Project 3 studies the regulation of mood and motivational state by feeding peptides via innervation of the VTA (ventral tegmental area) and one of its major targets, the NAc (nucleus accumbens). The Project focuses on three peptides: MCH (melanin concentrating hormone), orexin (hypocretin), and leptin. Each is a well known regulator of feeding behavior via hypothalamic mechanisms. Less appreciated, however, is the strong connection[unreadable]both anatomical and functional[unreadable]between the peptides and the VTA-NAc. The MCH receptor is highly enriched in NAc, where we have shown it regulates dopamine signaling and exerts some of its pro-feeding effects. We have reported that loss of MCH function in NAc exerts an antidepressant-like effect in animal models, consistent with several reports by other groups of antidepressant actions of systemic administration of MCH antagonists. A similar situation exists for orexin and leptin. The VTA receives one of the richest orexin projections in brain, where orexin regulates the activity of dopamine neurons and drug reward. We have found that orexin knockouts also show abnormalities in mood regulation. While leptin's effects are best studied in hypothalamus, we and other groups have found leptin receptors in VTA dopamine neurons, and have shown that these receptors respond functionally to systemic leptin. Recent research indicates that leptin, acting in VTA, inhibits feeding and promotes depression-like behavior. Our hypothesis is that these (and other) feeding peptides provide a critical link between the hypothalamus's function in consummatory behavior and the VTA-NAc's function in reward, and that these links are critical regulators of mood and motivational state. The goal of the proposed studies is to further delineate the circuitry of these peptide systems in the VTA-NAc pathway, and establish the role these peptides play in the regulation of mood and motivation in animal models of depression and antidepressant action. The recent recruitment of Joel Elmquist, a leading authority on feeding peptides, to UT Southwestern and to this Center, represents a major leap forward. We will utilize mice with mutations in these various peptides or their receptors as well as viral vectors and receptor agonists and antagonists to manipulate peptide action in the VTA or NAc. We also will characterize regulation of these peptides by stress and antidepressant treatments. The theme of CREB continues in Project 3, since different forms of stress induce CREB in subsets of hypothalamic neurons that express orexin or MCH, and since these peptides regulate CREB activity in the VTA-NAc reward pathway.