Feedforward Activation of AgRP Neurons and Hunger

AgRP神经元在引起饥饿--寻找和消费食物的欲望--中起着至关重要的作用。因此，它是重要的 了解AgRP神经元的活动是如何被控制的。传统的观点是反馈信号， 它们跟踪能量平衡的变化，是AgRP神经元的主要调节因子。例如，禁食- AgRP神经元活性的诱导增加被认为是由瘦素和胰岛素的下降引起的，而一种 胃促生长素的增加。相反，最近使用实时活体监测神经活动的研究已经 出人意料地发现了新的监管形式，这些形式显然与能源商店的反馈无关。 例如，检测与食物有关的感官线索，以及摄取食物，都会迅速降低AgRP 神经元活动--早在能量储存受到影响之前。虽然这些例子清楚地证明了 对于AgRP神经元的快速“前馈”抑制，到目前为止还没有相反的例子--即 AgRP神经元的快速前馈激活。通过对AgRP神经元进行长期活体记录 作为一种活动，我们最近发现，在30-60分钟内，拒绝获得食物的行为迅速激活 AgRP神经元。重要的是，这种快速激活达到了一个高水平，不会像禁食那样进一步增加 进步了。这种相对快速的“方波”激活模式强烈地表明，它肯定是由 通过与反馈信号的变化无关的新机制来实现。这一发现，即 可能导致AgRP神经元调节模型的修订，表明禁食相关的激活，如 与摄食相关的抑制，利用前馈机制。鉴于AgRP神经元的活动对 食欲，并考虑到前馈激活不是目前AgRP神经元调节模型的一部分，我们 相信揭示这一现象的神经基础，并建立其功能，就像我们最近对感觉所做的那样 食物提示抑制AgRP神经元，将提供重要的，以前未知的洞察力 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， 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。 突触发生的可塑性--我们认为它具有放大和维持AgRP前馈激活的功能 神经元。因此，这笔赠款的总体目标是发现快速行动的基础并了解其目的， 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数据集和 标记基因重组酶驱动小鼠，为这一调控建立神经传入基础。在《目标2》中我们将 确定触发前馈激活的行为场景-我们假设 意识到没有食物可用。在目标3中，我们将建立其功能-这将通过阻止 负责任的传入，然后检查后果。最后，在目标4中，我们将识别分子 兴奋性传入AgRP中活性依赖性突触发生/可塑性的介体及其作用 神经元回路-我们假设Cbln2和BDNF在突触前释放中起重要作用。

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.