INTRACELLULAR ANALYSIS OF AIRWAY MOTONEURONS DURING SLEEP

University Of California Los Angeles, Los Angeles CA

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Abstract

The clinical signs of obstructive sleep apnea are reflected in abnormal patterns of upper airway motor control. These patterns of control are evidenced by changes in airway patency, which are dependent on the activity of cells that innervate the airway musculature, most specifically hypoglossal and ambiguus motoneurons. The objective of the proposed research is to generate basic data relating to the circuitry, neurotransmitters and neuromodulators responsible for the control of these motoneurons. Intracellular recordings will be obtained from hypoglossal and ambiguus motoneurons; extracellular recording will be obtained by neurons of the medullary motor inhibitory area that provide a monosynaptic inhibitory input to these motoneurons. Electrical stimulation will be applied to the site of REM sleep generation in the pons (the nucleus pontis oralis) to examine the circuitry that controls the excitability of the preceding airway patency motoneurons. The neurochemical control of these motoneurons will be determined by recording from them intracellularly, while simultaneously ejecting neurotransmitter and neuromodulator antagonists and agonists juxta-cellularly. These studies will first be undertaken in an animal model of sleep in which atonia is induced via the pontine microiontophoretic application of carbachol, and subsequently in chronic animals during naturally occurring sleep and wakefulness. The significance of our proposed studies is based upon the following factors. First, in order to understand and treat obstructive sleep apnea, it is essential to clarify the mechanisms that control the activity of airway patency motoneurons. Second, only by recording intracellularly can one differentiate between the two fundamental processes, postsynaptic and presynaptic, that can promote a decrease in motoneuron activity during sleep. In preparation for this application, we recorded intracellularly from hypoglossal motoneurons and found that they are postsynaptically inhibited during REM sleep. This finding, which was obtained by recording with intracellularly-placed microelectrodes, contradicts previous data obtained by indirect means which did not reveal the presence of postsynaptic control during this state. These data therefore suggest that the currently purported airway control mechanisms that operate during sleep need to be reexamined and direct data relating to the state- dependent control of the responsible motoneurons must be developed.