AgRP neurons: circadian control and interactions with the HPA axis

AgRP神经元：昼夜节律控制和与HPA轴的相互作用 AgRP神经元在驱动进食中起着关键作用。它们被报告低能量的反馈信号激活 储存，它们的激活促进了食物的寻找和进食。值得注意的是，它们也受到 预测未来需求和结果的前馈线索。AgRP神经元的中心作用是进一步的 突出的是它们能够引起对禁食的许多适应性生理反应。考虑到 对于AgRP神经元，重要的是我们要了解它们是如何被调节的，它们控制什么过程， 如何实现这样的控制。考虑到这一点，这笔赠款追求以下两个目标： 目的1：研究SCN /AgRP神经元的昼夜前馈激活和摄食。在这个目标中，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， 积极安排每日喂养，防止未来的能量不足。虽然我们知道， 昼夜节律控制，这是重要的，因为不定时喂养会导致疾病，这是完全未知的 昼夜节律系统是如何运作的。为了研究SCN对AgRP神经元的控制，我们开发了 独特的能力，连续监测AgRP神经元活动在体内许多天，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，我们已经发现：i）AgRP神经元活动以24小时周期振荡（在24小时后达到峰值）， 白天，在晚上晚些时候下降）在亮/暗和恒定的黑暗条件下，ii） AgRP神经元活动与SCN神经元同相，和iii）与“时差”（光提前6小时）同相 周期），AgRP神经元节律在8天内逐渐恢复，与摄食、Tb和 LMA。基于这一点和光遗传学刺激研究，我们提出SCN，通过抑制一个干预性的 GABA能神经元激活（解除抑制）AgRP神经元，并且这引起进食的昼夜节律控制。 目的2：探讨AgRP神经元与HPA轴之间的相互作用。在这个目标中，我们 检查AgRP神经元和HPA轴之间的相互作用。首先，我们要跟进我们的发现 皮质酮直接激活AgRP神经元，通过建立电生理，转录和 表观基因组机制的这种激活。此外，我们确定是否激活AgRP神经元的皮质酮 会导致库欣综合征和慢性压力的代谢后果。第二，我们扩大了 AgRP神经元通过建立它们在驱动HPA轴中的作用而引起基于大脑的禁食适应。 我们已经发现AgRP神经元有效地激活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，将目标1和2联系起来，我们同时评估了AgRP和PVH-Crh神经元的节律， 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.