parietal cortex by drugs acting on the cAMP/protein kinase A signalling pathway
Behav Pharmacol
(1997)
B. Ferry et al.
Basolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between beta- and alpha1-adrenoceptors
J Neurosci
(1999)
C.K. McIntyre et al.
Amygdala norepinephrine levels after training predict inhibitory avoidance retention performance in rats
Eur J Neurosci
(2002)

E.S. Lovitz et al.

Memory-enhancing intra-basolateral amygdala clenbuterol infusion reduces post-burst afterhyperpolarizations in hippocampal CA1 pyramidal neurons following inhibitory avoidance learning

Neurobiol Learn Mem

(2015)

T. Smeets et al.

True or false? Memory is differentially affected by stress-induced cortisol elevations and sympathetic activity at consolidation and retrieval

Psychoneuroendocrinology

(2008)

K.L. Felmingham et al.

Sex differences in emotional memory consolidation: the effect of stress-induced salivary alpha-amylase and cortisol

Biol Psychol

(2012)

S.M. Southwick et al.

Relationship of enhanced norepinephrine activity during memory consolidation to enhanced long-term memory in humans

Am J Psychiatry

(2002)

S.J. Sara et al.

Orienting and reorienting: the locus coeruleus mediates cognition through arousal

Neuron

(2012)

S. Nieuwenhuis et al.

Decision making, the P3, and the locus coeruleus-norepinephrine system

Psychol Bull

(2005)

B. de Martino et al.

Noradrenergic neuromodulation of human attention for emotional and neutral stimuli

Psychopharmacology

(2008)

E.J. Hermans et al.

Stress-related noradrenergic activity prompts large-scale neural network reconfiguration

Science

(2011)

V. Menon

Large-scale brain networks and psychopathology: a unifying triple network model

Trends Cogn Sci

(2011)

S.B. Hamann et al.

Amygdala activity related to enhanced memory for pleasant and aversive stimuli

Nat Neurosci

(1999)

L. Cahill et al.

Sex-related hemispheric lateralization of amygdala function in emotionally influenced memory: an FMRI investigation

Learn Mem

(2004)

O.A. Onur et al.

Noradrenergic enhancement of amygdala responses to fear

Soc Cogn Affect Neurosci

(2009)

H. Cousijn et al.

Acute stress modulates genotype effects on amygdala processing in humans

Proc Natl Acad Sci U S A

(2010)

D. Popa et al.

Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep

Proc Natl Acad Sci U S A

(2010)

M.T.R. van Kesteren et al.

Persistent schema-dependent hippocampal–neocortical connectivity during memory encoding and postencoding rest in humans

Proc Natl Acad Sci U S A

(2010)

F. Klumpers et al.

Impaired acquisition of classically conditioned fear-potentiated startle reflexes in humans with focal bilateral basolateral amygdala damage

Soc Cogn Affect Neurosci

(2015)

J.L. McGaugh

The amygdala modulates the consolidation of memories of emotionally arousing experiences

Annu Rev Neurosci

(2004)

S. Kety

Brain catecholamines, affective states and memory

The Chemistry of Mood, Motivation, and Memory

(1972)

T. Archer

DSP4 (N-2-chloroethyl-N-ethyl-2-bromobenzylamine), a new noradrenaline neurotoxin, and stimulus conditions affecting acquisition of two-way active avoidance

J Comp Physiol Psychol

(1982)

J.L. McGaugh

Memory—a century of consolidation

Science

(2000)

L. Cahill et al.

Beta-adrenergic activation and memory for emotional events

Nature

(1994)

R.E. O’Carroll et al.

Stimulation of the noradrenergic system enhances and blockade reduces memory for emotional material in man

Psychol Med

(1999)

G. Aston-Jones et al.

An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance

Annu Rev Neurosci

(2004)

C.L. Williams et al.

Norepinephrine release in the amygdala after systemic injection of epinephrine or escapable footshock: contribution of the nucleus of the solitary tract

Behav Neurosci

(1998)

J.R. McReynolds et al.

Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions

Neurobiol Learn Mem

(2010)

R.J. Valentino et al.

Convergent regulation of locus coeruleus activity as an adaptive response to stress

Eur J Pharmacol

(2008)

K.C. Liang et al.

