Mechanisms and sites of ventilatory neurogenesis

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DESCRIPTION (provided by applicant): "Automatic" breathing movements, which occur without conscious effort, are generated within the pontile and medullary portions of the brainstem. Eupnea is normal breathing. In eupnea, sufficient oxygen is supplied to the body and carbon dioxide is removed to meet the metabolic demands. If eupnea ceases, hypoxia will develop. Severe hypoxia recruits gasping, which is a mechanism for "autoresuscitation." We have proposed that fundamentally different mechanisms generate eupnea and gasping. Eupnea reflects the output of a pontomedullary neuronal circuit whereas gasping is generated by the discharge of medullary pacemakers. During eupnea, these pacemaker mechanisms are suppressed. Studies will evaluate multiple hypotheses concerning the neurophysiological mechanisms by which respiratory rhythms are generated. Included will be an evaluation that medullary neurons, with discharge characteristics consonant with generating the gasp, will continue rhythmic bursts following a blockade of synaptic transmission. Hence, these bursts are considered to represent a "pacemaker discharge." The studies require the reversible alteration from eupnea to gasping. Both extracellular and intracellular recordings of neuronal activities will be obtained continuously. Agents will be applied to block synaptic transmission. The in situ preparations of the "neonatal" and "juvenile" rats are uniquely suited for these studies. Hypoxia-induced gasping can be reversibly induced, viability is maintained following administration of pharmacological agents to block synaptic transmission, and the minimal movements of the brainstem make possible the extracellular and intracellular recordings of neuronal activities. Results of these studies will provide significant and unique information as to 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 apnea" or the "sudden infant death syndrome."