Locus coeruleus activity strengthens prioritized memories under arousal

60 Pages·2017·1.15 MB·English

This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version.
Research Articles: Behavioral/Cognitive
Locus coeruleus activity strengthens prioritized memories under arousal
David Clewetta, Ringo Huangb, Rico Velascob, Tae-Ho Leec and Mara Mathera,b
aNeuroscience Graduate Program, University of Southern California, USA 90089
bDavis School of Gerontology, University of Southern California, USA 90089
cDepartment of Psychology and Neuroscience, University of North Carolina at Chapel Hill, USA 27599
DOI: 10.1523/JNEUROSCI.2097-17.2017
Received: 25 July 2017
Revised: 16 November 2017
Accepted: 28 November 2017
Published: 4 January 2018
Author contributions: D.V.C. and M.M. designed research; D.V.C., R.H., and R.V. performed research; D.V.C.
contributed unpublished reagents/analytic tools; D.V.C., R.H., R.V., T.-H.L., and M.M. analyzed data; D.V.C.,
R.H., R.V., T.-H.L., and M.M. wrote the paper.
Conflict of Interest: The authors declare no competing financial interests.
This project was funded by federal NIH grant R01AG025340. This project was also funded by a USC Endowed
Fellowship (D.C.). The authors declare no competing financial interests. The authors thank Dr. Alexa Tompary
for her helpful comments on the manuscript and Avi Chanales for his assistance editing one of the figures.
Correspondence should be addressed to To whom correspondence should be addressed: University of
Southern California, 3715 McClintock Avenue, Room 351, Los Angeles, CA 90089, Email: [email protected],
Phone: [phone], Fax: [phone]
Cite as: J. Neurosci ; 10.1523/JNEUROSCI.2097-17.2017
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Copyright © 2018 the authors
RUNNING HEAD: LOCUS COERULEUS MOTIVATED MEMORY 1
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6 Locus coeruleus activity strengthens prioritized
7 memories under arousal
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9 David Clewetta*, Ringo Huangb, Rico Velascob, Tae-Ho Leec, & Mara Mathera,b
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12 aNeuroscience Graduate Program, University of Southern California, USA 90089
13 bDavis School of Gerontology, University of Southern California, USA 90089
14 cDepartment of Psychology and Neuroscience, University of North Carolina at Chapel Hill, USA
15 27599
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17 *To whom correspondence should be addressed:
18 University of Southern California
19 3715 McClintock Avenue, Room 351
20 Los Angeles, CA 90089
21 Email: [email protected]
22 Phone: [phone]
23 Fax: [phone]
24 Pages: 53
25 Figures/Tables: 6 and 6
26 Abstract: 224 words
27 Introduction: 646 words
28 Discussion: 1,990 words
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30 Acknowledgements: This project was funded by federal NIH grant R01AG025340. This project
31 was also funded by a USC Endowed Fellowship (D.C.). The authors declare no competing
32 financial interests. The authors thank Dr. Alexa Tompary for her helpful comments on the
33 manuscript and Avi Chanales for his assistance editing one of the figures.
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34 Abstract
35 Recent models posit that bursts of locus coeruleus (LC) activity amplify neural gain, such that
36 limited attention and encoding resources focus even more on prioritized mental representations
37 under arousal. Here, we tested this hypothesis in human males and females using functional
38 magnetic resonance imaging (fMRI), neuromelanin MRI, and pupil dilation, a biomarker of
39 arousal and LC activity. During scanning, participants performed a monetary incentive encoding
40 task in which threat of punishment motivated participants to prioritize encoding of scene images
41 over superimposed objects. Threat of punishment elicited arousal and selectively enhanced
42 memory for goal-relevant scenes. Furthermore, trial-level pupil dilations predicted better scene
43 memory under threat, but were not related to object memory outcomes. FMRI analyses
44 revealed that greater threat-evoked pupil dilations were positively associated with greater scene
45 encoding activity in LC and parahippocampal cortex, a region specialized to process scene
46 information. Across participants, this pattern of LC engagement for goal-relevant encoding was
47 correlated with neuromelanin signal intensity, providing the first evidence that LC structure
48 relates to its activation pattern during cognitive processing. Threat also reduced dynamic
49 functional connectivity between high (parahippocampal place area) and lower priority (lateral
50 occipital cortex) category-selective visual cortex in ways that predicted increased memory
51 selectivity. Together these findings support the idea that, under arousal, LC activity selectively
52 strengthens prioritized memory representations by modulating local and functional network-level
53 patterns of information processing.
