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The Science of Sleep II > 6 - The Pineal Gland and Melatonin > Flashcards

6 - The Pineal Gland and Melatonin Flashcards

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1
Q

What is the most important entrainer for the pacemaker of the circadian system?

A

Light

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2
Q

How was the Suprachiasmatic nucleus discovered?

A

IT was observed in the Syrian Hamster that there were fibres the split from the optic chiasm and connected with a nucleus (the suprachiasmatic nucleus).

This new tract was called the retinohypothalamic tract. Lesioning experiments with light showed that it was crucial for entrainment by light.

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3
Q

What is observed after lesioning of the LCN?

A

Light cannot entrain the circadian system

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4
Q

What is the path of fibres that split of from the optic chiasm and connect to the SCN?

A

Retinohypothalamic tract

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5
Q

What are the three criteria to being a pacemaker?

A
  • Has to be self sustained oscillator
  • Has to have access to light or other appropriate signal that entrains rhythms
  • Must impose its own rhythms on other systems
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6
Q

What happens when the SCN is lesioned?

A
  • Entrainment to light stops
  • Abolishment of rhythm

This does not prove that the SCN is the pacemaker of the brain, as it doesn’t prove that it generates its own reciprocity.

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7
Q

What proves that the SCN is a self sustained oscillator?

A

SCN firing rate is rhythmic even under continuous darkness (not complete proof)

Taking the SCN out of a brain slice (isolated) and observing the continuation of rhythms (this proves it).

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8
Q

How can other tissues (besides the SCN) show rhythms? Does this mean they are pacemakers?

A

Under the control of the SCN. They can continue to oscillate after isolation from the SCN, but it weakens after a while.

They are not pacemakers.

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9
Q

True or false? Circadian rhythms are seen in individual SCN neurons

A

True

BUT, the cells are not synchronous with each other (autonomous circadian rhythms that are completely independent from one another that run at different periods).

An intracellular process generates rythmicity

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10
Q

Each one of the 20,000 SCN neurons is an independent circadian rhythm oscillator. How? (BIG answer - 6)

A
  • CLOCK and BMAL1 are transcribed
  • CLOCK-BMAL1 heterodimer binds with E-box to promote expression of Per (period) gene and crytpochrome (CRY) gene
  • Per and Cry (transcriptional regulator clock proteins) build up in the cytoplasm
  • Per and Cry migrate back into the nucleus and prevent CLOCK-BMAL1 from producing more Per and Cry
  • Levels of Cry and Per decrease as they are metabolized
  • Inhibition of CLOCK-BMAL1 is lost and the cycle starts again

This cycle takes about 24 hours. This mechanism is very conserved across evolution.

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11
Q

Most biochemical processes oscillate in seconds and rarely minutes. The mammalian circadian clock takes about 24 hours to complete. Why?

A

Because the circadian clock is through clock gene components

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12
Q

How can you eliminate visual entrainment without blinding an animal?

A

Lesioning the connections between the base of the SCN and the retinohypothalamic tract.

This produces a free running rhythm (removes entrainment, but keeps the rhythm)

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13
Q

What happens to entrainment when you have mutations in mice (knockout) that causes the complete degeneration of rods and cones? Why?

A

The animal is blind, but entrainment still happens.

A photopigment in the retina of mice, melanopsin, that is not contained in rods, cones or bipolar cells, does this.

Melanopsin is contained in ganglion cells.

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14
Q

What is melanopsin?

A

A photopigment that is only contained in odd retinal ganglion cells.

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15
Q

What is different about retinal ganglion cells with melanopsin, compared to those without?

A
  • Bigger
  • Larger receptive fields
  • Suprachiasmatic nucleus receives huge projections from these cells
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16
Q

What do melanopsin-KO mice show?

A

Animals still entrained.

Retinal ganglion cells with melanopsin receive signals from rods and cones.

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17
Q

What sort of knockout will remove entrainment abilities from the retina?

A

Triple Knockout:

  • Ganglion cell melanopsin
  • Rod photopigment
  • Cone photopigments
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18
Q

What motor action does ganglion cell melanopsin regulate?

A

Dilation and contraction of the pupil

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19
Q

What happens if you take a fetal SCN and stick it into a brain of an animal that doesn’t have rhythm (eg. from SCN damage)?

