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食欲（食欲诱导）和食欲（食欲抑制）神经元群体之间的相对平衡。这些系统中活动的不正常平衡可能导致严重的健康问题，并带来高昂的相关经济成本。在美国，超过一半的人口被认为超重，估计每年的总经济成本超过600亿美元。营养不良也是一个严重的问题：在感染、老年或癌症期间可能发生的异常食欲抑制可能导致严重的低体重和营养不良。然而，尽管明显的重要性，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，两类神经元已经成为食欲和体重的关键调节因子。下丘脑中一组称为“AgRP神经元”的神经元感知来自身体的稳态信号并增加食欲。当受到刺激时，AgRP神经元会导致食物摄入量的大幅增加。相比之下，臂旁核（PBN）中的一组神经元称为“PBel CGRP神经元”，它们感知来自胃和内脏的信号并降低食欲。当受到刺激时，PBel CGRP神经元引起食物摄入的大幅减少。 食欲AgRP神经元和食欲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，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可以克服PBel CGRP神经元介导的食欲抑制。本建议的目的是确定如何orexigenic AgRP神经元的解剖学和功能相互作用的orexigenic PBel CGRP神经元调节食物摄入行为。在目的1中，我们将测试的假设，AgRP神经元发送直接的，单突触的预测PBel CGRP神经元。在目标2中，我们将测试抑制AgRP神经元或AgRP到PBN的投射减少食物摄入并增加PBel CGRP神经元的活性的假设。在目标3中，我们将检验以下假设：刺激AgRP神经元或AgRP至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，例如在内脏不适、疾病或饱腹感期间。为了实现这些目标，我们将在小鼠中使用尖端的病毒基因递送工具和遗传编码的示踪剂和神经调质，以提供大脑如何平衡食欲和食欲信息的新见解。

 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.