权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

确定促食欲 AgRP 神经元如何在解剖学和功能上与促食欲 PBel CGRP 神经元相互作用以调节食物摄入行为

基本信息

批准号：
9022820
负责人：
MATTHEW E CARTER
金额：
$ 36.15万
依托单位：
WILLIAMS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-16 至 2018-09-15
项目状态：
已结题

项目摘要

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.