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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

基本信息

批准号：
10461101
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
项目类别：
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/10461101
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

项目摘要

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：昼夜节律控制和与HPA轴的相互作用