Nigrostriatal dopamine signals sequence-specific action-outcome prediction errors.

Dopamine has been suggested to encode cue-reward prediction errors during Pavlovian conditioning, signaling discrepancies between actual versus expected reward predicted by the cues.1-5 While this theory has been widely applied to reinforcement learning concerning instrumental actions, whether dopamine represents action-outcome prediction errors and how it controls sequential behavior remain largely unknown. The vast majority of previous studies examining dopamine responses primarily have used discrete reward-predictive stimuli,1-15 whether Pavlovian conditioned stimuli for which no action is required to earn reward or explicit discriminative stimuli that essentially instruct an animal how and when to respond for reward. Here, by training mice to perform optogenetic intracranial self-stimulation, we examined how self-initiated goal-directed behavior influences nigrostriatal dopamine transmission during single and sequential instrumental actions, in behavioral contexts with minimal overt changes in the animal's external environment. We found that dopamine release evoked by direct optogenetic stimulation was dramatically reduced when delivered as the consequence of the animal's own action, relative to non-contingent passive stimulation. This dopamine suppression generalized to food rewards was specific to the reinforced action, was temporally restricted to counteract the expected outcome, and exhibited sequence-selectivity consistent with hierarchical control of sequential behavior. These findings demonstrate that nigrostriatal dopamine signals sequence-specific prediction errors in action-outcome associations, with fundamental implications for reinforcement learning and instrumental behavior in health and disease.

Differential inputs to striatal cholinergic and parvalbumin interneurons imply functional distinctions.

Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior.