Segregated basal ganglia output pathways correspond to genetically divergent neuronal subclasses

The basal ganglia control multiple sensorimotor behaviors through anatomically segregated and topographically organized subcircuits with outputs to specific downstream circuits. However, it is unclear how the anatomical organization of basal ganglia output circuits relates to the molecular diversity of cell types. Here, we demonstrate that the major output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr), is comprised of transcriptomically distinct subclasses that reflect its distinct progenitor lineages. We show that these subclasses are topographically organized within the SNr, project to distinct targets in the midbrain and hindbrain, and receive inputs from different striatal subregions. Finally, we show that these mouse subclasses are also identifiable in human SNr neurons, suggesting that the genetic organization of the SNr is evolutionarily conserved. These findings provide a unifying logic for how the developmental specification of diverse SNr neurons relates to the anatomical organization of basal ganglia circuits controlling specialized downstream brain regions.