Defining locus coeruleus-norepinephrine (LC-NE) circuits in feeding

定义喂养中的蓝斑-去甲肾上腺素 (LC-NE) 回路

• 批准号: 10394427
• 负责人: Natale R Sciolino
• 金额: $ 24.47万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394427
• 关键词: Address; Adrenergic Receptor; Affect; Agonist; American; Anxiety; Area; Arousal; Attenuated; Award; Axon; Behavior; Biological; Body Weight; Brain; Brain region; Cardiovascular Diseases; Chronic; Chronic Disease; Clinical; Clinical Data; Data; Development; Devices; Diabetes Mellitus; Dopamine-beta-monooxygenase; Drug Receptors; Eating; Emotions; Exposure to; Fasting; Feeding behaviors; Fiber; Food; Functional disorder; Glucose; Goals; Hunger; Hyperphagia; Hypothalamic structure; Investigation; K-Series Research Career Programs; Kidney Diseases; Knock-out; Lateral; Learning; Link; Locomotion; Malignant Neoplasms; Maps; Measurement; Mediating; Mentors; Metabolism; Molecular; Motivation; Motor Activity; Mus; Nervous system structure; Neural Pathways; Neurons; Neuropeptides; Neurosciences; Neurotransmitters; Norepinephrine; Obese Mice; Obesity; Pathway interactions; Pattern; Pharmacology; Pharmacology Study; Phase; Photometry; Physiological; Physiology; Population; Positioning Attribute; Publishing; Receptor Signaling; Regulation; Research; Resolution; Rewards; Risk; Role; Satiation; Scientist; Signal Transduction; Sleeplessness; Source; Stimulant; System; Tachycardia; Technology; Testing; Training; Weight-Loss Drugs; base; behavioral pharmacology; burden of illness; career; cell type; cost; diet-induced obesity; dietary; effective therapy; excessive weight gain; feeding; hypocretin; improved; locus ceruleus structure; melanin-concentrating hormone; neural circuit; noradrenergic; novel; obesity treatment; optogenetics; overweight adults; programs; receptor; relating to nervous system; response; side effect; skills; targeted treatment; tool; treatment strategy; weight loss intervention; wireless

PROJECT SUMMARY Overeating is a major contributor to excessive weight gain, involving the hypothalamus and innervating brain systems that control reward, motivation, learning and emotion. Accumulating clinical data indicate that disruptions to the norepinephrine (NE) signaling system underlie key aspects of obesity. NE stimulants are currently the most effective therapies for weight loss, but the precise neural circuits that underlie this regulation of feeding remain largely unresolved. The goal of this proposed K99-R00 research is to dissect the role of the locus coeruleus (LC) to lateral hypothalamus (LHA) noradrenergic circuit in feeding and dietary obesity. The central hypothesis is that increased LC-NE activity will suppress feeding through inhibition of LHA hunger- promoting neurons. The basis for this hypothesis comes from the candidate’s preliminary data, together with published findings. To test the central hypothesis, the candidate will carry out three Specific Aims: (1) Identify the natural population activity patterns of LC-NE neurons during feeding behaviors; (2) Identify the hypothalamic cell types involved in LC-NE suppression of feeding; and (3) Determine the involvement of the LC-LHA noradrenergic circuit in the physiology and treatment of obesity. These aims will be accomplished using state- of-the-art technologies developed and used by the candidate’s mentoring team, including wireless fiber photometry to visualize neuronal activity, optogenetics tools to manipulate neural activity, and devices for high- resolution measurements of feeding behavior. This career development award will build on the candidate’s skills in behavioral pharmacology and systems neuroscience, and will facilitate the candidate’s long-term career goal of developing an independent research program focused on the NE circuits underlying feeding. The ultimate goal of this research is to inform the development of novel treatment strategies that activate specific LC-NE circuits to suppress feeding without incurring the off-target side effects observed using strategies that affect the entire noradrenergic system.

项目概要 暴饮暴食是体重过度增加的主要原因，涉及下丘脑和神经大脑 控制奖励、动机、学习和情感的系统。不断积累的临床数据表明 去甲肾上腺素 (NE) 信号系统的破坏是肥胖的关键方面。 NE兴奋剂是 目前最有效的减肥疗法，但这种调节背后的精确神经回路 喂养问题在很大程度上仍未得到解决。这项拟议的 K99-R00 研究的目标是剖析 蓝斑（LC）到下丘脑外侧（LHA）去甲肾上腺素能回路在喂养和饮食肥胖中的作用。这 中心假设是，增加的 LC-NE 活性将通过抑制 LHA 饥饿来抑制进食。 促进神经元。这一假设的基础来自候选人的初步数据，以及 发表的研究结果。为了检验中心假设，考生将实现三个具体目标：(1) 识别 进食行为期间 LC-NE 神经元的自然群体活动模式； (2) 识别下丘脑 参与 LC-NE 摄食抑制的细胞类型； (3)确定LC-LHA的参与 去甲肾上腺素能回路在肥胖的生理学和治疗中。这些目标将通过国家来实现 候选人指导团队开发和使用的最先进技术，包括无线光纤 用于可视化神经元活动的光度测定、用于操纵神经活动的光遗传学工具以及用于高通量成像的设备 摄食行为的分辨率测量。该职业发展奖将建立在候选人的技能之上 行为药理学和系统神经科学领域，并将促进候选人的长期职业目标 开发一个独立的研究项目，重点关注喂养的 NE 回路。终极 这项研究的目标是为开发激活特定 LC-NE 的新型治疗策略提供信息 使用影响进食的策略观察到的抑制进食的电路，而不会产生脱靶副作用 整个去甲肾上腺素能系统。