The cholinergic hypothesis of rapid eye movement (REM) sleep generation proposes that the REM phase of the mammalian sleep cycle is generated, in part, by pontine cholinergic systems. The long term objectives of this proposal are to characterize the cholinergic mechanisms that generate REM sleep by linking behavioral level analyses with studies of cholinergic neurotransmission and cholinergic receptors. The proposed experiments will use the techniques of in vivo microdialysis and microinjection in intact, unanesthetized animals, and in vitro receptor autoradiography to test 4 hypotheses, as outlined in the following specific aims:
Aim 1 will test the hypothesis that the basal forebrain inhibits REM sleep by causing reduced acetylcholine (ACh) release in the gigantocellular tegmental field (FTG) of the pontine reticular formation. ACh will be measured in FTG dialysates using high performance liquid chromatography.
Aim 2 will use the microinjection technique to test the hypothesis that the inhibition of REM sleep produced by basal forebrain carbachol administration is anatomically site-specific within the forebrain, and is mediated by muscarinic cholinergic receptors (mAChRs).
Aim 3 will test the hypothesis that multiple mAChR subtypes in the pons are important for REM sleep generation by microinjecting mAChR subtype-selective antagonists into the FTG and quantifying the effects on sleep and wakefulness.
Aim 4 will use in vitro receptor autoradiography to localize and quantify the mAChR subtypes present in regions of cat brain known to be important for sleep cycle control. The potential health relatedness of studies designed to elucidate the neurobiologic mechanisms generating sleep is clearly relevant for several medical specialties. Most major psychiatric disorders are characterized by abnormal sleep, and common neurobiologic mechanisms are thought to underlie REM sleep and certain forms of depression. Sleep disorders affect approximately 80 million Americans, yet most sleep disorders are poorly understood at the mechanistic level. The loss of waking consciousness, due to onset of natural sleep or anesthesia, is characterized by respiratory depression. Sleep-disordered breathing is estimated to affect a significant number of Americans, and the same brain stem cholinergic systems that cause REM sleep are known to contribute to state-dependent respiratory depression. Thus, the basic information derived from the proposed studies will be of potential relevance to psychiatry, sleep disorders medicine, pulmonary medicine, and anesthesia.
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