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 神经元在引起饥饿（寻找和消费食物的欲望）方面发挥着至关重要的作用，因此，它很重要。 了解 AgRP 神经元的活动是如何控制的 传统观点是反馈信号 跟踪能量平衡的变化，是 AgRP 神经元的主要调节因子。 AgRP 神经元活性的诱导增加被认为是由瘦素和可能的胰岛素下降引起的，并且 最近使用实时体内神经活动监测的研究发现，离线生长素释放肽（ghrelin）的增加。 出人意料地发现了新的调节形式，这些形式显然与能量存储的反馈无关。 例如，检测与食物相关的感官线索以及摄入食物都会迅速降低 AgRP 神经活动——远在能量储存受到影响之前，而这些例子清楚地证明了这种情况的存在。 AgRP 神经元的快速“前馈”抑制，迄今为止还没有相反的例子——即 通过对 AgRP 神经元进行长期体内记录，快速前馈激活 AgRP 神经元。 活动，我们最近发现，在 30-60 分钟内迅速拒绝获取食物会激活 重要的是，这种快速激活水平不会像禁食时那样进一步增加。 这种相对快速的强烈激活“方波”模式表明它一定是由其引起的。 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。 可能会导致 AgRP 神经元调节模型的修订，表明与禁食相关的激活，例如 鉴于 AgRP 神经元活性对于进食相关抑制至关重要。 食欲，并且鉴于前馈激活不是当前 AgRP 神经元调节模型的一部分，我们 相信揭示其神经基础并建立其功能，就像我们最近为感觉所做的那样 AgRP 神经元的食物信号抑制，将为了解 AgRP 神经元的生物学提供重要的、以前未知的见解。 值得注意的是，在初步研究中，我们已经确定了这种快速前馈激活的来源。 将这种激活传递给 AgRP 神经元的兴奋回路显示出很大程度的活动依赖性 突触发生可塑性——我们认为它可以放大和维持 AgRP 的前馈激活 因此，这项资助的总体目标是发现快速神经元的基础并理解其目的。 AgRP 神经元的前馈激活在目标 1 中，我们将使用我们的单神经元转录组数据集和 在目标 2 中，我们将使用标记基因重组酶驱动小鼠来建立这种调节的神经传入基础。 确定触发前馈激活的行为场景——我们帮助发挥了关键作用 在目标 3 中，我们将建立其功能——这将通过阻止来实现。 最后，在目标 4 中，我们将识别分子。 兴奋性传入 AgRP 中活动依赖性突触发生/可塑性的中介者和作用 神经回路——我们追求 Cbln2 和 Bdnf 突触前释放的重要作用。