Meal size is a major determinant of total food intake and energy balance. Increased meal size is associated with positive energy balance and development of obesity in in rats and humans. Obesity has been identified as a major contributor to morbidity and mortality by virtually all major public health organizations. Understanding the neural mechanisms through which satiation occurs and meal size is controlled is seminal to the dissecting the pathophysiology of obesity. Mechanical, chemical and endocrine signals originating from the gastrointestinal tract contribute to meal termination and determination of meal size. These gastrointestinal signals are carried to the hindbrain by the afferent neurons of the vagus nerve. The vagus, therefore, provides the brain with information on the nutritional status of the organism, even before nutrient assimilation occurs. The amino acid, glutamate, is the principal neurotransmitter of vagal afferent neurons. In spite of its importance to vagal neurotransmission, the contribution of vagal and hindbrain glutamate receptors in the control of food intake is little investigated. However, we demonstrated that injection of antagonists of NMDA-type glutamate receptor antagonists systemically or into the hindbrain increases meal size. This increase in meal size requires intact central vagal afferent processes.
The aims of the current application are 1. to employ surgical or neurotoxic destruction of vagal afferents to identify the specific subpopulation(s) that participates in NMDA receptor-mediated control of food intake by the vagus nerve and hindbrain, 2. to use physiological manipulation, together with pharmacological and immunohistochemical methods to determine whether NMDA receptors in the hindbrain specifically modulate inhibition of food intake by gastric signals, and 3. to utilize near arterial application of NMDA agonists and antagonists to the gastrointestinal tract to determine whether glutamate receptors on peripheral vagal afferent elements participate in control food intake. Control of meal size is a principal determinant of total caloric intake and energy balance. The vagus nerve, which directly conveys gastrointestinal information to the brain controls meal size. This project aims to determine the role of NMDA-type glutamate receptors in the control of meal size by the vagus nerve.
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