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

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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.