NTS neurons integrate leptin and satiation signals to influence reward signaling

描述（由申请人提供）：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出了开发有效的抗肥胖药物治疗的紧迫性。由于肥胖在一定程度上是由摄入过多的热量或美味食物引起的，研究必须集中在确定控制这些食物摄入的神经回路上。瘦素是控制能量平衡的最重要的厌食信号之一，通过其受体（LepRb）在某些后脑、中脑和前脑核中发出信号，减少食物摄入和食物动机行为。尾侧脑干孤束核（NTS）中的瘦素受体信号对于控制食物摄入、体重和迷走神经来源的GI饱足信号的处理是必要的，最近它也被认为与食物动机和食欲行为的调节有关。这项提议的主要目的是测试NTS中神经元群体整合的新假设

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.