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，以防止过度或不足。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，如 食物的视觉和嗅觉以及食物线索可以加强进食，而来自食物的内部感官信息 胃肠道中的营养和膨胀可抑制进食。然而大脑是如何将这两者整合在一起的 调节摄食行为的信息流尚不清楚。Agouti-related peptide（AgRP）neurons 下丘脑弓状核（ARC）是这个问题的一个有用的切入点。ARCAgRP神经元是 这两种行为都是必要的，也是足够的，而且它们已经被证明可以整合这两种类型的行为。 在两个不同的时间尺度上的感觉信号：对食物的视觉和嗅觉的快速抑制， 胃内食物输送过程中抑制较慢。然而，这些信号的来源， 对ARCAgRP响应于感觉信息的活性知之甚少。我在此提议解决这一问题 问题通过系统地测试两个已知的神经输入ARCAgRP神经元：1。腺苷酸环化酶 激活下丘脑室旁核（PVHPACAP）中的肽表达神经元，和2. 下丘脑背内侧区瘦素受体表达神经元（DMHLepR）。我会检查 这些输入中的每一个代表的信息，以及这些输入中的两个在调制中的必要性。 AgRP神经元对感觉信息的反应。此外，我将研究一个潜在的机制， 这种营养状态改变了DMHLepR神经元对食物呈递的反应。这些结果一起 将揭示一个关键的神经摄食中心是如何调节的，并阐明潜在的机制， 这种感觉信号整合可能在适应不良的进食行为如肥胖中被破坏。