What is the flip-flop switch model of sleep regulation?

Updated: Sep 11, 2018
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Selim R Benbadis, MD  more...
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Answer

Saper and colleagues proposed the flip-flop switch model of sleep-wake regulation. [19] This flip-flop circuit consists of 2 sets of mutually inhibitory components. The sleep side is the VLPO, and the arousal side includes TMN histaminergic neurons and brainstem arousal regions (the DRN serotonergic neurons, VTA dopaminergic neurons, and LC noradrenergic neurons).

Each side of the switch inhibits the other. For example, when activation of one side is slightly stronger, the weaker side has increased inhibition, thus further tipping the balance toward the stronger side. This flip-flop switch allows for rapid state transitions. (See the schematic flip-flop switch model in the image below.)

Schematic flip-flop switch model. Adapted from Sap Schematic flip-flop switch model. Adapted from Saper C et al. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263.

Hypocretin neurons in the posterolateral hypothalamus are active during wakefulness and project to all of the wakefulness arousal systems described above. Hypocretin neurons interact with both the sleep-active and the sleep-promoting systems and act as stabilizers between wakefulness-maintaining and sleep-promoting systems to prevent sudden and inappropriate transitions between the 2 systems. [20]

Narcolepsy with cataplexy illustrates the disruption of this system. These patients have a greater than 90% loss of hypocretin neurons, and they have sleep-wake state instability with bouts of sleep intruding into wakefulness. [21]


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