Feedforward Activation of AgRP Neurons and Hunger

AgRP 神经元的前馈激活和饥饿

• 批准号: 10732358
• 负责人: BRADFORD B LOWELL
• 金额: $ 51.91万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732358
• 关键词: Affect; Afferent Neurons; Automobile Driving; Awareness; Behavioral; Biology; Brain; Cells; Confusion; Cues; Data; Data Set; Dehydration; Desire for food; Detection; Devices; Disease; Eating; Excitatory Synapse; Excretory function; Fasting; Feedback; Food; Future; Genes; Glutamates; Goals; Grant; Hunger; Individual; Ingestion; Insulin; Leptin; Link; Mediator; Modeling; Molecular; Monitor; Motivation; Mus; Neurobiology; Neurons; Nose; Nutrient; Obesity; Pattern; Play; Regulation; Role; Sensory; Signal Transduction; Source; Speed; Synapses; Synaptic plasticity; Thirst; Time; Training; Water; energy balance; falls; feeding; food consumption; ghrelin; in vivo; in vivo monitoring; increased appetite; insight; interest; neural; neuronal circuitry; novel; presynaptic; prevent; recombinase; selective expression; synaptogenesis; transcriptomics

AgRP neurons play a vital role in causing hunger – the desire to find and consume food. Hence, it is important to understand how the activity of AgRP neurons is controlled. The conventional view is that feedback signals, which track changes in energy balance, are the primary regulators of AgRP neurons. For example, the fasting- induced increase in AgRP neuron activity is thought to be caused by falls in leptin and perhaps insulin, and an increase in ghrelin. Conversely, recent studies using real-time in vivo monitoring of neural activity have unexpectedly uncovered novel forms of regulation that are clearly unrelated to feedback from energy stores. For example, detection of sensory cues related to food, and ingestion of food, both rapidly decrease AgRP neuron activity – well before energy stores are affected. While these examples clearly document the existence of rapid, “feedforward” inhibition of AgRP neurons, to date there have been no examples of the converse – i.e. rapid, feedforward activation of AgRP neurons. By performing long-term in vivo recordings of AgRP neuron activity, we have recently discovered that denial of access to food rapidly, within 30-60 minutes, activates AgRP neurons. Importantly, this rapid activation is to a high level that does not increase further as fasting progresses. This relatively rapid, “square wave” pattern of activation strongly indicates that it must be caused by novel mechanisms which, importantly, are unrelated to changes in feedback signals. This discovery, which could lead to a revision in models of AgRP neuron regulation, indicates that fasting-related activation, like feeding-related inhibition, utilizes feedforward mechanisms. Given that AgRP neuron activity is vital for appetite, and given that feedforward activation is not part of present models of AgRP neuron regulation, we believe that uncovering the neural basis for this, and establishing its function, as we recently did for sensory food cue inhibition of AgRP neurons, will provide important, previously unknown insights into the biology of hunger. In preliminary studies, we have identified the source of this rapid feedforward activation. Remarkably, the excitatory circuit carrying this activation to AgRP neurons shows a large degree of activity-dependent synaptogenesis plasticity – which we believe functions to amplify and sustain feedforward activation of AgRP neurons. Thus, the overall goal of this grant is to discover the basis for and understand the purpose of rapid, feedforward activation of AgRP neurons. In Aim 1 we will use our single neuron transcriptomic dataset and marker gene recombinase driver mice to establish the neural afferent basis for this regulation. In Aim 2 we will determine the behavioral scenarios that trigger feedforward activation – we hypothesize a key role for awareness that food is unavailable. In Aim 3 we will establish its function – this will be done by blocking the responsible afferents and then examining consequences. Finally, in Aim 4, we will identify the molecular mediators of and role for activity-dependent synaptogenesis / plasticity in this excitatory afferent à AgRP neuron circuit – we hypothesize important roles for presynaptic release of Cbln2 and Bdnf.

AGRP神经元在造成饥饿方面起着至关重要的作用 - 渴望找到和食用食物。因此，这很重要 了解如何控制AGRP神经元的活性。传统的观点是反馈信号， 能量平衡的轨迹变化是AGRP神经元的主要调节剂。例如，禁食 - 诱导的AGRP神经元活性的增加被认为是由瘦素和胰岛素下降引起的，并且 增长肽。相反，使用实时在体内监测神经活动的最新研究已有 出乎意料的发现的新型调节形式与能量存储的反馈显然无关。 例如，检测与食物有关的感觉线索和食物的摄入，都迅速降低了AGRP 神经元活性 - 在能量存储受到影响之前。这些例子清楚地记录了存在 迄今为止，尚无相反的例子，即 AGRP神经元的快速，前馈激活。通过进行AGRP神经元的长期体内记录 活动，我们最近发现，在30-60分钟内拒绝迅速获得食物的机会激活 AGRP神经元。重要的是，这种快速的激活是高水平的，不会进一步增加。 进展。这种相对较快的“方波”激活模式强烈表明必须引起它 通过新颖的机制，重要的是，这些机制与反馈信号的变化无关。这个发现，哪个 可能导致AGRP神经元调节模型的修订，表明与禁食相关的激活，例如 与进食相关的抑制作用，利用了前馈机制。鉴于AGRP神经元活性对于 食欲，鉴于前馈激活不是当前AGRP神经元调节模型的一部分，我们 相信为此揭示神经基础并建立其功能，就像我们最近为感官所做的那样 食品提示抑制AGRP神经元将为生物学提供重要的，以前未知的见解 饥饿。在初步研究中，我们已经确定了这种快速前馈激活的来源。值得注意的是 携带此激活到AGRP神经元的兴奋回路显示了很大程度的活性依赖性 突触形成可塑性 - 我们认为功能可以放大和维持AGRP的前馈激活 神经元。这是这笔赠款的总体目标是发现快速， AGRP神经元的前馈激活。在AIM 1中，我们将使用我们的单个神经元转录组数据集和 标记基因重组酶驱动小鼠以建立该调节的神经传入基础。在目标2中，我们将 确定触发前馈激活的行为方案 - 我们假设 意识到食物不可用。在AIM 3中，我们将确定其功能 - 这将通过阻止 负责任的传入，然后检查后果。最后，在AIM 4中，我们将确定分子 在这种兴奋性传入àagrp中，活动依赖性突触发生 /可塑性的介体和作用 神经元回路 - 我们假设重要的作用是突触前释放CBLN2和BDNF。