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Time-keeping System:Time-keeping System:Circadian RhythmsCircadian Rhythms
Helena IllnerováHelena IllnerováInstitute of PhysiologyInstitute of Physiology
Academy of Sciences of the Czech Rep.Academy of Sciences of the Czech Rep.
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CIRCADIAN RHYTHMSCIRCADIAN RHYTHMS
sleep-wake cyclesleep-wake cycle body temperaturebody temperature behaviourbehaviour food and water intakefood and water intake hormones hormones metabolismmetabolism body fluidsbody fluids expression of genesexpression of genes
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Subjective nightSubjective night
Evening:Evening: sleepiness increasessleepiness increasesmelatonin increasesmelatonin increasesbody temperature decreasesbody temperature decreases
Morning: Morning: cortisol increasescortisol increasesmelatonin decreasesmelatonin decreasesbody temperature increasesbody temperature increases
The subjective night is not The subjective night is not necessarily equal to the real night necessarily equal to the real night
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Tau > 24 h: daily phase advance is necessary
Tau < 24 h : daily phase delay is necessary
The outside period T = 24 h
Entrainment: Tau* = 24 h
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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-ACETYLSEROTONIN
MELATONIN
N-ACETYLTRANSFERASE
HYDROXYINDOL-O-METHYLTRANSFERASE
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DAY 0 DAY 1
TIME (h)
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THE MAMMALIAN CLOCK GENES
ClockBMal 1 (Mop 3), BMal 2Per 1, Per 2 (Period)Cry 1, Cry 2 (Cryptochrome)Rev – Erb αCK1 Є CK1 δ (kasein kinase)
CLOCK-CONTROLLED GENES
Per 3AVP (arginin vasopresin)Dbp (D-element binding protein)
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translation
+ ++ +++- DNA - - DNA - - DNA – + ++ +++
Per mRNA)
protein product of the clock
modification ?transcription
DNA(gene Per)
modified proteinof the clock
Protein transfer to the nucleus
Clock-controlled genes
Overt circadian rhythms
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Are the clock genes Are the clock genes responsible for responsible for CHRONOTYPES? CHRONOTYPES?
Larks vs. owls?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 First, second and third messengersmessengers
GLUTAMATEGLUTAMATE cAMP; cGMP; Ca ions; NOcAMP; cGMP; Ca ions; NO C-FOS; pCREB; PER1; PER2C-FOS; pCREB; PER1; PER2
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Hierarchy of the Circadian System
S C NLightMelatoninNPY
Glucocorticoids
Restricted feeding
kidney heart pancreaslungsliver
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ENTRAINMENT OF THE ENTRAINMENT OF THE TIME-KEEPING SYSTEMTIME-KEEPING SYSTEM
Entainment of the SCN: by lightEntainment of the SCN: by light Entrainment of peripheral Entrainment of peripheral
organs:organs:- From SCN From SCN - By feedingBy feeding- Via corticoidsVia 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 GenesExpression of Genes
About 10% of genes are About 10% of genes are expressed in a rhythmic way:expressed in a rhythmic way:
- CLOCK GENESCLOCK GENES- CELL CYCLE GENESCELL CYCLE GENES- GENES FOR APOPTOSISGENES FOR APOPTOSIS- ORGAN SPECIFIC GENESORGAN SPECIFIC GENES
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Partial hepatectomy
hourglass
Go
G1
S
M
G2
Liver growth
Clocks ofthe cell cycle
Circadianclocks
CDC 2CYCLIN B
CDC 25
WEE 1
BMAL 1CLOCK
REV-ERBQ
CRY 1, 2PER 1, 2
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TUMOUR GROWTH
• PER2 Bmal1/Clock c Myc
• PER2 p53 apoptosis
• A WEAK CIRCADIAN SYSTEM
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METABOLIC DISORDERS-METABOLIC DISORDERS-OBESITYOBESITY
- In food intake (night eating In food intake (night eating syndrom)syndrom)
- In balance of rhythms of leptin, In balance of rhythms of leptin, ghrelin, insulin (e.g., when sleep ghrelin, insulin (e.g., when sleep is insufficient )is insufficient )
- In loss of appetite (Clock mutant In loss of appetite (Clock mutant mice)mice)
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Disorders of the Circadian Disorders of the Circadian SystemSystem
Free-runFree-run DSPSDSPS ASPSASPS Fragmentation of sleepFragmentation of sleep Higher risk for oncologic Higher risk for oncologic
diseasesdiseases Metabolic disorders Metabolic disorders
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CHRONOBIOLOGYCHRONOBIOLOGYMolecular Biology
Neurobiology
Ethology
Internal Medicine
Sports and Labour
Medicine
Psychology
Psychiatry
Neurology
Oncology
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The wonder of the world,The wonder of the world,
the beauty and the power,the beauty and the power,
the shapes of things,the shapes of things,
their colour, lights and shades.their colour, lights and shades.
These I saw.These I saw.
Look ye also while life lasts.Look ye also while life lasts.