SUBCORTICAL MODULATION OF THE DORSAL VAGAL COMPLEX

背侧迷走神经复合体的皮层下调节

• 批准号: 2763507
• 负责人: WILLIAM E RENEHAN
• 金额: $ 20.35万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2763507
• 关键词: amygdala; appetite regulatory center; bombesin like peptide; corticotropin releasing factor; electrophysiology; endogenous opioid; galanin; gamma aminobutyrate; gastrointestinal absorption /transport; hypothalamus; incretin hormone; laboratory rat; microinjections; neural transmission; neurons; neuropeptide Y; neurophysiology; nutrient intake activity; oxytocin; prosencephalon; satiations; vagus nerve

DESCRIPTION (applicant's abstract): Disorders of appetite and feeding (including anorexia nervosa and bulimia nervosa) can have a profound impact on the quality of life and may even contribute to or cause death. Recent data indicate that certain forebrain structures, such as the hypothalamus and amygdala, play a particularly important role in feeding behavior. Unfortunately, while it is clear that these forebrain regions are important in the regulation of feeding, we know very little about the mechanism(s) of this regulation. Our preliminary studies, however, indicate that the hypothalamus and the amygdala have the ability to dramatically modify the response properties of neurons in the dorsal vagal complex. Increased or decreased activity in these descending pathways to the dorsal vagal complex has the potential to alter ascending satiety signals, modulate the cephalic phase of feeding and affect the absorption of nutrients from the gastrointestinal tract. Our data suggest that most gut-sensitive neurons in the nucleus of the solitary tract (NST) are inhibited by electrical stimulation of the paraventricular nucleus of the hypothalamus (PVN). We postulate that the NST neurons that are inhibited by the PVN will exhibit this response when the PVN is injected with neuropeptide Y (NPY) and/or galanin (GAL), with this influence mediated by the release of GAL from GAL-positive PVN neurons that terminate in the NST. We propose that the subset of NST neurons that is excited by the PVN will exhibit this response when the PVN is injected with corticotropin releasing hormone (CRH) and/or glucagon-like peptide-1 (GLP-1) and hypothesize that the excitatory influence of the PVN on the NST is mediated by bombesin-like peptides (BN-LP). Our data indicate that most of the NST neurons that respond to stimulation of the central nucleus of the amygdala (Ce) are inhibited by this input and we propose that these NST neurons will exhibit this response when the Ce is injected with GAL. We will demonstrate whether the Ce's inhibition of the NST is mediated by gamma-aminobutyric acid (GABA) and/or endogenous opioids. Finally, we will examine the response properties of gastric- and intestine-sensitive DMNV neurons that are modulated by descending inputs from the PVN. Our preliminary data indicate that the PVN inputs to the DMNV are primarily excitatory. We postulate that the DMNV neurons that are excited by the PVN will exhibit this response when the PVN is injected with NPY and/or GAL, an effect that we believe is mediated by oxytocin (OT). We will test these hypotheses with three Specific Aims that will employ a combination of extracellular and intracellular recording, intracellular labeling, microinjection of four peptides into the forebrain and picospritzer injection of multiple receptor agonists and antagonists in the dorsal vagal complex. Our goal is to provide data that will contribute to our understanding of the mechanisms underlying feeding behavior as well as form a foundation for future behavioral and pharmacological studies designed to ameliorate the devastating effects of feeding disorders.

描述（申请人的摘要）： 食欲和进食障碍（包括神经性厌食症和 神经性贪食症）会对生活质量产生深远的影响 甚至可能导致或导致死亡。最近的数据表明，某些 前脑结构，例如下丘脑和杏仁核，起着 在进食行为中发挥着特别重要的作用。不幸的是，虽然 很明显，这些前脑区域在调节中很重要 关于喂养，我们对其机制知之甚少 规定。然而，我们的初步研究表明 下丘脑和杏仁核有能力显着改变 背侧迷走神经复合体中神经元的反应特性。 这些下行通路的活性增加或减少 背侧迷走神经复合体有可能改变上升的饱腹感 信号，调节喂养的头相并影响 从胃肠道吸收营养。我们的数据 表明大多数肠道敏感神经元位于孤立神经元的核中 束（NST）受到电刺激的抑制 下丘脑室旁核（PVN）。我们假设 被 PVN 抑制的 NST 神经元将表现出这种反应 当PVN注射神经肽Y（NPY）和/或甘丙肽（GAL）时， 这种影响是由 GAL 阳性 PVN 释放 GAL 介导的 终止于 NST 的神经元。我们建议 NST 的子集 当PVN兴奋的神经元会表现出这种反应 PVN 注射促肾上腺皮质激素释放激素 (CRH) 和/或 胰高血糖素样肽-1 (GLP-1) 并假设兴奋性 PVN 对 NST 的影响是由铃蟾肽样肽介导的 （BN-LP）。我们的数据表明大多数 NST 神经元对 杏仁核中央核 (Ce) 的刺激受到抑制 通过这个输入，我们建议这些 NST 神经元将表现出这个 当 Ce 注入 GAL 时的响应。我们将证明是否 Ce 对 NST 的抑制是由 γ-氨基丁酸介导的 （GABA）和/或内源性阿片类药物。最后，我们将检查响应 胃和肠敏感 DMNV 神经元的特性 由来自 PVN 的下降输入进行调制。我们的初步数据 表明 PVN 对 DMNV 的输入主要是兴奋性的。我们 假设由 PVN 兴奋的 DMNV 神经元将表现出 当 PVN 注射 NPY 和/或 GAL 时会出现这种反应，这是一种效果 我们认为这是由催产素（OT）介导的。我们将测试这些 具有三个具体目标的假设将结合使用 细胞外和细胞内记录、细胞内标记、 将四种肽显微注射到前脑和 picospritzer 在背侧注射多种受体激动剂和拮抗剂 迷走神经复合体。我们的目标是提供有助于我们的数据 了解进食行为的潜在机制以及 为未来的行为和药理学研究奠定基础 旨在减轻喂养障碍的破坏性影响。