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

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

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

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

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

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

DAY 0DAY 1 TIME (h)  

THE MAMMALIAN CLOCK GENES Clock 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)

translation DNA - - DNA - - DNA –    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

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

Vision entrainment PHOTORECEPTORS retinal rods retinal ganglionic and cones cells PHOTOPIGMENTRodopsinMelanopsin Optic nervesRHT, GHT Optic cortexSCN; ?

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

Hierarchy of the Circadian System S C N Light Melatonin NPY Glucocorticoids Restricted feeding kidneyheartpancreaslungsliver

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

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

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

Partial hepatectomy hourglass GoGo G1G1 S M G2G2 Liver growth Clocks of the cell cycle Circadian clocks CDC 2 CYCLIN B CDC 25 WEE 1 BMAL 1 CLOCK REV-ERBQ CRY 1, 2 PER 1, 2

TUMOUR GROWTH PER2 Bmal1/Clock c Myc PER2 p53 apoptosis A WEAK CIRCADIAN SYSTEM

METABOLIC DISORDERS- OBESITY 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)

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

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

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