The objective of our research is to understand intrinsic and extrinsic factors that govern the electrical activity of hypoglossal motoneurons (HMs) because of the role this activity has in control of the tongue muscles and thus in the regulation of upper airway patency. Experiments proposed will employ the in vitro rhythmic neonatal mouse medullary slice preparation, to study both short- and long-time-scale properties of inspiratory-phase (I- phase) HM spike activity. Short-time-scale properties are associated with synchronous oscillations that are observed in all inspiratory motor pools in every mammalian species studied. They are of paramount importance in the formation of the pattern of I-phase activity.
Specific Aim 1 will test the hypothesis that synchronous oscillations arise from premotor neural networks containing inhibitory interneurons. We will use local application of blockers of inhibitory synaptic transmission to define the locus of these premotor neural networks.
Specific Aim 2 will test the hypothesis that the postnatal increase in oscillation frequency that we and others have observed arises from the speeding up of inhibitory synaptic transmission. In neurons comprising the region defined in Specific Aim 1 we will determine whether the time course of inhibitory synaptic transmission speeds up with postnatal development. This result will provide evidence for a primary role of such inhibitory interneurons and will be an important first step in establishing the neural network model responsible for the generation of synchronous oscillations.
Specific Aim 3 hypothesizes that HMs possess intrinsic resonance behavior and exhibit action potential firing resonance at a resonant peak frequency approximating the synchronous oscillation frequency or a sub- harmonic of that frequency. Such a finding will provide evidence of a functional link between synchronous oscillatory I-phase inputs to HMs and their firing output. We will investigate this in the rhythmic slice by intracellularly recording from HMs and studying both sub-threshold and firing resonance. We will also study firing resonance as a function of postnatal development, investigate the intrinsic mechanisms responsible for resonance, and study the effects of state-dependent neuromodulators, such as serotonin, on spike firing resonance behavior.
The public health relevance of our research arises from the fact that failure of upper airway patency is widely regarded as being responsible for obstructive sleep apnea, and may be important in the Sudden Infant Death Syndrome. Thus we believe that fundamental knowledge of the function, development and synaptic activation of HMs will lead to a better understanding and treatment for these disorders.
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