Locus coeruleus neuromodulation of memories encoded during negative or unexpected action outcomes

doi:10.1016/j.nlm.2014.03.006

Neurobiology of Learning and Memory

Volume 111, May 2014, Pages 65-70

https://doi.org/10.1016/j.nlm.2014.03.006 Get rights and content

Highlights

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Examined locus coeruleus functional connectivity during feedback phase of fMRI task.
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Memory for negative outcome trials was linked to positive coupling of LC and insula.
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Memory for low RT certainty trials was linked to positive coupling of LC and DLPFC.
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Results suggest that LC is involved in memory of negative or unexpected outcomes.

Abstract

When people experience surprising or sub-optimal performance outcomes, an increase in autonomic arousal helps allocate cognitive resources to adjust behavior accordingly. The locus-coeruleus–norepinephrine (LC–NE) system regulates a central orienting response to behaviorally relevant events, and might therefore signal the need to attend to and learn from performance feedback. Memories of such events also rely on elevated NE, suggesting that LC activity not only responds to salient performance outcomes but also strengthens memory for stimuli associated with their occurrence. In the present study, we used a monetary incentive delay paradigm to determine whether LC functional connectivity during reaction time feedback relates to trial-by-trial memory of preceding photo-objects. We used one psychophysiological interaction (PPI) analysis to examine patterns of LC functional connectivity that were associated with subsequent memory for picture trials in which negative or positive feedback was given, and a second PPI analysis to investigate whether successfully encoded objects from trials with uncertain outcomes were related to distinct patterns of LC functional connectivity across the brain. The PPI results revealed that successfully encoded negative feedback trials (i.e., responses exceeding the response deadline) were uniquely associated with enhanced functional coupling between the LC and left anterior insula. Furthermore, successful memory for objects in low reaction time certainty trials (i.e., responses closest to the response deadline) were linked to positive LC functional coupling with left dorsolateral prefrontal cortex. These findings suggest that noradrenergic influences help facilitate memory encoding during outcome processing via dynamic interactions with regions that process negative or unexpected feedback.

Introduction

Adaptive behavior relies on the ability to encode and remember information associated with sub-optimal or unexpected performance outcomes. Autonomic arousal contributes to this process by signaling erroneous action outcomes (Ullsperger et al., 2010, Wessel et al., 2011) and facilitating learning when task demands fluctuate unpredictably (Raizada and Poldrack, 2007, Yu and Dayan, 2005). Such behaviorally relevant events activate the locus coeruleus (LC), a small brainstem nucleus that serves as the primary supplier of norepinephrine (NE) to the neocortex, (Berridge & Waterhouse, 2003), which in turn initiates a central orienting response that helps reallocate attentional resources to adjust and optimize task performance (Aston-Jones and Bloom, 1981, Aston-Jones and Cohen, 2005, Aston-Jones et al., 1997, Bouret and Sara, 2005; Clayton et al., 2004). This framework is supported by evidence showing that neurophysiological markers of LC activity, including increased pupil dilation (Critchley et al., 2005, Rajkowski et al., 1993) and a greater P3 component of event-related potentials (Nieuwenhuis, Aston-Jones, & Cohen, 2005), accompany salient action outcomes, such as errors. In light of these convergent findings, it has been proposed that LC activity promotes both error perception (Ullsperger et al., 2010) and learning during unexpected uncertainty (Yu & Dayan, 2005).

The LC–NE system also augments memory encoding and consolidation of arousing stimuli, particularly during stress (McGaugh & Roozendaal, 2002). Exposure to acute stressors elevates the stress hormones NE and cortisol which each selectively strengthen memory for events associated with their release (Schwabe, Joëls, Roozendaal, Wolf, & Oitzl, 2011). For instance, neuroimaging studies have demonstrated that LC activity increases during successful encoding of emotionally arousing images (Sterpenich et al., 2006) and neutral images encoded under stress (Qin, Hermans, van Marle, & Fernández, 2012). Given the importance of LC neuromodulation in both behavioral adjustments and memory, it is possible that the LC interacts with higher brain regions to promote memory of information associated with salient performance feedback. To our knowledge, no previous study has tested this hypothesis in humans.

