权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neuropeptidergic control of environmental stimulus-driven feeding behavior

环境刺激驱动的进食行为的神经肽控制

基本信息

批准号：
8854077
负责人：
Scott Edward Kanoski
金额：
$ 8.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8854077
关键词：
Address Adipose tissue Adult Advertisements Association Learning Automobile Driving Axon Basic Science Behavior Therapy Behavioral Behavioral Genetics Bilateral Biological Brain Brain Stem Brain region Cell Nucleus Chemicals Communication Complement Consumption Cues Data Development Eating Environment Exposure to Fatty acid glycerol esters Feeding behaviors Food Funding Future GHS-R1a Genetic Health Health Care Costs Hippocampal Formation Hormones Hunger Hyperphagia Hypothalamic structure Immunohistochemistry Intake Investigation Lateral Hypothalamic Area Leptin Lesion Link Medial Mediating Mentored Research Scientist Development Award Methodology Neurobiology Neurons Neuropeptides Nucleus solitarius Obesity Overweight Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacological Treatment Physiological Population Prefrontal Cortex Prevalence Process Publishing RNA Interference Rattus Receptor Activation Receptor Signaling Research Rewards Role Signal Transduction Stimulus Structure of nucleus infundibularis hypothalami Synapses System United States United States National Institutes of Health Viral Vector Work adverse outcome bariatric surgery base billboard design feeding food consumption gastrointestinal ghrelin ghrelin receptor hypocretin innovation memory process motivated behavior motivational processes neural circuit neuroregulation neurotoxic novel strategies obesity treatment orexin 1 receptor orexin A programs receptor relating to nervous system research study response success sugar

项目摘要

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.

描述（由申请人提供）：与1980年的成年人相比，今天美国的成年人每天消耗的热量多约300-500 kcal 20，21，这一现象表明，在过去30年中，美国的肥胖患病率增加了75% 18，19。开发更有效的肥胖药物治疗需要更好地理解控制过度食物寻求和消费的神经生物学系统，该过度食物寻求和消费是由暴露于与可口的、容易获得的食物（例如，那些高%脂肪含量和单糖）。本提案中的研究与申请人的K 01奖项不同，但主题相关，旨在加深对可口的“西方”食物的线索增强暴食症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K 01奖期间收集的未发表的试验数据上，以探索以下假设：肠源性“饥饿”激素ghrelin在腹侧海马结构（vHPF）中的受体上发出信号，以通过与产生神经肽食欲素-A的下丘脑外侧区（LHA）中的神经元的神经通信来控制线索增强的摄食过多。该假设将通过以下方式进行评估：1）确定从vHPF到LHA的神经通信是否是由vHPF饥饿素信号传导诱导的摄食过多所必需的（使用神经元断开方法），以及2）检查由生长激素释放肽激活的vHPF神经元是否投射到LHA中的产生食欲素的神经元（使用束追踪和免疫组织化学策略），和3）通过检查vHPC -> LHA投射神经元是否与产生食物摄入刺激神经肽食欲素-A的LHA神经元突触。第二组实验将检查LHA产生食欲素A的神经元的上行通路，这些神经元控制对环境食物线索的过度食物寻求和暴食。在申请人的K 01奖励期间收集的初步数据表明，LHA产生食欲素的神经元投射到内侧前额叶皮层（mPFC），并且mPFC中的食欲素-1受体（ORX 1-R）信号传导增加大鼠的食物摄入。实验将建立在这些发现的基础上，使用行为和遗传（病毒载体介导的RNA干扰）方法来确定mPFC ORX 1-R信号传导是否与食物寻求和过度消费食物以响应环境食物相关刺激的生理相关性。这些实验直接补充了申请人的K 01奖项，该奖项专注于脂肪源性激素瘦素如何在vHPF中作用以影响食物动机行为。该R 03提案中的实验结果，加上申请人的K 01奖项的结果，将：1）大大支持申请人成功开发独立研究项目，该项目将在不久的将来对NIH R 01资金具有竞争力，以及2）加深对控制过量食物摄入的神经肽能系统的理解。