Dissecting the role of neural inputs in the regulation of AgRP neurons

剖析神经输入在 AgRP 神经元调节中的作用

• 批准号: 10520038
• 负责人: Tara J Aitken
• 金额: $ 4.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10520038
• 关键词: Ablation; Address; Anorexia; Blood - brain barrier anatomy; Brain; Calcium; Cells; Cues; Detection; Disease; Eating; Fasting; Feeding behaviors; Food; Food Intake Regulation; Gastrointestinal tract structure; Glutamates; Hormones; Hypothalamic structure; Image; Leptin; Life; Mediating; Mus; Neurons; Nutrient; Nutritional; Obesity; Pathway interactions; Peptides; Population; Process; Regulation; Role; Satiation; Sensory; Signal Transduction; Smell Perception; Source; Starvation; Stream; Structure of nucleus infundibularis hypothalami; Synapses; Testing; Time; Vision; Work; cellular imaging; experimental study; feeding; food consumption; gastrointestinal system; in vivo; in vivo imaging; leptin receptor; nerve supply; neural; neuroregulation; optogenetics; paraventricular nucleus; pituitary adenylate cyclase activating polypeptide; prevent; response; sensory stimulus

Project Abstract: Proper regulation of food intake is essential for survival to prevent over- or under-feeding. Sensory signals generated by the detection and consumption of food can modulate food intake. External sensory cues such as the sight and smell of food and food cues can potentiate feeding, while internal sensory information from nutrients and distension in the gastrointestinal tract can inhibit feeding. Yet how the brain integrates these two streams of information to modulate feeding behavior is unclear. Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC) are a useful entry point into this question. ARCAgRP neurons are both necessary and sufficient for feeding behavior, and they have been shown to integrate these two types of sensory signals across two different time scales: rapid inhibition in response to the sight and smell of food, and slower inhibition during intragastric delivery of food. However, the sources of these signals that modulate ARCAgRP activity in response to sensory information are poorly understood. I propose here to address this question by systematically testing two known neural inputs to ARCAgRP neurons: 1. Pituitary adenylate-cyclase activating peptide expressing neurons in the paraventricular nucleus of the hypothalamus (PVHPACAP), and 2. Leptin receptor expressing neurons in the dorsomedial hypothalamus (DMHLepR). I will examine the exact types of information each of these inputs represents, as well as the necessity of two of these inputs in modulating AgRP neurons in response to sensory information. Additionally, I will investigate a potential mechanism by which nutritional state alters the response of DMHLepR neurons to food presentation. Together these results would reveal how a critical neural feeding center is regulated, as well as illuminate potential mechanisms by which sensory signal integration could become disrupted in maladaptive feeding behaviors such as obesity.

项目摘要： 适当调节食物摄入量对于生存至关重要，可以防止喂食过多或不足。感觉信号 通过检测和消耗食物产生的能量可以调节食物摄入量。外部感官线索，例如 食物的视觉和气味以及食物线索可以增强进食，而来自内部的感官信息 营养物质和胃肠道扩张会抑制进食。然而大脑如何整合这两者 调节进食行为的信息流尚不清楚。刺鼠相关肽（AgRP）神经元 下丘脑弓状核（ARC）是解决这个问题的一个有用的切入点。 ARCAgRP 神经元是 对于进食行为来说既是必要的又是充分的，并且它们已被证明可以整合这两种类型 跨越两个不同时间尺度的感觉信号：对食物的视觉和气味的快速抑制反应，以及 胃内输送食物时抑制较慢。然而，这些调制信号的来源 人们对 ARCAgRP 响应感官信息的活动知之甚少。我在这里建议解决这个问题 通过系统测试 ARCAgRP 神经元的两个已知神经输入来回答这个问题： 1. 垂体腺苷酸环化酶 激活下丘脑室旁核神经元表达肽 (PVHPACAP)，以及 2. 下丘脑背内侧表达瘦素受体的神经元 (DMHLepR)。我将检查确切的类型 每个输入代表的信息，以及其中两个输入在调制中的必要性 AgRP 神经元对感觉信息作出反应。此外，我将通过以下方式研究潜在的机制 哪种营养状态会改变 DMHLepR 神经元对食物呈现的反应。综合这些结果 将揭示关键的神经喂养中心是如何调节的，并阐明潜在的机制 在肥胖等适应不良的进食行为中，感觉信号整合可能会受到干扰。