Involvement of amygdala pathways in the influence of post-training intra-amygdala norepinephrine and peripheral epinephrine on memory storage

Brain Res

(1990)

T. Hatfield et al.

Norepinephrine infused into the basolateral amygdala posttraining enhances retention in a spatial water maze task

Neurobiol Learn Mem

(1999)

B. Ferry et al.

Clenbuterol administration into the basolateral amygdala post-training enhances retention in an inhibitory avoidance task

Neurobiol Learn Mem

(1999)

F.-C. Yang et al.

Interactions of the dorsal hippocampus, medial prefrontal cortex and nucleus accumbens in formation of fear memory: difference in inhibitory avoidance learning and contextual fear conditioning

Neurobiol Learn Mem

(2014)

L. Bevilaqua et al.

Drugs acting upon the cyclic adenosine monophosphate/protein kinase A signalling pathway modulate memory consolidation when given late after training into rat hippocampus but not amygdala

Behav Pharmacol

(1997)

B. Ferry et al.

Involvement of alpha1-adrenoceptors in the basolateral amygdala in modulation of memory storage

Eur J Pharmacol

(1999)

K.C. Liang et al.

Modulating effects of posttraining epinephrine on memory: involvement of the amygdala noradrenergic system

Brain Res

(1986)

Cited by (32)

