Progressive neurodegeneration of the locus coeruleus drives rapid eye movement sleep fragmentation

Abstract

Sleep disturbances are common early features of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). AD progression is also characterized by early and substantial degeneration of the noradrenergic locus coeruleus (LC), beginning with tau pathology and progressing to major neuronal loss. Although LC degeneration and sleep disruption progress in parallel, whether LC degeneration causally contributes to sleep abnormalities, and which sleep changes are associated with this process, remain unresolved. Human studies are largely correlative, while existing rodent models poorly reproduce progressive LC degeneration. Here, we employed progressive Caspase-3 (Casp3)-mediated LC ablation, with longitudinal sleep and calcium fiber photometry to monitor LC activity across defined stages of degeneration in adult female DBH-Cre mice. Histological analysis demonstrated graded, time-dependent LC degeneration, yielding mild degeneration (~25% neuronal loss) by day 8 post Casp3 injection and moderate degeneration (~50% loss) by day 18. Relative to baseline and to control mice, LC degeneration led to REM sleep fragmentation, emerging already at the mild degeneration stage. By the moderate stage, total REM sleep during light hours had significantly increased, while EEG theta power during REM sleep progressively declined across all stages of degeneration. Degeneration also blunted state-dependent LC calcium activity, significantly reducing the contrast between wakefulness and REM signal. Together, these results establish Casp3-mediated ablation as a model of progressive LC neurodegeneration and identify REM fragmentation and blunted state-dependent LC activity as its early functional signatures, providing a platform for studying how degeneration of neuromodulatory systems shapes sleep in a neurodegenerative disease-like state.