Adaptation of Brainstem Circuits to Chronic Hypoxia

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Certain cardiovascular and respiratory disorders, such as Obstructive Sleep Apnea (OSA), manifest as episodic or unstable breathing and hypertension. OSA is associated with systemic hypertension, heart failure, respiratory alterations and cardiac arrhythmias. Exposure to chronic intermittent hypoxia (CIH) is a model for these disorders. Peripheral arterial chemoreflexes and cardiorespiratory parameters are augmented in humans with OSA and animal models following CIH. A role for serotonin (5-HT) has been suggested in OSA and CIH, but its mechanism(s) and its site of action remain unclear. This proposal will determine the role and mechanisms of 5-HT in the CIH-induced augmentation of carotid body chemoreflex. We have established in the nucleus of the solitary tract (NTS), the central termination site of carotid body sensory afferents, that 10 days of CIH increases basal presynaptic spontaneous neurotransmitter release and asynchronous release that occurs following a stimulus train that mimics chemoafferent discharge. This augmentation in total spontaneous release enhances postsynaptic action potential discharge and generates short-term facilitation in NTS cells. Also, baseline action potential discharge increases in NTS cells following CIH. Possibly to balance this pre- and postsynaptic enhancement, stimulus-evoked neurotransmitter release is attenuated. The facilitatory actions predominate and extend information transfer to cardiorespiratory nuclei in CIH. Our preliminary electrophysiological, molecular and imaging studies on CIH suggest that 5-HT has an important role on chemoafferent function, NTS neuronal activity and synaptic transmission at this primary synapse. The effect of 5-HT occurs through the activation of distinct 5-HT receptors, both inhibitory and excitatory, on the pre- and postsynaptic cell of the NTS synapse. The leading hypothesis is that 5-HT modulates the CIH-dependent plasticity of the arterial chemoreflex by actions at the chemosensory afferent, the postsynaptic NTS cell, and the information transfer between the two through its effect on ionic currents and neuronal activity. Furthermore, the function of distinct 5-HT receptors and their excitatory and inhibitory balance at the pre- and postsynaptic sites regulates such plasticity. The net effect is an increase in information transfer at the chemosensory-NTS synapse. The proposed studies will ascertain the function of 5-HT1/2 receptors in chemosensory neurons from the petrosal ganglia, NTS cells, and their synaptic connection. To test this hypothesis, the following specific aims will be addressed under control and following CIH conditions. Aim 1 will determine the role of 5-HT on ionic currents and action potential discharge in chemoreceptor sensory neurons. Aim 2 will ascertain the role of 5-HT on synaptic transmission between chemoreceptor sensory afferents and NTS second order cells. Aim 3 will resolve the role of 5-HT on ionic currents and action potential discharge in postsynaptic NTS cells. Taken together, these studies will enhance our understanding of the consequences of CIH-induced plasticity in the respiratory control system and provide insights into possible specific therapeutic interventions in OSA. 7. Project Narrative Exposure to chronic intermittent hypoxia is a model for cardiorespiratory diseases that manifest as periodic breathing and hypertension. Clinical and experimental data have suggested a role for the neurotransmitter serotonin. Results from these studies will determine the relevance and mechanism of serotonin's action in this disease model with the expectation of understanding potential therapeutic interventions.