Project Summary Dopamine (DA) neurons in the ventral tegmental area (VTA) modulate feeding and physical activity, but disruption of these behaviors has promoted the worldwide obesity epidemic. While subsets of VTA DA neurons promote or suppress feeding, the lack of molecular markers to distinguish these populations has prevented development of targeted therapies to support weight loss behaviors. The goal of this proposal is to determine whether a new molecularly-defined subset of VTA DA neurons that express neurotensin receptor-1 (NtsR1) may be useful to support weight loss; I refer to these as “VTA NtsR1 neurons”. Intriguingly, the ligand neurotensin only supports dual weight loss behaviors when injected into the VTA, although NtsR1 neurons are distributed throughout the brain. Furthermore, NtsR1 null mice have disrupted DA signaling, overconsume palatable foods and become overweight, indicating that some NtsR1 neurons are necessary for regulating body weight. I thus hypothesize that the DA-containing VTA NtsR1 neurons specifically incite weight loss behaviors via an NtsR1-dependent mechanism. To examine this, I will use DREADD technology to experimentally activate VTA NtsR1 neurons and to determine if they are sufficient to promote weight loss behaviors. I will also use new NtsR1flox mice to selectively delete NtsR1 from the VTA, thus determining its necessity for control of body weight. These data will reveal how VTA NtsR1 neurons modify body weight, and may guide the use of new agonists that selectively target this population for treating obesity. Simultaneously, I will learn cutting-edge skills bridging neuroscience and pharmacology that are necessary for my development into an independent academic faculty member studying disease pathogenesis and treatment.