1. Time-keeping System: Circadian Rhythms
Helena Illnerová
Institute of Physiology
Academy of Sciences of the Czech Rep.

2. CIRCADIAN RHYTHMS sleep-wake cycle body temperature behaviour
food and water intake
hormones
metabolism
body fluids
expression of genes

4. Subjective night
Evening: sleepiness increases melatonin increases body temperature decreases Morning: cortisol increases melatonin decreases body temperature increases
The subjective night is not necessarily equal to the real night

5. The outside period T = 24 h
Entrainment: Tau* = 24 h
Tau > 24 h: daily phase advance is necessary
Tau < 24 h : daily phase delay is necessary

6. Light Entrainment
Light in the evening and in the first half of the night delays phase of the rhythms.
Light in the second half of the night and in the morning advances phase of the rhythms
Light during the subjective day does not change phase of the rhythms

7. THE PINEAL GLAND:
SEROTONIN
N-ACETYLTRANSFERASE
N-ACETYLSEROTONIN
HYDROXYINDOL-O-METHYL
TRANSFERASE
MELATONIN

8. DAY 0
DAY 1  
TIME (h)

16. THE MAMMALIAN CLOCK GENES
BMal 1 (Mop 3), BMal 2
Per 1, Per 2 (Period)
Cry 1, Cry 2 (Cryptochrome)
Rev – Erb α
CK1 Є CK1 δ (kasein kinase)
CLOCK-CONTROLLED GENES
Per 3
AVP (arginin vasopresin)
Dbp (D-element binding protein)

18. translation
Per mRNA)
protein product of the clock
transcription
modification ?
DNA
(gene Per)
modified protein
of the clock
Protein transfer to the nucleus
Clock-controlled genes
Overt circadian rhythms
- DNA DNA DNA –
  

20. Are the clock genes responsible for CHRONOTYPES? Larks vs. owls?

22. Vision entrainment
PHOTORECEPTORS retinal rods retinal ganglionic
and cones cells
PHOTOPIGMENT Rodopsin Melanopsin
Optic nerves RHT, GHT
Optic cortex SCN; ?

23. First, second and third messengers
GLUTAMATE
cAMP; cGMP; Ca ions; NO
C-FOS; pCREB; PER1; PER2

24. Hierarchy of the Circadian System
S C N
Light
Melatonin
NPY
liver
lungs
kidney
heart
pancreas
Restricted feeding
Glucocorticoids

25. ENTRAINMENT OF THE TIME-KEEPING SYSTEM
Entainment of the SCN: by light
Entrainment of peripheral organs:
From SCN
By feeding
Via corticoids ?

26. Peripheral organs as clocks
- Oscillation in the organ culture
Different periods and phases
Oscillations persist even after the SCN lesion but become desynchronized
PERIPHERAL ORGANS ARE CLOCKS PER SE BUT SCN PLAYS THE COORDINATION AND SYNCHRONIZING ROLE

27. Expression of Genes
About 10% of genes are expressed in a rhythmic way:
CLOCK GENES
CELL CYCLE GENES
GENES FOR APOPTOSIS
ORGAN SPECIFIC GENES

28. Partial hepatectomy Clocks of the cell cycle Circadian clocks Go G1 M
BMAL 1
CLOCK G1 M
CDC 25
hourglass
CDC 2
CYCLIN B
WEE 1
REV-ERBQ S G2
CRY 1, 2
PER 1, 2
Liver growth

29. TUMOUR GROWTH
PER2 Bmal1/Clock c Myc
PER2 p apoptosis
A WEAK CIRCADIAN SYSTEM

30. METABOLIC DISORDERS-OBESITY
In food intake (night eating syndrom)
In balance of rhythms of leptin, ghrelin, insulin (e.g., when sleep is insufficient )
In loss of appetite (Clock mutant mice)

31. Disorders of the Circadian System
Free-run
DSPS
ASPS
Fragmentation of sleep
Higher risk for oncologic diseases
Metabolic disorders

32. CHRONOBIOLOGY Molecular Biology Neurobiology Ethology
Internal Medicine
Sports and Labour
Medicine
Psychology
Psychiatry
Neurology
Oncology

35. The wonder of the world,. the beauty and the power,
The wonder of the world, the beauty and the power, the shapes of things, their colour, lights and shades. These I saw. Look ye also while life lasts.