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: 8290732
• 负责人: Richard D. Palmiter
• 金额: $ 27.79万
• 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/8290732
• 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. PUBLIC HEALTH RELEVANCE: The major goal of this proposal is to decipher the neural circuitry controlling anorexia. We aim to discover the neurotransmitters and receptors involved in this circuit, identify molecular markers for the relevant neurons, and learn how the circuit adapts to changes in environment, for example, consumption of a high-fat diet. We anticipate that understanding this circuit will provide insight to how the brain integrates taste and palatability of food with visceral signals and energy balance.

描述（由申请人提供）：我们正在进行一项惊人的观察，即在成年而非新生小鼠中消融下丘脑AgRP神经元会导致严重厌食症。我们发现，厌食症是由于突然失去GABA信号的AgRP神经元的臂旁核（PBN），通过显示，可以防止致命的厌食症的慢性输液的苯二氮卓类GABAA受体激动剂进入PBN，但不是其他核。我们假设平衡的输入到PBN维持正常的喂养和PBN的过度活动（例如，由于GABA的损失）导致厌食症。我们建议使用药理学和遗传学工具来确定PBN的兴奋来源以及所涉及的神经递质和受体。我们还建议发现一个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，小鼠可以适应损失的AgRP神经元和恢复正常饮食，当长期治疗与GABAA激动剂（布他西尼），5HT 3拮抗剂（昂丹司琼），氯化锂或暴露于高脂肪饮食。我们将探讨的假设，这些治疗导致适应神经元的输入或输出的PBN，或可塑性内的相关PBN神经元本身。我们预计，这些实验将描绘出一个神经回路，这是重要的维持正常的进食行为。我们已经建立了强大的药理学和遗传学技术，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这种电路如何适应不断变化的环境条件，并确定所涉及的分子和细胞变化。这项研究有助于更好地理解正常和成瘾性进食行为、神经元可塑性和神经性厌食症等疾病。 公共卫生相关性：该提案的主要目标是破译控制厌食症的神经回路。我们的目标是发现参与这个回路的神经递质和受体，确定相关神经元的分子标记，并了解回路如何适应环境变化，例如，高脂肪饮食的消耗。我们预计，了解这个回路将有助于了解大脑如何将食物的味道和适口性与内脏信号和能量平衡相结合。