LOCUS COERULEUS DYSFUNCTION LEADS TO HIGHER REM PRESSURE IN AGING

Despite decades of research, the mechanism, functional role and importance of REM sleep remain open and intriguing questions. The quantity and quality of REM sleep changes over the lifespan; however, the mechanisms driving these changes are poorly understood. Here, we investigated age-related changes in REM sleep using young (3–5 months) and old (19–22 months) mice. Using fiber photometry to measure extracellular norepinephrine levels in combination with EEG and EMG recordings, we found that during natural sleep, REM bouts in older mice are shorter and more frequent, and there is an overall reduction in total REM sleep. In addition, older mice spend less time in wakefulness immediately following REM sleep. Notably, we observed no age-related differences in norepinephrine oscillation dynamics immediately preceding REM entry. We next employed a novel REM deprivation paradigm and found that older mice exhibit increased REM sleep pressure, as evidenced by earlier transitions into REM sleep following the deprivation period. Using microscopy and microdialysis, we further established that aging is associated with a loss of locus coeruleus neurons and a reduction in extracellular norepinephrine levels. Based on these findings, we hypothesize that loss of locus coeruleus neurons impairs the ability to sustain norepinephrine release (without compromising its natural oscillations), leading to repeated attempts to 'reset' the locus coeruleus circuit, ultimately manifesting as elevated REM pressure.