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Question 1

why do circadian rhythms exist?

Answer 1

• as the earth turns, our environment changes on a 24h cycle: darker at night, brighter in the day.
• to adapt, we have evolved circadian rhythms of physiology and behaviour

Question 1

how long are circadian rhythms?

Answer 1

roughly 24 hours

Question 2

in what organisms are circadian rhythms found?

Answer 2

bacteria, protozoa, plants, fungi, and animals

Question 3

humans have circadian rhythms of

Answer 3

behaviour, alertness, mood, body temperature, and hormone levels

Question 4

what does it mean for circadian rhythms to be endogenous?

Answer 4

they are internally generated, not simply responses to changes in the environment; rather, they continue even when the environment is held constant

Question 5

what is the smallest unit which operates a circadian rhythm? how can these units be regulated?

Answer 5

• almost every cell in your body has its own internal clock that oscillates on a roughly 24-hour schedule
• these clocks can be entrained (kept in sync) by sensory signals acting through the suprachiasmatic nuclei of the brain

Question 6

describe the two genes essential for circadian rhythms in flies

Answer 6

• period (per) on the X-chromosome, shows a 24 hour cycle - it is transcribed early in the night, so its mRNA is most abundant around 10pm. its protein product, PER is most abundant 6 hours later
• per and PER drive each other’s cycling in a transcription-translation feedback loop (TTFL): PER (with other factors) represses transcription of per. in the absence of PER, mRNA levels do not cycle
• tim mRNA and its protein product, TIM, oscillate much like per mRNA and PER
• TIM binds PER, and it is the dimer PER/TIM that represses transcription of tim and per.
• this self-repression drives a cycle; around 4am, high levels of PER/TIM shut off per and Tim, so PER/TIM levels gradually fall. so per and Tim, no longer repressed, rise to a peak in late evening, leading to another peak in PER/TIM next morning at 4am.
• if either TIM or PER is absent, neither one oscillates.

Question 7

draw a flowchart of the period-timeless TTFL

Question 8

draw a timeline of the period-timeless TTFL

Question 9

how do PER/TIM cause decreased expression of their respective genes?

Answer 9

• a gene called clock (or clk) codes a protein CLK, and a gene called cycle (or cyc) codes CYC
• in the daytime, the dimer CLK-CYC binds DNA and stimulates transcription of per and Tim
• in the night, PER/TIM blocks CLK-CYC binding to DNA, and so represses transcription of per and tim

Question 10

give a breakdown of the time it takes for gene expression

Answer 10

1. transcription:
   - takes 20-60s per kb of DNA
   - takes 1-10 mins per gene
2. translation:
   - ribosome speed: 5-10 AAs per second (eu)
   - small protein (100AAs): 10-20s
   - large protein (1000AAs): several minutes

Combined time for gene expression:
- for typical genes, 5-15 minutes to produce proteins

Question 11

if transcription and translation are so efficient, why does the PER protein lag behind per mRNA by several hours?

Answer 11

due to the double-time (dbt) gene: the protein DBT binds PER, causing it to break down, so levels of PER rise much more slowly than they otherwise would, and so they do not peak until 6 Horus after per, resulting in an overall cycle length near 24 hours

Question 12

how does the mammalian system of circadian rhythms compare to that of fruit flies?

Answer 12

• mammals have homologs of per that play a similar role, though mammalian PER forms a dimer not with TIM but with a protein called CRY, from the cryptochrome or cry gene
• mammals have homologs of Tim, but their functions are unclear
• mammalian homologs of clk, cyc, and dbt are called clk, bmal1, and ck1ε
• in mice and likely other mammals, a CLK/BMAL1 dimer stimulates transcription of per and cry when not blocked by PER/CRY. CK1ε slows the rise of PER protein levels

Question 13

how are the body’s cellular clocks kept in sync?

Answer 13

by several external factors, eg light, temperature, feeding, exercise, and social interactions; all such cues are called zeitgeber

Question 14

what is the main zeitgeber? what is this sensed by?

Answer 14

light sensed by melanopsin retinal ganglion cells, which project to the master clock: the suprachiasmatic nucleus (SCN) of the hypothalamus

Question 15

where is the SCN located? label its location on a diagram

Answer 15

sits above the optic chiasm

Question 16

what is the effect of light on the cellular clocks in the SCN?

