Astrocyte-Dependent Modulation of Synaptic Strength in Response to Acute High Fat Diet

摘要 据估计，在美国，超过三分之一的成年人受到肥胖症及其共病疾病的影响。 仅此一人，并正在迅速增长，成为一个世界性的健康问题。肥胖率的急剧上升突显了 了解与能量平衡和内脏功能有关的神经机制的重要性 比如进食和消化。而饮食诱导的肥胖(DIO)和长期暴露于高脂饮食(HFD) 已被证明调节脑干许多区域的神经传递，包括迷走神经 神经回路，我们之前已经证明，即使是急性暴露于HFD也能调节迷走神经 神经回路。具体地说，短期暴露于HFD(3-5天)可调节谷氨酸能传递 迷走神经背侧运动核(DMV)，增加突触NMDA电流，DMV神经元兴奋性和， 反过来，增加胃张力和胃动力。我们实验室最近的研究也表明，激活 星形胶质细胞或突触外NMDA受体可能参与了这种调节。导致这一结果的机制 然而，这种在急性HFD暴露后增加的NMDA电流还没有被阐明。 先前的研究表明，突触NMDA受体激活增加可能发生在 激活突触外NMDA受体，导致足够的局部去极化来清除镁离子 阻断突触NMDA受体。此外，先前的研究表明，星形细胞释放谷氨酸 可能是这种突触外NMDA受体激活的原因。这项研究的目的是检验这一假说 也就是说，急性HFD暴露诱导星形细胞谷氨酸的释放，激活突触外和突触 DVC中NMDA-R的激活。目标1将调查假设，在急性HFD暴露后， 星形胶质细胞神经递质释放增加急性HFD暴露后NMDA受体的激活。目标2将 研究以下假设：急性HFD诱导的突触NMDA电流增加依赖于 星形细胞释放谷氨酸。 检查营养改变导致的脑干神经回路可塑性的可能性 带来了揭示大脑-肠道动态平衡和调节的机制基础的机会 摄食行为，进而可能提供对这些途径的失调的洞察，从而导致 能量平衡受损和肥胖。

ABSTRACT Obesity and its comorbid disorders are estimated to affect more than one-third of adults in the U.S. alone, and is rapidly growing as a worldwide health concern. The dramatic rise in obesity has underscored the importance of understanding the neural mechanisms involved in energy homeostasis and visceral functions such as feeding and digestion. While diet-induced obesity (DIO) and long-term exposure to high-fat diet (HFD) have been shown to modulate neurotransmission in many areas of the brainstem, including vago-vagal neurocircuits, we have demonstrated previously that even acute exposure to HFD modulates vagal neurocircuits. Specifically, short term exposure to HFD (3-5 days) modulates glutamatergic transmission in the dorsal motor nucleus of the vagus (DMV), increasing synaptic NMDA currents, DMV neuronal excitability and, in turn, increases gastric tone and motility. Recent studies from our lab have also suggested that activation of astrocytes or extrasynaptic NMDA receptors may be involved in this modulation. The mechanism that results in this increased NMDA current following acute HFD exposure has, however, not been elucidated. Previous studies have suggested that increased synaptic NMDA receptor activation may occur subsequent to activation of extrasynaptic NMDA receptors, which causes sufficient local depolarization to remove the Mg2+ block on synaptic NMDA receptors. Furthermore, previous studies suggest that astrocytic release of glutamate may responsible for this extrasynaptic NMDA receptor activation. The aim of this study is to test the hypothesis that, acute HFD exposure induces the release of astrocytic glutamate that activates extrasynaptic and synaptic NMDA-R activation in the DVC. Aim 1 will investigate the hypothesis that, following acute HFD exposure, astrocytic gliotransmitter release increases NMDA receptor activation following acute HFD exposure. Aim 2 will investigate the hypothesis that, acute HFD-induced increase in synaptic NMDA currents is dependent upon astrocytic glutamate release. The potential to examine plasticity in brainstem neurocircuitry resulting from alterations in nutrition brings with it the opportunity to uncover the mechanistic basis for brain-gut homeostasis and regulation of feeding behavior which, in turn, may provide insights into the dysregulation of these pathways which leads to impaired energy balance and obesity.