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56 Significance Statement
57 Adaptive behavior relies on the ability to select and store important information amidst
58 distraction. Prioritizing encoding of task-relevant inputs is especially critical in threatening or
59 arousing situations, when forming these memories is essential for avoiding danger in the future.
60 However, little is known about the arousal mechanisms that support such memory selectivity.
61 Using fMRI, neuromelanin MRI, and pupil measures, we demonstrate that locus coeruleus (LC)
62 activity amplifies neural gain, such that limited encoding resources focus even more on
63 prioritized mental representations under arousal. For the first time, we also show that LC
64 structure relates to its involvement in threat-related encoding processes. These results shed
65 new light on the mechanisms by which we process important information when it is most
66 needed.
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70 1. Introduction
71 Adaptive behavior relies on the efficient selection and storage of important information
72 among competing inputs, particularly under threatening or arousing conditions. Indeed,
73 emotionally arousing stimuli are preferentially attended and encoded, often at the cost of
74 processing surrounding neutral information (Anderson et al., 2006; Bisby & Burgess, 2014;
75 Hurlemann et al., 2005; Kensinger et al., 2007; Knight & Mather, 2009; LaBar & Cabeza, 2006;
76 Phelps et al., 2006; Strange et al., 2003). However, arousal’s influence on cognition isn’t limited
77 to enhancing emotional memoranda and suppressing neutral stimuli. Rather, arousal seems to
78 enhance processing prioritized (e.g., goal-relevant) representations regardless of their
79 emotionality, while also suppressing less salient representations (Easterbrook, 1959; Mather &
80 Sutherland, 2011; Sakaki et al., 2014; Sutherland & Mather, 2012).
81 For instance, emotional sounds or images enhance memory of goal-relevant neutral
82 stimuli seen just beforehand (Lee et al., 2015b; Sakaki et al., 2014) and impair memory of less
83 salient neutral information (Clewett et al., 2017a; Hurlemann et al., 2005; Sakaki et al., 2014;
84 Strange et al., 2003). Similar memory enhancements have been reported in studies pairing
85 shock with neutral images (Dunsmoor et al., 2012; Dunsmoor et al., 2015; Schwarze et al.,
86 2012). Moreover, memory for neutral information benefits from the receipt of reward or
87 punishment (Adcock et al., 2006; Murty et al., 2012; Weymar et al., 2013). An important open
88 question is whether, like emotional stimuli, threat of punishment enhances memory for salient
89 neutral stimuli by activating arousal-related brain mechanisms.
90 Although the dopaminergic system facilitates reward-motivated encoding (Adcock et al.,
91 2006; Shohamy & Adcock, 2010), recent findings suggest that dopamine does not support
92 encoding of neutral items incentivized by threat of punishment (Murty et al., 2012). Instead,
93 threat-motivated encoding appears to be driven by the amygdala, a region that enhances
94 emotional memories via NE modulation (Markovic et al., 2014; McGaugh, 2013; McGaugh &
95 Roozendaal, 2002; Strange & Dolan, 2004). Further, the LC coordinates processing of a wide
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96 range of motivationally significant stimuli (Aston-Jones et al., 1999; Berridge & Waterhouse,
97 2003; Bouret & Richmond, 2015; Mohanty et al., 2008; Sara, 2009; Varazzani et al., 2015).
98 Thus, the LC is well equipped to amplify task-relevant encoding when it is most needed.
99 Theoretical models posit that phasic LC activity enhances neural gain, such that strong
100 inputs are further enhanced, while weaker inputs are further inhibited (Aston-Jones & Cohen,
101 2005; Eldar et al., 2013; Usher et al., 1999). According to the recent ‘glutamate amplifies
102 noradrenergic effects’ (GANE) model, neural gain is achieved via local interactions between NE
103 release and excitatory glutamate transmission, which signals the activation strength of a mental
104 representation (Mather et al., 2015). In this framework, local NE-glutamate interactions up-
105 regulate excitation in regions transmitting important information, leading to more selective
106 neuronal processing and memory outcomes. These local excitatory effects are also thought to
107 engage lateral inhibitory processes that suppress weaker, competing inputs.
