SUBCORTICAL MODULATION OF THE DORSAL VAGAL COMPLEX

描述(申请人摘要)： 食欲和进食障碍(包括神经性厌食症和 神经性暴食症)会对生活质量和 甚至可能导致或导致死亡。最近的数据表明，某些 前脑结构，如下丘脑和杏仁核，发挥着 在进食行为中起着特别重要的作用。不幸的是，虽然 很明显，这些前脑区域在调节中起着重要作用。 关于摄食，我们对此的机制(S)知之甚少 监管。然而，我们的初步研究表明， 下丘脑和杏仁核具有戏剧性地改变 迷走神经背侧复合体神经元的反应特性。 这些下行通路中的活动增加或减少 迷走神经背侧复合体有可能改变上升性饱足感 信号调节摄食的头部阶段，并影响 从胃肠道吸收营养。我们的数据 提示孤束核中的大多数肠道敏感神经元 束(NST)受电刺激的抑制 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阳性的PVN释放GAL所介导的 终止于NST的神经元。我们提出NST的子集 由室旁核兴奋的神经元将表现出这种反应，当 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)与兴奋性 下丘脑室旁核对NST的影响是由蛙皮素样肽介导的 (BN-LP)。我们的数据表明，大多数NST神经元对 杏仁中央核(Ce)的刺激受到抑制 通过这一输入，我们认为这些NST神经元将表现出 当CE注射GAL时的反应。我们将演示是否 Ce对NST的抑制作用是由γ-氨基丁酸介导的 (GABA)和/或内源性阿片类药物。最后，我们将研究人们的反应 胃和肠敏感DMNV神经元的特性 由来自PVN的下行输入调制。我们的初步数据 说明DMNV的PVN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被注射NPY和/或GAL时，这种反应产生效果 我们认为这是由催产素(OT)介导的。我们将测试这些 具有三个特定目标的假设将采用以下组合 细胞外和细胞内记录，细胞内标记， 前脑内微量注射四种多肽及微刺法 背部注射多种受体激动剂和拮抗剂 迷走情结。我们的目标是提供数据，为我们的 理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 旨在减轻进食障碍的破坏性影响。

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.