Abstract Losing weight can be life saving for people with obesity. Although many people with obesity lose weight with diet and exercise, the vast majority regain this lost weight over time. Multiple pharmacological treatments have been approved by the US Food and Drug Administration (FDA) to help patients lose weight. However, in each case the effect of these treatments is temporary, and weight is regained when the treatment is stopped. This means that patients must take these medications for the rest of their lives to realize their health benefits. In addition to the financial cost of life-long medication, patients must contend with side effects and medication resistance. As such, there remains an unmet need for new medical interventions that produce weight loss without lifelong treatment. In this proposal we aim to investigate how dopamine function is altered as animals gain weight. Reductions in dopamine function have been linked to obesity, and drugs that decrease dopamine function (such as antipsychotic medications) cause weight gain. This leads to our central hypothesis that obesity reduces dopamine release in the nucleus accumbens (NAc), which causes overeating and weight gain. A corollary of this hypothesis is that boosting dopamine release would lead to weight loss. Indeed, either direct stimulation of dopamine neurons or administration of drugs that increase dopamine release (such as amphetamine) cause weight loss. However, due to side effects and abuse liability, dopaminergic stimulants are not useful therapeutics. For this reason, our primary Aim is to understand the cellular changes in dopamine function that occur as animals become obese, to inform the design of neuromodulation approaches to permanently reverse these changes to drive lasting weight loss without life- long medication. To test this hypothesis, we propose to compare in vivo dopamine release in the nucleus accumbens of control vs. obese mice (Aim 1). We will also employ ex vivo electrophysiological approaches to determine the cellular mechanisms underlying changes in dopamine neuron activity in obese mice (Aim 2). And finally, we will engage neuroplasticity in dopamine neurons to chronically boost dopamine release, to test whether this causes long-lasting reductions in food intake and body weight (Aim 3). This research will provide a critical foundation to advance efforts for modulating food seeking and intake, to inform and improve weight loss outcomes in people with obesity.