A Nociceptin Central Amygdala to Hindbrain Circuit for the Control of Palatable Food Consumption

用于控制可口食物消耗的伤害感受肽中央杏仁核到后脑回路

• 批准号: 10103903
• 负责人: James Andrew Hardaway
• 金额: $ 8.48万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10103903
• 关键词: Nociceptin; Central; Amygdala; Hindbrain; Circuit

Project Summary Candidate: I am an NIH T32 Postdoctoral Fellow within the Bowles Center for Alcohol Studies and the UNC Center of Excellence for Eating Disorders in the Departments of Pharmacology and Psychiatry at the University of North Carolina at Chapel Hill. Career Goals: My ultimate goal is to understand the neural circuits that regulate palatable food intake that contribute to diseases like obesity and binge eating disorder. By researching the underlying signaling pathways and molecular circuitry in these neurochemically defined neuron ensembles, I will develop targeted, novel preclinical treatments for obesity and binge eating disorder for testing in construct valid animal models of obesity and binge eating disorder. Career Development: My current expertise is in molecular neuroscience and genetics, so I hope to gain additional mentored training in 1) circuit neuroscience including photometry, advanced optogenetics, chemogenetics, and electrophysiology; 2) mouse operant behavior; and 3) clinical obesity phenotypes and metabolism within the current proposal. Research Project: This project leverages preliminary data that shows a specific role for prepronociceptin-expressing neurons in the central amygdala (PnocCeA neurons) in: promoting palatable food intake, modulating the severity of diet-induced obesity, and promoting reward through its inputs to the parabrachial nucleus (PBN) and nucleus of the solitary tract (NTS). I aim to 1) measure the dynamic activity state of PnocCeA neurons during operant palatable food intake using in vivo fiber photometry, 2) determine the role of nociceptin signaling in the PBN and NTS on neural activity and the requisite role of this pathway in operant palatable food intake, and 3) use pathway- specific inhibitory optogenetics and chemogenetics to probe the specific role of the PnocCeA pathway to the PBN and NTS during operant palatable food intake. In future independent applications (R01s), I will assess circuit and molecular plasticity of PnocCeA networks following chronic palatable food access and diet-induced obesity. Environment: Research will be primarily performed at the University of North Carolina at Chapel Hill with some experiments performed at the National Institute of Environmental Health Sciences research program at Research Triangle Park in Durham, NC. Mentorship: The core mentorship team consists of Dr. Thomas Kash, lead mentor, who is a leading researcher in circuit neuroscience and consummatory behavior, and Dr. Cynthia Bulik, co-lead mentor, who is a nationally renowned expert in obesity and eating disorder research. Dr. Kari North, a co-mentor, is a leading researcher in clinical obesity phenotyping and genetics. Dr. Joyce Besheer, a co-mentor, is a very experienced researcher in rodent operant behavior. Dr. Guohong Cui and Dr. Michael Krashes, both consultants, have equipment for and routinely use in vivo fiber photometry of genetically encoded Ca2+ indicators in awake, freely-behaving mice. Dr. Todd Thiele, a consultant, is an expert in neuropeptide signaling and local pharmacological manipulations during mouse behavior. Together, they will provide expertise to accomplish the scientific aims, mentorship for me to complete my training, and leadership to promote my transition to being an independent investigator.

项目概要 候选人：我是鲍尔斯酒精研究中心的 NIH T32 博士后研究员 北卡罗来纳大学药理学系饮食失调卓越中心 北卡罗来纳大学教堂山分校的精神病学。 职业目标：我的最终目标是了解调节可口食物摄入的神经回路 导致肥胖和暴食症等疾病。通过研究底层 这些神经化学定义的神经元集合中的​​信号传导途径和分子电路，我将 开发针对肥胖和暴食症的有针对性的新型临床前治疗方法，以进行测试 构建有效的肥胖和暴食症动物模型。 职业发展：我目前的专长是分子神经科学和遗传学，所以我希望 获得 1) 电路神经科学方面的额外指导培训，包括光度测定、高级 光遗传学、化学遗传学和电生理学； 2）鼠标操作行为； 3) 临床 当前提案中的肥胖表型和代谢。 研究项目：该项目利用了显示特定作用的初步数据 中央杏仁核中表达前原诺西肽的神经元（PnocCeA 神经元）： 可口的食物摄入量，调节饮食引起的肥胖的严重程度，并通过以下方式促进奖励 其输入至臂旁核（PBN）和孤束核（NTS）。我的目标是 1) 测量操作性可口食物摄入期间 PnocCeA 神经元的动态活动状态 体内纤维光度测定，2)确定PBN和NTS中伤害感受素信号传导对神经的作用 该途径的活性和在操作性可口食物摄入中的必要作用，以及3)使用途径- 特异性抑制光遗传学和化学遗传学来探讨 PnocCeA 通路的特定作用 操作性可口食物摄入期间的 PBN 和 NTS。在未来的独立应用程序（R01s）中，我 将评估长期可口食物后 PnocCeA 网络的电路和分子可塑性 获取和饮食引起的肥胖。 环境：研究将主要在北卡罗来纳大学教堂山分校进行 在国家环境健康科学研究所进行的一些实验 北卡罗来纳州达勒姆三角研究园的研究项目。 导师：核心导师团队由首席导师Thomas Kash博士组成，他是一位领先的导师。 回路神经科学和完美行为研究员，Cynthia Bulik 博士，联合负责人 导师，是全国知名的肥胖和饮食失调研究专家。卡里·诺斯 (Kari North) 博士 共同导师，是临床肥胖表型和遗传学领域的领先研究员。乔伊斯·贝希尔博士 共同导师，是一位在啮齿动物操作行为方面经验丰富的研究员。崔国宏博士和 迈克尔·克拉什 (Michael Krashes) 都是顾问，拥有并经常使用体内光纤光度测定的设备 在清醒、自由行为的小鼠中基因编码的 Ca2+ 指标。 Todd Thiele 博士是一名顾问 小鼠行为过程中神经肽信号传导和局部药理学操作的专家。 他们将共同提供专业知识来实现​​科学目标，并指导我完成 我的培训和领导力促进我向独立调查员过渡。