Effect of killing or removing GABA from NPY/AgRP neurons

杀死或去除 NPY/AgRP 神经元中 GABA 的作用

• 批准号: 8446978
• 负责人: Richard D. Palmiter
• 金额: $ 26.7万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446978
• 关键词: ART protein; Ablation; Adult; Agonist; Aminobutyric Acids; Animals; Anorexia; Anorexia Nervosa; Attention; Benzodiazepines; Body Weight; Brain; Cell Nucleus; Cells; Chronic; Consumption; Diet; Disease; Eating; Emotional; Employee Strikes; Environment; Equilibrium; Exhibits; Fatty acid glycerol esters; Feeding behaviors; Food; Functional disorder; Genes; Genetic; Genetic Markers; Genetic Techniques; Goals; Hypothalamic structure; Infusion procedures; Lead; Learning; Maintenance; Malaise; Mediating; Metabolism; Modeling; Molecular; Mus; Neonatal; Neuronal Plasticity; Neurons; Neurotransmitter Receptor; Neurotransmitters; Obesity; Ondansetron; Output; Pro-Opiomelanocortin; Production; Regulation; Research; Signal Pathway; Signal Transduction; Source; Taste Perception; Visceral; base; coping; energy balance; environmental change; expectation; feeding; gamma-Aminobutyric Acid; gastrointestinal; insight; killings; molecular marker; neural circuit; neuropeptide Y; parabrachial nucleus; prevent; receptor; recombinase; research study; response; tool

DESCRIPTION (provided by applicant): We are pursuing the striking observation that ablation of hypothalamic AgRP neurons in adult, but not neonatal, mice results in severe anorexia. We discovered that the anorexia is due to sudden loss of GABA signaling by AgRP neurons to the parabrachial nucleus (PBN) by showing that the lethal anorexia can be prevented by chronic infusion of a benzodiazepine GABAA receptor agonist into the PBN, but not other nuclei. We hypothesize that balanced input to the PBN maintains normal feeding and that excessive activity of the PBN (e.g. due to loss of GABA) results in anorexia. We propose to identify the source of the excitation to the PBN, as well as the neurotransmitter(s) and receptor(s) involved using pharmacological and genetic tools. We also propose to discover a gene that is specifically expressed in the critical PBN neurons that mediate anorexia, and then target Cre recombinase to that gene, which would greatly facilitate further genetic, tracing and electrophysiological studies. Our experiments indicate that mice can adapt to loss of AgRP neurons and resume normal eating, when chronically treated with a GABAA agonist (bretazenil) a 5HT3 antagonist (ondansetron), LiCl or exposed to a high-fat diet. We will explore the hypothesis that these treatments lead to adaptations in neuronal inputs or outputs of the PBN, or plasticity within the relevant PBN neurons themselves. We anticipate that these experiments will delineate a neural circuit that is important for maintenance of normal feeding behavior. We have established powerful pharmacological and genetic techniques that will allow us to identify the critical neurotransmitters and receptors that are used by neurons within that circuit. Our ultimate goals are to understand how this circuit adapts to changing environmental conditions and identify the molecular and cellular changes involved. This research is relevant to a better understanding normal and addictive feeding behavior, neuronal plasticity, and diseases such as anorexia nervosa.

描述（由申请人提供）：我们正在进行惊人的观察，即消融成年小鼠而非新生小鼠的下丘脑 AgRP 神经元会导致严重的厌食症。我们发现厌食症是由于 AgRP 神经元向臂旁核 (PBN) 发出的 GABA 信号突然丧失造成的，结果表明，通过向 PBN（而非其他核团）长期输注​​苯二氮卓类 GABAA 受体激动剂可以预防致命性厌食症。我们假设 PBN 的平衡输入可维持正常进食，而 PBN 的过度活动（例如由于 GABA 的损失）会导致厌食。我们建议使用药理学和遗传工具来确定 PBN 的兴奋源，以及涉及的神经递质和受体。我们还建议发现一种在介导厌食症的关键 PBN 神经元中特异性表达的基因，然后将 Cre 重组酶靶向该基因，这将极大地促进进一步的遗传、追踪和电生理学研究。我们的实验表明，当长期接受 GABAA 激动剂（布他西尼）、5HT3 拮抗剂（昂丹司琼）、LiCl 治疗或暴露于高脂肪饮食时，小鼠可以适应 AgRP 神经元的损失并恢复正常饮食。我们将探讨以下假设：这些治疗会导致 PBN 神经元输入或输出的适应，或相关 PBN 神经元本身的可塑性。我们预计这些实验将描绘出对于维持正常进食行为非常重要的神经回路。我们已经建立了强大的药理学和遗传技术，使我们能够识别该回路中神经元使用的关键神经递质和受体。我们的最终目标是了解该电路如何适应不断变化的环境条件并识别所涉及的分子和细胞变化。这项研究有助于更好地了解正常和成瘾的进食行为、神经元可塑性和神经性厌食症等疾病。