Abstract Our health and well being depend on our ability to make adaptive decisions that take into account information about the expected value and availability of potential behavioral goals. It is believed that dysfunction within the neural systems that support goal-directed decision making can result in maladaptive reward-seeking behavior that is either exaggerated and difficult to control, such as with compulsive drug seeking and overeating, or becomes weakened to an unhealthy degree, such as with the apathy apparent in various psychiatric and neurodegenerative disorders (e.g., Alzheimer's disease and schizophrenia). Advances in our understanding of the neural systems that support adaptive decision making are needed so that we are better able to pinpoint the specific aberrations in neural function that give rise to pathological forms of reward seeking. The current project will use an integrative approach to provide novel tests of the decision-making functions of anatomically distinct pathways connecting the medial (MOFC) and lateral (LOFC) orbitofrontal cortices to each other and to the mediodorsal thalamus (MDTHAL). Our behavioral approach will make use of well-validated assays of cue- and value-based decision making in rats. The influence of reward-predictive cues on action selection will be probed using the outcome-specific Pavlovian-to-instrumental transfer task, in which noncontingent presentations of a cue that signals the availability of a specific reward outcome (e.g., sucrose solution) biases rats to selectively pursue that outcome instead of a different but equally valuable outcome (e.g., grain pellets). To probe value- based decision making, we will use outcome-specific reward devaluation tasks, in which rats demonstrate their capacity to flexibly suppress their performance of instrumental actions or Pavlovian conditioned approach responses when an expected reward is devalued through specific satiety. In Aim 1 we will virally express hM4Di, a Gi-coupled DREADD (Designer Receptors Exclusively Activated by Designer Drugs), in the MOFC, LOFC, or MDTHAL, allowing us to determine how inhibiting neurons in these areas (via systemic hM4Di activation) or specific pathways connecting these areas (via local hM4Di activation) impacts cue-based decision making (Pavlovian-instrumental transfer). In Aim 2 we will use the same basic chemogenetic approach to investigate the neural circuitry required for value-based decision making (instrumental and Pavlovian reward devaluation). Together these experiments will provide rigorous tests of innovative hypotheses regarding the behavioral functions of these understudied pathways within the broader orbitothalamic network. Given evidence that dysfunction within these pathways contributes to aberrations in reward-motivated behavior, we believe that this work will have a broad scientific impact, and will lay the groundwork for our own future research investigating neural mechanisms of maladaptive decisions.