Physiological arousal guides situational appraisals and metacognitive recall for naturalistic experiences
2023, Neuropsychologia
As individuals navigate the world, they are bound to have emotionally intense experiences. These events not only influence momentary physiological and affective responses, but may also have a powerful impact on one's memory for their emotional experience. In this research, we used the naturalistic context of a haunted house to examine how physiological arousal is associated with metacognitive emotional memory (i.e., the extent to which an individual remembers having experienced a certain emotion). Participants first navigated the haunted house while heart rate and explicit situational appraisals were recorded, and then recalled specific events from the haunted house and the intensity of these affective events approximately one week later. We found that heart rate predicted both the intensity of reported scariness in the haunted house and meta-cognitive memory of affect during recall. Critically, we found evidence for malleability in metacognitive emotional memory based on how the event was initially labeled. Individuals tended to recall events that they explicitly labeled as fear-evoking as being more intense than they reported at the time of the event. We found the opposite relationship for events that they labeled as not fear-evoking. Taken together, this indicates that there are strong relationships between physiological arousal and emotional experiences in naturalistic contexts, but that affective labeling can modulate the relationship between these features when reflecting on the emotionality of that experience in memory.
Corticosterone differentially modulates time-dependent fear generalization following mild or moderate fear conditioning training in rats
2021, Neurobiology of Learning and Memory
Stressful and emotionally arousing experiences create strong memories that seem to lose specificity over time. It is uncertain, however, how the stress system contributes to the phenomenon of time-dependent fear generalization. Here, we investigated whether post-training corticosterone (CORT-HBC) injections, given after different training intensities, affect contextual fear memory specificity at several time points. We trained male Wistar rats on the contextual fear conditioning (CFC) task using two footshock intensities (mild CFC, 3 footshocks of 0.3 mA, or moderate CFC, 3x 0.6 mA) and immediately after the training session we administered CORT-HBC systemically. We first tested the animals in a novel context and then in the training context at different intervals following training (2, 14, 28 or 42 days). By measuring freezing in the novel context and then contrasting freezing times shown in both contexts, we inferred contextual fear generalization for each rat, classifying them into Generalizers or Discriminators. Following mild CFC training, the glucocorticoid injection promoted an accurate contextual memory at the recent time point (2 days), and increase the contextual memory accuracy 28 days after training. In contrast, after the moderate CFC training, CORT-HBC facilitated contextual generalization at 14 days, compared to the control group that maintained contextual discrimination at this timepoint. For this training intensity, however, CORT-HBC did not have any effect on recent memory specificity. These findings indicate that treatment with CORT-HBC immediately after the encoding of mild or moderately arousing experiences may differentially modulate memory consolidation and time-dependent fear generalization.
Stress, memory, and implications for major depression
2021, Behavioural Brain Research
The stress response comprises a phylogenetically conserved set of cognitive, physiological, and behavioral responses that evolved as a survival strategy. In this context, the memory of stressful events would be adaptive as it could avoid re-exposure to an adverse event, otherwise the event would be facilitated in positively stressful or non-distressful conditions. However, the interaction between stress and memory comprises complex responses, some of them which are not yet completely understood, and which depend on several factors such as the memory system that is recruited, the nature and duration of the stressful event, as well as the timing in which this interaction takes place. In this narrative review, we briefly discuss the mechanisms of the stress response, the main memory systems, and its neural correlates. Then, we show how stress, through the action of its biochemical mediators, influences memory systems and mnemonic processes. Finally, we make use of major depressive disorder to explore the possible implications of non-adaptive interactions between stress and memory to psychiatric disorders, as well as possible roles for memory studies in the field of psychiatry.
Higher post-encoding cortisol benefits the selective consolidation of emotional aspects of memory
2021, Neurobiology of Learning and Memory
Emotional experiences create durable memory traces in the brain, especially when these memories are consolidated in the presence of stress hormones such as cortisol. Although some research suggests cortisol elevation can increase long-term memory for emotional relative to neutral content, the impact of stress and cortisol on the consolidation of emotional and neutral aspects of memories when they are part of the same experience remains unknown. Here, after encoding complex scenes consisting of negative or neutral objects placed on neutral backgrounds, participants were exposed to a psychosocial stressor (or matched control condition) in order to examine the impact of stress and cortisol on early consolidation processes. The next day, once cortisol levels had returned to baseline, specific and gist recognition memory were tested separately for objects and backgrounds. Results indicate that while there was a numerical increase in memory for negative objects in the stress group, higher endogenous cortisol concentrations were specifically associated with decreased memory for the neutral backgrounds originally paired with negative objects. Moreover, across all participants, cortisol levels were positively correlated with the magnitude of the emotional memory trade-off effect. Specifically, while memory for negative objects was preserved, elevated cortisol during early consolidation was associated with decreased memory for neutral backgrounds that were initially paired with negative objects. These memory effects were observed in both the stricter specific measure of memory and the less conservative measure of gist memory. Together, these findings suggest that rather than influencing all aspects of an experience similarly, elevated cortisol during early consolidation selectively preserves what is most emotionally salient and adaptive to remember while allowing the loss of memory for less important neutral information over time.
Psychostimulants may block long-term memory formation via degraded sleep in healthy adults
2021, Neurobiology of Learning and Memory
Citation Excerpt :
Though some have highlighted their “cognitive enhancement” potential (Greely, Sahakian, & Harris, 2008), positive effects have been mostly reported in simple executive function tasks (i.e. vigilance, sustained attention, working memory; see Tselha, Whitehurst, Yetton, Vo, and Mednick (2019) for negative impact on working memory), whereas empirical studies of more complex cognitive processes have yet to show conclusive results (Ilieva, Boland, & Farah, 2013; Mommaerts, Beerens, & van den Block, 2013; Repantis, Schlattamann, Laisney, & Heuser, 2010; Smith & Farah, 2011; Volkow, Wang, & Fowler, 2004). On one hand, psychostimulants have been shown to enhance emotional memory in humans (Ballard, Gallo, & de Wit, 2013; Roozendaal & Hermans, 2017), however, they have also shown null effects (Weafer, Gallo, & de Wit, 2014). Additionally, studies of non-emotional, neutral stimuli have shown positive (Ballard et al., 2013; Linssen, Vuurman, Sambeth, & Riedel, 2012; Soetens et al., 1993, 1995), null (de Wit, Enggasser, & Richards, 2002; Ilieva et al., 2013; Mommaerts et al., 2013) and negative effects (Elliot et al., 1997; Ilieva et al., 2013).
Sleep is vital for biological function and long-term memory formation, with preferential enhancement of emotionally laden content. A growing trend in healthy young adults is the non-medical use of psychostimulants, or “smart drugs”, to prevent sleep and, hopefully, enhance cognition. However, the effect of these drugs on sleep-dependent memory processes are unclear. Here, in a within-subject, double-blind, placebo-controlled design, we investigated the impact of morning administration of dextroamphetamine on memory retention of negative and neutral pictures after 1) 12 h of wake, and 2) 24 h with sleep. After 12-hrs of wake, stimulants increased hit rate for neutral, but not negative, pictures, compared to placebo. No differences in memory discrimination were found. In addition, stimulants impaired nighttime sleep and significantly reduced memory for neutral pictures at 24-hrs, compared to placebo. Again, no performance differences between drug conditions were found for negative pictures. Together, these findings suggest that stimulants impairment of nighttime sleep likely leads to next day memory costs.
Opioid withdrawal and memory consolidation
2020, Neuroscience and Biobehavioral Reviews
It is well established that learning and memory are central to substance dependence. This paper specifically reviews the effect of opioid withdrawal on memory consolidation. Although there is evidence that opioid withdrawal can interfere with initial acquisition and retrieval of older memories, there are several reasons to postulate a facilitatory action on the consolidation of newly acquired memories. In fact, there is substantial evidence that memory consolidation is facilitated by the release of stress hormones, that it requires the activation of the amygdala, of central noradrenergic and cholinergic pathways, and that it involves long-term potentiation. This review highlights evidence that very similar neurobiological processes are involved in opioid withdrawal, and summarizes recent results indicating that naltrexone-precipitated withdrawal enhanced consolidation in rats. From this neurocognitive perspective, therefore, opioid use may escalate during the addiction cycle in part because memories of stimuli and actions experienced during withdrawal are strengthened.

