Biology of Sleep & Wakefulness

The biology of sleep and wakefulness

Key Topics

The suprachiasmatic nucleus (the master timekeeper) to adjust the production and release of melatonin and, in turn, the timing of our internal clock with help from the retinohypothalamic pathway.
Orexin (aka hypocretin), which acts via the flip-flop switch, and is notably dysregulated in narcolepsy.
Wake-promoting cells that are: cholinergic, histaminergic, dopaminergic, serotinergic, noradrenergic.

suprachiasmatic circuitry & melatonin

Melatonin helps drive us to sleep.

Key Anatomy

The suprachiasmatic nucleus lies just above the optic chiasm in the anterior hypothalamus and the paraventricular nucleus lies above it.

Dark Phase

During the DARK phase, descending hypothalamospinal projections from the paraventricular nucleus excite the cervical spinal cord.
The cervical spinal cord, in turn, excites the superior cervical ganglion.
The superior cervical ganglion activates the production of melatonin from within the pineal body, causing its release into circulation, which helps promote sleep.

Light Phase

During the LIGHT phase, light passes along the retinohypothalamic pathway to excite the suprachiasmatic nucleus.
The suprachiasmatic nucleus inhibits the paraventricular nucleus, which causes inhibition of the production and release of melatonin, thus promoting wakefulness.

The neurobiology of wakefulness

In the 1940s and 1950s neurophysiologists Giuseppe Moruzzi and H. W. Magoun performed a series of EEG studies to prove the existence of the wakefulness center.
They described an active arousal generator in the brainstem reticular formation, coined the ascending reticular activating system, which was shown to directly and indirectly activate the cerebral cortex by way of diff use projection fibers; we addressed these intralaminar thalamic projections in the thalamus section.

Key nuclear groups

The cholinergic basal forebrain nuclei in the ventral surface of the frontal lobe (orbitofrontal gyri).
The tuberomammillary nucleus in the center of the hypothalamus: it is the sole source of histamine in the brain.
The substantia nigra and ventral tegmental area (which are dopaminergic): in the anterior midbrain.
The laterodorsal tegmental and pedunculopontine nuclei in the lower midbrain and upper pons (which are cholinergic).
The locus coeruleus (which is noradrenergic): in the posterior pons - (the largest concentration of locus coeruleus neurons lies within the pons).
The dorsal group of raphe nuclei and (serotinergic) - in the central upper pons and midbrain.

Pharmacologic corollaries

Wake-promoting

Serotonin-norepinephrine reuptake inhibitors (as their name states) increase serotonin and norepinephrine, which are wake-promoting.
Cholinesterase inhibitors (like donepezil) are mentally energizing and used to help memory.

Sleep-inducing

Tricyclic antidepressants can be especially sedating because they often have both anti-cholinergic and anti-histaminergic properties.
Diphenhydramine (Benadryl) is an anti-histamine, so it causes drowsiness and is used in over-the-counter sleep aids.

orexin and the flip-flop switch

Wakefulness

Wake-promoting cells inhibit the sleep center and that the orexigenic cells excite the wake-promoting cells: they stabilize the biphasic aspect of this physiology.

Sleep

Flip-Flop Circuit

An electrical engineering term for a switch that avoids transitional states; the circuit is in either one of two states but not a blend of both.
If you are tired when you lie down, you quickly fall asleep, and when you're ready to rise, you suddenly wake up.
This is unlike most other key physiologic processes, which function along a continuum (eg, heart rate or respiratory rate).

Sleep Center

For reference, the SLEEP CENTER is the following important hypothalamic areas: the ventrolateral preoptic area and the median preoptic nucleus.

Wakefulness stabilizer

OREXIN AREA is the region in the perifornical-lateral hypothalamic populated with orexigenic cells, which form the wakefulness stabilizer.

Wake-promoting cells

Wake-promoting cells are those we addressed in our section on wakefulness neurobiology.