The broad, long-term objectives of this application are to specify, at the level of muscarinic cholinergic receptors (mAChRs) and mAChR-coupled signal transduction pathways, the mechanisms generating and modulating REM sleep.
The specific aims are unified by their focus on cholinergic neurotransmission, mAChRs, and mAChR- activated guanine nucleotide binding proteins (G proteins) in pontine and forebrain nuclei known to regulate REM sleep. The proposed studies will advance scientific knowledge by localizing a specific signal transduction pathway to REM-sleep-related brain stem regions, by demonstrating GABAergic modulation of acetycholine (Ach) release in the medial pontine reticular formation (mPRF), and by elucidating the relationship between pontine muscarinic autoreceptors and electroencephalographic (EEG) spindle generation.
Aims 1 and 2 will use techniques of in vitro autoradiography and [35s]GTPGS binding to localize and quantify cholinergically-activated G proteins in specific brain nuclei.
Aim 1 will test the hypothesis that a pertussis toxin sensitive (Gi- like) G protein is activated by stimulating mACHRs in REM sleep- related nuclei of the pontine brain stem.
Aim 2 will test the hypothesis that cholinergic agonists activate G proteins in forebrain regions known to modulate cortical EEG arousal and sleep/wake states.
Aims 3 and 4 will use techniques of in vivo microdialysis, HPLC and polygraphic recordings of sleep/wake states.
Aim 3 will test the hypothesis that GABAergic neurotransmission at the GABAa receptor alters REM sleep, in part, by modulating Ach release in the mPRF.
Aim 4 will test the hypothesis that muscarinic autoreceptors in the mPRF modulate the cortical EEG, in part, by altering thalamic Ach release. Basic studies of sleep neurobiology continue to provide insight into brain mechanisms regulating human sleep and mental health. Most psychiatric disorders are characterized by disrupted sleep, and altered cholinergic neurotransmission is thought to contribute to the etiology of certain types of depression. The potential health relatedness of the proposed project derives from the good correspondence between pre-clinical and clinical research demonstrating that pontine cholinergic neurotransmission contributes to the regulation of sleep and affective states. This application proposes novel experiments aiming to elucidate the role of mAChRs, ACH release, and cholinergically activated G proteins in the regulation of REM sleep.
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