Biological rhythms
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Types of biological rhythms
• what do we call rhythm in a living
organism? – physiological events occurring
at approximately regular times
• internally controlled rhythms: breathing,
heart beat, gut motility, brain waves, etc.
• externally determined rhythms: singing in
certain birds, tulips, etc.
• rhythms controlled by an internal clock
that is synchronized to the environment by
Zeitgebers (synchronizing factors) – when
these are missing: free-running rhythm
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External-internal rhythms
• De Mairan (1729): leaf movement of
mimosa continues in darkness
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Rhythms with various periods
• period – determined by the external
geophysical variable:
– tidal: rhythm of high and low tides
• period: 12.8 h
• synchronizing factor: pressure, mechanical stimuli
– daily: rhythm of days and nights
• period: 24 h
• synchronizing factor: light, (temperature,
activity)
– lunar: rhythm of moon phases
• period: 29.5 days
• synchronizing factor: full moon?
– annual: rhythm of seasons
• period: 365 days
• synchronizing factor: ???
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Circannual rhythm in hibernation
group 1 – DD, blinded ground squirrels
group 2 – LL (500 lux) group 3 – LL (500 lux), blinded
group 4 – LL (20 lux) group 5 – LD12:12 (200:0 lux)
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Circadian rhythm in hamster
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Temperature dependency of
circadian rhythms
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Light effects
• circadian period (T) of diurnal and
nocturnal animals change in opposite
direction in constant light (LL) :
– Aschoff’s rule:
diurnal animal: T decreases with light intensity
nocturnal animal: T increases with light
intensity
– circadian rule:
diurnal animal: wake/sleep ratio increases with
light intensity
nocturnal animal: wake/sleep ratio decreases
with light intensity
• the strong physiological effect of light is
also shown by persistent oestrus
• short light impulses can change the phase
of circadian rhythms
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Phase-response curve I. (PRC)
Hannibal, Cell & Tissue Res. 309:73,2002
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Phase-response curve II. (PRC)
1-Sarcophaga 5-Gonyaulax 9-Peromyscus
2-Coleus 6-Anopheles 10-Mus
3-Periplaneta 7-Mesocricetus 11-Chiroptera
4-Euglena 8-Peromyscus 12-Drosophila
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Uses of the biological clock
• prediction of environmental events –
burrowing animals, intertidal zone
• navigation based on celestial objects
• „waggle dance” – orientation based on the
position of the Sun
• measuring the length of days –
photoperiodism
• timing of reproduction – Palolo worm
• „gating” – timing of events occurring once in a
lifetime – hatching of Drosophila
Palolo (mbalolo) feast
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Jan. Febr. March April May June July Aug. Sept. Oct. Nov. Dec.
I. II. III. IV.
9:00 12:00 15:00 18:00 21:00 24:00
24:00 3:00 6:00
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Master clock of daily rhythms
• daily rhythms can be examined the most
easily and probably they are the most
important
• master clock was sought along the optic
pathway lesioning various neuron groups
• two teams, independently, but
simultaneously located the master clock:
• Stephan and Zucker, 1972
• Moore and Eichler, 1972
• it is the tiny, paired nucleus in the
anterior hypothalamus, above the crossing
of the optic tract: the nucleus
suprachiasmaticus (SCN)
• in non-mammalian species, clock is also
associated with the optic pathway
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Location ofonthe
Publications theSCN
SCN
300
250
200
150
100
50
0
1965 1970 1975 1980 1985 1990 1995 2000 2005 2010
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Effect of SCN ablation in rats
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Basic questions about the master
clock
1. How does it generate the rhythm?
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Discovery of clock genes
• 1985 – Martin Ralph – tau-mutant
hamster
• short period in continuous dark (DD),
Mendelian inheritance (20/22/24)
• breakthrough in 1994 using forward
genetics – Vitaterna (PhD student)
• Clock mutant among the first 42 mice –
abnormally long period, ceases in DD
• the mutation caused loss of a glu-rich
region characteristic for bHLH type
transcription factors
• conclusion: CLOCK is a transcription factor
• CLOCK also contains a PAS (Per-Arnt-Sim)
domain – ability to form dimers with
similar proteins
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Clock mechanism (mammals)
Bmal1
B
Clk Clock
B C
P Per1-3
Cry Cry1-2
P Cry
degradation
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Basic questions about the master
clock
1. How does it generate the rhythm?
2. How is the rhythm adjusted to the
external cycles?
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Layers of the retina
light
Szentágothai, Medicina, 1971, Fig.8-60 Berne and Levy, Mosby Year Book Inc, 1993, Fig. 9-6
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Photosensitive ganglion cells
1 mm
Hannibal, J., Cell Tissue Res., 309:73, 2002
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Ganglion cells of the retina
Berne and Levy, Mosby Year Book Inc, 1993, Fig. 9-16
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Inputs to the SCN
CTX, BF, HT, etc.
raphe
5-HT
shell NPY
SCN core GHT
Glut
PACAP
RHT
retina IGL
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Basic questions about the master 3
clock
1. How does it generate the rhythm?
2. How is the rhythm adjusted to the
external cycles?
3. How does the clock regulate the
biological rhythms of the body?
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SCN activity in vivo
SCN
HT
Meijer
Meijer, J.H., Watanabe, K., Schaap, J., Albus, H., Détári, L.., J. Neurosci. 18(1998):9078
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SCN activity in vitro
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CT 6
CT 3 CT 9
CT 0 CT 12
CT 21 CT 15
CT 18
Meijer, J.H., Watanabe, K., Schaap, J., Albus, H., Détári, L.., J. Neurosci. 18(1998):9078
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Role of pineal gland in sparrow
blinded sparrow, in LD
1 – removal of feathers from
the back
2 - removal of feathers
from the head
3 – removal of regrown
feathers
4 – subcutaneous Chinese
ink injection
5 – removal of skin and ink
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Pineal gland in mammals
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Output of the SCN
PVN
medial HT
MPOA
PVN, sPVN
DMH, VMH IGL
endocrine neurons
CRF, TRH, GnRH
vegetative neurons
other
sympathetic,
parasympathetic SCN targets
integrating neurons
shell
core
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One clock or several clocks?
• several organs posses the clock mechanism
(genetically all)
• explanation for the persistence of rhythms
in isolated organs
• the master clock regulates through the
hormonal system and through the behavior
• rhythms might get desynchronized:
– travel through time zones
– blind people
– limitation of access to food in time
– in certain cases constant (no Zeitgebers)
environment
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Desynchronization in humans
