PROJECT SUMMARY A core feature of a number of psychiatric illnesses is the disordered estimation of the predictive relationship between a given cue and an outcome. This failure to appraise and generate appropriate behavioral responses is true for cues that both are rewarding and aversive. For example, in post-traumatic stress disorders innocuous stimuli can elicit intense aversive motivational responses even though these were encountered in a safe and familiar context. On the other hand, in substance use disorders previously drug-paired cues can elicit intense craving and trigger relapse, despite these cues being encountered in settings where drug use never occurred. As a result, it is critical to understand the factors and neural systems that support and regulate cue-triggered motivations in the hope of identifying potential treatments for disorders of motivation. Dopamine neurons within the ventral tegmental area (VTA) are well known to be responsible for reward-related learning, yet subsets of VTA dopamine neurons are excited by aversive stimuli which opposes an exclusive role for these neurons in reward. However, there is limited understanding of how such heterogeneity in VTA dopamine neurons contributes to the dynamic control of reward and aversion as these are primarily assessed in conditions where animals learn cue-outcome associations that are rigid and stable which occlude the ability to differentiate the encoding of value and valence. Here, I propose a novel behavioral approach that dynamically alters the relations between cues and either rewarding or aversive outcomes on a trial-to-trial basis to understand the contribution of VTA dopamine neurons to the flexible generation of motivated behaviors. This behavioral approach will allow me to test whether defined subsets of VTA dopamine neurons encode the long-running learned value versus the immediate motivational significance of cues that are otherwise ambiguously rewarding or aversive which has important implications for our understandings of these neurons in health and disease. The primary goals are to (1) apply a large-scale electrophysiological approach to detail correlates of reward and aversion in projection- defined VTA dopamine neurons, (2) assess the contribution of distinct VTA dopamine neurons to the flexible control of reward and aversion, and (3) detail the computations supported by ventral basal ganglia inputs onto VTA dopamine neurons that make possible the generation of flexible motivated behavior. Collectively the proposed research provides me extensive training that translates my skills into mice, integrates optogenetics with large-scale recording approaches, and develops an approach for the recording of neurons in a cell-type and circuit-defined manner during complex behaviors. Deconstructing the function of VTA dopamine neurons in the rapid regulation of reward and aversion is a significant step in our understanding of the contributions of these neurons in psychiatric illness and has potential for generating novel interventions and therapies.

PROJECT NARRATIVE Aberrant motivational responses to cues and the inability to in turn properly regulate resulting behavioral responses are core features of numerous psychiatric illnesses. This proposal exploits recent technological advances to describe and manipulate the activity of large numbers of precisely defined populations of neurons during the rapid regulation of cue-triggered motivation. Ultimately the goal of the proposed research is to identify future interventions that can be explored for human treatment.