Swallowing, one of the more complex motor behaviors, is programmed centrally by a medullary central pattern generator located in and around the nucleus of the solitary tract. The generation and modulation of neuronal patterned motor activity by the central pattern generator is dependent upon endogenous excitatory and inhibitory mechanisms and requisite central and peripheral afferent contacts. A significant imbalance in the relative contribution of excitation via NMDA and inhibition via GABA receptors may form the basis of dysfunctional swallowing present in neurological disease. Utilizing the rat as animal model, the anatomic basis of the excitatory and inhibitory processes critical to the coordination of the buccopharyngeal and esophageal phases of swallowing will be studied. Transsynaptic tracing with Pseudorabies Virus in conjunction with: (1) Fluorescent retrograde tracing will be utilized to study the anatomical connections between the buccopharyngeal and esophageal central pattern generator networks at the premotor neuron level; (2) In situ hybridization with oligonucleotide probes for the different N-Methyl-D-aspartate (NMDA) receptor subunits (R1, R2A-D) and GABAA receptor subunits (alpha1-6, Beta1-3, gamma1-3, delta) will be utilized to determine the NMDA and GABAA receptor subunits expressed by premotor neurons;(3) immunocytochemistry for glutamate and GABA will be utilized to determine location and organization of glutaminergic and GABAergic neurons constituting and projecting to the central pattern generator; (4) immunocytochemistry for NMDAR1 receptor protein and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry (triple labeling method) for nitric oxide synthase will be utilized to determine the anatomic relationship between the NMDAR1 receptor protein and nitric oxide synthase in premotor neurons. Nitric oxide production in response to NMDA receptor activation plays a prominent role in chemical synaptic signaling and integration of neuronal activity. Since alterations in excitatory and inhibitory synaptic function could contribute to the pathogenesis of swallowing disorders, these studies may have a direct bearing on the future clinical management of patients with dysphagia.
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