BRAINSTEM CIRCUITRY UNDERLYING THE COORDINATION OF SLEEP AND CARDIOVASCULAR FUNCTION

Sleep research has long centered on brain function, but growing evidence highlights its broader physiological roles and essential brain–body interactions during sleep. We previously identified the noradrenergic locus coeruleus (LC) as a coordinator between forebrain and autonomic activities during sleep. LC activity fluctuates in phase with heart rate during non-rapid eye movement (NREM) sleep, through parasympathetic modulation, playing a key role in maintaining sleep continuity and modulating arousability. However, the neuronal pathways enabling this integrative function remain poorly understood.
We used a functional approach combining electrophysiological recordings with stereotaxic surgery in Dopamine- ß-hydroxylase::Cre mice. Anterograde and retrograde tracing revealed a distinct subpopulation of LC neurons projecting to the parasympathetic nucleus ambiguus in the brainstem, which regulates heart rate via the vagus nerve. Dual-virus injections and tissue clearing experiments further showed that these LC neurons also send projections to the paraventricular thalamus. Quantification in six injected animals showed about 87 ± 3 tyrosine hydroxylase-positive LC neurons projecting to the nucleus ambiguus per LC, representing 6.5 ± 0.5% of LC neurons, with about half also projecting to the paraventricular thalamus. Fiber-photometry recordings in nine mice revealed a distinct activity profile for this LC subpopulation, with increased activity during rapid eye movement (REM) sleep compared with NREM sleep.
This work provides the first anatomical identification of LC neurons with dual projections to both brainstem and forebrain areas, reinforcing the LC’s role as a central integrator. We propose that this unique connectivity and state-dependent activity supports a specialized function in arousal control during sleep.