Block B Lecture 2 - Circadian Rhythm

Question 1

What are the 4 types of cyclic variation rhythms, and how long do they each last?

Answer 1

Ultradian rhythms - anything less than a day - such as REM)

Circadian rhythms ~ 24 hours such as the sleep wake cycle

Infradian rhythm - more than a day e.g menstrual cycle

Circannual rhythm - yearly - such as hibernation

(Slide 3)

Question 2

What does crepuscular mean?

Answer 2

Most active in twilight (nocturnal but mostly active at dawn and dusk)
(Slide 4)

Question 3

What is Siffre’s cave experiment and what did it tell us?

Answer 3

He isolated himself in a cave with no sunlight and with constant temperature for 179 days but he thought that only 151 days passed, confirming we have a built in body clock which cycles ~ every 25 hours
(Slide 5)

Question 4

What can reset the rhythm of the suprachiasmatic nuclelus?

Answer 4

Light entering the eye
(Slide 8)

Question 5

What is a zeitgeber and what is an example of one of these?

Answer 5

An external or environmental cue that helps to regulate and synchronize an organism’s internal biological clock with the 24-hour cycle of the Earth’s rotation. - one example is light (another is food)
(Slides 8 and 23)

Question 6

What does light inhibit?

Answer 6

The release of melatonin from the pineal gland
(Slide 8)

Question 7

What do photosensitive retinal ganglion cells (pRGCs) connect to?

Answer 7

The optic nerve
(Slide 9)

Question 8

What receptor do photosensitive retinal ganglion cells (PRGCs) contain?

Answer 8

melanopsin (OPN4) receptors
(Slide 9)

Question 9

What colour of light do melanopsin receptors detect?

Answer 9

Blue (wavelength 450-480nm)
(Slide 9)

Question 10

What is the function of melatonin?

Answer 10

It has an important role in regulating the circadian rhythm, sleep control and signalling to other parts of the body and in mammals, it can also regulate seasonal cycles (circannual rhythms) which are controlled by the length of the daily photoperiod

It also has roles in reproduction, coat colour, fat accumulation, hibernation and many more!
(Slide 11)

Question 11

How does melatonin deal with reactive oxygen species (ROS)?

Answer 11

As it’s an antioxidant, enabling it to donate a proton to stabilise radical ROS .

Note: This makes melatonin become a radical itself, but double bonds can stabilise it

(Slide 12)

Question 12

What are two-component oscillators?

Answer 12

Systems that use two interacting elements or components to generate rhythmic or oscillatory behaviour, often seen in biological processes

e.g genes or proteins that inhibit or activate each other in a cyclical manner
(Slide 14)

Question 13

What did the D. Melanogaster (fruit fly) experiment involve and what did it tell us?

Answer 13

Larvae usually emerge at night;
Scientists performed mutagenesis and then looked for mutants which didn’t emerge at the right time (known as eclosion mutants)

This told us that the oscillator which controls circadian rhythm must be regulated by genes and their products
(Slide 15)

Question 14

What are eclosion mutants?

Answer 14

Circadian rhythm mutants
(Slide 16)

Question 15

What did Jeffery Hall, Michael Rosbash and Michael Young win a Nobel prize in 2017 for?

Answer 15

For their discoveries of molecular mechanisms controlling the circadian rhythm
(Slide 16)

Question 16

What gene did Jeffery Hall, Michael Rosbash and Michael Young isolate and identify?

Answer 16

The PERIOD (PER) gene in fruit flies
(Slide 16)

Question 17

How does the PER gene in fruit flies work?

Answer 17

The per protein accumulates overnight, which then inhibits its own gene’s transcription
(Slide 16)

Question 18

Why do basic helix-loop-helix transcription factors often operate as heterodimers?

Answer 18

To bind to E-box motifs in target gene promoters
(Slide 17)

Question 19

What are 2 examples of basic Helix-Loop-Helix transcription factors?

Answer 19

Clock-BMAL 1 heterodimer
PER-CRY heterodimer
(Slide 17)

Question 20

How does the Clock-BMAL1 heterodimer work?

Answer 20

1. Clock and BMAL1 form a heterodimer
2. This heterodimer binds to E-box sequences in the promoters of genes that control circadian rhythms (like PER and CRY genes), thereby initiating transcription of those genes
3. This activation leads to the production of proteins involved in maintaining the circadian clock

(Slide 17)

Question 21

How does the PER-CRY heterodimer work?

Answer 21

1. After Clock-BMAL1 activates PER and CRY expression, the PER and CRY proteins accumulate in the cytoplasm
2. PER and CRY eventually form a heterodimer and move back into the nucleus
3. They then interact with and inhibit the Clock-BMAL1 complex, stopping further activation of PER and CRY transcription
   (Slide 17)

Question 22

What 4 proteins make up the “core oscillator” of the body?

Answer 22

Cry, Per, Clock and Bmal
(Slide 20)

Question 23

How many oscillating ancillary loops are involved in the circadian transcriptome?

Answer 23

2
(Slide 20)

Question 24

What do the extra oscillating ancillary loops function to do?

Answer 24

Maintain accuracy and robustness of the circadian system
(Slide 20)

Question 25

What does the circadian system feed into?

Answer 25

Regulation of many output genes which control physiology
(Slide 20)

Question 26

Does blood pressure increase or decrease at night?

Answer 26

Decreases
(Slide 23)

Question 27

What are 3 examples of things that oscillate in a circadian rhythm (other than the sleep-wake cycle)?

Answer 27

Motility of the GI tract
Acid secretion
Maintenance of the mucosa
Digestive enzyme production

(Slide 23)

Question 28

What is Clock-Bmal1 DNA binding activity modulated by and what does this indicate?

Answer 28

Its modulated by the ratio of NAD+/NADH indicating that the energy state / redox state of the cell that can influence circadian rhythm
(Slide 24)

Question 29

What do Bmal1-KO mice have impaired production of?

Answer 29

Glucose-stimulated insulin secretion
(Slide 24)

Question 30

Why do cold symptoms worsen in the evening?

Answer 30

As innate immune response varies over the course of the day
(Slide 24)

Question 31

What is familial advanced sleep phase disorder (FASPD)?

Answer 31

A circadian rhythm sleep disorder which is characterised by early habitual sleep times with individuals tending to feel tired in the early afternoon
(Slide 25)

Question 32

What mutation causes familial advanced sleep phase disorder (FASPD) and how?

Answer 32

A missense mutation in the PER2 gene which prevents phosphorylation by casein kinases Iδ and Iε (CKIδ/ε)
(Slide 25)

Question 33

What cases jet lag to occur?

Answer 33

When the sleep-wake cycles are out of phase with the local environment
(Slide 28)

Question 34

Most people find out that jet lag is worse when travelling east than travelling west. Why is this?

Answer 34

As it is usually easier to delay your internal clock than it is to advance it
(Slide 28)

Question 35

What are 2 diseases which chronic jet lag may have a link to?

Answer 35

Cancer and type II diabetes
(Slide 31)