Serotonin (5HT), thyrotropin releasing hormone (TRH) and substance P (SP) are three neurotransmitters with important central effects upon the control of respiration. However, relatively little is known about the neuroanatomic sites and neuropharmacologic mediators responsible for these respiratory effects. One important site that may be involved in the effects of 5HT, TRH and SP is the nucleus tractus-solitarius (NTS). The NTS is a site of respiratory integration, containing the terminations of pulmonary vagal afferents and the respiratory neurons of the dorsal respiratory group. Specific, high affinity receptors for all three neurotransmitters are present in the NTS. Furthermore, 5HT, TRH and SP are colocalized in raphe neurons that project to the NTS. We will study this raphe-NTS projection in order to understand the role of the NTS in the neurochemical control of breathing. First, we will use quantitative autoradiography to localize and quantify receptors for 5HT, TRH and SP in the NTS. Since the projections to the NTS are viscerotopically organized, we will determine the relative concentrations of receptors for 5HT, TRH and SP in the subnuclei of the NTS. These receptor distributions will then be related to the distributions of pulmonary vagal afferent terminals and respiratory neurons in the NTS. Second, we will identify what NTS cytoarchitectural elements these receptors are localized upon. We will determine whether these receptors are postsynaptic upon NTS neurons, and therefore directly mediated the respiratory effects of 5HT, TRH and SP. We will also examine the alternative concept that these receptors are localized upon the dendritic processes of adjacent hypoglossal and vagal motor neurons extending into the NTS. Third, having determined the distribution and localization of these receptors, we will further characterize the anatomic pathway of the neurons that stimulate these receptors. Using retrograde fluorescent tracing techniques, we will determine if the raphe neurons that project to the NTS also project divergent axon collaterals to respiratory motoneuron pools. Fourth, having anatomically examined both these receptors and the neurons that stimulate them, we will pharmacologically study the activity of this raphe-NTS pathway. We will test the hypothesis that raphe neurons tonically modulate NTS neurons by destroying NTS-projecting raphe neurons, and identifying up-regulation of these receptors.
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