Obstructive apneas/hypopneas occur during sleep in 3-5% of adult population as a result of decrements in the activity of upper airway dilator muscles caused, at least in part, by a sleep-related withdrawal of excitatory effects on upper airway motoneurons (mns). This excitation in wakefulness originates in serotonin, noradrenaline (NE) and other cells of the brainstem whose activity decreases during sleep. The project focuses on the role of NE in the control of hypoglossal (XII) mns, important airway dilators It is hypothesized that NE cells of the dorsolateral pontine tegmentum, using different membrane receptors, have direct excitatory effects on mns and also act to enhance the central respiratory drive and reflexes transmitted to XII mns from upper airway mechanoreceptors through the superior laryngeal nerve (SLN). Thus, selected NE cells should be excited by SLN afferents and: 1) project to the XII nucleus, where they have prolonged excitatory effects on XII mns and modulate afferent pathways from the SLN; 2) project to the rostral ventrolateral medulla (RVLM), where they decrease the respiratory rate. Furthermore, NE cells with relevant axonal projects to the XII nucleus and/or RVLM should be depressed during pontine injections of carbachol, which produce a electrophysiologic signals similar to REM sleep: depression of XII nerve activity, EEG desynchronization and theta rhythm. These predictions will be tested using urethan-anesthetized rats as a model. The experiments in Specific Aim 1 will determine: 1) the effects of microinjections of alpha/1 and beta receptor agonists and antagonists into the XII nucleus on the tonic and respiratory phasic modulation of XII nerve activity; 2) which NE receptor mRNAs are present in the XII nucleus and how their levels change following mn degeneration; and 3) using NE iontophoresis onto the single XII mns, whether there is a functional amplification of the central respiratory drive. The experiments in Specific Aim 2 will determine: 1) using local microinjections to suppress NE cell activity or antagonize NE effects within the RVLM or XII nucleus, which NE cells mediate, and at which sites, the long-term enhancement of XII nerve activity and respiratory rate decrease that follows the period of SLN stimulation; 2) the nature and time course of responses to SLN stimulation and negative pressure pulses applied to the upper airway of electrophysiologically identified NE cells projecting to the XII nucleus and the RVLM in relation to the response of the XII nerve; and 3) the role of alpha/2 receptors located within the XII nucleus in modulating the transmission of reflexes from airway receptors to XII mns. The experiments in Specific Aim 3 will determine the changes in spontaneous and reflexly evoked activity of pontine NE cells that project to the XII nucleus and RVLM during the depression of XII nerve activity induced by pontine injections of carbachol. These studies will provide new information (pathways, receptors, cellular behaviors and modes of interaction) about the mechanisms underlying the maintenance and restoration of upper airway patency.
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