This application's long-term objective is to understand the mechanisms of REM sleep and dPBO wave generation. More specifically, its goal is to determine how the """"""""executive nuclei"""""""" of the REM sleep signs are triggered and modulation by excitatory and inhibitory inputs from the brainstem cholinergic and aminergic neurons. A better understanding of the brainstem PGO wave generation mechanism would provide insight into a number of clinically important sleep related disorders. PGO waves precede REM sleep and play an important role in triggering and maintaining REM sleep. The phemomenology and neurochemistry of narcolepsy, cataplexy, excessive daytime sleepiness, hypnogogic hallucinations, depression and many other major psychiatric and neurological disorders may share some features of normal REM sleep, suggesting a convergence of mechanisms at the level of the brainstem. This application proposes a series of experiments to investigate the basic mechanism of PGO wave generation and its state-dependent modulation. First, retro- and anterograde tracers will be injected into the pharmacologically defined PGO trigger zone of the caudolateral peribrachial are (C-PBL) of the cat to determine its afferent and efferent connections. In identifying the input-output organization of the C-PBL PGO trigger zone, special attention will be paid to the following structures: pedunculopontine tegentum (PPT), laterodorsal tegmentum (LDT), vestibular nucleus (VSN), locus coeroleus (LC), dorsal raphe (DR), and suprachiasmatic nucleus (SCN). In a second series of experiments, extracellular single cell neuronal activity will be recorded continuously for one to three sleep-wake cycles in the aminergic (LC and DR) and cholinergic (PPT and LDT) neurons projecting to the C-PBL. These results will provide quantitative information on whether aminergic and cholinergic neurons projecting to the C-PBL show corresponding decreases or increases of activity in advance of the PGO-related states of SP (slow-wave sleep with PGO waves) and REM sleep. Finally experiments will be conducted to determine if the influence of PPT, LDT, VSN, LC, DR, and SCN neuronal excitation on extracellularly recorded single cell neuronal activity of the C-PBL. Results of these studies are useful in understanding how the PPT, LDT, VSN, LC, DR, and SC N might modulate PGO wave triggering C-PBL cells.
