Melanin-concentrating hormone and the neural regulation of feeding

黑色素浓缩激素与进食的神经调节

• 批准号: 10319590
• 负责人: Emily Elizabeth Noble
• 金额: $ 15.29万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-26 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319590
• 关键词: 3-Dimensional; Affect; Anatomy; Anti-Obesity Agents; Appetite Stimulants; Behavior; Behavior Therapy; Behavioral; Behavioral Mechanisms; Behavioral Paradigm; Brain; Brain Mapping; Brain region; Chronic; Data; Desire for food; Detection; Development; Development Plans; Eating; Energy Intake; Feeding behaviors; Fluorescence; Food; Funding; Gene Proteins; Goals; Health Care Costs; Hippocampus (Brain); Hyperphagia; Image; Immunohistochemistry; Impulsivity; In Situ Hybridization; Injections; Intake; Investigation; Lateral Hypothalamic Area; Lead; Mediating; Messenger RNA; Methods; Neuromodulator; Neurons; Neuropeptides; Obesity; Output; Palate; Pathway interactions; Perfusion; Pharmacology; Pharmacotherapy; Phenotype; Play; Prevalence; Public Health; RNA Interference; Rattus; Receptor Signaling; Regional Blood Flow; Regulation; Research; Research Assistant; Resolution; Rest; Rewards; Rodent; Role; Signal Pathway; Signal Transduction; Site; Slice; System; Techniques; Testing; Therapeutic; Transgenic Organisms; United States; Viral; Virus; Weight Gain; adverse outcome; awake; bariatric surgery; base; career; career development; comorbidity; conditioned place preference; diet-induced obesity; energy balance; experimental study; feeding; gastrointestinal; hormonal signals; hormone deficiency; increased appetite; innovation; insight; interest; knock-down; melanin-concentrating hormone; melanin-concentrating hormone receptor; mind control; multimodality; neural circuit; neural network; neurochemistry; neurogenetics; neuroimaging; neuronal circuitry; neuroregulation; neurotransmission; novel; obesogenic; overexpression; professor; protein expression; receptor; receptor function; relating to nervous system; response; skills; success; tenure track

Project Summary/Abstract Obesity and its associated comorbidities pose a major burden to public health, and existing therapeutics are only minimally effective or have major adverse consequences. The brain plays a central role in mediating energy balance. Melanin-concentrating hormone (MCH), a neuropeptide produced primarily in the lateral hypothalamic area (LHA) increases energy intake and body weight gain, and therefore there is recent interest in developing obesity therapeutics that block the hyperphagic effects of MCH. Preliminary data herein suggest that in addition to generally increasing food intake, MCH contributes to excessive feeding via conditioned appetitive mechanisms, such as food impulsivity and conditioned place preference for palatable food. Furthermore, these mechanisms can be attributed to specific nodes of MCH neuronal circuitry such as the ventral hippocampus (vHP), a region that contains high levels of MCH receptor but where the function of MCH with regard to feeding behavior has not previously been investigated. Through studying the MCH system and its contributions to the central regulation of ingestive behavior, the principal goal of the proposed 5-year research career development plan is to facilitate the applicant's transition from Research Assistant Professor to Tenure-track Assistant Professor with independent R01 funding. The proposed research will enable the applicant to master several virus-based neuroanatomical and chemogenetic techniques, rodent behavioral paradigms, high- resolution whole brain mapping with functional connectivity analyses. Using these techniques, she will determine the role of MCH to vHP neuronal circuitry in mediating feeding behavior, the relevance of this pathway to obesity, and will identify collateral projections, functional connections, and downstream targets. Specific Aim 1 utilizes dual virus chemogenetic techniques to selectively activate MCH neurons that project to the vHP in order to study the role of vHPà MCH neuronal circuitry in mediating several aspects of feeding behavior. Specific Aim 2 uses viral-based neural tracing, immunohistochemistry and in situ hybridization to further characterize these neurons by their collateral projections and phenotypic gene/protein expression profiles. Aim 3 uses the novel combination of dual virus chemogenetics with whole brain perfusion mapping to determine downstream regions engaged by activating MCH neurons that project to the vHP. Additionally, experiments in Aim 3 will determine how MCH to vHP neuronal circuitry augments regional brain activity during food impulsivity. This novel combination of approaches allows for investigation of the interaction between activating specific nodes of a defined circuit and immediate behavioral effects. Results from these experiments will be generative as pilot data for an R01 submission by the applicant, will provide significant contributions to ingestive behavior research, and will overall provide the applicant with a unique set of skills for her independent research career.

项目摘要/摘要 肥胖及其相关的合并症为公共卫生带来了主要的伯宁，现有的治疗是 只有最小有效或带来重大不利后果。大脑在介导中起着核心作用 能量平衡。黑色素浓缩马酮（MCH），一种主要在后来产生的神经肽 下丘脑区域（LHA）增加了能量摄入和体重增加，因此最近有兴趣 在开发肥胖疗法中，以阻止MCH的倍感作用。此处的初步数据建议 除了通常增加食物摄入量外，MCH还会导致通过条件的过量喂养 食欲的机制，例如食物冲动和适应可口食品的条件地点偏好。 此外，这些机制可以归因于MCH神经元电路的特定节点，例如 腹侧海马（VHP），该区域含有高水平的MCH受体，但MCH的功能 关于喂养行为，以前尚未研究。通过研究MCH系统和 它对摄入行为的中心监管的贡献，是拟议的5年的主要目标 研究职业发展计划是为了促进申请人从研究助理教授的过渡 拥有独立R01资金的任期助理助理教授。拟议的研究将使 申请人掌握几种基于病毒的神经解剖学和化学遗传技术，啮齿动物行为 范式，高分辨率的整个大脑映射，并通过功能连通性分析。使用这些 技术，她将确定MCH对VHP神经元电路的作用 这种途径与肥胖的相关性，并将确定附带项目，功能连接以及 下游目标。特定目标1利用双重病毒化学发生技术选择性激活MCH 向VHP投射的神经元，以研究VHPàMCH神经元电路中介导的作用 喂养行为的几个方面。特定目标2使用基于病毒的神经跟踪，免疫组织化学和 原位杂交以进一步通过其附带项目和表型来表征这些神经元 基因/蛋白质表达谱。 AIM 3使用双重病毒化学遗传学与整体的新型组合 大脑灌注映射以确定通过激活投影到的MCH神经元参与的下游区域 VHP。此外，AIM 3中的实验将确定MCH到VHP神经元电路如何增强 食物冲动期间的区域大脑活动。这种新颖的方法可以进行投资 激活定义电路的特定节点与立即行为效应之间的相互作用。 这些实验的结果将是通用的，作为申请人提交R01提交的试验数据，将 为摄取行为研究提供了重大贡献，总体将为申请人提供 她独立研究职业的独特技能集。