Striatal neurons expressing dopamine D₁ receptor promote wakefulness in mice

Patients with Parkinson's disease (PD) suffer from severe sleep disorders. Pathophysiology of the basal ganglia (BG) underlies PD, and the dorsal striatum represents the major input pathway of the BG. However, the roles and mechanisms of the dorsal striatum in controlling sleep-wake cycles remain unknown. To demonstrate the contribution of dopamine D₁ receptor (D₁R)-positive neurons within the dorsal striatum in promoting wakefulness, we combined optogenetic manipulations and fiber photometry with electroencephalography/electromyography recording in D₁R-Cre mice. As a result, optogenetic activation of striatal D₁R neurons induced immediate transitions from non-rapid eye movement (NREM) sleep to wakefulness, whereas inhibition of striatal D₁R neurons attenuated wakefulness by chemogenetics. Multi-channel fiber photometry recordings revealed that the activity of striatal D₁R neurons synchronized with that of BG upstreams, namely the prefrontal cortex and mediodorsal thalamus, in terms of immediate increase in activity during NREM-to-wake transitions and rapid decease during wake-to-NREM transitions. Further optogenetic manipulations revealed a prominent contribution of striatal D₁R neurons in control of wakefulness by upstream, corticostriatal, thalamostriatal, and nigrostriatal projections and via downstream, striato-entopeduncular, or striatonigral pathways. Taken together, our findings revealed a circuit regulating wakefulness through striatal D₁R neurons. Striatal D₁R neurons play an important role in controlling wakefulness by integrating the corticostriatal, thalamostriatal, and nigrostriatal projections and innervation of striato-entopeduncular or striatonigral pathways.