The goal of the present study was to determine whether feedback-related functional interactions between the LC and rest of the brain predicted subsequent memory for photo-objects associated with specific performance outcomes. To this end, we used functional magnetic resonance imaging (fMRI) to examine LC functional connectivity during the feedback period of a monetary incentive delay (MID) task (e.g., Knutson et al., 2000, Mather and Schoeke, 2011). Approximately 25 min prior to task-related scanning, a cold pressor stressor (CPS) was used to induce stress, as measured by an increase in the stress hormone cortisol that peaks approximately 15–30 min after stressor onset (Dickerson & Kemeny, 2004). Given evidence that the LC responds to both reward and punishment (Bouret and Sara, 2004, Sara and Segal, 1991), we modeled brain activity during positive and negative feedback periods. Previous research suggests that positive outcomes relate to dopamine release (Adcock, Thangavel, Whitfield-Gabrieli, Knutson, & Gabrieli, 2006), whereas memory for aversive events has been consistently linked to activity in central nodes within the LC–NE system, including the amygdala (Murty et al., 2012, Sterpenich et al., 2006), insula (Rasch et al., 2009), and LC itself (Knutson et al., 2000). Thus, we hypothesized that enhanced functional connectivity between the LC and aversive-related memory processing regions would predict subsequent memory for pictures encoded in negative but not positive feedback trials. Motivated by evidence that the LC also promotes learning during unexpected uncertainty (Yu & Dayan, 2005), we also examined whether patterns of LC activity following low certainty responses (i.e., reaction times that occurred closest to a dynamic response deadline) were associated with memory of pictures in those trials.

Section snippets

2.1 Sample

Twenty-one male participants (age: M = 23.63, SD = 3.95; range = 18–31) underwent scan sessions on two separate days, and were randomly assigned to the stress or control condition on their first day. Scanning was conducted between 2 and 5 p.m. when cortisol levels are relatively stable. Participants also refrained from eating, caffeine intake, and exercise for at least 1 h and sleeping for at least 2 h prior to arrival. All participants provided written informed consent approved by the University of

3.1 Reaction time results

The adaptive response deadline algorithm produced a mean RT hit rate of 60.12% (SD = 2.23%). Since the CPS failed to induce stress, RT performance values and memory data were collapsed across both experimental sessions. We performed two separate 2 × 3 × 2 repeated-measures ANOVAs for RT and memory performance with Feedback (hit or miss), Money (lose, none or win) and Certainty (high or low) modeled as within-subjects factors. The results (in milliseconds) revealed that participants responded faster

4. Discussion

To our knowledge, our results provide the first human evidence that LC functional connectivity with the left anterior insula and DLPFC are associated with later memory for stimuli encoded during negative or uncertain action outcomes, respectively. Our findings support current theories positing a link between noradrenergic activity and action outcomes by showing that LC functional coupling may be a common neural mechanism underlying both the monitoring and encoding of negative or surprising

Acknowledgments

We thank Zara Abrams and Jiancheng Zhuang, Ph.D., for their assistance with scanning participants. We also thank Dr. Keren and colleagues (2009) for providing us with their standard-space LC mask. This project was funded by federal NIH Grants R01AG038043 and K02AG032309.

