Determination of how orexigenic AgRP neurons anatomically and functionally interact with anorexigenic PBel CGRP neurons to regulate food intake behavior

 描述(由申请人提供)：进食的动机取决于大脑中神经元的食欲增加(食欲诱导)和厌食(食欲抑制)群体之间的活动的相对平衡。这些系统中不正常的活动平衡可能会导致严重的健康问题，并伴随着高昂的相关经济成本。在美国，超过一半的人口被认为超重，每年的总经济成本估计超过600亿美元。营养不良也是一个实质性的问题：在感染、老年或癌症期间可能发生的食欲异常抑制，可能会导致体重严重偏低和营养不良。然而，尽管有明显的重要性，饥饿和食欲抑制的神经基础在神经元水平上仍然知之甚少。近年来，两类神经元已经出现，成为食欲和体重的关键调节因素。下丘脑中的一组神经元被称为“AgRP神经元”，它感知体内的动态平衡信号，从而提高食欲。当受到刺激时，AgRP神经元会导致食物摄入量的强劲增加。相反，臂旁核(PBN)中的一组神经元被称为“PBel CGRP神经元”，这些神经元感觉来自胃和内脏的信号，并降低食欲。当受到刺激时，PBel CGRP神经元会导致食物摄入量的大幅减少。嗜食性AgRP神经元和厌食性PBel CGRP神经元的相反作用提出了关于它们如何相互作用的重要问题。AgRP神经元释放抑制性神经递质GABA，并投射到PBel CGRP神经元所在的区域。然而，目前尚不清楚AgRP神经元是否直接抑制PBel CGRP神经元，也不知道这种抑制是否能克服PBel CGRP神经元介导的食欲抑制。这项建议的目的是确定厌食性AgRP神经元如何在解剖和功能上与厌食性PBel CGRP神经元相互作用来调节摄食行为。在目标1中，我们将检验这样一个假设，即AgRP神经元向PBel CGRP神经元发送直接的单突触投射。在目标2中，我们将检验这样一个假设，即抑制AgRP神经元或AgRP到PBN的投射减少了食物的摄入量，并增加了PBel CGRP神经元的活动。在目标3中，我们将测试一种假设，即刺激AgRP神经元或AgRP到PBN的投射抑制PBel CGRP神经元，并在食欲通常受到抑制的情况下增加食物摄入量，例如在内脏不适、疾病或饱腹感期间。为了实现这些目标，我们将使用尖端的病毒基因传递工具以及小鼠的遗传编码示踪剂和神经调节剂，为大脑如何平衡厌食和厌食信息提供新的见解。

 DESCRIPTION (provided by applicant): The motivation to eat depends on the relative balance of activity between orexigenic (appetite inducing) and anorexigenic (appetite suppressing) populations of neurons in the brain. An abnormal balance of activity in these systems can lead to substantial health problems with high associated economic costs. In the United States, over half the population is considered overweight, and the aggregate economic cost is estimated in excess of $60 billion per year. Undernourishment is also a substantial problem: abnormal appetite suppression, as can occur during infection, old age, or cancer, can lead to severely low body weight and malnutrition. However, despite obvious importance, the neural basis of hunger and appetite suppression continues to be poorly understood at a neuronal level. In recent years, two populations of neurons have emerged as key regulators of appetite and body weight. A group of neurons in the hypothalamus called "AgRP neurons" sense homeostatic signals from the body and increase appetite. When stimulated, AgRP neurons cause a robust increase in food intake. In contrast, a group of neurons in the parabrachial nucleus (PBN) called "PBel CGRP neurons" sense signals from the stomach and viscera and decrease appetite. When stimulated, PBel CGRP neurons cause a substantial decrease in food intake. The opposing roles of orexigenic AgRP neurons and anorexigenic PBel CGRP neurons raise important questions about how they interact. AgRP neurons release the inhibitory neurotransmitter GABA and project to the region where PBel CGRP neurons are located. However, it is unknown whether AgRP neurons directly inhibit PBel CGRP neurons, nor is it known whether this inhibition could overcome PBel CGRP neuron-mediated suppression of appetite. The purpose of this proposal is to determine how orexigenic AgRP neurons anatomically and functionally interact with anorexigenic PBel CGRP neurons to regulate food intake behavior. In Aim 1, we will test the hypothesis that AgRP neurons send direct, monosynaptic projections to PBel CGRP neurons. In Aim 2, we will test the hypothesis that inhibition of AgRP neurons or AgRP-to-PBN projections decreases food intake and increases activity in PBel CGRP neurons. In Aim 3, we will test the hypothesis that stimulation of AgRP neurons or AgRP-to-PBN projections inhibits PBel CGRP neurons and increases food intake during conditions when appetite is normally suppressed, such as during visceral malaise, illness, or satiety. To pursue these aims, we will use cutting edge viral gene delivery tools and genetically encoded tracers and neuromodulators in mice to provide new insights into how the brain balances orexigenic and anorexigenic information.