Identification and Modulation of Respiratory Neurons in the Brainstem Open Access
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Interactions between the cardiovascular and respiratory systems are well established, and alterations in one system lead to changes in the other. For example, heart rate is determined by the respiratory cycle, with increases occurring with inspiration and decreases during expiration. The inspiratory increase in heart rate is mediated by increased inhibitory (both GABAergic and glycinergic) neurotransmission to cardioinhibitory cardiac vagal neurons during the inspiratory phase of the respiratory cycle. The location of these inhibitory GABAergic neurons however, is unknown. In the first part of this dissertation, I used transgenic mice expressing green fluorescent protein and spatially focused photo-excitation (via caged glutamate) to identify 4 discretely localized populations of GABAergic neurons that synapse upon cardiac vagal neurons. In the second study I characterized the two populations of GABAergic neurons from these regions that receive increased excitatory input during inspiration. To accomplish this we used an in vitro medullary slice that allowed simultaneous examination of rhythmic respiratory-related activity and synaptic neurotransmission to GABAergic neurons. We showed that GABAergic neurons ventral to the nucleus ambiguus receive increased neurotransmission that is completely abolished with the glutamatergic antagonists, AP-5 and CNQX but not nicotinic acetylcholine receptor antagonists, DHβE and α-Btx. In addition, we demonstrated two distinct populations of respiratory-modulated GABAergic neurons using current clamp configuration. Action potential firing was completely abolished in the presence of glutamatergic antagonists in the first population, while in the second population, action potential firing continued in the absence of excitatory network activity, indicating these cells possess pacemaker activity. The pacemaker activity was not blocked by bath application of cadmium chloride, a calcium channel blocker, suggesting that these neurons operate independently of calcium flux. This work not only addresses basic functions of cardiorespiratory networks in the brainstem but also identifies GABAergic projections to cardiac vagal neurons. Furthermore, my work characterizes two distinct populations of inspiratory GABAergic neurons, one non-pacemaker and one pacemaker.
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