Project 3 studies the regulation of mood and motivational state by feeding peptides via innervation of theVTA (ventral tegmental area) and one of its major targets, the NAc (nucleus accumbens). The Projectfocuses on three peptides: MCH (melanin concentrating hormone), orexin (hypocretin), and leptin. Each is awell known regulator of feeding behavior via hypothalamic mechanisms. Less appreciated, however, is thestrong connectionboth anatomical and functionalbetween the peptides and the VTA-NAc. The MCHreceptor is highly enriched in NAc, where we have shown it regulates dopamine signaling and exerts someof its pro-feeding effects. We have reported that loss of MCH function in NAc exerts an antidepressant-likeeffect in animal models, consistent with several reports by other groups of antidepressant actions of systemicadministration of MCH antagonists. A similar situation exists for orexin and leptin. The VTA receives one ofthe richest orexin projections in brain, where orexin regulates the activity of dopamine neurons and drugreward. We have found that orexin knockouts also show abnormalities in mood regulation. While leptin'seffects are best studied in hypothalamus, we and other groups have found leptin receptors in VTA dopamineneurons, and have shown that these receptors respond functionally to systemic leptin. Recent researchindicates that leptin, acting in VTA, inhibits feeding and promotes depression-like behavior. Our hypothesis isthat these (and other) feeding peptides provide a critical link between the hypothalamus's function inconsummatory behavior and the VTA-NAc's function in reward, and that these links are critical regulators ofmood and motivational state.The goal of the proposed studies is to further delineate the circuitry of these peptide systems in the VTA-NAcpathway, and establish the role these peptides play in the regulation of mood and motivation in animalmodels of depression and antidepressant action. The recent recruitment of Joel Elmquist, a leading authorityon feeding peptides, to UT Southwestern and to this Center, represents a major leap forward. We will utilizemice with mutations in these various peptides or their receptors as well as viral vectors and receptor agonistsand antagonists to manipulate peptide action in the VTA or NAc. We also will characterize regulation ofthese peptides by stress and antidepressant treatments. The theme of CREB continues in Project 3, sincedifferent forms of stress induce CREB in subsets of hypothalamic neurons that express orexin or MCH, andsince these peptides regulate CREB activity in the VTA-NAc reward pathway.
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