The Role of Glutamate in the Control of Food Intake

摘要 这一申请延续了对胃肠动力学的神经机制的持久兴趣。 (GI)饱足信号通过迷走神经传入孤束核（NTS）， 传入，并与其他控制食物摄入。谷氨酸是主要的神经递质 由孤束核（NTS）中的迷走传入终末释放。因此， NTS是饱足信号传输和处理的关键。我们公布的结果， 这表明，后脑注射N-甲基-D-天冬氨酸型谷氨酸受体（NMDAR） 拮抗剂增加膳食量和防止胆囊收缩素（CCK）减少食物摄入支持这一点 断言。虽然胃肠道刺激引起的迷走神经传入激活减少了进食量，但中枢神经肽和 循环激素也通过控制膳食量来控制食物摄入，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相互作用以控制膳食量 通过调节孤束核中的交感神经能迷走神经传入突触的强度。我们的初步结果 表明迷走神经传入NMDAR和黑皮质素4受体（MC 4 R）相互作用触发了持久的 迷走神经传入突触蛋白磷酸化的变化与迷走神经传入增强一致 突触功能目的1的实验利用药理学、免疫化学、化学遗传学和生物化学。 电生理学方法来确定NMDAR参与MC 4 R对迷走神经的作用的性质 传入突触功能和膳食量的控制。迷走神经传入纤维表达1型和2型NPY 受体（Y1 R和Y2 R）以及MC 4 R和NMDAR。我们发现孤束核注射NPY或Y2 R 激动剂PYY 3-36增加食物摄入，这种作用被NTS共注射SP-cAMP减弱。在 本申请的目的2，我们检验迷走传入Y2 R通过拮抗 MC 4 R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。我们长久以来- 长期目标是确定NMDAR如何参与迷走神经传入突触强度的调节， 食物摄入量详细了解肽和激素相互作用的机制 NMDAR控制食物摄入量对人类健康具有重要意义，因为它可能为控制食物摄入量提供途径 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.