A CONSERVED LOCUS COERULEUS FMRI SIGNATURE OF BRAIN-STATE TRANSITIONS ACROSS SLEEP, ANESTHESIA, AND WAKEFULNESS

Neuromodulatory systems dynamically reconfigure large-scale brain networks to support adaptation across behavioral and cognitive states. The locus coeruleus (LC), which broadcasts noradrenaline throughout the forebrain, is a central regulator of arousal and state-dependent dynamics. Yet how LC activity reshapes brain-wide organization across physiological contexts, and how it influences resting-state functional MRI (rs-fMRI) connectivity, remains unclear.
Here we use an optogenetically-informed, cross-species framework to define an LC fMRI signature under causal control in mice and test its generalizability across progressively naturalistic conditions. We first derive a low-dimensional spatiotemporal signature from optogenetic LC stimulation that captures a stereotyped sequence of brain-wide BOLD responses. We then track its expression across progressively naturalistic conditions, from endogenous LC calcium surges during simultaneous fiber photometry–fMRI in urethane-anesthetized mice, to spontaneous sleep–wake transitions in mice and humans, and during awake human rs-fMRI at 7T.
Across datasets, the LC-derived signature re-emerges with conserved spatial structure and state-dependent timing, leaving an imprint on the BOLD signal during arousal fluctuations and sleep-stage transitions. Critically, the prevalence of LC events systematically biases functional connectivity metrics in human fMRI, indicating that LC-driven state dynamics systematically shape rs-fMRI connectivity metrics.
These findings establish LC activity as a mechanistically interpretable source of variability in resting-state measurements. As the field advances toward precision medicine with rs-fMRI biomarkers, accounting for LC-related network dynamics may refine the interpretation of functional connectivity differences across individuals and patient populations and provide a quantitative index of arousal and state regulation.