Role of Parabrachial Nucleus Neuropeptides in Feeding

臂旁核神经肽在进食中的作用

• 批准号: 7856882
• 负责人: JOHN-PAUL BAIRD
• 金额: $ 14.13万
• 依托单位: AMHERST COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7856882
• 关键词: Accounting; Affect; Agonist; Anorexia; Anosmia; Appetitive Behavior; Attention; Basic Science; Behavioral; Brain; Brain Stem; Bulimia; Cachexia; Cell Nucleus; Cerebral Ventricles; Clinical; Complex; Data Reporting; Diabetes Mellitus; Disease; Dorsal; Dysgeusia; Eating; Failure to Thrive; Feedback; Feeding behaviors; Future; Gastrointestinal tract structure; Gastroparesis; Goals; Health Care Costs; Heart Diseases; Hormones; Hypertension; Hypothalamic structure; Infusion procedures; Injection of therapeutic agent; Insulin; Leptin; Ligands; Link; Location; Mediating; Mediation; Mediator of activation protein; Metabolic Diseases; Metabolism; Movement; Neurons; Neuropeptide Receptor; Neuropeptides; Neurophysiology - biologic function; Nucleus solitarius; Obesity; Oral; Output; Phase; Physiological; Play; Pontine structure; Process; Prosencephalon; Rattus; Reflux; Research; Resolution; Role; SHU 9119; Satiation; Sensory; Signal Transduction; Site; Stimulus; Stomach; Stroke; Structure; Structure of area postrema; System; Taste Perception; Techniques; Testing; Ventricular; Visceral; Visceral Afferents; behavior test; computerized data processing; density; dorsal motor nucleus; feeding; gastrointestinal; ghrelin; hindbrain; insight; melanocortin receptor; melanotan-II; neural circuit; neuropeptide Y; neurophysiology; obesity treatment; orexin A; orexin A receptor; parabrachial nucleus; public health relevance; receptor; relating to nervous system; research study; response; sensory stimulus; therapeutic target

DESCRIPTION (provided by applicant): Advances in obesity treatment may be provided by continued resolution of the neural circuits that mediate leptin, ghrelin, and insulin responses. Considerable recent research has detailed first and second order sites in hypothalamic regions that are sensitive to leptin, insulin, and ghrelin input. Forebrain neurons expressing neuropeptides throughout the brain are sensitive to these hormones and act as downstream mediators to influence feeding and metabolism. These neuropeptides, such as neuropeptide Y (NPY), and orexin-A (ORX), and pro- opioimelanocortin products (MC), act or have receptors in forebrain and hindbrain locations. An important goal for future research is to determine how such neuropeptides function in brainstem nuclei and to determine how these nuclei interact with forebrain nuclei (e.g., hypothalamus) that are sensitive to leptin, ghrelin, and insulin. This proposal will continue to evaluate the effects of NPY, MC, and ORX receptor ligands on feeding and electrophysiological taste and visceral responses in the pontine parabrachial nucleus (PBN), a brainstem nucleus that receives significantly overlapping taste and visceral afferent inputs, receives direct NPY, MC, and ORX input from the hypothalamus, and sends output to brainstem nuclei controlling oral movement. The first experiments assess the effects of direct PBN microinjectons of NPY, MC, and ORX receptor antagonists on feeding microstructure. The following experiments assess the effects of NPY, MC, and ORX receptor antagonists on neural PBN gustatory and gastric distension responses when NPY, MC, and ORX agonists are applied to brain ventricles or their antagonists are microinjected directly around PBN neurons. If direct PBN application of NPY, MC, or ORX receptor ligands affect feeding, this should be observed at the neurophysiological level and will serve to better clarify the functional role(s) of hypothalamic neuropeptides in the brainstem. PUBLIC HEALTH RELEVANCE Feeding and metabolic disorders such as obesity, anorexia, bulimia, failure to thrive, gastric reflux, cachexia, early satiety, delayed gastric emptying, dysgeusia, and anosmia contribute to diseases including hypertension, stroke, diabetes, and heart disease, and they account for many health-care costs. Elucidating the neural systems that control feeding is, therefore, a fundamental goal for clinical as well as basic science. This proposal will continue to explore the role of the brainstem as a site of feeding-related hypothalamic neuropeptide action and thus contribute to basic research that could help to identify potential pharmacological therapeutic targets.

描述（由申请人提供）：肥胖治疗的进展可以通过介导瘦素、生长素释放肽和胰岛素反应的神经回路的持续解决来实现。最近的大量研究详细介绍了下丘脑区域对瘦素、胰岛素和生长素释放肽输入敏感的一级和二级位点。在整个大脑中表达神经肽的前脑神经元对这些激素敏感，并充当影响摄食和新陈代谢的下游介质。这些神经肽，例如神经肽 Y (NPY) 和食欲素-A (ORX) 以及阿片黑皮质素原产物 (MC)，在前脑和后脑位置发挥作用或具有受体。未来研究的一个重要目标是确定此类神经肽如何在脑干核中发挥作用，并确定这些核如何与对瘦素、生长素释放肽和胰岛素敏感的前脑核（例如下丘脑）相互作用。该提案将继续评估 NPY、MC 和 ORX 受体配体对脑桥臂旁核 (PBN) 的摄食、电生理味觉和内脏反应的影响，PBN 是一个脑干核，接收明显重叠的味觉和内脏传入输入，接收来自下丘脑的直接 NPY、MC 和 ORX 输入，并将输出发送到脑干核 控制口腔运动。第一个实验评估了直接 PBN 显微注射 NPY、MC 和 ORX 受体拮抗剂对摄食微观结构的影响。以下实验评估了当 NPY、MC 和 ORX 激动剂应用于脑室或将其拮抗剂直接显微注射在 PBN 神经元周围时，NPY、MC 和 ORX 受体拮抗剂对神经 PBN 味觉和胃扩张反应的影响。如果直接 PBN 应用 NPY、MC 或 ORX 受体配体影响进食，则应在神经生理学水平上进行观察，这将有助于更好地阐明下丘脑神经肽在脑干中的功能作用。公共卫生相关性 肥胖、厌食、贪食症、发育迟缓、胃反流、恶病质、早饱感、胃排空延迟、味觉障碍和嗅觉丧失等进食和代谢紊乱会导致高血压、中风、糖尿病和心脏病等疾病，并造成许多医疗保健费用。因此，阐明控制进食的神经系统是临床和基础科学的基本目标。该提案将继续探索脑干作为与进食相关的下丘脑神经肽作用部位的作用，从而有助于基础研究，有助于确定潜在的药理学治疗靶点。