Circadian Rhythms

Question 1

Circadian vs. infraradian vs. ultraradian cycles and examples of each?

Answer 1

Circadian cycles (24 hours) - sleep/wake
Infraradian cycles (> 24 hours) - menstrual cycle
Ultraradian cycles (<24 hours) - REM/non REM sleep

Question 2

Endogenous rhythm vs. entraining circadian rhythm?

Answer 2

In absence of external cues/Zeitgebers living biological system will undertake an endogenous, spontaneous “free-running” rhythm (i.e. plant in complete darkness).

Entraining circadian rhythm is a process by which external cues/Zeitgebers over a period of time influences the circadian rhythm.

A one-time/acute exposure to a stimulus would not make that stimulus a Zeitgeber!

Question 3

What does the period of a circadian rhythm measure?

Answer 3

The length of the full cycle (tau) of ENDOGENOUS rhythm in the absence of Zeitgebers.

Question 4

Phase shifts: Phase delay vs. phase advance

what influences direction and magnitude of shift?

Answer 4

Phase delay - sleep shifted forward/later
Phase advance - sleep shifted backward/earlier

1) phase the zeitgeber is given during cycle
2) magnitude of zeitgeber
3) duration of exposure
4) previous exposure
5) zeitgeber characteristic

Question 5

Process C vs. Process S

Answer 5

Process C = alertness/alerting signal
Process S = sleep load/homeostatic drive for sleep

At night at ~ 9PM, both process S and C reach peaks but eventually accumulated sleep debt overwhelms process C to initiate sleep.

Sleep then reduces sleep debt to minimum until the alerting signal of process C begins to rise again in the AM.

Question 6

What is the mechanism behind the need to nap?

Answer 6

Sleep deprivation results in accumulated sleep debt, resulting in sleep debt that overwhelms process C in the day that maintains alertness.

Consequently, this reduces the sleep pressure at night when we should normally be asleep.

Question 7

What factor is responsible for sleep drive/process S? How does caffeine work to promote wakefulness?

Answer 7

Wake-promoting neurons in the basal forebrain accumulates wakefulness, and sleep-promoting adenosine levels rise to inhibit cholinergic neurons.

Caffeine is an adenosine receptor antagonist that promotes waking!

Question 8

What is the relationship between CBT and sleep onset?

Answer 8

Sleep onset occurs as CBT begins to fall, whereas wakefulness generally occurs with elevated CBT.

Question 9

When is the CBT minimum? Night owl and morning lark CBT minimums relative to “normal?”

Answer 9

CBT minimum occurs in early AM ~ 2 hours before wake. Waking starts when CBT begins to rise.

Night owls have, accordingly, delayed drop in CBT and as a result delayed sleep phase.
On the other hand, morning larks have an earlier rise (“advanced”) in CBT and advanced sleep phase.

Question 10

What type of light is the most potent zeitgeber in entraining circadian rhythm? Giving bright light during which time window will provide the greatest effects of phase shifting?

Answer 10

Short wavelength blue BRIGHT light. Very dim light (VDL) has minimal phase shifting effects UNLES subject has been exposed to prolonged darkness.

Giving within 3-4 hours of CBT MINIMUM:

• -> 3-4 hours prior will phase delay
• -> 3-4 hours after will phase advance

Question 11

Where is melatonin synthesized? Mechanism of action?

Answer 11

Produced by pineal gland–made from dietary tryptophan, to 5-HT, to ultimately melatonin.

Melatonin binds to GPCRs M1 and M2, both of which are localized to various areas but most importantly the suprachiasmatic nucleus (SCN) in anterior hypothalamus that acts as pacemaker of circadian biology.

M1 activation accounts for hypnotic effect of melatonin by INHIBITING SCN neuron firing. M2 activation responsible for sleep phase shifting.

Question 12

Melatonin peak and minimum? How are its levels regulated?

Answer 12

Melatonin peaks in the middle of the night and falls early morning–levels actively suppressed in pineal gland by light.

Melanopsin retinal ganglion cells (MERGs) is sensitive to light and sends light information to SCN of hypothalamus. Main neurotransmitter utilized by MERGs is glutamate–release less glutamate with light activation.

Question 13

When does melatonin administration/exposure provide greatest phase shifting effects?

Answer 13

Similar to light but in opposite time windows–will provide greatest effects during low endogenous melatonin concentrations before DLMO at night or in AM:
Phase advance–> exposure at night 1-2 hours before endogenous levels rise (DLMO)
Phase delay–> exposure in AM after CBT

Question 14

What does it mean for melatonin to be both chronobiotic and hypnotic?

Answer 14

Chronobiotic - causes shift in endogenous rhythm

Hypnotic - induces sleep

Question 15

4 key genes in circadian rhythm?

Answer 15

CLOCK
BMAL1
per - low at night, high in day
cry

Gene behavior and their products in molecular events generally similar in different organs.

Question 16

What are the molecular mechanisms generating endogenous circadian rhythms?

Answer 16

CLOCK and BMAL1 activated during day and form heterodimers, bind promoter region of per/cry genes to activate transcription.

per/cry products form heterodimers and accumulate to point where they inhibit CLOCK/BMAL1 from binding to promoter regions, thereby decreasing per/cry transcription through negative feedback.

Question 17

How does light entrainment alter molecular components of circadian rhythms?

Answer 17

If bright light is given at night, when per levels are low, per levels and activity will rise to cause phase advance.

Question 18

Basic pathophysiology for sundowning and seasonal affective disorders? Treatment?

Answer 18

Sundowning - degeneration of SCN, common in institutionalized patients with dementia and manifesting as confusion/anxiety; give late afternoon and evening bright light exposure

Seasonal affective disorder - depression occurring late fall/early winter when less sunlight resulting in phase delay of circadian rhythms; bright light therapy in the AM to promote phase advance