The focus of this proposal is the neural control of upper airway muscle activity in intact animals during natural sleep states and wakefulness. The intent is to understand more completely the neural components of the pathogenesis of obstructive sleep disordered breathing events. The proposed program incorporates the necessary neuroscience training in techniques and theory with specific research projects addressing the roles of certain neurochemicals in the control of upper airway dilator motoneuron activity during sleep and wakefulness. We believe 1) that serotonin and other neurotransmitters in raphe neurons are important excitatory neuromodulators for upper airway dilator motoneurons and 2) that periodic withdrawal of raphe input during rapid eye movement sleep may result in depression of upper airway muscle activity and airway collapse in this state in anatomically predisposed animals or persons. A series of projects will employ naturally sleeping and acute decerebrate cats, and a natural animal model for sleep disordered breathing, the English bulldog. The proposed program consists of two phases. Phase One is of three years duration and emphasizes research training through the execution of three protocols; each protocol will be performed under the supervision of independent investigators with extensive experience in the techniques required by the protocol. In addition, graduate neuroscience courses will be taken. The first protocol evaluates the importance of serotonin for the maintenance of patent airways in our model of sleep-disordered breathing, the English bulldog. We will evaluate the effects of systemic serotonin agonists on motor control and breathing during rapid eye movement (REM) sleep. The second protocol will evaluate serotonin activity at trigeminal motoneurons during wakefulness and sleep. This study tests our hypothesis in normal cats using brainstem motor nucleus microdialysis, a technique which has been refined for this nucleus. The third protocol will begin to evaluate what inputs to the hypoglossal motor nucleus increase serotonin activity at this nucleus. Phase Two is of two years duration and will utilize the research training and information learned in Phase One in protocols evaluating serotonin activity during natural sleep and wakefulness at the hypoglossal motor nucleus in normal cats and in response to serotonergic stimuli determined in Protocol 3. Microdialysis at this nucleus will be used to determine fluctuations in serotonin activity in wakefulness and REM sleep.
