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: 10369832
• 负责人: Natale R Sciolino
• 金额: $ 24.9万
• 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/10369832
• 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; System; Tachycardia; Technology; Testing; Training; Weight-Loss Drugs; Wireless Technology; 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

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.

项目摘要 暴饮暴食是体重增加过度，假设和支配大脑的主要贡献者 控制奖励，动机，学习和情感的系统。 肥胖症的关键方面是对去甲肾上腺素（NE）信号系统的破坏 目前，减肥最有效的疗法，但基于该法规的精确神经回路 喂食仍然没有解决。 在喂食和饮食观察中，位于下丘脑（LHA）甲肾上腺素能回路的基因座（LC） 中心假设是，尽管抑制了LHA饥饿，但通过抑制喂养而增加了LC-NE活性。 促进神经元。 已发表的发现。 喂养行为期间LC-神经元的自然人口活动； LC-NE抑制的细胞类型；（3）确定LC-LHAA的参与 在生理和治疗中，将使用状态 - 候选人指导团队开发和使用的技术技术，包括无线光纤 可视化神经元活动的光度法，操纵神经活动的光遗传学工具以及高 - 喂养行为的解决方案将基于候选人的技能 在行为药理学和系统神经科学方面，将促进候选人的长期职业目标 开发一个独立的研究计划，重点是喂食的基础电路 这样做的目的是告知激活特定LC-NE的新型曲目的新型治疗方法的发展 通过使用影响该策略的策略，观察到的脱靶副作用来抑制喂养的电路以抑制进食 整个去甲肾上腺素能系统。