AgRP neurocircuitry regulating energy expenditure

描述（由申请人提供）：大脑如何维持能量稳态尚未得到很好的理解，使其成为一个关键的研究领域。agouti相关肽（AgRP）神经元位于下丘脑弓状核（ARC），对能量平衡的调节至关重要。这些神经元通过药物遗传刺激的特异性激活产生强烈的饥饿感以及能量消耗的迅速减少。值得注意的是，很少有人关注AgRP神经元产生能量消耗抑制的机制，使得介导这种作用的下游电路未知。这部分是由于ARC内存在复杂的电路，其中AgRP神经元存在于其他功能相反或不相关的神经元之间，这些神经元在电路中也有部分重叠。为了揭示AgRP神经元减少代谢的功能过程，首先必须了解介导AgRP神经元激活的生理反应的电路。传统的通道追踪方法无法进行细胞特异性靶向和功能连接评估，然而，最近创新的光遗传学和药物遗传学技术的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使用cre依赖的基因靶向方法，该应用程序提出将下游的位点定位到AgRP神经元，并确定负责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结合将允许对特定AgRP突触进行分离操作，以揭示介导能量消耗抑制的必要和/或充分的传出靶点。从这些研究中产生的发现将为agrp介导的能量消耗抑制提供一个接线图，这可能为从饮食失调到肥胖等广泛的代谢疾病的潜在贡献提供见解。

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.