Striosome circuitry stimulation inhibits striatal dopamine release and locomotion

The mammalian striatum is divided into two types of anatomical structures: the island-like, mu opioid receptor (MOR)-rich striosome compartment and the surrounding matrix compartment. Both compartments have two types of spiny projection neurons (SPNs), dopamine receptor D1 (D1R)-expressing direct pathway SPNs (dSPNs) and dopamine receptor D2 (D2R)-expressing indirect pathway SPNs. These compartmentalized structures have distinct roles in the development of movement disorders, although the functional significance of the striosome compartment for motor control and dopamine regulation remains to be elucidated. The aim of this study was to explore the roles of striosome in locomotion and dopamine dynamics in freely moving mice. We targeted striosomal MOR-expressing neurons with male MOR-CreER mice, which express tamoxifen-inducible Cre recombinase under MOR promoter, and Cre-dependent adeno-associated virus vector. The targeted neuronal population consisted mainly of dSPNs. We found that the Gq-coupled designer receptor exclusively activated by designer drugs (DREADD)-based chemogenetic stimulation of striatal MOR-expressing neurons caused a decrease in the number of contralateral rotations and total distance traveled. Wireless fiber photometry with a genetically-encoded dopamine sensor revealed that chemogenetic stimulation of striatal MOR-expressing neurons suppressed dopamine signals in the dorsal striatum of freely moving mice. Furthermore, the decrease in mean dopamine signal and the reduction of transients were associated with ipsilateral rotational shift and decrease of average speed, respectively. Thus, a subset of striosomal dSPNs inhibits contralateral rotation, locomotion, and dopamine release in contrast to the role of pan-dSPNs. Our results suggest that striatal MOR-expressing neurons have distinct roles in motor control and dopamine regulation. Significance of statement The striatum plays a crucial role in motor control, and it consists of two anatomical compartments: mu opioid receptor (MOR)-rich striosomes and the surrounding matrix. The striosome sends efferent inhibitions to midbrain dopaminergic neurons, but it remains unknown whether striosomes are involved in motor control and dopamine regulation in behaving animals. We used MOR-expression based targeting, chemogenetics and wireless fiber photometry with a genetically-encoded dopamine sensor, and we found that chemogenetic stimulation of striosomal MOR-expressing neurons inhibits contralateral rotations, locomotion, and dopamine release in the dorsal striatum. The rotational shift and the locomotion decrease might be differently associated with dopamine dynamics. This study provides compelling evidence that striosomal MOR-expressing neurons inhibit motor behavior and dopamine release in freely moving animals.