The Indirect Pathway of the Basal Ganglia Promotes Negative Reinforcement, But Not Motor Suppression

Summary Optogenetic stimulation of Adora2a receptor expressing spiny projection neurons (A2A-SPN) in the striatum drives locomotor suppression and negative reinforcement, results attributed to activation of the indirect pathway. The sole long-range projection target of A2A-SPNs is the external globus pallidus (GPe). Unexpectedly, we found that inhibition of the GPe did not suppress movement, but did drive robust negative reinforcement in a real-time place preference assay. Within the striatum, A2A-SPNs inhibit other SPNs through a short-range inhibitory collateral network, and we found that optogenetic stimuli that drove motor suppression shared a common mechanism of recruiting this inhibitory collateral network. Our results suggest that the indirect pathway plays a more prominent role in negative reinforcement than in motor control and challenges the assumption that activity of A2A-SPNs is synonymous with indirect pathway activity.