108 In this fMRI study we tested GANE’s core prediction that arousal recruits LC activity to
109 enhance task-relevant memory representations and suppress task-irrelevant representations
110 (Mather et al., 2015). During scanning, participants performed a monetary incentive encoding
111 task in which they prioritized a background scene in attention and memory while ignoring a
112 transparent foreground object. Sympathetic arousal was induced on some trials by threatening
113 to deduct money from a preset account if participants later forgot loss-cued scenes. We
114 hypothesized that pupil dilations, a biomarker of phasic LC activity (Joshi et al., 2015; Murphy et
115 al., 2014; Reimer et al., 2016; Varazzani et al., 2015), would predict enhanced scene memory
116 and impaired object memory. We also hypothesized that pupil dilation would selectively
117 modulate successful scene encoding activity in LC and parahippocampal place area (PPA), a
118 region specialized to process scenes (Epstein & Kanwisher, 1998), and queried whether such
119 patterns were related to LC neuromelanin signal intensity (Keren et al., 2009). Finally, we
120 investigated whether threat-related LC activity amplifies competition within relevant functional
121 networks, yielding greater memory selectivity under arousal.
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122 2. Methods
123 2.1 Participants. Thirty-two healthy young adults were recruited from the University of Southern
124 California’s Psychology Subject Pool and nearby community to participate in this experiment. All
125 participants provided written informed consent approved by the University of Southern California
126 Institutional Review Board and received monetary compensation for their participation and
127 performance on the task. All eligible individuals had normal or normal-to-corrected vision and
128 hearing and were not taking beta-blockers or psychoactive drugs. To limit the influence of sex
129 hormones (i.e., progesterone and estradiol) on the predicted memory and arousal effects,
130 female participants had to be: 1) using monophasic hormonal contraceptives and 2) using those
131 contraceptives for at least 3 months. Female participants only completed the experiment on
132 their active pill days (days 8-21).
133 Six participants were excluded from data analysis: two participants fell asleep during the
134 scan; one participant had excessive head movement during the scan (> 2mm); two participants
135 violated recruitment criteria on the day of their scan; and one participant failed to follow task
136 instructions. Because the focus of this paper was on examining LC activity, as indexed by pupil
137 dilation, an additional four participants were excluded due to poor eye-tracking quality (e.g.,
138 pupil values were unattainable for > 50% of the encoding trials). This resulted in 22 participants
139 (M = 22.18; SD = 2.44; 10 female) for all analyses.
age age
140 2.2 Monetary Incentive Encoding Task
141 2.2.1 Stimuli. The visual stimuli consisted of 96 neutral objects and 96 neutral scenes
142 images selected from previous datasets (Gabrieli et al., 1997; Kensinger et al., 2006) and the
143 Internet. Objects consisted of animals or kitchen utensils centered on a white background. Half
144 of the scene images depicted indoor scenes, while the other half depicted outdoor scenes. Each
145 of these images was resized to be 300 x 300 pixels and rendered in grayscale. From these
146 images, 96 “overlap” stimuli were created by overlaying one object image on top of one scene
147 image; the object image was rendered transparent using Adobe Photoshop 5.0, such that the
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148 foreground object and background scene images were equally discernable. Each of the
149 grayscale, un-merged object and scene stimuli were yoked with a categorically similar but
150 perceptually different image that served as a foil during the recognition memory test. This
151 resulted in a total of 192 scene and object images.
152 To isolate cognitive-related changes in pupil dilation, image luminance was normed
153 across all of the task screens (i.e., overlap stimuli, fixation crosses, scrambled images, and
154 money symbols) using the SHINE toolbox in MATLAB (Willenbockel et al., 2010). In order to
155 model an “active baseline” (Stark & Squire, 2001) in the FMRI analyses, scrambled overlap
156 images were generated by shuffling a 0.27° x 0.27° box in a random fashion using MATLAB.
157 Threat cues were accompanied by a negative buzzer sound acquired from the
158 International Affective Digitized Sounds (Bradley & Lang, 2007); Sound ID #712; M = 7.98,
Arousal
159 SD = 1.62; M = 2.42, SD = 1.62). No sound was paired with the neutral money
Arousal Valence Valence
160 cues.
161 2.2.2 Task design. FMRI data was acquired during the monetary incentive encoding
162 task. The overall structure of the experiment was a 2 (Priority: high vs. low) x 2 (Arousal: threat
163 vs. neutral) within-subjects design. There was a total of 96 encoding trials in the task, which
164 were subdivided into four blocks of 24 trials each. Half of the trials in each block belonged to the
165 threat condition and the other half to the neutral condition. Stimulus order was randomized
166 across all blocks and the order of the arousal trials was randomized within each block.
