The role of the dorsal respiratory group in the modulation of breathing in the rat

The purpose of this thesis project was to determine first, the role of neurons in the dorsal respiratory group (DRG) in the rat and, second, reveal the importance of specific neurochemical modulators of these neurons. In order to realize these aims, bilateral microinjection of drugs that inhibit or disfacilitate neurons were performed in the ventrolateral nucleus of the solitary tract (vlNTS), the site of respiratory neurons of the DRG, and the resulting changes in cardiorespiratory activity were monitored in anesthetized, vagotomized and spontaneously breathing rats. Microinjection of the sodium channel blocker tetrodotoxin or the inhibitory amino acid GABA produced an immediate and severe prolongation of inspiratory duration (Ti) characterized by apneustic breathing in all animals studied. These experiments established that a role of respiratory neurons in the DRG is to function as part of the "Inspiratory Off-Switch". Bilateral microinjection of agonists of GABAA or GABAB receptors in the DRG also produced apneustic breathing. Endogenous release of GABA was demonstrated by apneustic breathing following microinjection of the GABA reuptake antagonist nipecotic acid, as well as by unilateral microinjection of GABA receptor subtype-specific antagonists. Unilateral microinjection of the GABAA receptor antagonists produced an immediate and potentially fatal apnea while microinjection of a GABA B receptor antagonist had little effect. Immunohistochemistry demonstrated dense GABAA receptor immunoreactivity on processes while GABA B receptors, in contrast, were located on neuronal somata suggesting endogenous GABA release act primarily through GABAA receptors on processes. Preliminary studies also indicated that endogenous glutamate release imparts an excitatory drive to these DRG neurons as microinjection of the ionotropic glutamate receptor antagonist kynurenic acid produced apneustic breathing. Microinjection studies using the inhibitory amino acid glycine or strychnine suggest glycine appears to have little functional role within the region. Lastly, apneusis demonstrates "Ti stratification" in which values for Ti during an apneustic period appear to jump between narrow ranges at one of several discrete levels. These random jumps between Ti levels suggest this characteristic pattern of apneusis may be caused by fluctuations not in the vlNTS but in another part of the respiratory network.