Phasic dopamine release in the nucleus accumbens influences REM sleep timing

Based on the activity of dopamine (DA) neurons during behavioral states, the DA system has long been thought to be foundational in regulating sleep-wake behavior; over the past decade advances in circuit manipulation and recording techniques have strengthened this perspective. Recently, several studies have demonstrated that DA release in regions of the limbic system is important in the promotion of REM sleep. Yet how DA dynamics change within bouts of sleep, how these changes are regulated, and whether they influence future state changes remains unclear. To address these questions, in mice of both sexes we used in vivo fiber photometry and inhibitory optogenetics to identify a specific role of DA transients in the nucleus accumbens (NAcc) in state transitions from NREM sleep. We found that DA transients increase their frequency and amplitude over the duration of NREM sleep and that this increase is more pronounced during NREM bouts that transition into REM sleep. Next, we found that DA transients in NREM sleep are influenced by changes in REM sleep pressure. Finally, we show that transient DA release in the NAcc plays a functional role in regulating the timing of REM sleep entrances, as inhibition of midbrain DA neuron terminals in the NAcc prolonged bouts of NREM sleep and decreased the frequency of bouts of REM sleep. These findings demonstrate that DA release in the NAcc is dynamically regulated by sleep pressure and has a functional role in transitions from NREM sleep, particularly those into REM sleep. Significance Statement Sleep is a central component of daily life and is heavily influenced by midbrain dopamine neurons. Dopamine release in limbic regions, such as the nucleus accumbens, has been implicated in the promotion of REM sleep. However, dopamine release dynamics during sleep and how these influence future changes in state remain unclear. We used a fluorescence-based dopamine biosensor to elucidate the pattern of dopamine release during sleep and inhibitory optogenetics to disrupt dopamine release. Dopamine release increases across the duration of NREM sleep bouts and is sensitive to REM sleep need. Inhibition of dopamine terminals in the nucleus accumbens decreases the frequency of REM sleep. This suggests that phasic dopamine release during NREM sleep functionally influences REM sleep timing.