PROJECT SUMMARY/ABSTRACT Decision-making is an important cognitive function that animals use to seek life-preserving rewards like food while avoiding dangers like predation and injury. Understanding how animals balance between risk and reward is important, with implications for psychiatric disorders like substance use disorder (SUD), in which decision-making is impaired. The orbitofrontal cortex (OFC) and dorsal medial striatum (DMS) are brain regions that are part of the decision-making circuitry. The OFC sends a strong projection to the DMS and it has been found that OFC-DMS plasticity is important for punishment-resistant reward-seeking behavior. Dopamine (DA) signaling in the DMS has also been found to play a crucial role in the development of punishment-resistant reward-seeking behavior. However, whether DA controls changes at OFC-DMS synapses that are important for punishment-resistant reward-seeking behavior is not known. The Lerner Lab found that mice prone to developing punishment-resistance have increased phasic DA activity in the DMS on rewarded nosepokes and dips in DA activity on unrewarded nosepokes. I hypothesize that both events (increases and dips in DA) are important for the development of punishment-resistant reward- seeking behavior because they separately control the plasticity of OFC synapses onto D1- and D2-receptor expressing DMS neurons. In Aim 1, I will test OFC-DMS plasticity in punishment-resistant sucrose seeking mice, to understand how plasticity changes with a natural reward. I will use an operant behavior that elicits punishment- resistant behavior and then look at plasticity using whole cell electrophysiology. In Aim 2, I will investigate if DA increases in the DMS lead to plasticity changes in the OFC-DMS circuity using optogenetics and whole cell electrophysiology. In Aim 3, I will test if dips in DA lead to punishment-resistant behavior as well as plasticity changes in the OFC-DMS circuit. My proposal, in accordance with NIDA’s mission statement, will aide in the advancement of science on drug use and drug addiction by providing a better understanding of the decision- making circuitry that is impaired in SUD. Under this training grant, I will receive training in oral and written communication skills through presenting at conferences, and through supervised grant and manuscript writing. I will also receive training in programming, data analysis, and mentoring. The training under this grant will provide me with the tools necessary to become a high-achieving postdoctoral fellow and eventually a successful principal investigator.