Temporally-precise dopamine neuron inhibition disrupts reward seeking behavior

Midbrain dopamine (DA) neurons are phasically activated in response to unexpected reward presentation and are depressed by reward omission; these phasic responses are proposed to contribute to learning. In addition, because DA release in the nucleus accumbens precedes initiation of instrumental actions, and DA receptor blockade in the nucleus accumbens decreases effortful behavioral responding, DA is thought to be necessary to initiate and maintain motivated responding. Hence, midbrain DA signaling may be critically involved in multiple, temporally-specific, behavioral processes. Notably, previous findings were based on long-term perturbations such as dopamine depletion and receptor antagonism, which do not assess the contribution of DA to behavior on short time scales. Therefore, in this study, we used in vivo optogenetic techniques to inhibit midbrain DA neurons of mice in real time to investigate how the precise timing of DA neural activity contributes to the decision to exert effort and to maintain cue-reward associations. We found that inhibiting DA neurons while mice were engaged in a bout of operant nose-poke responses decreased the probability of continued nose-poke behavior. Conversely, we found that inhibiting DA neurons while mice were engaged in off-task behavior decreased the probability of initiating a nose-poke response. Finally, we found that inhibiting DA neurons during reward consumption extinguished learned cue-reward associations, but did not alter effortful responding. We conclude that DA is required at multiple specific phases in behavior to differentially support reward prediction, and both initiation and maintenance of motivation to respond for reward