NEURONAL BASIS OF RESPIRATORY PATTERNING DURING HYPOXIA

In peripherally chemodenervated animals, exposure to hypoxia results in phrenic neurogram depression followed by gasping, a respiratory pattern which is thought to be important for quick reoxygenation following remission of hypoxia. During eupnea, respiratory patterning is determined by phase-specific inhibitory interactions between the neuronal components of the respiratory pattern generator. The alterations of this circuit which are the presumed bases of the effects of hypoxia on respiratory patterning are unknown. The studies in this proposal seek to determine how the interaction of respiratory neurons is modified during hypoxia with resultant changes in respiratory patterning. The following hypotheses will be tested: 1) Hypoxic respiratory depression results from alteration of the balance between inhibitory and excitatory inputs to respiratory neurons with GABAergic inhibition predominating. This hypothesis will be tested by examining the response of respiratory neurons to iontophoretic application of inhibitory neurotransmitter antagonists and glutamate during eupnea and hypoxic depression; 2) The respiratory pattern generation circuit during gasping is a reduced circuit consisting of primarily inspiratory elements and few propriobulbar inhibitory or expiratory elements. This hypothesis will be directly tested by determining which populations of respiratory neurons are active during gasping; 3) Inspiratory neurons are disinhibited during gasping. The response of inspiratory neurons to the inhibitory neurotransmitter, gamma- aminobutyric acid (GABA), will be tested during eupnea and gasping to differentiate between potential pre- and postsynaptic mechanisms of disinhibition during gasping; 4) Excitatory neurotransmission in the respiratory pattern generator during gasping requires activation of ionotropic glutamergic pathways. We will test this hypothesis by assessing the response of respiratory neurons to ionotropic glutamergic antagonists during eupnea and gasping. Taken together, these studies will permit detailed evaluation of the changes in respiratory neuronal activity and synaptic interactions which underlie the respiratory patterning changes seen during hypoxia.