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

星形胶质细胞依赖性突触强度调节对急性高脂肪饮食的反应

• 批准号: 9756639
• 负责人: Courtney E Clyburn
• 金额: $ 3.17万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756639
• 关键词: Acute; Adult; Affect; Area; Astrocytes; Attention; Brain; Brain Stem; Cell Nucleus; Cells; Chronic; Comorbidity; Complex; Data; Development; Diet; Digestion; Disease; Dorsal; Electrophysiology (science); Energy Intake; Exposure to; Feeding behaviors; Food; Gliosis; Glutamates; Health; Heart Diseases; High Fat Diet; Homeostasis; Hyperphagia; Hypertension; Hypothalamic structure; Impairment; In Vitro; Inflammation; Laboratories; Mechanics; Metabolic Diseases; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Output; Pathway interactions; Peripheral; Receptor Activation; Regulation; Role; Signal Transduction; Stomach; Structure of area postrema; Synapses; Testing; Upper digestive tract structure; Visceral; Work; base; cell motility; cost; dorsal motor nucleus; energy balance; feeding; gamma-Aminobutyric Acid; glutamatergic signaling; in vivo; insight; neuromechanism; neuronal excitability; neurotransmission; novel; nutrition; obesity development; patch clamp; prevent; relating to nervous system; response; transmission process

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.

摘要 据估计，肥胖及其共病疾病影响了美国三分之一以上的成年人。 这是一个单独的问题，并正在迅速发展成为一个全球性的健康问题。肥胖症的急剧上升凸显了 理解能量稳态和内脏功能的神经机制的重要性 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） 已被证明可以调节脑干许多区域的神经传递，包括迷走神经-迷走神经 神经回路，我们以前已经证明，即使急性暴露于HFD调节迷走神经， 神经回路具体地说，短期暴露于HFD（3-5天）调节了大鼠脑组织中的神经递质传递。 迷走神经背侧运动核（DMV），增加突触NMDA电流，DMV神经元兴奋性， 进而增加胃张力和运动性。我们实验室最近的研究也表明， 星形胶质细胞或突触外NMDA受体可能参与这种调节。这种机制导致 然而，在急性HFD暴露后这种增加的NMDA电流还没有被阐明。 以前的研究表明，增加的突触NMDA受体激活可能发生在 激活突触外NMDA受体，引起足够的局部去极化以清除Mg 2 + 阻断突触NMDA受体。此外，以前的研究表明，星形胶质细胞释放谷氨酸， 可能负责这种突触外NMDA受体激活。本研究的目的是检验这一假设 急性HFD暴露诱导星形胶质细胞谷氨酸的释放，激活突触外和突触 DVC中的NMDA-R活化。目的1将研究以下假设，即急性HFD暴露后， 急性HFD暴露后星形胶质细胞胶质递质释放增加NMDA受体活化。目标2将 研究假设，急性HFD诱导的突触NMDA电流增加依赖于 星形胶质细胞谷氨酸释放。 检查由营养改变引起的脑干神经回路可塑性的潜力 它带来了机会，揭示脑肠道稳态和调节的机制基础， 进食行为，反过来，这可能会提供这些途径的失调，导致 能量平衡受损和肥胖。