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Biology of Sleep & Wakefulness

Notes

Biology of Sleep & Wakefulness

Sections


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

  • Amphetamines are adrenergic reuptake inhibitors and are stimulatory
    • They increase the amount of circulating monoamines.
  • 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

  • The sleep center inhibits the wake-promoting cells and the orexin area.

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.

Full-Length Text

  • Here, we will learn the biology of sleep and wakefulness.
  • Start a table.
  • Denote that we will address: 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.
  • We'll address orexin (aka hypocretin), which acts via the flip-flop switch, and is notably dysregulated in narcolepsy.
  • And we'll address key wake-promoting cells that are: cholinergic, histaminergic, dopaminergic, serotinergic, noradrenergic.
  • First: suprachiasmatic circuitry and its regulation of the release of melatonin, which helps drive us to sleep.
  • Draw an outline of the hypothalamus.
  • Label the suprachiasmatic nucleus just above the optic chiasm in the anterior hypothalamus and the paraventricular nucleus above it.
  • Next, show that during the dark phase, descending hypothalamospinal projections from the paraventricular nucleus excite the cervical spinal cord, which, in turn, excites the superior cervical ganglion, which activates the production of melatonin from within the pineal body, causing its release into circulation, which helps promote sleep.
  • Now, show that during the light phase, light passes along the retinohypothalamic pathway to excite the suprachiasmatic nucleus.
  • Then, indicate that the suprachiasmatic nucleus inhibits the paraventricular nucleus, which causes inhibition of the production and release of melatonin, thus promoting wakefulness.

Next, let's address the neurobiology of wakefulness, specifically the neurotransmitters that promote it.

  • 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.
  • Here, we draw the basal forebrain, hypothalamus, and three brainstem levels: midbrain, pons, and medulla, so we can address the wake-promoting cellular regions that have been discovered in each of these anatomic areas.
  • First, include the cholinergic basal forebrain nuclei in the ventral surface of the frontal lobe.
  • Next, draw the tuberomammillary nucleus in the center of the hypothalamus; it is the sole source of histamine in the brain.
  • In the anterior midbrain, group the substantia nigra and ventral tegmental area together and show that they are dopaminergic.
  • Then, indicate the laterodorsal tegmental and pedunculopontine nuclei in the lower midbrain and upper pons and show that they are cholinergic.
  • Next, in the posterior pons, draw the locus coeruleus and label it as noradrenergic (the largest concentration of locus coeruleus neurons lies within the pons).
  • And finally, in the central upper pons and midbrain, draw the dorsal group of raphe nuclei and indicate that they are serotinergic.
  • As a pharmacologic corollary to the list of neurotransmitters involved in wakefulness, consider that amphetamines are adrenergic reuptake inhibitors and are stimulatory — they increase the amount of circulating monoamines; serotonin-norepinephrine reuptake inhibitors (as their name states) increase serotonin and norepinephrine, which are wake-promoting, and cholinesterase inhibitors (like donepezil) are mentally energizing and used to help memory.
  • Regarding sleep-inducing medications, consider that tricyclic antidepressants can be especially sedating because they often have both anti-cholinergic and anti-histaminergic properties, and diphenhydramine (Benadryl) is an anti-histamine, so it causes drowsiness and is used in over-the-counter sleep aids.

Next, we will draw the key function of orexin and its role in the so-called flip-flop switch. Show that it refers to the circuit for the transition between sleep and wake.

First, we'll show the circuit in a state of wakefulness.

  • Establish three main centers: the Sleep center, the Wake-promoting cells, & the Orexin area.
  • Show that the 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.
  • A flip-flop circuit is 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).
    • For reference, the SLEEP CENTER is the following important hypothalamic areas: the ventrolateral preoptic area and the median preoptic nucleus and the OREXIN AREA is the region in the perifornical-lateral hypothalamic populated with orexigenic cells, which form the wakefulness stabilizer, and the Wake-promoting cells are those we addressed in our section on wakefulness neurobiology.
  • Next, reestablish the circuitry.

Here, let's show the flip-flop circuitry in the sleep state.

  • Re-draw the sleep and wake states and the flip-flop switch, and then again include the previously listed structures.
  • Now, show that in the sleep state, the sleep center inhibits the wake-promoting cells and the orexin area.

Additional Information on Clinical Aspects of Sleep

Sleep Stages

  • Here we address the various sleep stages, the percentage of the night the typical adult spends in them, and some of their EEG characteristics.

See Sleep Stages

Wakefulness

  • W - Wakefulness
    • Characterized by alpha waves (posterior dominant, 8 - 12 Hz frequency, observable on eyelid closure).

Non-REM Sleep

  • N1 - Stage 1 - 5%
    • Low-amplitude mixed-frequency (LAMF). For instance, theta activity. Vertex waves can be observed.
  • N2 - Stage 2 - 50%
  • N3 - Stage 3 - 20%
    • Slow wave activity (delta frequency) greater than 20% of the 30 second page.

REM Sleep

  • R - REM - 25%
    • Rapid eye movements and saw-toothed waves.
    • Occurs ~ every 90 minutes; 4 times per night; length of REM extends with every epoch of REM during the night and the time between REM epochs reduces during the course of the night. Less REM earlier in the night/More REM later in the sleep phase.

Effects of items on Sleep Stages

  • Here, we address how various conditions impact the sleep stages, especially REM sleep.

Age

  • INCREASE in overall sleep latency (time to falling asleep) and REM latency (time to first REM cycle).
  • DECREASE in REM sleep.
  • INCREASE in sleep fragmentation.

Depression

  • INCREASE in REM sleep (and also a reduction in REM latency).
  • ALTERATION in the distribution of N3 sleep throughout the night.
  • INCREASE in insomnia (especially difficulties with maintenance of sleep); less common is hypersomnia.

Antidepressants (broad generalization)

  • DECREASE REM sleep (and increase REM latency)
    • As one important exception, buproprion does NOT significantly affect sleep (it does NOT impact REM sleep).
  • INCREASE N3 sleep.
  • Sedating agents (tricyclic antidepressants) INCREASE sleep continuity.
  • Non-sedating agents (eg, serotonin-norepinephrine reuptake inhibitors) can DECREASE sleep continuity.

Alcohol Abuse

  • DECREASE in sleep continuity.
  • DECREASE in N3.
  • INCREASE in REM.