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: 10116601
• 负责人: BRADFORD B LOWELL
• 金额: $ 60.73万
• 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/10116601
• 关键词: Address; Adrenal Glands; Automobile Driving; Base of the Brain; 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; Interneurons; Jet Lag Syndrome; Light; Link; Metabolic; Metabolic Diseases; Mind; Monitor; Motivation; Motor Activity; Mus; Neurons; Outcome; Phase; Physiological; Pituitary Gland; Play; Process; Regulation; Reporting; Role; Schedule; Sensory; Signal Transduction; Stress; System; Time; Work; base; circadian; circadian regulation; egg; energy balance; epigenomics; falls; feeding; follow-up; in vivo; increased appetite; inhibitory neuron; insight; mental state; neural circuit; optogenetics; prevent; relating to nervous system; 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：昼夜节律和与HPA轴的相互作用 AGRP神经元起驱动喂养的关键作用。它们通过报告低能的反馈信号激活 商店及其激活促进了食物的寻求和进食。值得注意的是，它们也受 预见未来需求和结果的进餐线索。 AGRP神经元的核心作用进一步 他们有能力引起许多自适应生理反应对禁食的能力。鉴于至高无上 在AGRP神经元中，重要的是要了解它们的监管方式，他们控制的过程以及 他们如何实现这样的控制。考虑到这一点，该赠款追求以下两个目标： 目标1：研究AGRP神经元和喂养的SCN /昼夜节律喂食。在这个目标中，我们 通过确定SCN是否接合AGRP神经元来扩展预期调节的概念 主动安排日常进食并防止未来的能源缺陷。虽然众所周知喂养不在 昼夜节律的控制很重要，因为错位的喂养会导致疾病，这是完全未知的 昼夜节系统如何做到这一点。为了研究AGRP神经元的SCN控制，我们已经开发了 多天在体内连续监测AGRP神经元活性的独特能力，同时 监测进食，体温（TB），运动活性（LMA）和其他神经元中的节奏。使用 这种方法，我们发现：i）AGRP神经元活性以24小时的周期振荡（以后达到峰值 白天，晚上晚些时候）在光明/黑暗和恒定的黑暗条件下，ii）达到顶峰 AGRP神经元的活性是SCN神经元的同相，iii）具有“喷射滞后”（光线的6小时进步 循环），AGRP神经元节律与喂养，结核病和 LMA。基于此和光遗传刺激研究，我们建议SCN通过抑制中间 GABA能神经元，激活（抑制）AGRP神经元，这会导致昼夜节律对喂养的控制。 目标2：研究AGRP神经元与HPA轴之间的相互相互作用。在这个目标中，我们 检查AGRP神经元与HPA轴之间的相互相互作用。首先，我们跟进发现 皮质酮直接通过建立电生理，转录和 这种激活的表观基因组机制。另外，我们确定皮质酮激活AGRP神经元是否激活 导致库欣综合征和慢性压力的代谢后果。其次，我们扩展了 AGRP神经元通过确定驱动HPA轴的作用来引起大脑的适应性。 我们发现AGRP神经元可能激活PVHCRH神经元和HPA轴，我们建议 他们通过抑制将AGRP神经元与PVH-CRH神经元联系起来的GABA能“网关”神经元来做到这一点。 最后，链接目标1和2，我们只是评估AGRP和PVH-CRH神经元中的节奏，以及 研究AGRP神经元的SCN调节是否驱动昼夜节律对HPA轴的控制，反之亦然。