Brainstem neuromodulation and REM sleep

The REM phase of sleep has long been of interest because of its association with dreaming and its presence in almost all mammals. We are now beginning to understand the mechanisms of its rhythmic generation, and we review current hypotheses in this article. A group of cholinergic neurons at the junction of the pons and midbrain, in the laterodorsal and pedunculopontine tegmental nuclei, begins to discharge before the onset of this phase of sleep. Projections to key brainstem reticular formation regions lead, primarily through actions of non-M1 muscarinic receptors, to heightened excitability and discharge activity in these effector regions for the phenomena of REM sleep. Cholinergic projections to the thalamus promote EEG activation. These mesopontine cholinergic neurons are, in turn, modulated by inhibitory and REM-suppressive projections: norepinephrinergic locus coeruleus projections act at α₂ and serotonergic dorsal raphe projections act at 5-HT(1A) receptors. These mesopontine cholinergic neurons are self-modulating through recurrent collaterals and projections between different subgroups that act at muscarinic and nicotinic receptors. In addition, metabolically generated adenosine acts to inhibit these cholinergic neurons. All of the preceding inhibitory effects are mediated by inwardly rectifying potassium currents. Implications of this neural network for a model of REM sleep cycle generation are discussed.