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

• 批准号: 10668332
• 负责人: BRADFORD B LOWELL
• 金额: $ 50.56万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668332
• 关键词: Address; Adrenal Glands; Automobile Driving; Blood; Body Temperature; Brain; Chickens; Chronic stress; Circadian Rhythms; Corticosterone; Corticotropin; Cues; Cushing Syndrome; Darkness; Disease; Disinhibition; Eating; Electrophysiology (science); Energy Metabolism; Enteral Feeding; Fasting; Feedback; Feeding behaviors; Food; Future; Genetic Transcription; Glucocorticoids; Grant; Hormones; Hunger; Hypothalamic structure; Jet Lag Syndrome; Light; Link; Metabolic; Metabolic Diseases; Monitor; Motivation; Motor Activity; Mus; Neurons; Outcome; Phase; Physiological; Pituitary Gland; Play; Process; Regulation; Reporting; Role; Schedule; Sensory; Signal Transduction; Stress; System; Time; Work; brain based; circadian; circadian regulation; egg; energy balance; epigenomics; falls; feeding; follow-up; in vivo; increased appetite; inhibitory neuron; insight; mental state; neural; neural circuit; optogenetics; prevent; response; restoration

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.

AgRP神经元：昼夜节律控制及其与HPA轴的相互作用 AgRP神经元在驱动摄食方面起着关键作用。它们由报告低能量的反馈信号激活 它们的激活促进了人们对食物的寻找和进食。值得注意的是，它们也受到 预测未来需求和结果的前馈提示。AgRP神经元的中心作用是进一步 突出的是它们有能力引起对禁食的许多适应性生理反应。鉴于它的首要地位 对于AgRP神经元，重要的是我们了解它们是如何调节的，它们控制着什么过程，以及 他们是如何实现这种控制的。有鉴于此，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。为了实现这一目标，我们 通过确定SCN是否与AgRP神经元接触来扩展前馈预期调控的概念 主动安排每日喂养计划，防止未来的能量不足。虽然我们知道进食是在 昼夜节律控制，这一点很重要，因为不当的喂养会导致疾病，这是完全未知的 生物钟系统是如何做到这一点的。为了研究SCN对AgRP神经元的控制，我们开发了 独一无二的能力，可连续监测体内多天的AgRP神经元活动，同时 监测摄食、体温(TB)、运动活动(LMA)和其他神经元的节律。vbl.使用 通过这种方法，我们发现：i)AgRP神经元的活动以24小时为周期振荡(在 白天，在晚上晚些时候落下)在明/暗和持续的黑暗条件下，ii)在 AgRP神经元的活动与SCN神经元同相，以及iii)与“时差”(光的提前6小时)同步 周期)，AgRP神经元节律在8天内逐渐重新进入，与摄食、TB和 LMA。基于这一点和光遗传刺激的研究，我们提出了SCN，通过抑制一种干预 GABA能神经元激活(去抑制)AgRP神经元，从而引起摄食的昼夜节律控制。 目的2：研究AgRP神经元与HPA轴之间的相互作用。为了实现这一目标，我们 研究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 皮质酮直接激活AgRP神经元是通过建立电生理的、转录的和 这种激活的表观基因组机制。此外，我们还确定了皮质酮是否激活了AgRP神经元 导致库欣综合症和慢性应激的代谢后果。第二，我们扩大了 AgRP神经元通过确定它们在驱动HPA轴中的作用而导致基于大脑的禁食适应。 我们已经发现AgRP神经元能够有效地激活PVHCrh神经元和HPA轴，我们提出 这是通过抑制连接AgRP神经元和PVH-CRH神经元的GABA能“网关”神经元来实现的。 最后，连接目标1和2，我们同时评估了AgRP和PVH-CRH神经元的节律，以及 研究SCN对AgRP神经元的调节是否驱动HPA轴的昼夜节律控制，或者相反。