View all citing articles on Scopus

View full text

Norepinephrine effects on the encoding and consolidation of emotional memory: improving synergy between animal and human studies

Highlights

Introduction

Section snippets

Norepinephrine actions on memory consolidation

Norepinephrine actions on memory encoding

Interactions between noradrenergic actions during encoding and consolidation

Conclusions and future directions

References and recommended reading

Conflicts of interest

Acknowledgements

Behav Biol

Curr Opin Neurobiol

Nat Neurosci

Behav Neurosci

Learn Mem

Neurobiol Learn Mem

Front Behav Neurosci

Behav Pharmacol

J Neurosci

Eur J Neurosci

Neurobiol Learn Mem

Psychoneuroendocrinology

Biol Psychol

Am J Psychiatry

Neuron

Psychol Bull

Psychopharmacology

Science

Trends Cogn Sci

Nat Neurosci

Learn Mem

Soc Cogn Affect Neurosci

Proc Natl Acad Sci U S A

Proc Natl Acad Sci U S A

Proc Natl Acad Sci U S A

Soc Cogn Affect Neurosci

The amygdala modulates the consolidation of memories of emotionally arousing experiences

Annu Rev Neurosci

Brain catecholamines, affective states and memory

The Chemistry of Mood, Motivation, and Memory

DSP4 (N-2-chloroethyl-N-ethyl-2-bromobenzylamine), a new noradrenaline neurotoxin, and stimulus conditions affecting acquisition of two-way active avoidance

J Comp Physiol Psychol

Memory—a century of consolidation

Science

Beta-adrenergic activation and memory for emotional events

Nature

Stimulation of the noradrenergic system enhances and blockade reduces memory for emotional material in man

Psychol Med

An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance

Annu Rev Neurosci

Norepinephrine release in the amygdala after systemic injection of epinephrine or escapable footshock: contribution of the nucleus of the solitary tract

Behav Neurosci

Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions

Neurobiol Learn Mem

Convergent regulation of locus coeruleus activity as an adaptive response to stress

Eur J Pharmacol

Involvement of amygdala pathways in the influence of post-training intra-amygdala norepinephrine and peripheral epinephrine on memory storage

Brain Res

Norepinephrine infused into the basolateral amygdala posttraining enhances retention in a spatial water maze task

Neurobiol Learn Mem

Clenbuterol administration into the basolateral amygdala post-training enhances retention in an inhibitory avoidance task

Neurobiol Learn Mem

Interactions of the dorsal hippocampus, medial prefrontal cortex and nucleus accumbens in formation of fear memory: difference in inhibitory avoidance learning and contextual fear conditioning

Neurobiol Learn Mem

Drugs acting upon the cyclic adenosine monophosphate/protein kinase A signalling pathway modulate memory consolidation when given late after training into rat hippocampus but not amygdala

Behav Pharmacol

Involvement of alpha1-adrenoceptors in the basolateral amygdala in modulation of memory storage

Eur J Pharmacol

Modulating effects of posttraining epinephrine on memory: involvement of the amygdala noradrenergic system

Brain Res