AgRP neurons: circadian control and interactions with the HPA axis

AgRP 神经元：昼夜节律控制以及与 HPA 轴的相互作用 AgRP 神经元在驱动进食方面发挥着关键作用。它们由报告低能量的反馈信号激活 商店，它们的激活促进了对食物的寻找和食用。值得注意的是，它们还受到监管 预测未来需求和结果的前馈线索。 AgRP 神经元的核心作用进一步 其突出特点是它们能够引起对禁食的许多适应性生理反应。鉴于首要地位 对于 AgRP 神经元来说，了解它们的调节方式、它们控制的过程以及它们的作用非常重要。 他们如何实现这种控制。考虑到这一点，这笔赠款旨在实现以下两个目标： 目标 1：研究 AgRP 神经元的 SCN/昼夜前馈激活和喂养。为了这个目标，我们 通过确定 SCN 是否参与 AgRP 神经元来扩展前馈预期调节的概念 主动安排每日喂养并防止未来的能量不足。虽然众所周知，喂养不足 昼夜节律控制，这很重要，因为不合时宜的喂养会导致疾病，但这是完全未知的 昼夜节律系统是如何做到这一点的。为了研究 AgRP 神经元的 SCN 控制，我们开发了 具有独特的能力，能够在多天内连续监测体内 AgRP 神经元活动，同时 监测进食、体温 (Tb)、运动活动 (LMA) 和其他神经元的节律。使用 通过这种方法，我们发现： i) AgRP 神经元活动以 24 小时为周期振荡（在 白天，晚上晚些时候）在光明/黑暗和持续黑暗的条件下，ii）峰值和低谷 AgRP 神经元活动与 SCN 神经元同相，并且 iii) 与“时差反应”（光线提前 6 小时） 周期），AgRP 神经元节律在 8 天内逐渐重新产生，与进食节律、Tb 和 LMA。基于此和光遗传学刺激研究，我们建议 SCN 通过抑制干预 GABA 能神经元激活（抑制）AgRP 神经元，这会导致进食的昼夜节律控制。 目标 2：研究 AgRP 神经元和 HPA 轴之间的相互作用。为了这个目标，我们 检查 AgRP 神经元和 HPA 轴之间的相互作用。首先，我们跟进我们的发现 皮质酮通过建立电生理、转录和信号通路直接激活 AgRP 神经元 这种激活的表观基因组机制。此外，我们还确定皮质酮是否激活 AgRP 神经元 导致库欣综合征和慢性压力的代谢后果。其次，我们扩大作用 AgRP 神经元通过确定其在驱动 HPA 轴中的作用，引起大脑对禁食的适应。 我们发现 AgRP 神经元有效激活 PVHCrh 神经元和 HPA 轴，我们提出 他们通过抑制连接 AgRP 神经元和 PVH-Crh 神经元的 GABA 能“网关”神经元来做到这一点。 最后，连接目标 1 和 2，我们同时评估 AgRP 和 PVH-Crh 神经元的节律，并且 研究 AgRP 神经元的 SCN 调节是否驱动 HPA 轴的昼夜节律控制，反之亦然。

AgRP neurons: circadian control and interactions with the HPA axis AgRP neurons play a key role driving feeding. They are activated by feedback signals reporting low energy stores, and their activation promotes the seeking and eating of food. Remarkably, they are also regulated by feedforward cues that anticipate future needs and outcomes. The central role of AgRP neurons is further highlighted by their ability to cause many of the adaptive physiologic responses to fasting. Given the primacy of AgRP neurons, it is important that we understand how they are regulated, what processes they control, and how they bring about such control. With this in mind, this grant pursues the following two Aims: Aim 1: To study SCN / circadian feedforward activation of AgRP neurons and feeding. In this Aim, we extend the concept of feedforward anticipatory regulation by determining if the SCN engages AgRP neurons to proactively schedule daily feeding and prevent future energy deficits. While it is known that feeding is under circadian control, and that this is important because mis-timed feeding causes disease, it is entirely unknown how the circadian system does this. To investigate SCN control of AgRP neurons, we have developed the unique ability to continuously monitor AgRP neuron activity in vivo over many days, while simultaneously monitoring rhythms in feeding, body temperature (Tb), locomotor activity (LMA), and in other neurons. Using this approach, we have found that: i) AgRP neuron activity oscillates with a 24 hr cycle (peaking later in the day, falling later in the night) in both light/dark and constant darkness conditions, ii) that peaks and troughs in AgRP neuron activity are in-phase with SCN neurons, and iii) that with “jet lag” (6 hr advancement of the light cycle), the AgRP neuron rhythm re-entrains gradually over 8 days in parallel with rhythms in feeding, Tb and LMA. Based on this and optogenetic stimulation studies, we propose that the SCN, by inhibiting an intervening GABAergic neuron, activates (disinhibits) AgRP neurons, and that this causes circadian control of feeding. Aim 2: To investigate reciprocal interactions between AgRP neurons and the HPA axis. In this Aim, we examine reciprocal interactions between AgRP neurons and the HPA axis. First, we follow up on our discovery that corticosterone directly activates AgRP neurons by establishing the electrophysiologic, transcriptional and epigenomic mechanism for this activation. Also, we determine if activation of AgRP neurons by corticosterone causes the metabolic consequences of Cushing’s syndrome and chronic stress. Second, we extend the role of AgRP neurons in causing brain-based adaptations to fasting by establishing their role in driving the HPA axis. We have discovered that AgRP neurons potently activate PVHCrh neurons and the HPA axis, and we propose that they do this by inhibiting GABAergic “gateway” neurons that connect AgRP neurons to PVH-Crh neurons. Finally, linking Aims 1 and 2, we simultaneously assess rhythms in AgRP and PVH-Crh neurons, and investigate if SCN regulation of AgRP neurons drives circadian control of the HPA axis, or vice versa.