Time-keeping System: Circadian Rhythms

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Time-keeping SystemCircadian Rhythms

• Helena Illnerová
• Institute of Physiology
• Academy of Sciences of the Czech Rep.

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CIRCADIAN RHYTHMS

• sleep-wake cycle
• body temperature
• behaviour
• food and water intake
• hormones
• metabolism
• body fluids
• expression of genes

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Subjective night
Evening sleepiness increases melatonin
increases body temperature decreases Mornin
g cortisol increases melatonin
decreases body temperature increases
The subjective night is not
necessarily equal to the real night
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The outside period T 24 h Entrainment Tau
24 h
Tau gt 24 h daily phase advance is necessary Tau
lt 24 h daily phase delay is necessary
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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

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THE PINEAL GLAND
SEROTONIN
N-ACETYLTRANSFERASE
N-ACETYLSEROTONIN
HYDROXYINDOL-O-METHYL TRANSFERASE
MELATONIN
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DAY 0
DAY 1
?
?
TIME (h)
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THE MAMMALIAN CLOCK GENES Clock BMal 1 (Mop 3),
BMal 2 Per 1, Per 2 (Period) Cry 1, Cry 2
(Cryptochrome) Rev Erb a CK1 ? CK1 d (kasein
kinase) CLOCK-CONTROLLED GENES Per 3 AVP
(arginin vasopresin) Dbp (D-element binding
protein)
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translation
Per mRNA)
protein product of the clock
modification ?
transcription
DNA (gene Per)
modified protein of the clock
Protein transfer to the nucleus Clock-controlled
genes Overt circadian rhythms
- DNA -
- DNA - - DNA ? ?
?
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Are the clock genes responsible
for CHRONOTYPES? Larks vs.
owls?
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Vision entrainment PHOTORECEPTORS
retinal rods retinal ganglionic
and cones
cells
PHOTOPIGMENT Rodopsin Melanopsin Optic
nerves RHT, GHT Optic cortex SCN ?
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First, second and third messengers

• GLUTAMATE
• cAMP cGMP Ca ions NO
• C-FOS pCREB PER1 PER2

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Hierarchy of the Circadian System
S C N
Light Melatonin NPY
kidney
heart
pancreas
lungs
liver
Restricted feeding
Glucocorticoids
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ENTRAINMENT OF THE TIME-KEEPING SYSTEM

• Entainment of the SCN by light
• Entrainment of peripheral organs
• From SCN
• By feeding
• Via corticoids
• ?

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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

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Expression of Genes

• About 10 of genes are expressed in a
  rhythmic way
• CLOCK GENES
• CELL CYCLE GENES
• GENES FOR APOPTOSIS
• ORGAN SPECIFIC GENES

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Partial hepatectomy
Clocks of the cell cycle
Circadian clocks
Go
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
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• TUMOUR GROWTH
• PER2 Bmal1/Clock c Myc
• PER2 p53 apoptosis
• A WEAK CIRCADIAN SYSTEM

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• 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)

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Disorders of the Circadian System

• Free-run
• DSPS
• ASPS
• Fragmentation of sleep
• Higher risk for oncologic diseases
• Metabolic disorders

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CHRONOBIOLOGY
Molecular Biology Neurobiology Ethology Internal
Medicine Sports and Labour Medicine Psychology Psy
chiatry Neurology Oncology
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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.