Upper airway obstructions during sleep affect 2-5% of adults, leading to hypoxemia, hypersomnolence and secondary morbidity/mortality (hypertension, accidents). There is a major neural component--the symptoms occur only during sleep, and rapid eye movement (REM) sleep in particular. The physiology and pharmacology of the state-dependent control of upper airways is still poorly understood and no satisfactory pharmacological treatment of the disease is available. Our studies have shown that a sleep-related decrease in the excitatory effect of serotonin (5HT) on hypoglossal (XII) motoneurons may play a major role in the decrements of upper airway muscle tone. We also found a distinct group of medullary raphe cells having the following common features: send axons to the XII and viscerosensory nucleus of the solitary tract (NTS), decrease activity during a pharmacologically evoked REM sleep-like state, are suppressed by 5HT1A serotonergic agonists, and have low conduction velocities. We hypothesize that these cells: 1) control the motor output at both brainstem and spinal cord level, including respiratory and, perhaps, cardiovascular sympathetic neurons; 2) control visceral afferent and central respiratory inputs to upper airway motoeuons by means of their presynaptic action on afferent pathways; 3) are themselves under a dual inhibitory/excitatory control of the serotonergic system. Consequently, we propose to determine whether these neurons are critical state-dependent modulators at many levels of the neuraxis and provide a comprehensive description of the role of 5HT at both the afferent and the efferent end of these neurons. To assess the anatomical (cord/brainstem) and functional (motor/cardiovascular/viscerosensory) divergence, we will: 1) electrophysiologically search in the spinal cord for axonal ramifications of raphe neurons having projections to the XIl nucleus and/or NTS(antidromic mapping); 2) by means of intracellular labeling, trace the course of axon collaterals of these neurons through the XII nucleus and NTS and search for their close appositions with neural elements in these two sites. To further our understanding of presynaptic effects of SHT on afferent pathways to XII motoneurons, we will study the effects of microinjections into the XIl nucleus of agonists and antagonists of the presynaptic (5HT1B) receptors on: 3) the central respiratory input to XIl motoneurons and 4) the reflex input from the well defined lingual nerve reflex pathway. To define the role of SHT in the afferent control of raphe cells projecting to the XII nucleus, we will: 4) study the in vivo response of these cells to iontophoretic application of SHT with and without pharmacological blockade of the inhibitory effects mediated by 5HT1A autoreceptors, and 5) intracellularly record in vitro from raphe cells identified as SHT-containing and determine their membrane properties and currents activated by SHT agonists and antagonists. This project will thoroughly characterize the physiology of a major state-dependent neural system and the role of 5HT at its distinct efferent and afferent levels. This system is important for the control of upper airways and, when fully understood, may become a target for pharmacological interventions.
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