The long term goals of this project are to understand the functional anatomy of central cholinergic pathways that contribute to behavioral state control mechanisms and higher cortical function. A substantial body of evidence suggests that the cholinergic brainstem nuclei, the pedunculopontine tegmental nucleus (PPT) and laterodorsal tegmental nucleus (LDT), modulate behavioral arousal through widespread innervation of the thalamus, and perhaps through innervation of the lateral hypothalamus and basal forebrain as well. Additional evidence suggests that cholinergic brainstem mechanisms may mediate the onset of rapid-eye-movement (REM) sleep including the generation of pontine-geniculate-occipital (PGO) waves that precede the onset of REM sleep, and the cortical desynchronization and postural atonia that accompany REM sleep. There is also evidence to suggest that brainstem cholinergic pathways may participate in the generation of patterned motor behavior. The major goals of the proposed project are to investigate the anatomical basis of the functional role of these nuclei in arousal and sleep/wakefulness mechanisms, as well as to better define the relationship of these nuclei to brainstem motor generating regions. The first studies will confirm putative PPT/LDT afferents from the periaqueductal gray, dorsal raphe and lateral hypothalamus using anterograde axonal tracing combined with choline acetyltransferase immunohistochemistry analyzed at the ultrastructural level. These putative afferents were identified previously by retrograde tracing and they have been implicated functionally in behavioral state control processes. A second set of experiments will determine if cholinergic PPT and LDT neurons receive synaptic input from catecholaminergic and/or serotonergic brainstem nuclei, using co-localization immunocytochemical techniques at the ultrastructural level. These monoaminergic systems have also been implicated in behavioral state control. The third set of experiments will examine PPT innervation of the midbrain extrapyramidal area, the medial pontine reticular formation, and the medullary gigantocellular field in order to identify anatomical connections which mediate the physiological correlates of REM sleep (ie. PGO waves, rapid eye movements, and postural atonia). The fourth series of experiments will investigate the hypothesis that the midbrain extrapyramidal area might participate in the atonia that accompanies REM sleep by further examination of its afferent and efferent connections. Finally, putative connections of the brainstem cholinergic system with the basal forebrain cholinergic system will be investigated using anterograde tracing from the PPT and LDT to the nucleus basalis and lateral septal areas. The results of these studies will provide anatomical evidence for participation of the PPT/LDT complex in specific physiological processes related to behavioral state.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology A Study Section (NEUA)
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University of Chicago
Schools of Medicine
United States
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