0059 Causative Role of Hyperactive Locus Coeruleus in Insomnia Disorder: A REM Sleep Instability Model Using Closed-Loop Optogenetics

Abstract Introduction Insomnia disorder (ID) is characterized by chronic difficulty initiating or maintaining sleep despite adequate opportunity, accompanied by daytime cognitive and emotional impairment. Fragmented rapid eye movement sleep (REMS) and maladaptive affective responses in ID suggest REMS instability (REMSI) as a central mechanism. Complete silencing of noradrenergic neurons in locus coeruleus (LC) and associated norepinephrine (NE) decline during REMS are required for stable, emotionally restorative REMS, whereas stress-induced LC hyperactivation has been proposed to impair this silencing in ID. However, direct evidence for the causative role of REMSI in ID has not been elucidated. To address this gap, we sought to develop an animal model of REMSI with a closed-loop optogenetic system and examine whether chronic REMSI can lead to ID. Methods TH::Cre mice underwent stereotaxic surgery for EEG/EMG, virus injection for optogenetic stimulation of the LC (AAV5-EF1a-DIO-hChR2-EYFP), and measurement of NE dynamics in the medial prefrontal cortex (AAV9-hSyn-GRABNE2m, a genetically encoded fluorescent norepinephrine sensor). After 3 weeks of recovery, REMS-specific LC stimulation was performed for 1 week based on the real-time detection of REMS from 5-s EEG epochs using delta/theta power ratios. Results Preliminary experiments are expected to result in fragmented REM sleep, elevated NE levels during REM sleep, and prolonged sleep latency during the period of REMS-specific LC stimulation and to persist beyond the stimulation period. In addition, increased wake theta power and reduced NREM sleep are expected to be maintained after stimulation. Experimental results are pending. Conclusion These hypothetical findings would support the conclusion that LC hyperactivity during REMS is sufficient to induce insomnia-like sleep phenotypes, and that sustained REMS disruption may drive the transition from acute insomnia to chronic insomnia disorder. Further investigation is warranted. Support (if any) This research was supported by the Korean Society of Sleep Medicine Research Fund (Trainee Academic Research Program).