NTS neurons integrate leptin and satiation signals to influence reward signaling

描述(申请人提供)：肥胖是一个主要的公共卫生问题，特别是在美国，因为目前超过三分之二的美国人口被认为超重或肥胖。缺乏安全有效的肥胖治疗方法，突显了开发有效的抗肥胖药物疗法的紧迫性。由于肥胖在一定程度上是由对美味食物的过量卡路里摄入推动的，因此研究必须集中于确定参与控制这种食物摄入量的神经回路。瘦素是参与控制能量平衡的最关键的厌食信号之一，通过其受体(LepRb)在某些后脑、中脑和前脑核团中发出信号，减少食物摄入量和食物动机行为。脑干尾侧孤束核(NTS)中的瘦素受体信号对控制食物摄入量、体重和处理迷走神经GI饱足信号是必需的，最近还参与了食物动机和食欲行为的调节。这一提议的主要目的是检验新的假设，即NTS中的一群神经元整合 瘦素和GI衍生的饱腹感信号直接投射到中脑和前脑与奖励相关的结构，这些结构有助于控制食物动机和食欲(寻找食物)行为。具体目的I研究NTS神经元与三个奖赏相关核团[腹侧被盖区(VTA)、伏隔核(NAC)壳和下丘脑外侧核(LH)]对瘦素和胃刺激作出反应的解剖连接性。瘦素诱导的pSTAT3(一个公认的LepRb信号标志)、GI刺激诱导的CFO和神经元示踪物(荧光金和逆行珠子)的三重免疫组织化学将用于识别整合这些厌食信号并投射到一个或多个奖赏相关核团的神经元。在《特定目的II》中提出的实验检验了一种假设，即NTS瘦素信号对食物摄取和与奖励相关的摄食行为的影响可能涉及VTA、NAC壳和/或LH中能量平衡相关基因转录的变化，并且这些变化可能被GI衍生的饱和信号所增强。这项实验将利用定量聚合酶链式反应来检测一组演绎选择的基因，这些基因的蛋白质产物影响与奖励相关的进食和食物动机行为。在这项申请中提出的研究有可能加深对调节美味食物摄入量的解剖学和分子机制的理解。

DESCRIPTION (provided by applicant): Obesity is a major public health concern, especially in the United States, as currently over two-thirds of the US population is considered overweight or obese. The lack of safe and effective obesity treatments highlights the urgency of developing effective anti-obesity drug therapies. Since obesity is driven, in part, by excess caloric intake o palatable foods, research must focus on defining the neural circuits involved in the control of such food intake. Leptin is among the most critical anorectic signals involved in the control of energy balance, and signaling through its receptor (LepRb) in certain hindbrain, midbrain, and forebrain nuclei reduces food intake and food-motivated behaviors. Leptin receptor signaling in the nucleus tractus solitarius (NTS) of the caudal brainstem is necessary for the control of food intake, body weight, and processing of vagally-derived GI satiation signals, and recently it has also been implicated in the regulation of food-motivated and appetitive behaviors. The main goal of this proposal is to test the novel hypothesis that a population of neurons in the NTS integrates leptin and GI-derived satiation signals and projects directly to midbrain and forebrain reward- related structures that contribute to the control of food-motivated and appetitive (food-seeking) behaviors. Specific Aim I investigates the anatomical connectivity of NTS neurons that respond to both leptin and gastric stimulation with three reward-related nuclei [ventral tegmental area (VTA), nucleus accumbens (NAc) shell, and lateral hypothalamus (LH)]. Triple immunohistochemistry for leptin-induced pSTAT3 (a well-established marker of LepRb signaling), GI-stimulation-induced cFos, and neuronal tracers (Fluorogold and Retrobeads) will be used to identify neurons that integrate these anorectic signals and project to one or more reward-related nuclei. The experiment proposed in Specific Aim II examines the hypothesis that effects of NTS leptin signaling on food intake and reward-related feeding behavior may involve changes in the transcription of energy-balance relevant genes in the VTA, NAc shell, and/or LH, and that these changes may be potentiated by GI-derived satiation signals. This experiment will utilize qPCR to examine a deductively-chosen set of genes whose protein products influence reward-related feeding and food-motivated behaviors. Research proposed in this application has the potential to deepen the understanding of the anatomical and molecular mechanisms that mediate the control of palatable food intake.