Integration of Hypothalamic and Limbic Pathways to Regulate Motivation for Food
整合下丘脑和边缘通路来调节食物动机
基本信息
- 批准号:9910392
- 负责人:
- 金额:$ 42.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-20 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAdultAffectAgonistAmericanAreaBehaviorBehavioralBehavioral ResearchBiologyBody WeightBody Weight decreasedBrainCardiovascular DiseasesCell NucleusConsumptionDataDiabetes MellitusDietDietary FatsDiseaseEatingEnergy IntakeEnkephalinsFastingFatty acid glycerol estersFeeding behaviorsFoodFoundationsFutureG-Protein-Coupled ReceptorsGenesGoalsHealthHigh Fat DietHypothalamic structureImageIntakeLateralLeadLightLinkMajor Depressive DisorderMalignant NeoplasmsMapsMediatingMessenger RNAMetabolicMetabolic DiseasesMolecularMotivationMusNaltrexoneNeural PathwaysNeurobiologyNeuromedin UNeuronsNeuropeptide ReceptorNucleus AccumbensObesityOpioidOpticsOutputPathway interactionsPeptidesPharmacologyPhysiologicalPhysiologyProcessPropertyProteinsRNA InterferenceRattusRegulationResearchResearch Project GrantsRewardsRoleSignal TransductionStructureSubstance Use DisorderSystemTechniquesTestingTherapeuticTimeTracerViral VectorVirusWeightWeight GainWorkbasebehavioral phenotypingbrain tissueburden of illnesscomorbidityenergy balanceexperiencefeedingfood cravinghedonicimprovedin vivoinnovationinnovative technologiesinsightmRNA Expressionmesolimbic systemmotivated behaviormu opioid receptorsneural circuitneuromedin U receptornonhuman primatenovelobesity treatmentparaventricular nucleuspre-clinicalpreferencepsychologicpublic health relevancereceptorreinforcerrelating to nervous systemsmall hairpin RNAsmall molecule
项目摘要
DESCRIPTION (provided by applicant): Safe and effective approaches for the treatment of obesity are needed to address the tremendous burdens of this disease such as diabetes, cardiovascular disease, and even some cancers. Although studied as distinct pathways for decades, processes regulating eating and motivation are now thought to be driven by overlapping neural circuits. Studying this overlap may provide important insights into the basis of excess caloric intake and lead to the identification of novel pharmacological targets for treating metabolic diseases, the long-term goal of our research. A potential novel and innovative target in this regard is neuromedin U (NMU), a peptide shown to suppress food intake and cause weight loss. These effects of NMU are related to its actions at the NMU receptor 2 (NMUR2) in the hypothalamus, particularly in the paraventricular nucleus (PVN), which is enriched for NMUR2. We have previously found that selective depletion of NMUR2 in the PVN of rats potentiates the intake of a high-fat diet, increases weight gain, and enhances a dietary preference specifically for fat but not sucrose. The goals of the present project are to explore NMUR2 signaling as a key interface between the hypothalamic and mesolimbic systems, and to further evaluate the action of NMUR2 agonists on feeding behavior. Our preliminary data indicate that NMUR2 neurons in the hypothalamus are directly connected to the nucleus accumbens, a key region of the mesolimbic system that regulates reward and motivated behavior. We have, for the first time, evaluated small-molecule NMUR2 agonists in vivo. Our preliminary data indicate that these compounds suppress feeding on a high-fat diet. To accomplish our goals, our Specific Aims are 1) To evaluate the structural link between the hypothalamic and mesolimbic circuits, 2) To establish a functional link between these areas involving enkephalins and opioid signaling, and 3) To determine if NMUR2 is a target to inhibit motivation for high-fat food and regulation of metabolic physiology. These aims will be achieved using such innovative technologies as viral-vector tracers to map neural pathways in the brain, optical clearing with CLARITY visualize these pathways in clarified, intact brains, and virus-mediated RNA interference study the effects of the NMUR2 gene on food intake, body weight, and motivation for food. Overall, these studies will lay the foundation for understanding neural pathways that regulate motivation for food, and for future work developing NMUR2-based therapeutics for the treatment of obesity.
描述(由申请人提供):需要用于治疗肥胖症的安全有效的方法来解决这种疾病如糖尿病、心血管疾病甚至某些癌症的巨大负担。虽然几十年来一直被研究为不同的通路,但现在认为调节进食和动机的过程是由重叠的神经回路驱动的。研究这种重叠可能会为了解过量热量摄入的基础提供重要见解,并导致识别治疗代谢疾病的新型药理学靶点,这是我们研究的长期目标。在这方面,一个潜在的新的和创新的目标是神经介肽U(NMU),一种肽显示抑制食物摄入和导致体重减轻。NMU的这些作用与其对下丘脑中的NMU受体2(NMUR2)的作用有关,特别是在室旁核(PVN)中,其富含NMUR2。我们以前已经发现,选择性消耗大鼠PVN中的NMUR2增强了高脂肪饮食的摄入,增加了体重增加,并增强了对脂肪而不是蔗糖的饮食偏好。本项目的目标是探索NMUR2信号传导作为下丘脑和中脑边缘系统之间的关键接口,并进一步评估NMUR2激动剂对摄食行为的作用。我们的初步数据表明,下丘脑中的NMUR2神经元直接连接到中脑边缘系统的一个关键区域,调节奖励和动机行为。我们首次在体内评估了小分子NMUR2激动剂。我们的初步数据表明,这些化合物抑制高脂肪饮食的喂养。为了实现我们的目标,我们的具体目标是1)评估下丘脑和中脑边缘回路之间的结构联系,2)建立这些区域之间的功能联系,包括脑啡肽和阿片类信号传导,3)确定NMUR2是否是抑制高脂肪食物动机和代谢生理调节的靶点。这些目标将通过使用创新技术来实现,例如病毒载体示踪剂来绘制大脑中的神经通路,光学透明化,在澄清,完整的大脑中可视化这些通路,以及病毒介导的RNA干扰研究NMUR2基因对食物摄入量,体重和食物动机的影响。总的来说,这些研究将为理解调节食物动机的神经通路奠定基础,并为未来开发基于NMUR 2的治疗肥胖的疗法奠定基础。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jonathan Dean Hommel其他文献
Jonathan Dean Hommel的其他文献
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{{ truncateString('Jonathan Dean Hommel', 18)}}的其他基金
Chronic alcohol regulates circuitry structure and demand for alcohol
慢性酒精调节回路结构和对酒精的需求
- 批准号:
10373655 - 财政年份:2022
- 资助金额:
$ 42.4万 - 项目类别:
Chronic alcohol regulates circuitry structure and demand for alcohol
慢性酒精调节回路结构和对酒精的需求
- 批准号:
10684127 - 财政年份:2022
- 资助金额:
$ 42.4万 - 项目类别:
Hypothalamic-Striatal Control of Motivation for Obesogenic Food
下丘脑-纹状体对致胖食物动机的控制
- 批准号:
10027208 - 财政年份:2020
- 资助金额:
$ 42.4万 - 项目类别:
Neuromedin U as a Novel Mechanism Underlying Cocaine Addiction
Neuromedin U 作为可卡因成瘾的新机制
- 批准号:
8446059 - 财政年份:2013
- 资助金额:
$ 42.4万 - 项目类别:
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