Dopamine receptor type 2-expressing medium spiny neurons in the ventral lateral striatum have a non-REM sleep-induce function.

Dopamine receptor type 2-expressing medium spiny neurons (D2-MSNs) in the medial part of the ventral striatum (VS) induce non-REM (NREM) sleep from the wake state in animals. However, it is unclear whether D2-MSNs in the lateral part of the VS (VLS), which is anatomically and functionally different from the medial part of the VS, contribute to sleep-wake regulation. This study aims to clarify whether and how D2-MSNs in the VLS are involved in sleep-wake regulation. Our study found that specifically removing D2-MSNs in the VLS led to an increase in wakefulness time in mice during the dark phase using a diphtheria toxin-mediated cell ablation/dysfunction technique. D2-MSN ablation throughout the VS further increased dark phase wakefulness time. These findings suggest that VLS D2-MSNs may induce sleep during the dark phase with the medial part of the VS. Next, our fiber photometric recordings revealed that the population intracellular calcium (Ca 2+ ) signal in the VLS D2-MSNs increased during the transition from wake to NREM sleep. The mean Ca 2+ signal level of VLS D2-MSNs was higher during NREM and REM sleep than during the wake state, supporting their sleep-inducing role. Finally, optogenetic activation of the VLS D2-MSNs during the wake state always induced NREM sleep, demonstrating the causality of VLS D2-MSNs activity with sleep-induction. Additionally, activation of the VLS D1-MSNs, counterparts of D2-MSNs, always induced wake from NREM sleep, indicating a wake-promoting role. In conclusion, VLS D2-MSNs could have an NREM sleep-inducing function in coordination with those in the medial VS. Significant Statement The sleep-inducing function of D2-MSNs in the medial part of the ventral striatum (VS) has been previously reported; however, their function in the lateral part of the VS (VLS) has not been elucidated. We demonstrated that the diphtheria toxin-induced ablation of D2-MSNs in the VLS, as well as in the entire VS, increased wakefulness time in mice during the dark phase. VLS D2-MSNs had higher average Ca 2+ signals during NREM and REM sleep than wake state via fiber photometric recording. Furthermore, optogenetic activation of VLS D2-MSNs during wake state induced NREM sleep in mice. In conclusion, D2-MSNs in the VLS have an NREM sleep-inducing function in coordination with those in the medial VS.