The vagus or Xth cranial nerve contains both the sensory and motor divisions of the parasympathetic nervous system that regulate the heart, lungs and digestive tract - regulatory activities that are required to sustain life. The sensory division of the vagus is composed of several functional systems, each consisting of a pool of sensory receptors defined by the type of stimulus they transduce (e.g., mechanoreceptor vs. chemoreceptor), by their structure (e.g., the type of mechanoreceptor), and by their location (organ or tissue they innervate). Progress in understanding the structural and functional organization of these vagal sensory channels has to a large extent been elusive. This is mainly because it has been difficult to selectively label or manipulate vagal sensory systems due to their close association with vagal motor, sympathetic, and enteric systems. We propose that a better understanding of the genetic programs that orchestrate development of each vagal sensory channel could provide means to develop tools for selective manipulation of these channels. In the proposed experiments we will first characterize in detail the changes in both the number and the morphology of vagal afferents that innervate the gastrointestinal (Gl) tract in mice with a mutation in either the brain-derived neurotrophic factor (BDNF) gene or the neurotrophin-3 (NT-3) gene. Second, BDNF and NT-3 expression in tissues associated with developing and mature vagal Gl afferents will be mapped in normal mice. Then analysis of the relationship of these expression patterns to the remodeled vagal pathways in the neurotrophin mutants will be used to develop hypotheses about where and when BDNF and NT-3 are essential for development of these pathways. To test these hypotheses, application of the cre-lox recombination system in mice will be used to create conditional BDNF or NT-3 knockouts that are targeted to specific tissues and developmental stages, and then vagal Gl afferent remodeling in these mice will be characterized. Mice with these conditional BDNF or NT-3 knockouts will also be subject to behavioral tests to make an initial assessment of whether this remodeling might affect vagal Gl sensory function. This work will provide novel information about the roles of BDNF and NT-3 in the development of vagal Gl afferent organization. Moreover, it will form an essential foundation for further research on the development of, and the structural and functional organization of, the diverse systems that form the vagal sensorium.
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