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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052849-12
Application #
8102906
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Yanovski, Susan Z
Project Start
1998-08-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
12
Fiscal Year
2011
Total Cost
$309,117
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Campos, Carlos A; Ritter, Robert C (2015) NMDA-type glutamate receptors participate in reduction of food intake following hindbrain melanocortin receptor activation. Am J Physiol Regul Integr Comp Physiol 308:R1-9
Zhao, Huan; Peters, James H; Zhu, Mingyan et al. (2015) Frequency-dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract. J Physiol 593:111-25
Campos, Carlos A; Shiina, Hiroko; Ritter, Robert C (2014) Central vagal afferent endings mediate reduction of food intake by melanocortin-3/4 receptor agonist. J Neurosci 34:12636-45
Campos, Carlos A; Shiina, Hiroko; Silvas, Michael et al. (2013) Vagal afferent NMDA receptors modulate CCK-induced reduction of food intake through synapsin I phosphorylation in adult male rats. Endocrinology 154:2613-25
Gallaher, Z R; Ryu, V; Herzog, T et al. (2012) Changes in microglial activation within the hindbrain, nodose ganglia, and the spinal cord following subdiaphragmatic vagotomy. Neurosci Lett 513:31-6
Campos, Carlos A; Wright, Jason S; Czaja, Krzysztof et al. (2012) CCK-induced reduction of food intake and hindbrain MAPK signaling are mediated by NMDA receptor activation. Endocrinology 153:2633-46
Zhang, Jingchuan; Ritter, Robert C (2012) Circulating GLP-1 and CCK-8 reduce food intake by capsaicin-insensitive, nonvagal mechanisms. Am J Physiol Regul Integr Comp Physiol 302:R264-73
Ritter, Robert C (2011) A tale of two endings: modulation of satiation by NMDA receptors on or near central and peripheral vagal afferent terminals. Physiol Behav 105:94-9
Wright, Jason; Campos, Carlos; Herzog, Thiebaut et al. (2011) Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors. Am J Physiol Regul Integr Comp Physiol 301:R448-55
Ruiter, Marieke; Duffy, Patricia; Simasko, Steven et al. (2010) Increased hypothalamic signal transducer and activator of transcription 3 phosphorylation after hindbrain leptin injection. Endocrinology 151:1509-19

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