The Role of Glutamate in the Control of Food Intake

描述(由申请者提供)：胃肠道(GI)向大脑告知进餐期间食物的摄入量和质量。因此，GI信号驱动饱腹感，并对控制食物摄入量具有开创性意义，无论启动它的条件如何。这种应用或更新延续了人们对神经机制的持久兴趣，通过这种机制，饱腹感信号被传递到孤束核(NTS)的后脑核，并与其他食物摄取控制相结合。谷氨酸是孤束核迷走神经传入终末释放的主要神经递质。因此，NTS中的谷氨酸受体在迷走神经饱足信号的传递和处理中起着关键作用。我们先前的研究表明，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拮抗剂延迟终止进食依赖于NTS内完整的迷走神经传入终末。最后，CCK诱导的MAPK信号转导需要激活NTS中的NMDAR，从而导致典型的胃肠道饱满肽CCK(CCK)减少摄食量。然而，我们仍然对NMDAR导致CCK诱导的食物摄入量减少的具体机制一无所知。因此，这项应用的一个目的是使用多种体内和体外准备来检验嵌套假设，即CCK减少摄食需要依赖NMDAR激活NTS迷走神经传入终末的MAPK信号；MAPK信号导致pERK1/2介导的突触蛋白1在迷走神经传入终末的磷酸化；并导致NTS迷走神经传入突触功能增强，从而减少摄食量。其他研究人员已经报道，后脑黑素皮质素受体激活(MC4R)有助于CCK诱导的后脑MAPK信号和食物摄入量的减少。结合我们的研究结果，NTS NMDAR的激活对于减少CCK的摄食是必要的，这表明NTS MC4R和NMDAR在控制摄食量方面存在重要的相互作用。因此，这项应用的第二个目标是建立NTS NMDAR和MC4R之间的基本关系，使两者都对CCK诱导的食物摄入量减少至关重要。具体地说，我们将应用药理学和免疫化学方法来确定NTS NMDAR的激活是在NTS MC4R的功能上游还是在NTS MC4R的下游控制CCK的摄食。此外，我们还将评估NTS NMDAR通过NTS内源性MC4R配体参与控制摄食的可能性，从而可能参与黑素皮质素能控制摄食与迷走神经传入激活的整合。我们的 长期目标是确定NMDAR的独特性质如何有助于饱腹感的过程，以及将GI饱腹感信号与其他食物摄入量控制相结合。详细了解NTS NMDAR对控制食物摄入量的贡献对人类健康具有重要意义，因为它可能为饮食失调和肥胖的治疗干预提供途径。

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.