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

项目3研究通过神经支配喂食肽来调节情绪和动机状态。 VTA(腹侧被盖区)及其主要靶点之一的NAC(伏隔核)。《项目》 重点关注三种多肽：MCH(黑色素浓缩激素)、增食欲素(下丘脑泌素)和瘦素。每一个都是一个 众所周知，通过下丘脑机制调节摄食行为。然而，不太受欢迎的是， 这些多肽与VTA-NAC在解剖和功能上都有很强的联系。妇幼保健院 受体在NAC中高度丰富，我们已经证明它调节多巴胺信号并施加一些 它的亲喂食效果。我们已经报道，NAC患者MCH功能的丧失会产生一种类似于抗抑郁药的作用 在动物模型中的作用，与其他小组关于全身性抗抑郁作用的几个报告一致 妇幼保健素拮抗剂的应用。食欲素和瘦素也存在类似的情况。VTA接收以下之一 大脑中最丰富的食欲素投射，在那里食欲素调节多巴胺神经元和药物的活动 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 最好的研究是在下丘脑，我们和其他小组已经在VTA多巴胺中发现了瘦素受体 并表明这些受体对全身瘦素有功能性的反应。最新研究 表明瘦素作用于VTA，抑制进食并促进抑郁样行为。我们的假设是 这些(和其他)摄食性多肽在下丘脑的功能之间提供了关键的联系 消费行为和VTA-NAC在奖励中的作用，这些环节是关键的调节因素 情绪和动机状态。 拟议研究的目标是进一步描绘这些肽系统在VTA-NAC中的回路。 途径，并确定这些多肽在动物情绪和动机调节中所起的作用 抑郁和抗抑郁作用的模型。最近招募的Joel Elmquist，一位领先的权威 关于喂养多肽，到德克萨斯大学西南部和这个中心，代表着一个重大的飞跃。我们将利用 这些多肽或其受体以及病毒载体和受体激动剂发生突变的小鼠 和拮抗剂来操纵肽在VTA或NAC中的作用。我们还将描述监管的特点 这些多肽通过应激和抗抑郁药物治疗。CREB的主题在项目3中继续，因为 不同形式的应激诱导表达增食欲素或MCH的下丘脑神经元亚群中的CREB，以及 因为这些多肽调节VTA-NAC奖赏通路中的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.