Striatal dopamine regulates sleep states and narcolepsy-cataplexy

Disruptions to sleep can be debilitating and have a severe effect on daily life. Patients with the sleep disorder narcolepsy suffer from excessive daytime sleepiness, disrupted nighttime sleep, and cataplexy - the abrupt loss of postural muscle tone (atonia) during wakefulness, often triggered by strong emotion. The dopamine (DA) system is implicated in both sleep-wake states and cataplexy, but little is known about the function of DA release in the striatum - a major output region of midbrain DA neurons - and sleep disorders. To better characterize the function and pattern of DA release in sleepiness and cataplexy, we combined optogenetics, fiber photometry, and sleep recordings in a murine model of narcolepsy (orexin-/-; OX KO) and in wildtype mice. Recording DA release in the ventral striatum revealed OX-independent changes across sleep-wake states as well as striking increases in DA release in the ventral, but not dorsal, striatum prior to cataplexy onset. Tonic low frequency stimulation of ventral tegmental efferents in the ventral striatum suppressed both cataplexy and REM sleep, while phasic high frequency stimulation increased cataplexy propensity and decreased the latency to rapid eye movement (REM) sleep. Together, our findings demonstrate a functional role of DA release in the striatum in regulating cataplexy and REM sleep.