AgRP neurocircuitry regulating energy expenditure

AgRP 神经回路调节能量消耗

• 批准号: 9132255
• 负责人: Jon Resch
• 金额: $ 5.61万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132255
• 关键词: Area; Attention; Behavioral; Body Weight; Brain; Brown Fat; Cells; Complex; Data; Development; Disease; Eating Disorders; Energy Metabolism; Expenditure; Fasting; Feeding behaviors; Gene Targeting; Goals; Health; Homeostasis; Hunger; Hypothalamic structure; Left; Light; Maps; Measures; Mediating; Melanocortin 4 Receptor; Metabolic; Metabolic Diseases; Metabolism; Methods; Mus; Neurons; Obesity; Oxygen Consumption; Peptides; Pharmacogenetics; Physiological; Population; Prevalence; Process; Regulation; Reporter; Research; Site; Structure of nucleus infundibularis hypothalami; Synapses; Synaptophysin; Technology; Testing; Thermogenesis; Transgenic Mice; cell type; chromophore; combat; designer receptors exclusively activated by designer drugs; energy balance; feeding; innovation; insight; interest; neglect; optogenetics; paraventricular nucleus; receptor expression; research study; response; synaptic inhibition; tool

DESCRIPTION (provided by applicant): How the brain maintains energy homeostasis is not well understood making it a critical area of research. Agouti-related peptide (AgRP) neurons located in the arcuate nuclei (ARC) of the hypothalamus are essential for the regulation of energy balance. Specific activation of these neurons through pharmacogenetic stimulation produces intense hunger as well as a rapid decrease in energy expenditure. Remarkably, little attention has been paid to the mechanisms producing suppression of energy expenditure by AgRP neurons, leaving the downstream circuitry mediating this effect unknown. This is due, in part, to the complex circuitry that exists within the ARC, where AgRP neurons exist among other neurons of opposite or unrelated function that also share partial overlap in circuitry. To unravel the process by which AgRP neurons function to decrease metabolism, there must first be an understanding of the circuitry mediating the physiological response to AgRP neuron activation. Traditional tract tracing methods are incapable of cell-specific targeting and assessment of functional connectivity, however, recent development of innovative optogenetic and pharmacogenetic technologies now permit the study of complex circuits controlling feeding behavior and metabolism. By utilizing Cre-dependent gene-targeting approaches in transgenic mice, this application proposes to map sites downstream to AgRP neurons and identify the specific neuronal population responsible for AgRP- mediated suppression of energy expenditure. Subsequently, a combination of pharmacogenetic and optogenetic tools will allow for isolated manipulation of specific AgRP synapses to reveal the necessary and/or sufficient efferent targets that mediate suppression of energy expenditure. The findings generated from these studies will provide a wiring diagram for AgRP-mediated suppression of energy expenditure, which could provide insight into potential contributions to a wide range of metabolic diseases, ranging from eating disorders to obesity.

描述（由申请人提供）：大脑如何维持能量稳态尚不清楚，这使其成为研究的关键领域。位于下丘脑弓状核 (ARC) 的刺鼠相关肽 (AgRP) 神经元对于能量平衡的调节至关重要。通过药物遗传学刺激对这些神经元的特异性激活会产生强烈的饥饿感以及能量消耗的快速减少。值得注意的是，人们很少关注 AgRP 神经元抑制能量消耗的机制，因此介导这种效应的下游电路尚不清楚。这在一定程度上是由于 ARC 内存在复杂的电路，其中 AgRP 神经元存在于其他具有相反或不相关功能的神经元之间，这些神经元也共享电路的部分重叠。为了揭示 AgRP 神经元降低新陈代谢的过程，首先必须了解介导 AgRP 神经元激活的生理反应的电路。传统的纤维束追踪方法无法进行细胞特异性靶向和功能连接评估，然而，创新光遗传学和药物遗传学技术的最新发展现在允许研究控制摄食行为和代谢的复杂电路。通过在转基因小鼠中利用 Cre 依赖性基因靶向方法，该申请提出将下游位点定位到 AgRP 神经元，并鉴定负责 AgRP 介导的能量消耗抑制的特定神经元群。随后，药物遗传学和光遗传学工具的组合将允许对特定 AgRP 突触进行单独操作，以揭示介导能量消耗抑制的必要和/或足够的传出目标。这些研究的结果将为 AgRP 介导的能量消耗抑制提供一个接线图，这可以深入了解从饮食失调到肥胖等多种代谢疾病的潜在贡献。