Neurosciences 28
HC 8
Circadian Rhythm
Many functions and processes in living systems portray a 24-hours cycle, known as the
circadian rhythm. Not all systems have this biological rhythm, there are more lie the annual
or lunar rhythm. The source of the rhythm must be several external cues, so the movement
of the sun or the rotation of the earth. The rotation of the moon around the earth may for
example give rise to the tidal rhythms.
Hence, there are external forces guiding our rhythm. With the cues, individuals maintain a
steady 24-hour rhythm whereby they eat and sleep at around the same times. As the
external cues are removed, it is seen that the clock starts to run free, with individuals
sleeping until longer and going to bed later. Still, the cycle is 24 hours, but now with
different reference points – no longer waking up at 8 but at 10 o’clock. This indicates the
existence of an internal clock which also guides us. It keeps ticking even though the external
information about the time of day is absent.
Initial experiments into the circadian rhythm was done using rodents and the amount of
time they were actively running in their wheel. Rodents turn out to be primarily active
during the dark, at night – they are nocturnal animals. The activity thus indicates if one is
diurnal or nocturnal. If a diurnal animal sleeps during the day, you know the system is down.
The source of the rhythm primarily turns out to be light but also noise. During time-isolation
experiments, it was also shown that sleep-wake cycles shift relative to the actual alternation
of day and night. It shifts to the right, staying awake slightly longer and sleeping longer as
well, having a 26-hour rhythm without external cues. The individual had a cycle based on
the endogenous clock, which is still a rhythm, but 26 hours, not 24. It is postulated the
longer isolation occurs, the longer this rhythm will become. As soon as the isolation
experiment was over, the shift and return to normal occurred almost instantaneously. So,
from these experiments, we can conclude there is an internal clock with which we maintain
a rhythm in absence of external timing cues. Also, the external sources help us synchronize
the internal clock with the external world. At synchronization, the sleep rhythm matches the
24-hour cycle; if the external cues are taken away, the endogenous rhythm as said takes
over so that now a 26.1-hour length rhythm occurs. The means to synchronize lacks in
newborns, they do not have this 24-hour clock entrainment yet, meaning they show a
sleeping plot with complete random rhythms. It takes around four months to develop such a
circadian rhythm. Aside from external cues, there may also be internal cues that regulate
rhythm – especially in babies; hunger.
Not only humans portray a circadian rhythm and internal clock; experiments on fruit flies
exposed to constant light showed that their circadian rhythm increased by 35 minutes. Also
in animals, like us, the internal clock is trained by external, environmental stimuli which
hence serve as a zeitgeber. The zeitgeber in circadian rhythm is light, with day/night
conditions training the internal clock. The training does not, predominantly, require the
visual system. Experiments whereby the optical tract was cut, but still leaving connections
from retina to hypothalamus, showed the internal clock was still trained. Blind animals,
thus, also show an internal clock that notices the light in the environment. There must be
then some other biological structure rather active in determining and registering day length
and training your internal clock accordingly.
