Neurophysiology and plasticity of cardiorespiratory circuits to hypoxia

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 DESCRIPTION (provided by applicant): The nucleus tractus solitarii (nTS) is the first central termination and integration site for sensory reflexes, including the carotid body chemoreflex that is augmented during chronic intermittent hypoxia (CIH) and obstructive sleep apnea (OSA). The glutamatergic synapse between the primary afferent and second-order nTS neuron is highly modifiable, expressing multiple forms of synaptic plasticity and enhanced by CIH. This nTS synapse is closely associated with astrocytes (glia) that actively contribute to synaptic and neuronal activity and plasticity through the release of gliotransmitters and by uptake of neurotransmitter from the synaptic cleft. The interaction among glia, presynaptic terminals and postsynaptic neurons is referred to as the "tripartite synapse". Several gliotransmitters have been identified, including glutamate and ATP. Astrocytes in the nTS release glutamate in response to afferent sensory input to modify neuronal activity. Uptake of afferent and network released glutamate and GABA by their respective transporters is critical for shaping and synchronizing activity, and preventing excitotoxicity. Glia modify synaptic transmission in response to acute hypoxia, and prolonged hypoxia alter the expression and/or function of components of the tripartite synapse, and likely glia-neural communication. The role of astrocytes, gliotransmitters and their role in neurotransmitter uptake in synaptic plasticity in normoxia, let alone its enhancement in CIH, is unknown. Moreover, how astrocyte-mediated effects on synaptic plasticity augment cardiorespiratory reflexes is unknown. Our central hypothesis is glial transporters basally restrain synaptic activity, but increased activation of astrocytes within the tripartite synapse enhances synaptic and neuronal function to augment the cardiorespiratory system. CIH enhances nTS neurotransmission and hypoxic cardiorespiratory responses due to elevated astrocyte activity and excitatory GT release, and altered balance of Glu and GABA uptake. Aim 1 will define the magnitude by which nTS (a) neuronal and synaptic function, and their plasticity, are modulated by astrocytes and influenced by gliotransmitters, (b) astrocytes are activated by neuronal activity, (c) tripartite synapses modulate respiration, sympathetic nerve activity and their coupling, and (d) excitability is augmented in CIH due to astrocyte activation. Aim 2 will determine the magnitude by which astrocyte Glu or GABA transporters (a) influence nTS neuronal function, (b) activate synaptic and extra-synaptic receptors, (c) regulate cardiorespiratory function, and (d) are altered by or contribute to CIH-induced augmentation of nTS neurotransmission. This study presents an integrative approach to exploring important basic and clinical questions, including the recording of neurons and astrocytes, imaging, molecular biology, optogenetics, DREADD manipulation and in vivo physiology. Understanding the circuits, and their glia-neural- interactions, involved in cardiorespiratory diseases will advance our understanding of its development and potentially lead to its treatment.