Three-dimensional characterization of medium spiny neuron heterogeneity in the adult mouse striatum.

Striatal dopamine (DA) neurotransmission is critical for an array of reward-related behaviors and goal-directed motor control. In rodents, 95% of striatal neurons are GABAergic medium spiny neurons (MSNs) that have been traditionally segregated into two subpopulations based on the expression of stimulatory DA D 1 -like receptors versus inhibitory D 2 -like receptors. However, emerging evidence suggests that striatal cell composition is anatomically and functionally more heterogenous than previously appreciated. The presence of MSNs that co-express multiple DA receptors offers a means to more accurately understand this heterogeneity. To dissect the precise nature of MSN heterogeneity, here we used multiplex RNAscope to identify expression of three predominantly expressed DA receptors in the striatum: DA D 1 (D1R), D 2 (D2R), and D 3 (D3R) receptors. We report heterogenous subpopulations of MSNs that are distinctly distributed across the dorsal-ventral and rostral-caudal axes of the adult mouse striatum. These subpopulations include MSNs that co-express D1R and D2R (D1/2R), D1R and D3R (D1/3R), and D2R and D3R (D2/3R). Overall, our characterization of distinct MSN subpopulations informs our understanding of region-specific striatal cell heterogeneity.