, The internal clock and circadian rhythm presumably evolved to ensure a rhythm despite one
would experience different times/amounts of daylight throughout the seasons. The
biological clock nevertheless is able to detect variations in light levels, which occurs in the
retina and the associated neurons and superchiasmatic nucleus (SCN). The neurons, which
lie within the ganglion cell layer of the retina, are depolarized by light whereby they release
melanopsin. The conventional rods and cones in the retina actually become hyperpolarized
when activated by light. The specific neurons thus are unusual photoreceptors encoded to
record the environmental illumination and entrain the biological clock. The intrinsic
photosensitive retinal ganglion cells, containing melanopsin, have as primary role to signal
light for unconscious visual reflexes, like pupil contraction. The melanopsin-containing
neurons project towards the SCN, in the anterior hypothalamus. This is the central site of
the circadian control of homeostatic functions. The retino-hypothalamic pathway following
activation of SCN by the retinal ganglion cells, when light (as zeitgeber) is detected, includes:
SCN activation invokes response in paraventricular nucleus of the hypothalamus
activates preganglionic sympathetic neurons in intermediolateral zone of the lateral horns
of the thoracic spinal cord modulate neurons in the superior cervical ganglia these
postganglionic axons project towards pineal gland synthesizes the neurohormone
melatonin from tryptophan. Melatonin modulates neuronal activity by binding to receptors
on the SCN which in turn influences the sleep-wake cycle. Actually, the SCN experiences a
negative feedback signal during darkness. So, the zeitgeber light trains the endogenous
clock in the SCN to take on the day/night cycle. Melatonin increases if light decreases,
making one sleepy in the end. Melatonin always increases during the dark period,
irrespective of the fact that the animal is diurnal or nocturnal; its rise is just interpreted
differently in different animals. Elderly people sleep less at night because their pineal gland
produces less melatonin. The SCN is the master clock of the biological rhythm, as becomes
clear when removing the SCN. Without the SCN, there is no rhythm at all, subjecting the test
subject to complete chaos. Also, SCN cells in vitro portray a certain rhythmicity. In
experiments, lesions in the SCN disrupts a previously functioning day/night rhythm, despite
that the visual system was kept intact. When placed in continuous light, the animal’s activity
becomes completely random, as the endogenous rhythm has been eliminated. Even
transplanting cells of a mutant SCN, with an endogenous rhythm of 20 hours, into a subject
without a SCN, re-established a rhythm of indeed 20 hours.
Molecular clock
The molecular machinery behind the biological clock includes the following steps:
1. Light dependent increase in transcription of Clk and Bmal1 genes
2. Increased appearance of CLOCK and BMAL1 proteins leads association of the two
and thus formation of a heterodimer.
3. The heterodimers bind to E-boxes in the DNA where they act as transcriptional
enhancers of several genes (or indirectly, proteins).
4. The temporally regulated proteins are synthesized and produced:
a. REV-ERBalpha, inhibits further transcription of CLOCK and BMAL1
b. CCG, proteins that activate the metabolic system
c. CRY + PER2, these dimerize as well and stop transcription of themselves and
the other two above.
5. The previously made mRNA and proteins degrade over time and because CRY/PER
dimers inhibit further production, stores deplete. When they are completely gone,
HC 8
Circadian Rhythm
Many functions and processes in living systems portray a 24-hours cycle, known as the
circadian rhythm. Not all systems have this biological rhythm, there are more lie the annual
or lunar rhythm. The source of the rhythm must be several external cues, so the movement
of the sun or the rotation of the earth. The rotation of the moon around the earth may for
example give rise to the tidal rhythms.
Hence, there are external forces guiding our rhythm. With the cues, individuals maintain a
steady 24-hour rhythm whereby they eat and sleep at around the same times. As the
external cues are removed, it is seen that the clock starts to run free, with individuals
sleeping until longer and going to bed later. Still, the cycle is 24 hours, but now with
different reference points – no longer waking up at 8 but at 10 o’clock. This indicates the
existence of an internal clock which also guides us. It keeps ticking even though the external
information about the time of day is absent.
Initial experiments into the circadian rhythm was done using rodents and the amount of
time they were actively running in their wheel. Rodents turn out to be primarily active
during the dark, at night – they are nocturnal animals. The activity thus indicates if one is
diurnal or nocturnal. If a diurnal animal sleeps during the day, you know the system is down.
The source of the rhythm primarily turns out to be light but also noise. During time-isolation
experiments, it was also shown that sleep-wake cycles shift relative to the actual alternation
of day and night. It shifts to the right, staying awake slightly longer and sleeping longer as
well, having a 26-hour rhythm without external cues. The individual had a cycle based on
the endogenous clock, which is still a rhythm, but 26 hours, not 24. It is postulated the
longer isolation occurs, the longer this rhythm will become. As soon as the isolation
experiment was over, the shift and return to normal occurred almost instantaneously. So,
from these experiments, we can conclude there is an internal clock with which we maintain
a rhythm in absence of external timing cues. Also, the external sources help us synchronize
the internal clock with the external world. At synchronization, the sleep rhythm matches the
24-hour cycle; if the external cues are taken away, the endogenous rhythm as said takes
over so that now a 26.1-hour length rhythm occurs. The means to synchronize lacks in
newborns, they do not have this 24-hour clock entrainment yet, meaning they show a
sleeping plot with complete random rhythms. It takes around four months to develop such a
circadian rhythm. Aside from external cues, there may also be internal cues that regulate
rhythm – especially in babies; hunger.
