Project Summary/Abstract The functions and computations supported by changes in the activity of meso-striatal dopamine systems are some of the most heavily researched, and hotly debated, topics in modern neuroscience. Predominant theories propose that they support reinforcement learning by broadcasting prediction-error signals, encode stimulus salience, or generally motivate reward seeking by representing internal states. Furthermore, it is widely accepted that these systems have been shaped by natural selection to reinforce adaptive behaviors. Eating, or the pursuit of nutrients, is fundamental for survival, and previous work has demonstrated that striatal DA circuits are critical components of the neurobiological systems that support this behavior. Importantly, emerging research supports a model whereby midbrain DA populations receive signals from the gut about food content that modify their activity and contribute to food learning and motivation. However, the timescale over which these gut-derived signals modulate DA release, and how they interact with DA signals previously identified as critical for food reward learning and motivation, is largely unknown. Here, we propose to address these gaps in our knowledge by using state of the art techniques to 1) Identify the ensembles of neurons in midbrain dopamine populations that are recruited by post-ingestive signals to control food reward. 2) Characterize the ability of post-ingestive signals to modify reward learning via effects on dopamine release in subregions of the striatum. 3)Test the causal role of post-ingestive signals for dopamine control of food reward. To accomplish these aims, we have assembled a team including behavioral and systems neuroscientists with expertise in modern technologies for recording and manipulating genetically defined cell populations, translational neuroscientists with expertise in the neurobiology of appetitive behaviors, statisticians specializing in big-data analysis, as well as leaders in the field of computational neuroscience. Completion of these studies will provide an opportunity to integrate peripheral modulation of midbrain dopamine systems into current models of dopamine control of reward learning and motivation, and provide a foundation for future studies of peripheral-central dopamine contributions to multiple adaptive functions and disease states.