The sleep apnea syndromes have been estimated to affect 1 to 5% of the older adult male population, while the sudden infant death syndrome (SIDS) is the leading cause of death in infants between 1 month and 1 year of age. Common to both disorders are respiratory pauses occurring during sleep (apneas) resulting in abnormalities in oxygenation, cardiovascular dysfunction, and sleep disruption. In affected individuals, breathing is particularly disrupted during rapid eye movement (REM) sleep but the exact neuronal mechanisms through which REM sleep induces respiratory abnormalities are unknown. The difficulty of studying breathing during REM sleep is accentuated by the transient occurrence of REM sleep and by the fact that REM sleep is disrupted by many experimental manipulations. The studies proposed here will overcome these difficulties by applying an established pharmacological model of REM sleep to the study of breathing. Microinjecting cholinergic agonists (e.g., carbachol) into the pontine reticular formation of awake, unanesthetized animals produces a state which is polygraphically similar to REM sleep. With this method one gains experimental control over the occurrence of the REM sleep-like state. This pharmacological model has made important contributions to our understanding of the cholinergic control of REM sleep but has not yet been systematically applied to the study of breathing during sleep. Accordingly, the long-term objectives of the proposed research are to determine whether cholinoceptive mechanisms in the pontine reticular formation causally mediate REM sleep- related respiratory alterations.
The specific aims of this 5 year research plan are: 1) To test the hypothesis that pontine carbachol administration alters breathing during sleep and upper airway muscle function; 2) To centrally administer cholinergic antagonists (atropine and pirenzepine) prior to carbachol in order to test the hypothesis that reticular M1 and M2 muscarinic cholinergic receptor mechanisms can cause state-dependent respiratory changes; 3) Chemosensitivity is depressed during natural REM sleep but the mechanisms of decreased responsivity to hypoxia are not clear. In order to test the hypothesis that cholinergic mechanisms contribute to this diminished chemosensitivity, Year 3 studies will characterize and compare the hypoxic ventilatory response during natural REM sleep and during the REM sleep-like state caused by carbachol; 4) Since the discharge level of pontine respiratory group (PRG) neurons may be of special relevance for apneic breathing, Year 4 studies will test the hypothesis that the REM sleep depression of PRG neuron discharge will also occur during the carbachol induced REM sleep-like state; 5) To date, there have been no recordings of any respiratory neurons during the carbachol induced REM sleep-like state. Year 5 studies will test the hypothesis that cholinoceptive reticular mechanisms contribute a diminished respiratory drive to PRG neurons during sleep.
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