AgRP neurocircuitry regulating energy expenditure

描述(申请人提供)：大脑如何维持能量平衡还不是很清楚，这使它成为一个关键的研究领域。刺鼠相关肽(AgRP)神经元位于下丘脑弓状核(ARC)，是调节能量平衡所必需的。通过药物遗传刺激对这些神经元的特定激活会产生强烈的饥饿感，并迅速减少能量消耗。值得注意的是，对AgRP神经元产生能量消耗抑制的机制关注很少，留下了介导这一效应的下游电路未知。这在一定程度上是由于ARC内存在复杂的电路，其中AgRP神经元与其他功能相反或无关的神经元一起存在，这些神经元也共享部分电路重叠。要揭开AgRP神经元降低新陈代谢的过程，首先必须了解调节AgRP神经元激活的生理反应的回路。传统的示踪方法不能进行细胞特异性靶向和功能连接的评估，然而，最近创新的光遗传学和药物遗传学技术的发展使得研究控制摄食行为和新陈代谢的复杂回路成为可能。通过在转基因小鼠中利用依赖于Cre的基因打靶方法，该应用程序提出了定位AgRP神经元下游的位置，并识别负责AgRP介导的能量消耗抑制的特定神经元群体。随后，药物遗传学和光遗传学工具的结合将允许单独操纵特定的AgRP突触，以揭示介导抑制能量消耗的必要和/或足够的传出靶点。这些研究的结果将为AgRP介导的能量消耗抑制提供一个线路图，这可能为从饮食失调到肥胖等一系列代谢性疾病的潜在贡献提供洞察。

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.