The Role of Glutamate in the Control of Food Intake

摘要 这种更新的申请延续了人们对胃肠道神经机制的持久兴趣 (Gi)饱腹感信号通过迷走神经传递到孤束核(NTS) 并与食物摄入量的其他控制相结合。谷氨酸是主要的神经递质 由孤束核(NTS)的迷走神经传入终末释放。因此，谷氨酸受体在体内 NTS对于饱和信号的传输和处理是至关重要的。我们公布的结果， 后脑注射N-甲基-D-天冬氨酸型谷氨酸受体 拮抗剂增加进食量并防止由CCK引起的摄食量减少支持这一点 断言。虽然胃肠道刺激激活迷走神经传入可以减少进食，但中枢神经肽和 循环中的荷尔蒙也通过控制进食量来控制食物的摄入量，这表明它们可能调节或 模仿胃肠道刺激的效果。我们假设脑肽与NMDAR相互作用来控制食物的大小 通过调节孤束核内谷氨酸能迷走神经传入突触的强度。我们的初步结果 提示迷走神经传入NMDAR和黑素皮质素4受体(MC4R)的相互作用可触发长时间持续 迷走神经传入突触蛋白磷酸化的变化与迷走神经传入的增强一致 突触功能。AIM 1的实验利用药理、免疫化学、化学发生和 电生理学方法确定NMDAR参与迷走神经MC4R效应的性质 传入突触功能与进食大小控制。迷走神经传入表达1型和2型神经肽Y 受体(Y1R和Y2R)以及MC4R和NMDAR。我们发现NTS注射NPY或Y2R 激动剂PYY 3-36可增加摄食量，这种作用可被NTS联合注射SP-cAMP减弱。在……里面 应用目标2检验迷走神经传入通过拮抗Y2R控制摄食量的假设 MC4R对PKA激活、突触蛋白磷酸化和迷走神经传入突触强度的影响。我们的长- 术语目标是确定NMDAR如何参与迷走神经传入突触强度的调节以降低 食物摄入量。对多肽和激素相互作用的机制进行详细的评价 NMDAR控制食物摄入量对人类健康具有重要意义，因为它可能为 饮食失调和肥胖症的治疗干预。

ABSTRACT This application for renewal continues an enduring interest in neural mechanisms by which gastrointestinal (GI) satiation signals are communicated to the hindbrain nucleus of the solitary tract (NTS) by vagal afferents and are integrated with other controls of food intake. Glutamate is the principal neurotransmitter released by vagal afferent terminals in the nucleus tractus solitarius (NTS). As such, glutamate receptors in the NTS are pivotal to the transmission and processing of satiation signals. Our published results, demonstrating that hindbrain injections of N-methyl-D-aspartate-type glutamate receptor (NMDAR) antagonists increase meal size and prevent reduction of food intake by cholecystokinin (CCK) support this assertion. Although vagal afferent activation by GI stimuli reduce meal size, central neuropeptides and circulating hormones also control food intake by controlling meal size, suggesting that they may modulate or imitate the effects of GI stimuli. We postulate that brain peptides interact with NMDAR to control meal size by modulating the strength of glutamatergic vagal afferent synapses in the NTS. Our preliminary results suggest that interaction of vagal afferent NMDAR and melanocortin 4 receptors (MC4R) triggers long-lasting changes in vagal afferent synapsin phosphorylation that are consistent with strengthened vagal afferent synaptic function. Experiments of Aim 1 utilize pharmacological, immunochemical, chemogenetic and electrophysiological approaches to determine the nature of NMDAR participation in MC4R effects on vagal afferent synaptic function and control of meal size. Vagal afferents express type 1 and type 2 NPY receptors (Y1R and Y2R) as well as MC4R and NMDAR. We find that NTS injection of NPY or the Y2R agonist, PYY 3-36, increases food intake, an effect that is attenuated by NTS co-injection of SP-cAMP. In Aim 2 of the application we test the hypothesis that vagal afferent Y2R control food intake by antagonizing MC4R effects on PKA activation, synapsin phosphorylation and vagal afferent synaptic strength. Our long- term goal is to determine how NMDAR participate in modulation of vagal afferent synaptic strength to reduce food intake. A detailed appreciation of the mechanisms by which peptides and hormone interact with NMDAR to control of food intake is of significance to human health because it may provide avenues for therapeutic intervention in eating disorders and obesity.