Understanding Rem Sleep Flip-Flop: Brain's Unique Wake-Up Call

The neuronal circuits responsible for switching between REM and non-REM sleep remain poorly understood. A putative flip-flop switch for the control of REM sleep has been proposed, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. The REM-off region is identified by the overlap of inputs from the orexin neurons and the extended ventrolateral preoptic nucleus (eVLPO). These neurons in the ventrolateral periaqueductal grey matter (vlPAG) and the lateral pontine tegmentum (LPT) have a mutually inhibitory interaction with REM-on GABAergic neurons of the ventrolateral sublaterodorsal nucleus (vSLD), but also inhibit REM generator circuitry in the remainder of the SLD and the precoeruleus (PC) region. 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.

The neuronal circuits responsible for switching between REM and non-REM sleep

The REM-off area is composed of GABAergic neurons in the ventrolateral periaqueductal grey matter (vlPAG) and the lateral pontine tegmentum (LPT). The REM-on area is composed of glutamatergic neurons in the sublaterodorsal nucleus (SLD) and precoeruleus (PC) area.

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.

The brainstem flip-flop switch

Each side of the brainstem flip-flop switch contains GABA (gamma-aminobutyric acid)-ergic neurons that heavily innervate the other side. The REM-on area also contains two populations of glutamatergic neurons. One set of glutamatergic neurons projects to the basal forebrain and regulates EEG components of REM sleep. The other set 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.

The REM-off region

The vlPAG is a critical structure in the brainstem that is involved in various functions, including pain modulation, fear responses, and sleep regulation. It receives inputs from several brain regions, such as the amygdala, hypothalamus, and cortex, and sends outputs to various brainstem nuclei and spinal cord regions. The LPT, on the other hand, is a region located near the vlPAG and is also implicated in sleep regulation.

The inhibitory nature of the REM-off region and its interplay with the REM-on region form a flip-flop switch, which enables sharp transitions between REM and non-REM sleep. This switch is hypothesized to contribute to the vulnerability of sudden and unwanted transitions between sleep states, as seen in conditions like narcolepsy.

The REM-on region

The SLD, which is part of the REM-on region, plays a crucial role in promoting REM sleep. It contains glutamatergic neurons that project to two distinct areas: the basal forebrain and the medulla-spinal cord. The projections to the basal forebrain are responsible for regulating the electroencephalogram (EEG) components of REM sleep, including the characteristic rapid eye movements. On the other hand, the projections to the medulla and spinal cord are involved in regulating atonia, or muscle paralysis, during REM sleep. This ensures that the body remains relaxed and immobile while the brain is active during dreaming.

The PC area, also part of the REM-on region, has a distinct role in activating hippocampal theta activity during REM sleep. Hippocampal theta waves are associated with memory consolidation and spatial navigation. The activation of these waves by the PC area suggests a potential link between REM sleep and memory processing.

The identification of the REM-on region and its functions has provided valuable insights into the complex neuronal circuits that govern sleep. By understanding the role of this region, researchers can further explore the underlying mechanisms of sleep regulation and its potential links to various physiological processes, such as memory and cognitive function.

The interrelationship of the two halves of the REM switch

The mutually inhibitory interactions between the REM-on and REM-off areas form a flip-flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions, such as in narcolepsy. The REM-on area includes the sublaterodorsal nucleus and precoeruleus, while the REM-off area includes the ventrolateral periaqueductal grey matter and the lateral pontine tegmentum.

The REM-on and REM-off areas have distinct functions and work together to regulate the transition between REM and non-REM sleep. The REM-off area is responsible for inhibiting REM generator circuitry and plays a role in muscle atonia during REM sleep. On the other hand, the REM-on area is involved in regulating EEG components and atonia during REM sleep.

The cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei are also worth noting as they are REM-on and may inhibit the REM-off area. Additionally, serotoninergic dorsal raphe and noradrenergic locus coeruleus neurons activate the REM-off circuitry, which can be suppressed by monoamine re-uptake inhibitors.

Overall, the interrelationship of the two halves of the REM switch involves a complex interplay between various brain regions and neurotransmitter systems, which work together to regulate the transition between REM and non-REM sleep.

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