Locus coeruleus noradrenaline elicits response profiles distinct from natural arousal in hippocampal neurons and astrocytes
During arousal and stress, the locus coeruleus (LC) releases noradrenaline (NA) throughout the brain, including hippocampus. It remains, however, unclear how LC activity contributes to the cellular response profiles observed during natural arousal. Here we directly compared effects of natural arousal and isolated LC activation in mouse CA1 using physiologically titrated optogenetics, combined with fiber photometry of NA and calcium signals, chronic two-photon imaging, and behavioral monitoring. We found that natural arousal robustly activated all three major cell types - astrocytes, pyramidal cells, and inhibitory interneurons - on a population level. In contrast, stimulation of the LC alone exerted a slow inhibitory influence on pyramidal cells and interneurons, with only a subset of interneurons exhibiting a transient activation by LC stimulation. Interneurons, but not pyramidal cells, segregated into functionally consistent LC-responsive subpopulations (activated vs inhibited) with distinct laminar positions in CA1. However, these LC-responsive subpopulations of interneurons did not reliably map onto response subpopulations defined by activity patterns during natural arousal. Astrocytes were strongly activated by both natural arousal and LC stimulation. However, single-cell responses of astrocytes to LC stimulation only partially aligned with their activity during natural arousal responses, indicating distinct driving forces across the two conditions. Together, these results show that LC-driven NA release produces distinct, cell-specific effects that do not align with hippocampal dynamics during natural arousal. Thus, our findings highlight the need to rethink how the locus coeruleus influences the main hippocampal cell types in vivo. ### Competing Interest Statement The authors have declared no competing interest. ETH Zurich, ETH-20 19-1 Swiss National Science Foundation, 310030_172889, 310030_204372, 310030B_170269, PZ00P3_209114 Botnar Research Center for Child Health Swiss 3R Competence Center Roche (Switzerland), https://ror.org/00by1q217 Hochschulmedizin Zürich Flagship project STRESS European Research Council, 670757
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