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The effect is deceptively simple: by boosting activity patterns in a widespread fashion, those regions with an intermediate level of activity can now cross a nonlinear barrier that drastically increases their firing rate (known as a ‘bifurcation’ in dynamical systems theory [43]). In other words, neurons that are already partially active (i.e., processing glutamatergic inputs) can now ‘stand out’ from the background activity [44] and, hence, have an impact on the evolving spatiotemporal brain state that controls a diverse set of brain states, including cognitive function [45,46], memory encoding [47,48], perceptual learning [49,50], motor performance [51], and perceptual awareness [38,52,53]. There is now empirical evidence to support this relatively global effect of the LC on whole-brain dynamics in both rodents [10] and humans [18,19,38,54–57].
Neural dynamics are shaped and constrained by the projections of a small nucleus in the pons: the noradrenergic locus coeruleus (LC). Much like a bow to the brain’s violin, activity in the LC lacks content specificity, but instead dynamically shapes the excitability and receptivity of neurons across the brain. In this review, we explain how the style of the bowing technique, which is analogous to different firing modes in the LC, affects distinct activity patterns in the rest of the brain. Through this analogical lens, we provide intuitive insights into how the complex activity of the LC acts to coordinate adaptive neural dynamics.
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For example, there is evidence that items associated with outcomes of monetary reward were remembered more accurately than those with outcomes of monetary punishment (Eppinger et al., 2010), and that the memory enhancement was modulated by the amount of monetary reward associated with the items (Madan et al., 2012; Mason et al., 2017). A similar effect on memories by reward outcomes has been found in the memory enhancement of objects associated with feedbacks of receiving rewards, as well as avoiding punishments (Clewett et al., 2014; Mather and Schoeke, 2011). These findings suggest that memories are enhanced by outcomes of social and monetary rewards.
Social interactions enhance human memories, but little is known about how the neural mechanisms underlying episodic memories are modulated by rewarding outcomes in social interactions. To investigate this, fMRI data were recorded while healthy young adults encoded unfamiliar faces in either a competition or a control task. In the competition task, participants encoded opponents' faces in the rock-paper-scissors game, where trial-by-trial outcomes of Win, Draw, and Lose for participants were shown by facial expressions of opponents (Angry, Neutral, and Happy). In the control task, participants encoded faces by assessing facial expressions. After encoding, participants recognized faces previously learned. Behavioral data showed that emotional valence for opponents' Angry faces as the Win outcome was rated positively in the competition task, whereas the rating for Angry faces was rated negatively in the control task, and that Angry faces were remembered more accurately than Neutral or Happy faces in both tasks. fMRI data showed that activation in the medial orbitofrontal cortex (mOFC) paralleled the pattern of valence ratings, with greater activation for the Win than Draw or Lose conditions of the competition task, and the Angry condition of the control task. Moreover, functional connectivity between the mOFC and hippocampus was increased in Win compared to Angry, and the mOFC-hippocampus functional connectivity predicted individual differences in subsequent memory performance only in Win of the competition task, but not in any other conditions of the two tasks. These results demonstrate that the memory enhancement by context-dependent social rewards involves interactions between reward- and memory-related regions.
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This may be related to the wiring properties of LC-NE system: LC projections to the frontal cortex are more numerous, fire faster, are more excitable, and contain more glutamate receptors than projections to other regions of the cortex (Chandler et al., 2014a). Increased functional coupling between LC and the frontal cortex was associated with better behavioral performance in the monetary incentive delay task (Clewett et al., 2014), suggesting that the LC-NE system monitors behavioral outcomes and triggers memory processes to modify subsequent behavior. Different terms have been employed to refer to the role of LC in brain function and behavior: a switch in the trade-off between exploitation and exploration, a brain reset signal, a learning signal or a temporal filter.
Several lines of evidence have suggested for decades a role for norepinephrine (NE) in the pathophysiology and treatment of schizophrenia. Recent experimental findings reveal anatomical and physiological properties of the locus coeruleus-norepinephrine (LC-NE) system and its involvement in brain function and cognition. Here, we integrate these two lines of evidence. First, we review the functional and structural properties of the LC-NE system and its impact on functional brain networks, cognition, and stress, with special emphasis on recent experimental and theoretical advances. Subsequently, we present an update about the role of LC-associated functions for the pathophysiology of schizophrenia, focusing on the cognitive and motivational deficits. We propose that schizophrenia phenomenology, in particular cognitive symptoms, may be explained by an abnormal interaction between genetic susceptibility and stress-initiated LC-NE dysfunction. This in turn, leads to imbalance between LC activity modes, dysfunctional regulation of brain network integration and neural gain, and deficits in cognitive functions. Finally, we suggest how recent development of experimental approaches can be used to characterize LC function in schizophrenia.
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We remember when things change. Particularly salient are experiences where there is a change in rewards, eliciting reward prediction errors (RPEs). How do RPEs influence our memory of those experiences? One idea is that this signal directly enhances the encoding of memory. Another, not mutually exclusive, idea is that the RPE signals a deeper change in the environment, leading to the mnemonic separation of subsequent experiences from what came before, thereby creating a new latent context and a more separate memory trace. We tested this in four experiments where participants learned to predict rewards associated with a series of trial-unique images. High-magnitude RPEs indicated a change in the underlying distribution of rewards. To test whether these large RPEs created a new latent context, we first assessed recognition priming for sequential pairs that included a high-RPE event or not (Exp. 1: n = 27 & Exp. 2: n = 83). We found evidence of recognition priming for the high-RPE event, indicating that the high-RPE event is bound to its predecessor in memory. Given that high-RPE events are themselves preferentially remembered (Rouhani, Norman, & Niv, 2018), we next tested whether there was an event boundary across a high-RPE event (i.e., excluding the high-RPE event itself; Exp. 3: n = 85). Here, sequential pairs across a high RPE no longer showed recognition priming whereas pairs within the same latent reward state did, providing initial evidence for an RPE-modulated event boundary. We then investigated whether RPE event boundaries disrupt temporal memory by asking participants to order and estimate the distance between two events that had either included a high-RPE event between them or not (Exp. 4). We found (n = 49) and replicated (n = 77) worse sequence memory for events across a high RPE. In line with our recognition priming results, we did not find sequence memory to be impaired between the high-RPE event and its predecessor, but instead found worse sequence memory for pairs across a high-RPE event. Moreover, greater distance between events at encoding led to better sequence memory for events across a low-RPE event, but not a high-RPE event, suggesting separate mechanisms for the temporal ordering of events within versus across a latent reward context. Altogether, these findings demonstrate that high-RPE events are both more strongly encoded, show intact links with their predecessor, and act as event boundaries that interrupt the sequential integration of events. We captured these effects in a variant of the Context Maintenance and Retrieval model (CMR; Polyn, Norman, & Kahana, 2009), modified to incorporate RPEs into the encoding process.
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Rapid CommunicationLocus coeruleus neuromodulation of memories encoded during negative or unexpected action outcomes