Not only humans portray a circadian rhythm and internal clock; experiments on fruit flies
exposed to constant light showed that their circadian rhythm increased by 35 minutes. Also
in animals, like us, the internal clock is trained by external, environmental stimuli which
hence serve as a zeitgeber. The zeitgeber in circadian rhythm is light, with day/night
conditions training the internal clock. The training does not, predominantly, require the
visual system. Experiments whereby the optical tract was cut, but still leaving connections
from retina to hypothalamus, showed the internal clock was still trained. Blind animals,
thus, also show an internal clock that notices the light in the environment. There must be
then some other biological structure rather active in determining and registering day length
and training your internal clock accordingly.
, The internal clock and circadian rhythm presumably evolved to ensure a rhythm despite one
would experience different times/amounts of daylight throughout the seasons. The
biological clock nevertheless is able to detect variations in light levels, which occurs in the
retina and the associated neurons and superchiasmatic nucleus (SCN). The neurons, which
lie within the ganglion cell layer of the retina, are depolarized by light whereby they release
melanopsin. The conventional rods and cones in the retina actually become hyperpolarized
when activated by light. The specific neurons thus are unusual photoreceptors encoded to
record the environmental illumination and entrain the biological clock. The intrinsic
photosensitive retinal ganglion cells, containing melanopsin, have as primary role to signal
light for unconscious visual reflexes, like pupil contraction. The melanopsin-containing
neurons project towards the SCN, in the anterior hypothalamus. This is the central site of
the circadian control of homeostatic functions. The retino-hypothalamic pathway following
activation of SCN by the retinal ganglion cells, when light (as zeitgeber) is detected, includes:
SCN activation invokes response in paraventricular nucleus of the hypothalamus
activates preganglionic sympathetic neurons in intermediolateral zone of the lateral horns
of the thoracic spinal cord modulate neurons in the superior cervical ganglia these
postganglionic axons project towards pineal gland synthesizes the neurohormone
melatonin from tryptophan. Melatonin modulates neuronal activity by binding to receptors
on the SCN which in turn influences the sleep-wake cycle. Actually, the SCN experiences a
negative feedback signal during darkness. So, the zeitgeber light trains the endogenous
clock in the SCN to take on the day/night cycle. Melatonin increases if light decreases,
making one sleepy in the end. Melatonin always increases during the dark period,
irrespective of the fact that the animal is diurnal or nocturnal; its rise is just interpreted
differently in different animals. Elderly people sleep less at night because their pineal gland
produces less melatonin. The SCN is the master clock of the biological rhythm, as becomes
clear when removing the SCN. Without the SCN, there is no rhythm at all, subjecting the test
subject to complete chaos. Also, SCN cells in vitro portray a certain rhythmicity. In
experiments, lesions in the SCN disrupts a previously functioning day/night rhythm, despite
that the visual system was kept intact. When placed in continuous light, the animal’s activity
becomes completely random, as the endogenous rhythm has been eliminated. Even
transplanting cells of a mutant SCN, with an endogenous rhythm of 20 hours, into a subject
without a SCN, re-established a rhythm of indeed 20 hours.
Molecular clock
The molecular machinery behind the biological clock includes the following steps:
1. Light dependent increase in transcription of Clk and Bmal1 genes
2. Increased appearance of CLOCK and BMAL1 proteins leads association of the two
and thus formation of a heterodimer.
3. The heterodimers bind to E-boxes in the DNA where they act as transcriptional
enhancers of several genes (or indirectly, proteins).
4. The temporally regulated proteins are synthesized and produced:
a. REV-ERBalpha, inhibits further transcription of CLOCK and BMAL1
b. CCG, proteins that activate the metabolic system
c. CRY + PER2, these dimerize as well and stop transcription of themselves and
the other two above.
5. The previously made mRNA and proteins degrade over time and because CRY/PER
dimers inhibit further production, stores deplete. When they are completely gone,
