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，增加膳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主要因素。了解饱腹感发生和控制膳食量的神经机制对于剖析肥胖的病理生理学是至关重要的。源自胃肠道的机械、化学和内分泌信号有助于进餐终止和进餐量的确定。这些胃肠信号通过迷走神经的传入神经元传递到后脑。因此，甚至在营养同化发生之前，迷走神经就向大脑提供有关生物体营养状况的信息。谷氨酸是迷走神经传入神经元的主要神经递质。尽管它对迷走神经传递的重要性，迷走神经和后脑谷氨酸受体在控制食物摄入中的作用却很少研究。然而，我们证明了全身注射NMDA型谷氨酸受体拮抗剂或注射到后脑增加了膳食量。这种进食量的增加需要完整的中央迷走神经传入过程。本申请的目的是1.采用迷走神经传入的手术或神经毒性破坏来鉴定参与NMDA受体介导的迷走神经和后脑对食物摄取的控制的特定亚群，2.使用生理操作，连同药理学和免疫组织化学方法，以确定是否在后脑NMDA受体特异性调节胃信号抑制食物摄入，和3。利用NMDA激动剂和拮抗剂对胃肠道的近动脉应用，以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。控制膳食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的信息传递给大脑，它控制着进食量。本项目旨在确定NMDA型谷氨酸受体在迷走神经控制膳食量中的作用。

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.