The lateral cell columns of the midbrain periaqueductal gray (PAG) constitute a major anatomical link between hypothalamic regions implicated in sleep-wake control and respiratory control sites within the medulla. Stimulation of the PAG can alter respiration and neurons with respiratory- related discharge have been identified within the PAG of primates and cats. We hypothesize that hypothalamic sleep-wake control mechanisms modulate medullary respiratory control systems, in part, via effects on PAG neurons. Specifically, we hypothesize that gamma-aminobutyric acid (GABA)- containing neurons from the preoptic anterior hypothalamic area (POA) exert inhibitory effects on respiratory-related PAG neurons during non-REM sleep. We have previously demonstrated that thermosensitive neurons are a critical component of the POA sleep control mechanism, and we hypothesize that focal POA warming will enhance GABA-mediated inhibition of PAG respiratory-related activity. To test these hypotheses, we will: 1) document the extent of the direct GABAergic projection from the POA to the PAG in rats and cats; 2) determine the ability of PAG micro-infusions to suppress breathing and upper airway muscle activity in rat and cats during waking and sleep; 3) document the state dependency of respiratory-related neuronal activity within the lateral PAG cell columns using chronic micro-wire recording techniques, and determine whether or not changes observed in on-REM sleep are similar to those evoked by mild hypothalamic warning; 4) attempt to prevent non-REM sleep-related and POA-warming induced changes in PAG neuronal activity by concurrently delivering GABA-receptor antagonists to PAG micro-wire recording sites via an adjacent microdialysis probe. Proposed studies will be the first to directly examine the involvement of extensive POA>PAG> medullary pathways in state-dependent respiratory control. They will help to characterize the functional neuroanatomy and the neuropharmacology of normal and disordered breathing during sleep.
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