Time-keeping System:
Circadian Rhythms
Helena Illnerová
Institute of Physiology
Academy of Sciences of the Czech Rep.
CIRCADIAN RHYTHMS








sleep-wake cycle
body temperature
behaviour
food and water
intake
hormones
metabolism
body fluids
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
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
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-ACETYLTRANSFERASE
N-ACETYLSEROTONIN
HYDROXYINDOL-O-METHYL
TRANSFERASE
MELATONIN
DAY 0
DAY 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
Per mRNA)
protein product of the clock
transcription
modification ?
DNA
(gene Per)
modified protein
of the clock
Protein transfer to the nucleus
+
++
+++
- DNA - - DNA - - DNA –



+
++
+++
Clock-controlled genes
Overt circadian rhythms
Are the clock genes
responsible for
CHRONOTYPES?
Larks vs. owls?
Vision
entrainment
PHOTORECEPTORS retinal rods
and cones
retinal ganglionic
cells
PHOTOPIGMENT
Rodopsin
Melanopsin
Optic nerves
RHT, GHT
Optic cortex
SCN; ?
First, second and third
messengers



GLUTAMATE
cAMP; cGMP; Ca ions; NO
C-FOS; pCREB; PER1; PER2
Hierarchy of the Circadian System
SCN
Light
Melatonin
NPY
liver
lungs
kidney
heart
Restricted feeding
Glucocorticoids
pancreas
ENTRAINMENT OF THE
TIME-KEEPING SYSTEM


-
Entainment of the SCN: by light
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:
CLOCK GENES
CELL CYCLE GENES
GENES FOR APOPTOSIS
ORGAN SPECIFIC GENES
Partial hepatectomy
Go
Clocks of
the cell cycle
G1
M
Circadian
clocks
BMAL 1
CLOCK
CDC 25
hourglass
CDC 2
CYCLIN B
S
Liver growth
G2
REV-ERBQ
WEE 1
CRY 1, 2
PER 1, 2
TUMOUR GROWTH
• PER2
Bmal1/Clock c Myc
• PER2
p53
apoptosis
• A WEAK CIRCADIAN SYSTEM
-
-
METABOLIC DISORDERSOBESITY
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
DSPS
ASPS
Fragmentation of sleep
Higher risk for oncologic
diseases
Metabolic disorders
CHRONOBIOLOGY
Molecular Biology
Neurobiology
Ethology
Internal Medicine
Sports and Labour
Medicine
Psychology
Psychiatry
Neurology
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.