The Role of Glutamate in the Control of Food Intake

谷氨酸在控制食物摄入量中的作用

• 批准号: 8492068
• 负责人: Robert C Ritter
• 金额: $ 31.21万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492068
• 关键词: Afferent Neurons; Agonist; Area; Attenuated; Behavioral; Brain; Cholecystokinin; Coupling; Data; Development; Eating; Eating Disorders; Endocrine; Esthesia; Event; Excitatory Amino Acid Antagonists; Extracellular Signal Regulated Kinases; Fiber; Frequencies; Gastrointestinal tract structure; Glutamate Receptor; Glutamates; Goals; Health; Human; Hypothalamic structure; Injection of therapeutic agent; Intervention; Investigation; Lead; Ligands; Link; MAP Kinase Gene; MAPK3 gene; Mediating; Melanocortin 4 Receptor; Methods; Modification; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Nucleus solitarius; Obesity; Pathogenesis; Peptides; Phosphorylation; Play; Preparation; Process; Progress Reports; Property; Protein Kinase; Receptor Activation; Reporting; Research Personnel; Role; Satiation; Seminal; Signal Transduction; Site; Source; Synapses; Synapsins; Synaptic Transmission; Synaptic Vesicles; System; Testing; Therapeutic Intervention; Time; U-0126; Work; computerized data processing; feeding; food quality; gastrointestinal; hindbrain; in vivo; insight; interest; melanocortin receptor; neuromechanism; neurotransmitter release; prevent; receptor; receptor function; relating to nervous system; response; synaptic function; transmission process

DESCRIPTION (provided by applicant): The gastrointestinal (GI) tract informs the brain of the quantity and quality of food consumed during meals. Hence, GI signals drive satiation, and are seminal to control of food intake, regardless of the conditions that initiate it. This application or renewal continues an enduring interest in neural mechanisms by which satiation signals are communicated to the hindbrain nucleus of the solitary tract (NTS) and integrated with other controls of food intake. Glutamate is the principal neurotransmitter released by vagal afferent terminals in the NTS. As such, glutamate receptors in the NTS are pivotal to the transmission and processing of vagal satiation signals. Our prior investigations revealed that activation of NMDA-type glutamate receptors in the NTS participate in control of meal size. Moreover, delay of meal termination by NTS injection of NMDAr antagonists depends on intact vagal afferent terminals in the NTS. Finally, activation NMDAr in the NTS is required for CCK-evoked MAPK signaling and consequent reduction of food intake by cholecystokinin (CCK), the archetypical GI satiation peptide. Nevertheless, we remain ignorant of the specific mechanisms by which NMDAr enable CCK- induced reduction of food intake. Therefore, one aim of this application is to use multiple in vivo and ex vivo preparations to test the nested hypotheses that reduction of food intake by CCK requires NMDAr-dependent activation of MAPK signaling in vagal afferent terminals in the NTS; that MAPK signaling results in pERK1/2- mediated phosphorylation of synapsin 1 in vagal afferent terminals; and leads to strengthened vagal afferent synaptic function in the NTS with consequent reduction of food intake. Other investigators have reported that hindbrain melanocortin receptor activation (MC4r) contributes to CCK-evoked MAPK signaling in the hindbrain and reduction of food intake. This report, taken together with our findings that NTS NMDAr activation is necessary for reduction of feeding by CCK, suggests an important interaction between NTS MC4r and NMDAr in control of food intake. Therefore, the second aim of this application is to establish a basic relationship between NTS NMDAr and MC4r that makes both crucial for CCK-induced reduction of food intake. Specifically we will apply pharmacological and immunochemical methods to determine whether NTS NMDAr activation is functionally upstream or downstream of NTS MC4r in control of food intake by CCK. In addition we will assess the possibility that NTS NMDAr participate in control of food intake by endogenous MC4r ligands in the NTS, and thereby may participate in the integration of melanocortinergic controls of food intake with those arising from vagal afferent activation. Our long-term goal is to determine how the unique properties of NMDAr contribute to the process of satiation and integration of GI satiation signals with other controls of food intake. Detailed appreciation of NTS NMDAr contributions to control of food intake is of significance to human health because it may provide avenues for therapeutic intervention in eating disorders and obesity.

描述（由申请人提供）：胃肠道（GI）告知大脑在进餐时消耗的食物的数量和质量。因此，GI信号驱动饱食，是种子控制的食物摄入量，无论启动it. This应用程序或更新的条件下继续持久的兴趣，饱足信号被传达到后脑孤束核（NTS）的神经机制，并与其他控制的食物摄入量集成。谷氨酸是NTS迷走神经传入终末释放的主要神经递质。因此，NTS中的谷氨酸受体对于迷走神经饱足信号的传递和处理是关键的。我们以前的研究表明，激活NMDA型谷氨酸受体在NTS参与控制膳食的大小。此外，延迟终止进食NTS注射NMDAr拮抗剂依赖于完整的迷走神经传入末梢在NTS。最后，NTS中的NMDAr活化是CCK诱发的MAPK信号传导和随后的缩胆囊素（CCK）（原型GI饱足肽）减少食物摄入所必需的。然而，我们仍然不知道NMDAr使CCK诱导的摄食量减少的具体机制。因此，本申请的一个目的是使用多种体内和离体制备物来测试嵌套的假设，即通过CCK减少食物摄入需要NTS中迷走神经传入末端中MAPK信号传导的NMDAr依赖性激活; MAPK信号传导导致迷走神经传入末端中pERK 1/2介导的突触蛋白1磷酸化;并导致NTS中迷走神经传入突触功能增强，从而减少食物摄入。其他研究者报道，后脑黑皮质素受体激活（MC 4 r）有助于CCK诱发的MAPK信号在后脑和减少食物摄入。这份报告，结合我们的研究结果，NTS NMDAr激活是必要的，减少喂养CCK，表明一个重要的相互作用NTS MC 4 r和NMDAr在控制食物摄入量。因此，本申请的第二个目的是建立NTS NMDAr和MC 4 r之间的基本关系，使两者对CCK诱导的食物摄入减少至关重要。具体来说，我们将应用药理学和免疫化学方法，以确定是否NTS NMDAr激活的功能上游或下游的NTS MC 4 r在控制食物摄入的CCK。此外，我们将评估的可能性，NTS NMDAr参与控制的食物摄入量的内源性MC 4 r配体在NTS，从而可能参与整合黑皮质素能控制的食物摄入量与迷走神经传入激活所产生的。我们 长期目标是确定NMDAr的独特性质如何促进饱足过程以及GI饱足信号与其他食物摄入控制的整合。详细了解NTS NMDAr对控制食物摄入的贡献对人类健康具有重要意义，因为它可能为进食障碍和肥胖症的治疗干预提供途径。