A

it restores rhythmicity to the arrhythmic brain.

However, it cannot be entrained.

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20
Q

How do you prove that the SCN is the pacemaker, and not just producing a substance that is needed by the real pacemaker?

A

A mutant mice was found with an altered circadian rhythm (tau mutation)

She was put in constant darkness, generated a nice circadian rhythm, but with a 22 hr period.

Homozygote tau mutant (20 hr period) was given a fetal transplant of a wild type SCN and the wild type animal gets a mutant tau homozygote SCN.

Free running circadian rhythms developed.

Every cell in body is tau -/- except for wild type SCN, yet a 24 hr period developed! SCN is definitive pacemaker.

The wild type animal with tau mutant SCN generated a 19 hour free running rhythm.

The genotype of the SCN determines the phenotype of the rest of the body.

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21
Q

What is the tau mutation?

A

A single gene mutation (think Mendel level simplicity)

Homozygote wild type: 24 hr period
tau/wild type heterozygote: 22 hr period
tau/tau homozygote: 20 hr period

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22
Q

What happens to sleep if you get rid of the SCN?

A
  • Circadian mechanism is lost

- No circadian variation in the probability that they’re going to be awake (odd amounts of sleep throughout the day)

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23
Q

Why is drinking used as a measure for circadian rhythms?

A

Animal needs to drink to survive. Is reliable indicator of activity for many species.

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24
Q

When you sleep deprive an animal and lesion the SCN, what do you see?

A

A rebound increase in slow wave activity and longer duration of sleep

  • Homeostatic regulation of sleep unaffected
  • Without circadian rhythms, animals almost completely driven by homeostatic regulation. So anytime the animal gets sleepy, it goes to sleep!
  • Lesion monkeys have 3-4 hours more sleep than control monkeys (all stage 1)
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25
Q

What was observed in a women with a SCN lesion (from stroke?)

A
  • No specific impairment of cognitive function
  • She would perform normally or very poorly, depending on fluctuations in the level of her arousal
    -
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26
Q

Is the SCN a sleep regulator?

A

NO, not directly. It signals to regions that are though.

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27
Q

How does the SCN contribute to the circadian timing of sleep?

A
  • Projection to preoptic tract
  • Projections to subpar matricular zone (which sends a wide array of projections throughout brain)

SCN probably projects to these relay centres

OR

Release of substance.

28
Q

What type of substances might the SCN release to regulate sleep?

A
  • Prokinohesin
  • Vasopressin secretion is very rhythmic

(update this card later with better info)

29
Q

What is the Pineal gland and a bit of its history?

A
  • A gland inside the middle of the brain
  • Releases substances into the CSF that regulates sleep and other things
  • Used to be thought of as the ‘seat of the soul’ (containing animal spirits that gave information to the muscles to produce behaviour). Thought to be the place where the soul interacts with the rest of the body, spirits moved the pineal gland a little bit.
30
Q

Where is the pineal gland located? Where does it secrete to?

A
  • epithalamus (above thalamus)
  • Under cortex

*Where the cerebellum meets the cerebrum

Secretes into cerebrospinal fluid

31
Q

Why is the pineal gland a unique structure in the brain?

A
  • It is not lateralized, just sits in the middle

- Many sinuses meet at the pineal gland to expose it to many substances

32
Q

The pineal gland is associated with the eyes, and in non-mammals, it is very involved in the regulation of circadian rhythms. How is it in some ways better than the SCN? Is this true in mammals?

A
  • Better than SCN because you entrain it by shining light ‘on a slice of it’
  • Pineal gland the SCN of non–mammals
  • Melatonin oscillation of the isolated pineal gland does not occur in mammals (has become a slave of the SCN)
33
Q

What oscillates in the pineal gland?

A

Levels of melatonin
- Drops during night

AANAT and HIOMT rises at night to convert melatonin to?

34
Q

How does the SCN control the pineal gland?

A
  • SCN projects to the parventricular nucleus (PVN)
  • PVN projects to the spinal cord
  • Spinal cord projects to superior cervical ganglion in the sympathetic nervous system
  • Superior cervical ganglion project back into central nervous system via nervi conarii and terminate on the pineal gland
  • Pineal gland produces melatonin (immediately secreted as it’s made)
35
Q

What are the nervi conarii?

