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. It remains, however, unclear how LC activity contributes to the cellular response profiles observed during natural arousal. Here, we directly compared natural arousal with selective LC activation in mouse CA1 using physiologically titrated optogenetics, fiber photometry of NA and calcium signals, chronic two-photon imaging, and behavioral monitoring. Natural arousal robustly activated astrocytes, pyramidal cells, and inhibitory interneurons at the population level. In contrast, stimulation of the LC activated only astrocytes and, for higher stimulation intensities, resulted in a slow inhibition of pyramidal cells and interneurons at the population level. A subset of interneurons exhibited a transient activation by LC stimulation and occupied distinct laminar positions in CA1. However, these LC-responsive subpopulations of interneurons did not reliably map onto subpopulations defined by activity patterns during natural arousal. Similarly, single-cell astrocyte responses to LC stimulation only partially aligned with their activity profiles during natural arousal. Together, these findings demonstrate that LC-driven NA release produces cell-specific effects in hippocampal CA1 that are strikingly distinct from, and in some cases opposite to, cellular dynamics during natural arousal. These results challenge the idea that LC activity as a proxy for arousal recapitulates the cellular signatures of arousal in vivo.