Neuropeptidergic control of environmental stimulus-driven feeding behavior

描述(申请人提供)：与1980年20、21年的成年人相比，今天的美国成年人每天多摄入约300-500千卡的热量，这一现象的根本原因是美国的肥胖率在过去30年里增加了75%18、19。开发更有效的肥胖症药物治疗方法需要更好地了解神经生物系统，这些系统控制与美味、容易获得的食物相关的环境刺激(例如，那些高脂肪含量和单糖)引发的过度食物寻找和消耗。本提案中的研究与申请人的K01奖不同，但在主题上与申请者的K01奖相关联，旨在加深对线索强化的可口“西方”食物吞噬过度背后的功能神经回路的理解。实验直接建立在申请人最近发表的工作和最近在他的K01奖期间收集的未发表的试点数据的基础上，以探索这样的假设：胃肠来源的“饥饿”激素ghrelin信号在腹侧海马结构(VHPF)的受体上通过与下丘脑外侧区(LHA)中产生神经肽-A的神经元的神经通讯来控制线索增强的吞噬作用。这一假说将通过以下方法进行评估：1)确定vHPF ghrelin信号引起的吞噬反应是否需要从vHPF到LHA的神经通讯(使用神经元断开的方法)，2)检查由ghrelin激活的vHPF神经元是否投射到LHA中产生食欲素的神经元(使用轨迹追踪和免疫组织化学方法)，以及3)检查vHPC-和LHA投射的神经元是否突触产生食物摄入刺激神经肽-食欲素-A的LHA神经元。第二组实验将检测产生LHA增食欲素A的神经元的上升路径，这些神经元控制对环境食物提示的过度觅食和过度吞噬。在申请人的K01奖项期间收集的初步数据表明，产生LHA食欲素的神经元投射到内侧前额叶皮质(MPFC)，并且mPFC中的食欲素-1受体(ORX1-R)信号增加了大鼠的食物摄入量。实验将以这些发现为基础，使用行为和遗传(病毒载体介导的RNA干扰)方法来确定mPFC ORX1-R信号是否在生理上与食物寻找和对环境食物相关刺激的过度消费有关。这些实验直接补充了申请人的K01奖，该奖项专注于脂肪衍生激素瘦素如何在vHPF中发挥作用，以影响食物动机的行为。本R03提案中的实验结果，与申请人的K01奖项的结果相结合，将：1)大大支持为申请人开发一个成功的独立研究项目，该项目将在不久的将来成为NIH R01资金的竞争对手，以及2)加深对控制过量食物摄入的神经肽能系统的理解。

DESCRIPTION (provided by applicant): Adults in the United States today are consuming ~300-500 kcal per day more compared to adults in 1980 20,21, a phenomenon underlying the fact that obesity prevalence in the United States has increased by 75% in the past 30 years 18,19. The development of more effective pharmacological treatments for obesity requires a better understanding of the neurobiological systems controlling the excessive food seeking and consumption that is triggered by exposure to environmental stimuli associated with palatable, easily accessible foods (e.g., those high % fat content and simple sugars). Research in the present proposal is distinct from, yet thematically linked to the applicant's K01 award and is designed to deepen understanding of the functional neural circuitry underlying cue-potentiated hyperphagia of palatable "Western" foods. Experiments build directly on recent published work from the applicant and from unpublished pilot data recently collected during his K01 award to explore the hypothesis that the gut-derived "hunger" hormone ghrelin signals on receptors in the ventral hippocampal formation (vHPF) to control cue-potentiated hyperphagia via neural communication to neurons in the lateral hypothalamic area (LHA) that produce the neuropeptide orexin-A. This hypothesis will be assessed by, 1) determining whether neural communication from the vHPF to the LHA is required for the hyperphagia induced by vHPF ghrelin signaling (using a neuronal disconnection approach), and by 2) examining whether vHPF neurons that are activated by ghrelin project to orexin-producing neurons in the LHA (using tract tracing and immunohistochemical strategies), and 3) by examining whether vHPC -> LHA projecting neurons synapse on LHA neurons that produce the food intake stimulating neuropeptide, orexin-A. A second set of experiments will examine the ascending pathways from LHA orexin A-producing neurons that control excessive food seeking and hyperphagia in response to environmental food cues. Preliminary data collected during the applicant's K01 award demonstrate that LHA orexin-producing neurons project to the medial prefrontal cortex (mPFC), and that the orexin-1 receptor (ORX1-R) signaling in the mPFC increases food intake in rats. Experiments will build on these findings using behavioral and genetic (viral vector-mediated RNA-interference) methodologies to determine whether mPFC ORX1-R signaling is physiologically relevant for food-seeking and excessive consumption of food in response to environmental food-related stimuli. These experiments directly complement those of the applicant's K01 award that focus on how the adipose-derived hormone leptin acts in the vHPF to influence food-motivated behaviors. Results from the experiments in this R03 proposal, combined with results from the applicant's K01 award will: 1) substantially bolster the development of a successful independent research program for the applicant that will be competitive for NIH R01 funding in the near future, and 2) deepen understanding of the neuropeptidergic systems controlling excessive food intake.