167 2.2.3 Encoding phase. During the task, participants were presented with a series of
168 grayscale “overlap” images of a transparent object overlaid on a background scene (Figure 1).
169 At the beginning of each trial, participants were shown one of two gray monetary symbols for 1s.
170 In the threat condition, a “no symbol” cued participants that they would lose 50 cents if they
171 forgot the upcoming scene on the subsequent memory test. In the neutral condition, a gray
172 square symbol cued participants that, while they should still try to memorize the background
173 scene, they would not be punished for forgetting it later. To increase arousal on threat trials,
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174 each threat cue was accompanied by a highly arousing buzzer sound. The monetary cue was
175 followed by a jittered central fixation cross (2, 4 or 6s). After this variable anticipation period, the
176 overlap image appeared for 2.5 seconds.
177 To manipulate goal relevance (i.e., top-down priority), participants were instructed to
178 only focus on and memorize each scene in the overlap images while ignoring the foreground
179 object. To reduce the salience/priority of the object even further, participants were told that their
180 memory would not be tested for any of the objects and that they were only meant to be a
181 distraction. To facilitate encoding and ensure participants were prioritizing the scenes, they were
182 also instructed to categorize each scene as indoors or outdoors as quickly and accurately as
183 possible when the overlap image appeared. Regardless of the cue, participants were instructed
184 to categorize and memorize the exact scene image on each trial.
185 Following the overlap image, participants performed a brief scrambled-image detection
186 task, which was used to: (1) prevent memory rehearsal of recent scenes, and (2) provide an
187 active baseline period that could be modeled in the neuroimaging analyses. In this detection
188 task, participants saw three scrambled overlap images for 1s each, which were separated by 1s
189 fixation cross screens in between. Participants had to make a button response with their right
190 hand as quickly as possible when they saw each scrambled image. They pressed the left button
191 when they saw the first scrambled image, the right button when they saw the second scrambled
192 image, and the left button again for the third scrambled image. Each trial concluded with a 2-3s
193 jittered fixation cross, which served as the inter-trial-interval (ITI).
194 2.2.4 Memory test. Approximately 15 minutes after completing the monetary incentive
195 encoding task in the scanner, participants were administered a two-alternative forced choice
196 recognition memory test outside the scanner (Figure 1; top right). To examine the differential
197 effects of threat-related arousal on memory for high (scene) versus lower (object) priority
198 images, we tested memory for all scene and object images that appeared during the task. There
199 were 192 memory trials (96 of each visual category) in total. Prior to beginning the memory test,
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200 participants were told that their memory would be tested for all objects and scenes and to try
201 their best on every trial.
202 On each memory trial, one object or scene image from the previous encoding task was
203 displayed alongside a semantically similar but perceptually different (e.g., different shape,
204 orientation etc.) foil image. The order of stimulus presentation was randomized and an equal
205 number of old items appeared on the left and right of the screen. Participants had to indicate
206 which of the two images they had seen in the scanner.
207 After making their response via button press, participants were prompted to rate their
208 confidence in their memory accuracy according to one of three options: extremely confident,
209 somewhat confident, or just guessing. Participants had to make their memory responses within
210 10 seconds and their confidence rating within 5 seconds. If they failed to respond within these
211 response deadlines, the screen automatically advanced to the next trial and memory accuracy
212 was recorded as a miss. To prevent fatigue, the memory test was divided into three blocks.
213 2.3 Procedure. Upon arriving for the experiment, participants provided written informed consent
214 and completed several pen-and-paper questionnaires. Next, participants were given instructions
215 for the monetary incentive encoding task on a computer. To familiarize participants with the
216 experiment, they completed six task practice trials and three memory test practice trials prior to
217 entering the scanner.
218 Scanning procedures took approximately 1 hour. Inside the MRI scanner, participants
219 first completed the LOC/PPA functional localizer task (see Section 4.2.2 for details), which was
220 followed by a T1-weighted high-resolution neuroanatomical scan. After the structural scan,
221 participants completed 4 runs of the monetary incentive encoding task, which lasted
222 approximately 24 minutes. Between each run, participants were reminded of the task
223 instructions and to keep their head as still as possible. Scanning concluded with a ~2 minute
224 neuromelanin-sensitive weighted scan, which was used to help localize and delineate the LC in
225 the brainstem in each participant (Clewett et al., 2016; Keren et al., 2009; Shibata et al., 2006).
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