Neural mechanism of rapid eye movement sleep generation with reference to REM-OFF neurons in locus coeruleus.

The noradrenergic (NA-ergic) rapid eye movement (REM)-OFF neurons in locus coeruleus (LC) and cholinergic REM-ON neurons in laterodorsal/pedunculopontine tegmentum show a reciprocal firing pattern. The REM-ON neurons fire during REM sleep whereas REM-OFF neurons stop firing during REM sleep. The cessation of firing of REM-OFF neurons is a pre-requisite for the generation of REM sleep and non-cessation of those neurons result in REM sleep loss that is characterized by symptoms like loss of memory retention, irritation, hypersexuality, etc. There is an intricate interplay between the REM-OFF and REM-ON neurons for REM sleep regulation. Acetylcholine from REM-ON neurons excites the GABA-ergic interneurons in the LC that in turn inhibit the REM-OFF neurons. The cessation of firing of REM-OFF neurons withdraws the inhibition from the REM-ON neurons, and facilitates the excitation of these neurons resulting in the initiation of REM sleep. GABA modulates the generation of REM sleep in pedunculopontine tegmentum (PPT) by acting pre-synaptically on the NA-ergic terminals that synapse on the REM-ON neurons whereas in LC it modulates the maintenance of REM sleep by acting post-synaptically on REM-OFF neurons. The activity of REM sleep related neurons is modulated by wakefulness (midbrain reticular formation/ascending reticular activating system) and sleep inducing (caudal brainstem/medullary reticular formation) areas. Thus, during wakefulness the wake-active neurons keep on firing that excites the REM-OFF neurons, which in turn keeps the REMON neurons inhibited; therefore, during wakefulness REM sleep episodes are not expressed. Additionally, the wakefulness inducing area keeps the REM-ON neurons inhibited. In contrast, the sleep inducing area excites the REM-ON neurons. Thus, the wakefulness inducing area excites and inhibits the REM-OFF and REM-ON neurons, respectively, while the sleep inducing area excites the REM-ON neurons that facilitate the generation of REM sleep.