A

The nerves that project from the superior cervical ganglion to the pineal gland

  • Transmits with norepinephrine
36
Q

Does light inhibit or stimulate melatonin production?

A
  • Parventricular nucleus activates pathway to activate pineal gland
  • SCN inhibits parventricular nucleus
  • SCN activated by light
  • Lack of light prevents inhibition of parventricular nucleus by the SCN
  • Melatonin is the ‘hormone of darkness’
37
Q

When is the SCN most activated?

A

During the day

It inhibits the PVN from sending signals to pineal, so that no melatonin is made during the day. Even during darkness, the circadian rhythm shuts the SCN off at the beginning of the subjective night.

38
Q

What is photoperiod? Why is a change in this important for organisms?

A

The change in length of the light period of the day.

Gradual lengthening and shortening of the days across seasons is the main photoperiodic signal for organisms to prepare for the change in season

Pineal melatonin can detect the photoperiodic change by changing in response to length of dark period. Behaviour/physiology can change to prepare in response to different lengths of time for melatonin production.

39
Q

What interprets the lengthening and shortening of melatonin at nights during photoperiodic change? Evidence for this?

A

Comparing with the circadian clock

The length of time SCN is exposed to melatonin tells an animal how much of its day has been night and daytime.

If you destroy the SCN, animal doesn’t respond to changing length of the days.

40
Q

What happens to rodents with increasingly longer nights in the fall/winter? What conclusions about melatonin did people come to from this?

A

Reproductive system collapses

  • Male testis shrink
  • Females don’t become estrous anymore
  • Metabolism changes

They breed when the days are long (eg. spring and summer). So these changes conserve energy in the fall/winter when they’re not being reproductive.

However, this led to the belief that melatonin was anti-gonadal, which is not true. Melatonin makes deer more reproductive, because their rutting season is in the fall. Melatonin is not pro gonadal or pro reproductive or vice versa, in this case it just signals the length of days/nights.

41
Q

Melatonin is chronobiotic. What does this mean?

A

It can shift the circadian rhythm that’s controlled by the suprachiasmatic nucleus. This is a type of entrainment.

42
Q

What happens when you give someone melatonin before sleeping or after waking? (2)

A
  • Timing is critical
  • It produces a phase advance (shorten circadian period for that day) if given at a certain time before sleep (opposite of light, which would create a phase delay in this case)
  • It will produce a phase delay (lengthen circadian period for that day) if give at a certain after waking.

Melatonin acts like light in how it can change phase. Effect is much stronger for phase advance (given at night)

43
Q

What is a downside of melatonin treatment for making phase shifts (disregarding side effects and mistakes in taking it)?

A

It only shifts by about half an hour.

It will make the maximum phase shift that your body is capable of (which is never very much and an sometimes be in the wrong direction)

You want to take melatonin when your system is most sensitive to it.

44
Q

How can free-running circadian rhythm blind people be helped to keep consistent sleep phases?

A

Treatment with oral melatonin. (even with just .5 mg/day)

45
Q

True or false? Melatonin can reverse aging, fight disease and enhance sex.

A

No evidence supports ANY of these claims

46
Q

What happens 1 to 2 hours after melatonin levels start to rise? What precedes this period?

A

You begin to get sleepy

The period of circadian suppression of sleep (wake maintenance zone) precedes this period. So melatonin opens the ‘gates of sleep,’ so to speak.

47
Q

Why is the 28 hour period used in forced desynchronization (timeless environment)? What is the result of this? This shows when you are least likely to fall asleep, when is this?

A

The SCN and pineal gland can not entrain to 28 hours

As melatonin rises, your probability of falling asleep and staying asleep sharply increases. The rise of melatonin, regardless of sleep cycle, makes you sleepy!

You are least likely to fall sleep (peak of wake maintenance zone, aka forbidden zone of sleep) right before melatonin levels begin to rise.

48
Q

What is the signal for humans to get ready for nighttime sleep? How?

A

Melatonin

Blood vessels on surface of skin expand, leading to loss of heat and fall of core body temperature.

49
Q

What happens when you give rats melatonin?

A

You get increased brain temperature (marker of arousal/activation)

SO, melatonin still signals transition to night phase, even in nocturnal animals.

