The Flip-Flop Switch – Moving Between Waking and Sleep

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Falling Asleep

A part of the brain called the ventrolateral pre-optic (VLPO) area is important in the initiation of sleep. VLPO neurons fire at about 1 to 2 Hz during waking and several times faster during NREM sleep. When the individual has been deprived of sleep, the NREM firing rate is even higher – twice the normal rate.

Scientists have found that damage to the VLPO section (which is inside the thalamus, deep in the brain) can lead to reduction in normal sleeping times. As people age, neurons in the VLPO can die. This is thought to be part of the reason for decline in sleep quality with age.

The VLPO secretes the neurotransmitter GABA, which induces sleepiness and counteracts in some way excitatory neurotransmitters.

Networks in Your Head

Staying awake depends on several networks of cells in the thalamus and cerebral cortex. There is effectively a “switch” in the hypothalamus that turns the waking system off. It’s not actually a switch as in an electrical circuit, but it functions in a similar, if less definitive, way.  The neurons are activated during waking and REM sleep and are less active during NREM.

Orexin neurons keep us awake during the day. The proximate cause of wakefulness – the part of the physiology that makes us wake up in the morning and stay awake through the day – is a neural network inside the larger nervous system. A virtual circuit in the hypothalamus – a part of the brain lower in the head – shuts off this arousal during night and lets us sleep. Damage to the hypothalamus screws up normal function of this switch and can result in narcolepsy. In normal function, however, the arousal system of neurons secretes the neurotransmitter orexins during the day. This system runs through the thalamus into the cerebral cortex.

Extracellular sleep regulation chemicals including tumor necrosis factor a (TNF) and interleukin-1 act on neurons (brain cells that make up the network) to change their intrinsic membrane properties and sensitivities to brain chemicals including GABA (which is targeted by many sleep drugs), adenosine (which is inhibited by caffeine), and glutamate. These actions change the network input-output properties, i.e., a state shift for the network

This way of looking at sleep is that it is an emergent property of some of the brain’s neural networks. Emergence is a word used to describe characteristics of complex systems that arise from simpler interactions of small elements. Many properties in organismic and evolutionary biology are considered emergent, and the concept finds its way to explanations of the origins and physiology of higher order behavior. In this hypothesis, “sleep is this type of property of populations of subnetworks inside the brain undergoing state transitions”.

The Sleep Switch

We move between waking and sleep and between REM sleep and Non-REM sleep rapidly. On an EEG you can see the clear transitions and they take only a few seconds. This shows how the brain is largely an electrical system, but the explanation of how the switch occurs has been a mystery that only in recent years physiologists are starting to unravel.

In systems theory, a feedback loop with circuits running in opposite is called a flip flop switch. Because they are so clearly in one position or another, flip-flow switches are widely used in digital electronics. The activity of each circuit inhibits activity from the other circuit and therefore disinhibits itself. Flip-flop circuits avoid transitional states and are, from an external perceptive, either on or off. This matches with our empirical observation of healthy sleep. The person is either asleep or awake and the transition between the two is fast and distinct.

Systems theory shows that if one of the circuits in the flip-flop switch becomes weaker, the system operates closer to the transition point. We see this in the neural sleep control with parasomnias and sleep-wake disorders . People with lesions in the VPLO fall asleep more often that normal people. Narcoleptics have experienced death in their orexin cells and weakening of that side of the switch.

Poor, fragmented sleep during the night and drowsiness and napping during the day could be explained by similar phenomena. The healthy brain is one where both circuits are strong and self-stabilizing. If one weakens, the system becomes less stable, less decisive in its sleep or wakefulness. The aging brain often loses some of the cells that are part of the wake-promoting system and the sleep-promoting system. The person still goes through sleep and waking, but the systems are less stable and sleep is more likely to be fragmented.

It could also be that narcolepsy is due to a malfunction in the flip-flop switch.

If the flip-flop switch hypothesis is true, that means it is less likely scientists will find general biomarkers for sleepiness.

Starting REM

Another vexing question is the how the brain moves into REM sleep from NREM. A recent hypothesis is that the in an area near base of the brain called the mesopontine tegmentum are virtual switches – consisting of neurons – that regulate the change between REM and NREM.  In this model, both virtual switches include neurons that produce the neurotransmitter GABA. The switch that activates REM also contains glutamatergic neurons. These glutamatergic neurons project to both the basal forebrain and and to the medulla and spinal cord where they tell the skeletal muscles to freeze up during REM.

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