Highlights

Abstract

Introduction

Section snippets

2.1 Sample

3.1 Reaction time results

4. Discussion

Acknowledgments

Neuron

Brain Research

Neuroscience

Brain Research Reviews

Trends in Neurosciences

Neuroimage

Neuroimage

Neuroimage

Current Opinion in Neurobiology

Neuron

Progress in Brain Research

Neuron

Involvement of the insular cortex in the consolidation and expression of contextual fear conditioning

European Journal of Neuroscience

Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli

The Journal of Neuroscience

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

Annual Review of Neuroscence

Investigations into resting-state connectivity using independent component analysis

Philosophical Transactions of the Royal Society B: Biological Sciences

Reward expectation, orientation of attention and locus coeruleus-medial frontal cortex interplay during learning

European Journal of Neuroscience

Phasic activation of monkey locus ceruleus neurons by simple decisions in a forced-choice task

The Journal of neuroscience

Amygdala functional connectivity is reduced after the cold pressor task

Cognitive, Affective, & Behavioral Neuroscience

Acute stressors and cortisol responses: A theoretical integration and synthesis of laboratory research

Psychological Bulletin

Responses of human frontal cortex to surprising events are predicted by formal associative learning theory

Nature neuroscience

The human locus coeruleus: Computer reconstruction of cellular distribution

The Journal of Neuroscience

Rapid Communication
Locus coeruleus neuromodulation of memories encoded during negative or unexpected action outcomes