50
Q

Light at night affects human body temperature. What is the effect of turning a light on at night?

A
  • Body temperature goes up when light is turned on at night
  • If melatonin if given along with light, this effect is lost (replacing melatonin lost by light suppression through SCN)
51
Q

What does melatonin do when given medically?

A
  • Create desire for sleep if given before the natural endogenous rise of melatonin

This is a sleep permissive effect, not a sleep inducing effect. It makes you go to sleep faster, but doesn’t induce sleep (ie. barbiturates, opioids etc which will kill you at high enough dose).

You cannot force someone to fall asleep with any dose of melatonin.

52
Q

What are the two biggest criticisms against many of the first papers on melatonin treatment?

A
  • No control of timing (which is super important for melatonin!)
  • No attention to the fact that it is very effective for some populations and not others
53
Q

When is melatonin a good idea for kids?

A

Mentally impaired kids (mental retardation, autism etc.) with impaired sleep.

Melatonin on a daily basis is extremely effective at consolidating sleep and improving the quality of sleep

54
Q

What did longterm studies on melatonin’s effect on circadian rhythms in seniors show?

A
  • The small effect of melatonin is due to the very low amplitude of circadian oscillation. Cannot constrain sleep to one time of day
55
Q

Where are beta-adrenergic receptors?

A

The pineal gland

Norepinephrine activates these receptors from the nervi conarii

56
Q

What are beta blockers and how do they affect sleep? How can this be treated?

A

These are drugs that block beta-adrenergic receptors.

This negatively affects sleep onset because activation of the beta-adrenergic receptors from release of norepinerphrin from the nervi conarii (from SCN/PVN) are what activates the pineal gland

Melatonin benefits the sleep of these people, because it is missing from beta-adrenergic blocking.

57
Q

The effects of melatonin can last for weeks. Why?

A

Because it is ‘tuning’ the proper function of the SCN, which will be good for a while and then may ‘fall apart’ again.

58
Q

What are three potential beneficial effects of melatonin (outside of sleep)?

A
  • Good free radical scavenger
  • Boosts immune system function
  • Neuroprotective function
59
Q

What can a pineal tumour cause? How can this affect puberty?

A
  • Excess melatonin production
  • Loss of melatonin production

Making huge amounts of melatonin can prevent puberty

Making little melatonin can trigger the transition into puberty

This is related to species going into hibernation and other things like that.

60
Q

When does melatonin production significantly decline in men and women?

A

Women: menopause

Men: around the same time, but with no clear reproductive correlation

61
Q

What are arguments against freely taking melatonin? (2)

A
  • Anyone can make/sell melatonin (not patented)

- It plays a part in the regulation of reproductive development in humans

62
Q

What is agomelatine?

A

A melatonin agonist that can bind to and inhibit a class of serotonin receptor, may act as an antidepressant (in part because it can improve sleep)

63
Q

What three distinct roles does the suprachiasmatic nucleus (SCN) perform in creating daily rhythmicity in mammals?

A
  • Intrinsic generation of a circadian rhythm
  • Entrainment to external lighting cycles
  • Imposition of its periodicity on other physiological systems.
64
Q

Contrast the effects of SCN ablations on the amount and types of sleep shown by rats and monkeys.

A

In the absence of a circadian wake-promoting function opposing the effects of homeostasis, monkeys could not stay awake long enough to acquire the many hours of sleep debt that they normally accumulate by the end of a day. This interpretation suggests that one function of an intact circadian system in primates is to permit consolidation of a lengthy, sustained wake phase during the day. This consolidated waking enforces a delay in generating (most) recovery sleep until the nocturnal rest phase, despite the increasing pressure of cumulative sleep loss. One exception, as we discussed earlier, is the weak tendency to sleep during the early afternoon hours,

65
Q

What are two physiological differences between avian and mammalian pineal glands?

A

Avain

  • Self oscillating
  • Entrained by direct light stimulation
66
Q

What is the evidence that melatonin is a chronobiotic (entrainer) in mammals?

A

When taken orally by people, or injected either systemically or directly into the SCN of other species, melatonin can phase shift the circadian system, presumably by acting on the melatonin receptors located in the SCN

The Science of Sleep II (5 decks)

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