Project 3-The regulation of mood and motivational state by feeding via innervatio

项目3研究了通过神经支配的肽来调节情绪和动机状态。 VTA（腹侧被盖区）及其主要靶点之一，NAc（丘脑核）。项目 重点介绍三种肽：MCH（黑色素浓缩激素），食欲素（下丘脑分泌素）和瘦素。每个是一个 通过下丘脑机制的众所周知的进食行为调节剂。然而，不太受重视的是， 强的联系解剖和功能上和VTA-NAc之间的联系的MCH 受体在NAc中高度富集，我们已经证明它调节多巴胺信号传导，并发挥一些作用。 它的促食作用。我们曾报道过，在NAc中MCH功能的丧失会产生抗抑郁样的作用。 在动物模型中的作用，与其他组的全身抗抑郁作用的几个报告一致。 给予MCH拮抗剂。食欲素和瘦素也存在类似的情况。VTA接收以下内容之一： 大脑中最丰富的食欲素投射，其中食欲素调节多巴胺神经元和药物的活性 奖励我们发现，食欲素基因敲除也显示出情绪调节的异常。而瘦素 在下丘脑的研究效果最好，我们和其他小组已经发现腹侧被盖区多巴胺的瘦素受体 神经元，并已表明这些受体功能性地响应全身瘦素。最近的研究 表明，瘦素，在腹侧被盖区，抑制进食和促进抑郁样行为。我们的假设是 这些（和其他）摄食肽提供了下丘脑功能与下丘脑功能之间的关键联系， 完成行为和VTA-NAc在奖励中的功能，这些联系是 情绪和动机状态。 本研究的目的是进一步阐明VTA-NAc中这些肽系统的回路 途径，并建立这些肽在动物情绪和动机调节中的作用 抑郁症和抗抑郁作用的模型。乔尔·埃尔姆奎斯特最近的招聘， 对UT西南和这个中心来说，这是一个重大的飞跃。我们将利用 在这些不同的肽或其受体以及病毒载体和受体激动剂中具有突变的小鼠 和拮抗剂以操纵VTA或NAc中的肽作用。我们还将描述 这些肽通过压力和抗抑郁治疗。CREB的主题在项目3中继续，因为 不同形式的应激在表达食欲素或MCH的下丘脑神经元亚群中诱导CREB， 因为这些肽调节VTA-NAc奖赏途径中的CREB活性。

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 connectionboth anatomical and functionalbetween 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.