Chronic hypoxemic events occur in numerous pathologic conditions, such as lung disease and sleep apnea. The experiments outlined in this application examine a neuromodulatory mechanism involving the ventrolateral pons. The investigators hypothesize that the central respiratory pattern generator (RPG) is reconfigured under chronic hypoxic conditions and that these changes require the ventrolateral pons. They have shown that after acute hypoxia in anesthetized rats, breathing frequency declines below resting level (termed post-hypoxic frequency decline) due to significant increases in expiration. The posthypoxic pattern indicates a """"""""memory"""""""" or """"""""plasticity"""""""" in breathing frequency. This remodeling can be evaluated in terms of changes in the ventilatory pattern after chronic hypoxia.
The specific aims are: 1) To demonstrate that the RPG, remodeled after long-term exposure to hypoxia, depends upon the ventrolateral (vl) pons. The short-term response will be quantified in conscious rats before and after chronic intermittent and chronic sustained hypoxia; 2) To identify connections between vl pontine neurons that prolong expiration and other pontomedullary respiratory sites activated by hypoxia. Reciprocal pathways will be traced with anterograde (biotinylated dextran amine, BDA) and retrograde (cholera toxin B, CTB) tracers. Moreover, in the same experiments, neurons activated by hypoxia in the relevant pathways will be identified by Fos protein; and 3) To demonstrate that remodeling of the RPG after chronic hypoxia depends upon alterations in glutamatergic and noradrenergic mechanisms in the pontomedullary circuits containing v1 pontine neurons that prolong expiration. It is hypothesized that pharmacologic intervention at glutamatergic receptors and noradrenergic receptors alters the ventilatory response to hypoxia; i) N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists will be pressure ejected onto v1 pontine neurons and at the terminal fields of their axons identified in Specific Aim 2. Effects of these antagonists on expiratory duration (TE) after hypoxia will be quantified; ii) Changes in the levels of glutamate and monoamines (serotonin and noradrenaline) released following chronic intermittent and chronic sustained hypoxic exposures will be quantified (Palkovits punch technique) at sites identified in Specific Aim 2. The long-term objective is to identify the neuromodulatory mechanisms and pathways responsible for remodeling the central respiratory pattern generator during adaptation of ventilation to hypoxia.
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