Neurotransmitters in the Sleep-Wake Cycle

This content was developed using literature published in peer-reviewed journals.

Neurotransmitters in the Sleep-Wake Cycle

This content was developed using literature published in peer-reviewed journals.

Overview

Multiple neuronal systems are involved in promoting and stabilizing wakefulness.¹

Orexin (hypocretin) and histamine play distinct yet complementary roles, activating a wide network of downstream neurotransmitter systems in key areas of the brain to promote and stabilize wakefulness.^2-5

These neurotransmitters are produced by distinct nuclei at different levels of the forebrain and brainstem and send diffuse, widespread projections throughout the brain to regulate sleep and wakefulness.¹

These neurotransmitters include^1,6:

Norepinephrine, produced primarily by neurons in the locus coeruleus
Dopamine, mainly produced by the ventral tegmental area, substantia nigra, and ventral periaqueductal gray
Acetylcholine, released by neurons in the basal forebrain, laterodorsal tegmentum, and pedunculopontine tegmentum
Serotonin, produced by neurons in the dorsal and medial raphe nuclei

Figure showing the location of multiple neuronal systems in the brain

Select a neurotransmitter to see more information about it.

Orexin (hypocretin) (LH)
Norepinephrine (LC)
Dopamine (vPAG)
Dopamine (VTA)
Acetylcholine (BF)
Acetylcholine (LDT/PPT)
Serotonin (DR)

BF, basal forebrain; LC, locus coeruleus; LDT, laterodorsal tegmentum; LH, lateral hypothalamus; PPT, pedunculopontine tegmental nucleus; RN, raphe nuclei; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray; VTA, ventral tegmental area.

Orexin (hypocretin) neurons and histamine neurons^3,5,7-10

Are located in close proximity to one another in the hypothalamus
Activate cortical and subcortical neurons as well as wake-promoting neurons outside of the hypothalamus

Norepinephrine neurons^1,3,11

Originate in the locus coeruleus and play a central role in vigilance and arousal
Are active during attentive wakefulness and almost entirely silent during REM sleep
Fluctuate in activity during non-REM to define different states of non-REM sleep

Dopamine neurons^12-17

Release dopamine, which acts as an arousal agent in the brain, with elevated levels during wakefulness
Are stimulated by both orexin (hypocretin) and histamine-producing neurons to release dopamine in areas associated with higher cognitive, motivational, and goal-oriented behavior, such as the prefrontal cortex, ventral tegmental area, and nucleus accumbens
Are affected by histamine during development; their activity may also be differentially influenced by histamine, as shown in the ventral midbrain in rats

Acetylcholine neurons³

Are active during both wakefulness and REM sleep
Project to the sublaterodorsal nucleus region of the brain and play an important role in generating the muscle atonia of REM sleep

Serotonin neurons^3,18

Are known to promote wakefulness and inhibit REM sleep–promoting neurons during the day
Play a key role in maintaining arousal through activity of serotonergic cells in the dorsal raphe nucleus, regulating muscle tone and the phases of REM sleep

Learn more about the normal sleep-wake cycle.

References

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