Nucleus accumbens processing of reward-predictive cues

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Project Summary Salient sensory events can elevate the arousal level, increasing the subject's readiness to engage motor, cognitive and attentional resources. For example, arousal is increased when a sleeping person is shaken awake, or when a quiescent rat is transferred to a new cage or otherwise handled. Recent evidence shows that the dopamine projection from the midbrain ventral tegmental area to the nucleus accumbens (NAc) core serves to elevate arousal in response to such events, and that this effect likely involves both D1 and D2 dopamine receptor- expressing NAc neurons. Yet, this role for mesolimbic circuitry in arousal has not been reconciled with the large literature that interprets the behavioral effects of NAc dopamine manipulations as the result of altered motivation or reward. To investigate how arousal might contribute to the reward-seeking effects of dopamine, we first established a behavioral paradigm in which rats' performance of a cued operant task declines over time due to gradually decreasing arousal. We find that simply handling the animal for a few seconds dramatically restores high levels of performance for many minutes. Handling also increases dopamine levels in the NAc and the firing response of NAc neurons to reward-predictive cues, which are known to be dopamine-dependent and causal to the cued reward-seeking behavioral response. These results suggest that the dopamine increase caused by arousing events facilitates reward seeking. This is one of the major hypotheses tested in this proposal. This hypothesis suggests an even more provocative idea: that NAc dopamine promotes reward seeking by increasing arousal. If that were the case, then dopamine should act via the same local circuit mechanism within the NAc to increase both arousal and reward seeking. Previous studies point towards (but do not conclusively demonstrate) a specific circuit mechanism common to both processes: D1 neurons are the “effector” neurons whose firing drives both arousal and reward seeking, whereas D2 neurons strongly inhibit D1 neurons. Dopamine promotes arousal and reward seeking primarily by acting at the D2 receptor to reduce the inhibitory drive from D2 neurons onto D1 neurons, and only secondarily (if at all) by directly increasing the excitability of D1 neurons by acting at the D1 receptor. This circuit model receives a great deal of indirect support from disparate published experiments, as well as our pilot experiments, that have tested individual components of the model in isolation from the others. In this proposal, we aim to test the model cohesively and thoroughly, and in doing so, to establish that dopamine increases both arousal and reward seeking by the same local NAc circuit mechanism. Doing so will reframe current thinking regarding the behavioral role of mesolimbic dopamine in two ways; first, by establishing the causal contribution of D2 neurons' inhibition of D1 neurons (and the relief of this inhibition by dopamine) to both arousal and reward seeking; and second, by showing that dopamine facilitates arousal and reward seeking via the same local circuit mechanism – which will introduce the field to the hypothesis that dopamine's well-known ability to promote reward seeking could be due in part to increased arousal.