Regulation of Sleep and Wakefulness

Sleep and wakefulness are regulated by a number of neurotransmitters, as well as neuromodulators within specific brain regions1.

Physiology

The underlying physiology of sleep and wakefulness is complex. Different Neurons and Neurotransmitters promote different states of sleep and wakefulness. They are therefore categorised based on state-specific discharge patterns and/or transmitter release and other neurobiological classifications.

State-specific discharge patterns

Neurons are classifiable based on their discharge-pattern. During each behavioral state, there are neurons that fire at a higher rate as others. More specifically:

• Wake-On (/REM-Off)
• Wake-On/ REM-On
• REM-On
• NREM-On

State-specific transmitter secretion

In neurobiology, neurons are also classified by their state-specific transmitter release.

Monoamines (here: serotonin, norepinephrine, histamine): Densest release during wakefulness.

Acetylcholine: Densest release during both wakefulness and REM sleep.

GABA ( γ-aminobutyric acid): Densest release during NREM sleep.

Neurotransmitters regulating behavioral states

Wakefulness

Acetylcholine, Serotonin, Norepinephrine, Histamine, Dopamine, Orexins, Glutamate (,GABA)

NREM

GABA, Adenosine

REM

Acetylcholine, GABA

The neurotransmitter GABA has brain region specific effects on behavioral states.

GABA in the pontine reticular formation promotes sleep and decreases wakfulness, by inhibiting the secretion of acetylcholine, which promotes Rem-sleep.

However, neurons activated by GABA in the basal forebrain fire the fastest during NREM sleep, and is NREM promoting.

Adenosine, the other major neurotransmitter involved in the onset of NREM sleep, increases proportional to the time spent awake in the basal forebrain. It is the neurotransmitter thouoght to be the major regulator of Process S in the 2-Process Model of Sleep.

Models

In order to comprehend the mechanisms better, conceptual models of sleep-wake regulation have been created. In addition to the conceptualised models, mechanical models co-exist, that aim to describe the underlying physiology of the mechanisms in more detail.

Two-process model of sleep

The two-process model of sleep is a conceptual model that aims to relate the behavioral state regulation to two main procedures. Process-S describes the increasing homeostatic pressure, the more time spent awake (Adenosine-alertness hypothesis link) and deacreses during time spent asleep . Process C describes the ~24h circadian framework in which sleep can occur.

In order to visualise the components of the model, the graph of the study "A Two-Process Model for Circadian and Sleep-dependent Modulation of Pain Sensitivity" is used

https://www.biorxiv.org/content/10.1101/098319v1.full