NTS neurons integrate leptin and satiation signals to influence reward signaling

NTS 神经元整合瘦素和饱足信号来影响奖励信号

基本信息

批准号：
8647507
负责人：
Amber L Alhadeff
金额：
$ 4.27万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8647507
关键词：
Action Potentials Adipose tissue Adverse effects Anti-Obesity Agents Appetite Depressants Appetitive Behavior Attention Basic Science Behavior Behavior Therapy Behavioral Body Weight Brain Brain Stem Brain region Calories Cannabinoids Cell Nucleus Communication Cues Data Dopamine Eating Energy Intake Environmental Risk Factor Fatty acid glycerol esters Feeding behaviors Food Gastrointestinal Process Genes Genetic Transcription Glutamates Goals Hormones Hyperphagia Hypothalamic structure Immunohistochemistry Ingestion Intake Lateral Leptin Measures Mediating Midbrain structure Molecular Motivation Neurons Neuropeptides Neurosecretory Systems Neurotransmitters Nucleus Accumbens Nucleus solitarius Obesity Opioid Output Overweight Pharmacotherapy Play Population Process Prosencephalon Proteins Public Health Rattus Receptor Signaling Regulation Research Rewards Role Satiation Signal Pathway Signal Transduction Site Societies Stomach Structure Testing Tracer United States Ventral Tegmental Area Work bariatric surgery comorbidity design drug development energy balance feeding gamma-Aminobutyric Acid gastrointestinal hindbrain insight leptin receptor motivated behavior neural circuit neuroregulation novel obesity treatment preference public health relevance receptor relating to nervous system research study response sugar

项目摘要

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.

描述（由申请人提供）：肥胖是一个主要的公共卫生问题，尤其是在美国，因为目前美国三分之二的人口被认为超重或肥胖。缺乏安全有效的肥胖治疗凸显了开发有效的抗肥胖药物疗法的紧迫性。由于肥胖是由于过量的热量摄入量而驱动的，因此研究必须集中于定义与控制这种食物摄入有关的神经回路。瘦素是控制能量平衡控制的最关键的厌食信号之一，并通过其某些后脑，中脑和前脑核通过其受体（LEPRB）发出信号，可减少食物摄入量和食物动机行为。尾骨脑干的链托氏菌（NTS）中的瘦素受体信号传导对于控制食物摄入，体重和对模糊的gi gi齿状信号的处理是必要的，最近它也与食物的调节有关。积极进取的行为。该提案的主要目的是检验新的假设，即NTS中的神经元种群整合瘦素和GI衍生的饱满信号和项目直接向中脑和前脑奖励与相关结构，有助于控制食物动机和食欲（寻求食物）行为。具体目的我研究了NTS神经元的解剖连通性，这些连通性用三个与奖励相关的核[腹侧换膜面积（VTA），伏隔核（NAC）壳（NAC）壳和下丘脑（LH）响应瘦素和胃刺激。瘦素诱导的PSTAT3（LEPRB信号传导的标记），胃肠道刺激诱导的CFO和神经元示踪剂（荧光胶质和倒流）的三重免疫组织化学将用于鉴定整合这些启动信号和更多的神经元，以识别一个或更多的神经元奖励相关核。特定目标II中提出的实验研究了以下假设：NTS瘦素信号传导对食物摄入和与奖励相关的喂养行为的影响可能涉及VTA，NAC壳和/或LH和/或LH的能量平衡相关基因的转录变化这些变化可能会通过GI衍生的饱满信号增强。该实验将利用QPCR检查一组演绎选择的基因，该基因的蛋白质产物会影响与奖励相关的喂养和食物动机行为。该应用中提出的研究有可能加深对介导可口食品摄入控制的解剖学和分子机制的理解。