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bioRxiv · 10.1101/2025.05.10.653174

Locus coeruleus-related insula activation supports implicit learning

Dahl, M. J.·Li, T.·Mather, M.·Werkle-Bergner, M. J.
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Abstract

The noradrenergic locus coeruleus and its neuromodulatory cortical projections are critical for adaptive behavior, however how they contribute to human implicit learning in novel environments is not yet well understood, due to the challenges of assessing this system non-invasively. Here, we combined multimodal neuroimaging--including locus-coeruleus-sensitive structural MRI, concurrent pupillometry-EEG, pupillometry-fMRI, and PET-derived noradrenergic transporter maps--with repeated behavioral assessments to investigate noradrenergic contributions to implicit learning across younger and older adults (n = 77). Salient expectation-violating stimuli elicited pupil dilation, indicating enhanced neuromodulation, activated the action-mode network and deactivated the default-mode network. Pupil-linked BOLD responses suggested a functional coupling between the locus coeruleus and action-mode network, further supported by spatial overlap of activation patterns with PET-derived noradrenergic transporter maps. Locus coeruleus MRI-guided functional connectivity analyses demonstrated coupled locus coeruleus and anterior insula activity, suggesting a noradrenergic role in shifting cortical dynamics toward action-oriented processing. Behaviorally, participants implicitly learned the statistical task structure over time, shifting their response times based on stimulus probabilities. Critically, stronger locus coeruleus integrity, greater task-related anterior insula activation, and more pronounced pupil dilation were associated with enhanced implicit learning, highlighting the behavioral relevance of noradrenergic neuromodulation. Notably, noradrenergic responses and their link to learning were preserved across age groups, suggesting a robust noradrenergic role in supporting adaptive behavior throughout adulthood. Complementary electrophysiological analyses revealed pupil-linked increases in cortical excitability that were coupled with shifts from default-mode to action-mode network activation. Together, these findings provide novel insights into the neuromodulatory mechanisms underlying learning and cognitive flexibility, emphasizing the pivotal role of locus coeruleus-action-mode network interactions in behavioral adaptation.

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Dahl, M. J., Li, T., Mather, M., Werkle-Bergner, M. J.. 2025-05-11. Locus coeruleus-related insula activation supports implicit learning. https://doi.org/10.1101/2025.05.10.653174

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