Transcript Sleep wake cycle in a human being

Horacio de la Iglesia
Department of Biology
[email protected]
Organization of living matter
Spatial organization has been an key concept from the
earliest studies of biology, and particularly physiology.
Temporal organization is more subtle and usually
overlooked, but equally important.
The fitness of an organism depends on its physical
structure and its relationship with the environment. The
time domain of this physical structure, and of the
relationship with the environment, is as important as the
structural domain. Time as niche variable.
Sleep wake cycle in a human being
Wake
Sleep
Days
Wake
Sleep
Days
The persistence of rhythms in the absence of environmental cycles is
taken as evidence of an innate self-sustained timekeeping biological
mechanism, that is a Biological Clock
Components of a Generic Biological Timing System
Environmental
Cycle
(e.g.. light-dark
cycle)
Photoreceptors
(retina)
Clock
(suprachiasmatic nucleus)
Input
pathway
s
Output
pathways
I
IX
III
VI
Overt circadian rhythms
(e.g. sleep-wake cycle)
Virtually all known hormones show a
daily pattern of secretion
Analysis of circadian rhythms
locomotor activity in nocturnal rodents
Days
LD cycle
Period = 24 h
Free running in
constant conditions
(DD or LL)
Period circa-24 h
0
24
Clock time
48
0
24
Components of a Generic Biological Timing System
Environmental
Cycle
(e.g.. light-dark
cycle)
Photoreceptors
(retina)
Clock
(suprachiasmatic nucleus)
Input
pathway
s
Output
pathways
I
IX
III
VI
Overt circadian rhythms
(e.g. sleep-wake cycle)
The same circadian oscillator appears to control
locomotor activity and estrous
Fitzgerald and Zucker (1976) PNAS 73: 2923-2927
Looking for the Circadian Clock
 Lesions of suspected site should abolish rhythmicity
 Transplants of suspected site should restore circadian
rhythmicity in lesioned animals.
 Intrinsic properties of the suspected clock should be
rhythmic: in vivo and in vitro
 Identification of molecular and cellular mechanisms that
generate rhythmicity
 Mutations of specific genes should affect circadian
rhythms
 There should be a pathway communicating the
synchronizer with the clock
Lehman (1987)
J. Neurosci. 7:1626-38
The SCN is necessary and sufficient for expression
of locomotor activity circadian rhythmicity
Ralph & Lehman (1991) Trends Neurosci. 14:362
Lesions of the SCN
abolish all endocrine
circadian rhythms
?
0
24
SCN lesions abolish the rhythm of corticosterone release
Moore (1972) Brain Research 42: 201
The release of hormones is initiated in the brain:
Daily gating of the LH surge as an example
Everett and Sawer (1950) Endocrinol. 47:198
The release of hormones is initiated in the brain:
Daily gating of the LH surge as an example
% of women showing an LH
surge, as determined by
urinary LH
Edwards (1981) Nature 293:253-256
SCN transplants that restore locomotor activity rhythms
do not restore endocrine rhythms
Meyer-Bernstein et al. (1999) Endocrinol 140: 207-218
Identification of molecular components of the clock
The first mammalian clock mutant is found
•It is a semi-dominant mutation
•Heterozygous mice in constant darkness
have a longer period than wildtypes
•Homozygous mice in constant darkness have
initially a very long period and then become
arrhythmic
Vitaterna et al. (1994) Science 264:719-725
Transcription and translation feedback loops
constitute the core clock mechanism
Transcription
mRNA
Translation
Clock gene 1
Inhibition
Protein
(positive element)
-
Delay (~24 h)
+
Transcription
Translation
mRNA
mRNA or
Protein level
Clock gene 2
Time
Protein
(negative element)
Light
Per1
expression
Dark
This unparalleled localization of function within the SCN
makes the circadian system unique for the study of the
neural and molecular bases of behavior and physiology
Splitting in the hamster
De la Iglesia et al. (2000) Science 290:799-801
UNSPLIT HAMSTER
L
R
Right
SCN
Left
SCN
haPer1 RNA level
in situ
(SCN)
Time
Locomotor
activity
~24 hours
SPLIT HAMSTER
Right
SCN
Left
SCN
haPer1 RNA level
in situ
(SCN)
Time
Locomotor
activity
~24 hours
Dual Circadian Oscillators in the SCN
The ensemble of oscillators is reflected in overt behavior
Mechanism and “sticking” force?
Clock outputs?
The HPG Axis
Split female hamsters present a circa-12-h LH surge.
Swann and Turek (1985)
The SCN could have input the neuroendocrine hypothalamus
•SCN efferents project to
LHRH cells and these
projections are believed to
mediate the release of LHRH
that triggers the LH surge.
• The projections are
predominantly ipsilateral.
de la Iglesia et al. (2003) J. Neurosci., 23:7412-7412
.
.
.
. . .
. . .
.
.
.
.
.
. . .
.
.
.
.
.
.
. .
. ..
.
.
. .
. . .
.
Neural and diffusible outputs of the clock.
de la Iglesia and Schwartz Endocrinology (2006) 147:1148-1153
SCN lesions abolish the LH surge
Intracerebroventricular vasopressin induces a surge in the
SCN-lesioned animals
van der Beek et al. (1999) Neuroscience 93: 659-666
Endocrinology (2012) 153: 2839–2850
Smarr et al.
Input
pathways
I
IX
III
VI
SCN
Overt physiological
and behavioral
rhythms (activity,
feeding, core body
temperature, sleepwake)
Synchronization
of peripheral
clocks
Other entraining
inputs
Kidney
Liver
Skeletal
muscle
GnRH cells and the pituitary show autonomous oscillations
ov clock gene expression
Chappell et al. (2003) J. Neurosci. 23: 11202-11213
Yoo et al. (2003) PNAS 101-5339-5346
Sellix et al. (2003) Current Biol. 20:R266-R267
The HPG Axis
ERa
ERa
?
ERa
GnRH neurons
(slave oscillators?)
?
AVP
AVP
SCN
neurons
VIP
Median
eminence
GnRH
Portal system
Anterior pituitary
(Peripheral clock?)
LH
de la Iglesia and Schwartz
Endocrinology (2006) 147:1148-1153
E2
Ovary (Peripheral
clock?)
Miller et al.
The HPA Axis
Light induces expression of clock genes in the adrenal
Ishida et al. (2005) Cell Metabolism 2:297-307
Light induction of corticosterone release is ACTH-independent
Light induction of Per2 expression and of corticosterone
release depends on a n intact SCN
SCN control of glucocorticoid release
Pineal Melatonin
Melatonin tracks night length in humans
Light acutely inhibits melatonin production
When humans are given light during the dark phase or in complete darkness when
melatonin is high, melatonin levels in the blood quickly drop.
Czeisler (1995)
N.E.J.Medicine
Light acutely inhibits melatonin production
When humans are given
light during the dark phase
or in complete darkness
when melatonin is high,
melatonin levels in the
blood quickly drop. This is
even observed in some blind
patients.
Czeisler (1995)
N.E.J.Medicine
Melatonin and artificial light in humans
Melatonin is a night time signal
Humans are seasonal breeders
The reproductive axis a prominent
output of the circanual system
Entrainment and photoperiod measurement
Photoperiodic
measurement in
most species is
not based on an
hourglass
mechanism
But on a
circadian
oscillation of
photoinducibility
Clearly cannot be explained by hourglass mechanism
How is it explained?
Resonance cycles show an entrainment-based photoperiod
measurement
T cycles show an entrainment-based photoperiod
measurement
Gestational photoperiod measurement
Schematic design:
Pregnancy
After birth
12:12
Small testis
large testis