The Role of Glutamate in the Control of Food Intake

描述（由申请人提供）：膳食大小是总食物摄入量和能量平衡的主要决定因素。在大鼠和人类中，增加食量与正能量平衡和肥胖的发展有关。几乎所有主要的公共卫生组织都认为肥胖是导致发病率和死亡率的一个主要因素。了解饱腹感发生和食量控制的神经机制对解剖肥胖的病理生理学具有重要意义。来自胃肠道的机械、化学和内分泌信号参与了进食终止和进餐大小的决定。这些胃肠道信号通过迷走神经的传入神经元传递到后脑。因此，迷走神经向大脑提供生物体营养状况的信息，甚至在营养吸收发生之前。氨基酸谷氨酸是迷走神经传入神经元的主要神经递质。尽管迷走神经和后脑谷氨酸受体对迷走神经传递具有重要意义，但它们在控制食物摄入中的作用却很少被研究。然而，我们证明全身注射nmda型谷氨酸受体拮抗剂或后脑注射nmda型谷氨酸受体拮抗剂会增加进食量。这种食量的增加需要完整的中枢迷走神经传入过程。当前应用程序的目标是1。通过手术或神经毒性破坏迷走神经传入神经来确定参与NMDA受体介导的迷走神经和后脑对食物摄入的控制的特定亚群。2 .采用生理操作，结合药理学和免疫组织化学方法，确定后脑NMDA受体是否通过胃信号特异性调节食物摄入抑制；利用近动脉应用NMDA激动剂和拮抗剂胃肠道来确定外周迷走神经传入元件上的谷氨酸受体是否参与控制食物摄入。控制饭量是总热量摄入和能量平衡的主要决定因素。迷走神经直接将胃肠道信息传递给大脑，它控制着食物的大小。本项目旨在确定nmda型谷氨酸受体在迷走神经对食物大小的控制中的作用。

DESCRIPTION (provided by applicant): Meal size is a major determinant of total food intake and energy balance. Increased meal size is associated with positive energy balance and development of obesity in in rats and humans. Obesity has been identified as a major contributor to morbidity and mortality by virtually all major public health organizations. Understanding the neural mechanisms through which satiation occurs and meal size is controlled is seminal to the dissecting the pathophysiology of obesity. Mechanical, chemical and endocrine signals originating from the gastrointestinal tract contribute to meal termination and determination of meal size. These gastrointestinal signals are carried to the hindbrain by the afferent neurons of the vagus nerve. The vagus, therefore, provides the brain with information on the nutritional status of the organism, even before nutrient assimilation occurs. The amino acid, glutamate, is the principal neurotransmitter of vagal afferent neurons. In spite of its importance to vagal neurotransmission, the contribution of vagal and hindbrain glutamate receptors in the control of food intake is little investigated. However, we demonstrated that injection of antagonists of NMDA-type glutamate receptor antagonists systemically or into the hindbrain increases meal size. This increase in meal size requires intact central vagal afferent processes. The aims of the current application are 1. to employ surgical or neurotoxic destruction of vagal afferents to identify the specific subpopulation(s) that participates in NMDA receptor-mediated control of food intake by the vagus nerve and hindbrain, 2. to use physiological manipulation, together with pharmacological and immunohistochemical methods to determine whether NMDA receptors in the hindbrain specifically modulate inhibition of food intake by gastric signals, and 3. to utilize near arterial application of NMDA agonists and antagonists to the gastrointestinal tract to determine whether glutamate receptors on peripheral vagal afferent elements participate in control food intake. Control of meal size is a principal determinant of total caloric intake and energy balance. The vagus nerve, which directly conveys gastrointestinal information to the brain controls meal size. This project aims to determine the role of NMDA-type glutamate receptors in the control of meal size by the vagus nerve.