MECHANISMS AND SITES OF VENTILATORY NEUROGENESIS

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DESCRIPTION (Adapted from the applicant's abstract):"Automatic" breathing movements, which occur without conscious effort, are generated within the pontile and medullary portions of the brainstem. There are several patterns of "automatic" ventilation. Eupnea is "normal" breathing. In eupnea, sufficient oxygen is supplied to the body and carbon dioxide removed to meet metabolic demands. If eupnea ceases, hypoxia will develop. Severe hypoxia recruits gasping, which serves as a powerful defensive mechanism for "autoresuscitation." A fundamental question concerns the specific neurophysiological mechanisms which generate eupnea and gasping. In severe hypoxia, it is hypothesized that a latent pacemaker discharge of medullary respiratory neurons is released to generate the gasp. In eupnea, this pacemaker activity is incorporated into the pontomedullary neuronal circuits responsible for the neurogenesis of eupnea. A definition of the neurophysiological processes responsible for this incorporation will enhance our understanding of the neurogenesis of eupnea, per se. The studies proposed require the reversible alteration of eupnea to gasping. Moreover, in order to evaluate the role of various putative neurotransmitters in ventilatory neurogenesis, pharmacological agents will be administered systemically, as well as onto neurons by microiontophoresis. The perfused "juvenile rat" is uniquely suited for the successful performance of these studies. Since the systemic "respiratory" and "circulatory" systems of this preparation are "replaced" by an extracorporeal circuit, there is no possibility of cardiac failure during hypoxia-induced gasping. Likewise, pharmacological agents can be administered which would almost certainly compromise cardiovascular function and viability of an in vivo preparation. Results of these studies will provide significant information into the mechanisms by which normal breathing is generated. Such information might provide insights into dysfunctions of the control of ventilation in humans, such as in "sleep apneas" or the "sudden infant death syndrome."