The Role of Glutamate in the Control of Food Intake

描述（由申请人提供）：胃肠道（GI）告知大脑在用餐时所摄入食物的数量和质量。因此，GI信号驱动饱腹感，并对控制食物摄入至关重要，而不管触发它的条件是什么。这种应用或更新继续了对神经机制的长期兴趣，通过该机制，饱足信号被传递到孤立束（NTS）的后脑核，并与其他食物摄入控制相结合。谷氨酸是迷走神经传入末梢在NTS中释放的主要神经递质。因此，NTS中的谷氨酸受体对迷走神经饱足信号的传递和处理至关重要。我们之前的研究表明，NTS中nmda型谷氨酸受体的激活参与了对食物大小的控制。此外，NTS注射NMDAr拮抗剂延迟进食终止取决于NTS中完整的迷走神经传入终端。最后，NMDAr在NTS中的激活是CCK诱发的MAPK信号和随后的胆囊收缩素（CCK）的食物摄入减少所必需的，CCK是典型的GI饱足肽。然而，我们仍然不了解NMDAr使CCK诱导的食物摄入减少的具体机制。因此，本应用程序的一个目的是使用多种体内和体外制剂来测试嵌套假设，即CCK减少食物摄入需要nmdar依赖的迷走神经传入终端MAPK信号的激活；MAPK信号导致迷走神经传入末端的pERK1/2介导的突触蛋白1磷酸化；并导致NTS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素皮质素受体激活（MC4r）有助于cck在后脑诱发MAPK信号和减少食物摄入量。该报告和我们的研究结果表明，NTS NMDAr的激活对于减少CCK的摄食是必要的，这表明NTS MC4r和NMDAr在控制食物摄入方面存在重要的相互作用。因此，本应用的第二个目的是建立NTS NMDAr和MC4r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来确定NTS NMDAr激活在CCK控制食物摄入的NTS MC4r功能上是上游还是下游。此外，我们将评估NTS NMDAr参与NTS内源性MC4r配体对食物摄入的控制的可能性，从而可能参与黑素皮质能对食物摄入的控制与迷走神经传入激活引起的控制的整合。我们的

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.