The overall goal of the proposed work is to elucidate mechanisms underlying neurotransmission among respiratory-related brainstem neurons during postnatal development. A structure/function approach is taken in which neuroanatomical techniques are used to define neurotransmitter and receptor phenotype of rat brainstem neurons and in vitro electrophysiological approaches are used to determine cellular mechanisms that mediate effects of putative transmitters; developmental changes in neurotransmitter and receptor expression are correlated with concomitant changes in electrophysiological effects of relevant transmitters. This proposal focuses on the relationship between caudal raphe neurons and the hypoglossal motoneurons (HMs) they innervate, which may have important clinical relevance. The activity of HMs follows closely that of raphe cells, being lowest during sleep. Because HMs regulate upper airway patency and decreased activity of HMs during sleep can lead to airway obstruction, clarifying transmitter mechanisms within the raphe- hypoglossal system may be important in understanding certain respiratory pathologies of sleep (e.g., obstructive sleep apnea, Sudden Infant Death Syndrome). To this end, the effects on HMs of three transmitters synthesized by raphe cells [i.e., serotonin (5-HT), thyrotropin-releasing hormone (TRH), and substance P (SP)] are determined during postnatal development and correlated with levels of receptor and transmitter expression. Mechanisms underlying autoinhibition of raphe cells by 5-HT are also studied. The first specific aim is to test the hypothesis that differential effects of 5-HT in neonatal and adult HMs reflect differences in receptor expression. This is done pharmacologically using intracellular recording techniques in a thick-slice preparation; those results are correlated with postnatal changes in expression of 5-HT receptors by HMs determined anatomically by in situ hybridization and receptor autoradiography. The same approaches are used in the second specific aim to determine the pharmacological and ionic bases for effects of SP on HMs and to test the hypothesis that developmental changes in SP expression by raphe neurons are matched by changes in SP receptor expression in HMs. The third specific aim is to determine neuroanatomically if raphe neurons influence developmental patterns of receptor (5-HT, TRH and SP) expression in HMs using a specific neurotoxin (5,7-dihydroxytryptamine) to lesion serotonergic raphe neurons. The fourth specific aim is to test the hypothesis that TRH inhibits resting K+ channels in HMs via a soluble second messenger using single channel recording techniques in a medullary thin-slice preparation. The fifth specific aim is to test the hypothesis that 5-HT modulates Ca2+ and inwardly-rectifying K+ currents in caudal raphe neurons as a mechanism of autoinhibition; for these experiments whole-cell recordings are made from directly visualized ra he neurons in the thin-slice preparation.
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