A putative flip–flop switch for control of REM sleep

Abstract

Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip-flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (gamma-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip-flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions-for example, in narcolepsy.

Sleep stability and transitions in patients with idiopathic REM sleep behavior disorder and patients with Parkinson’s disease

“…Specifically, REM stability was affected, which involves the neurological networks controlling REM-NREM sleep transitions presented as consisting of REM-on and REM-off areas located in the brainstem (Lu et al, 2006;Luppi et al, 2011). The REM-on area is thought to contain two populations of neurons, where one set projects into the basal forebrain and regulates EEG components of REM sleep, and the other projects into the medulla and spinal cord and regulates atonia during REM sleep (Lu et al, 2006). As a diagnostic criterion of RBD is loss of atonia during REM sleep, the neurons regulating atonia must be affected to some degree in these patients.…”

Pharmacogenetic inhibition of the subcoeruleus region influences rem sleep and cataplexy in narcoleptic mice

“…Also, neurological tracing do not connect cholinergic groups to other critical REM centres such as the ventral gigantocellular reticular nucleus (GiV), a group critical to REM sleep atonia [26]. Last, lesions of the cholinergic LDT/PPT in rats did not change amounts of REM sleep [11]. From these findings it is clear that the onset and maintenance of REM sleep is due at least in part cholinergic and monoaminergic mechanisms.…”

“…Once the vlPAG is inhibited, the SubC is disinhibited, making entry into REM sleep more conducive [11]. How the SubC regulates the timing or exact entry into REM sleep is up to debate.…”

“…It has since been well established that connections between the pons and groups of the medial medulla play contribute to REM sleep atonia [5]. Lesion and pharmacological studies pointed to the SubC as the pontine group critical to REM sleep [11,29].…”

“…Fos staining refined the understanding by implicating a specific pontine cell population, in rodents an area named the sublaterodorsal nucleus (SubC), as the point of induction and maintenance of REM sleep and REM sleep atonia [8][9][10][11]. The SubC is a small pontine nucleus representing a mix of glutamateric and GABAergic neurons; located ventral to the locus coeruleus (LC), medial to the trigeminal motor nucleus (MO5) and ventromedial to the laterodorsal tegmental nucleus (LDT) and the parabrachial nucleus (PB).…”