Answer 16

• signals from melanopsin retinal ganglion cells reach certain neurons in the SCN, making them fire and resetting their clocks by a small amount
• the retinal signals cause chemical changes in these SCN cells that lead to a breakdown of PER/CRY
• if this drop in PER/CRY occurs after 4am, when PER/CRY levels are already falling, then it sets the clock forward a little; if it happens in the evening, when PER/CRY levels are rising, it sets the clock back

Question 17

from the SCN, how does information about light and dark spread throughout the body? what is this process called?

Answer 17

• the SCN neurons that receive retinal projections send signals onward to other neurons in the SCN, so their intracellular clocks are adjusted as well
• from there, neural signals pass to other brain areas, which in turn send neural and hormonal signals that adjust the intracellular clocks throughout the body
• this process of nudging a clock into synchrony with another rhythm is called entrainment. so the SCN becomes entrained to night and day, and other clocks are entrained to the SCN and through it to night and day

Question 18

what is the role of the SCN specifically in the dark?

Answer 18

• SCN neurons project, via other hypothalamus nuclei and then the sympathetic nervous system, to the pineal body, at the back of the diencephalon
• the pineal secretes melatonin, more in darkness, less in light. starting at dusk, blood levels rise 8-fold, peaking at 2am, then fall back to daylight levels by 8am
• melatonin acts via melatonin receptors in the SCN to reset the master clock toward night time

Question 19

label the location of the pineal gland

Question 20

when and how can melatonin pills be useful?

Answer 20

• in jet lag, the SCN master clock adjusts itself gradually to the new schedule of light and dark, but by only one hour per day
• melatonin pills can help if they are taken correctly (eg for eastward travel, 30 mins before your target bed time at your destination)

Question 21

do all animals sleep?

Answer 21

yes; all tested species sleep, including insects and jellyfish

Question 22

describe the ways in which sleep can differ among animals

Answer 22

• diurnal and nocturnal animals sleep at different times
• within a species there are chronotypes (eg human early birds/night owls)

Question 23

what is the reasoning behind the evolution chronotypes?

Answer 23

they likely evolved for the security of the herd, because they shorten the time when everyone is asleep

Question 24

how is the feeling of sleepiness regulated?

Answer 24

- in the daylight, the SCN indirectly excites neurons in the lateral hypothalamus (LH) so they release orexin, causing arousal; loss of orexin causes narcolepsy - in darkness, other cells in the LH are active they project throughout the brain, releasing the neuropeptide melanin-concentrating hormone (MCH) and inducing sleep - orexin and MCH neurons inhibit each other

Question 25

what is sleep pressure and how does it influence sleepiness?

Answer 25

while we are awake, breakdown of ATP in the brain causes a buildup of adenosine, making us sleepy. during sleep, ATP levels are restored and adenosine levels fall

Question 26

how does caffeine influence sleepiness?

Answer 26

- caffeine blocks adenosine receptors but does not lower adenosine levels, so when the caffeine wears off, we 'crash' - caffeine has a half-life of 6 hours

Question 27

describe the 4 stages of sleep

Answer 27

1. in rapid-eye-movement (REM) sleep, your eyes move, you dream, you have erratic 30-40Hz brain waves (as in wakefulness), and your muscle tone vanishes so you don't act out your dreams 2. non-REM (NREM) sleep is dreamless, with slower brain waves. it has three stages numbered 1-3 where stage 3 is deep NREM, with regular 2-4Hz brain waves

Question 28

what is the importance of NREM stage 3?

Answer 28

very important for physical restoration and growth - where your body repairs your tissues, strengthens immune system, and consolidates memories

Question 29

describe how the stages of sleep follow each other

Answer 29

the stages follow each other in a 90-minute cycle: - the first REM stage occurs after about 90 minutes - as the night progresses, sleep gets shallower and REM stages longer, and you may wake up occasionally

Question 30

why is sleep so essential?

Answer 30

- deprivation of sleep, or even of just REM sleep, causes problems with cognitive function, learning, and memory - after sleep deprivation, your first sleep will catch up on NREM, but the next few nights will have more REM than usual

Question 31

compare the sleep of humans to other primates

Answer 31

humans sleep less than other primates, but with more REM and on the ground rather than up a tree