Case 1: Circadian rhythm
maandag 27 mei 2024 10:32
1. Circadian rhythm definition
Circadian rhythm (= about, day) as it is about 24 hours due to earth rotation and changes
in light and temperature.
Other types of rhythms are:
• Tidal ~12h (sea tide high and low)
• Circadian ~24h (Day)
• Circatrignitan ~30 days (menstrual cycle)
• Circannual ~12 months (year)
To live with an internal clock has advantages as:
1) Anticipation to predicable changes is external conditions (e.g. temperature)
2) Efficient use of resources; produce offspring when circumstances are
optimal
3) Temporal segregation of incompatible processes (e.g. hibernation)
A rhythm consists of a period (full cycle (1)) with a phase (particular point in the
cycle (2)) and an amplitude (3) (the difference between peak (4) and trough (5) of
a cycle)
2. Terms you have to know
• Circadian rhythm: every 24h
• Ultradian rhythm: shorter/faster than 24h
• Infradian rhythm: longer/slower than 24h
• Diurnal rhythm: active during the day
• Nocturnal rhythm: active during the night
• Endogenous/ free running rhythm: genetically fixed biologic rhythm,
persistent in an environment without outside time cues (free running)
• Zeitgebers: ‘time-givers’ = factors that can (re)set/synchronize the
endogenous clock. They include light, exercise, temperature, sleep,
sound, social activity, melatonin or medicines)
• Entrainment: synchronized with Zeitgeber
3. How does the circadian rhythm work?
The human Central Circadian Clock is located in the suprachiasmatic nucleus
(SCN) of the hypothalamus.
Input: Light
Specialized ganglion cells contain the photopigments melanopsin and when light
enters the cells are activated and the signal travels down the retinohypothalamic
tract (RHT). Then Glutamate (via CaMK) or PACAP (via cAMP and PKA) activate
the phosphorylation of CREB proteins. These phosphorylated CREB proteins will
transcribe clock genes and produce clock proteins. The presence of the clock
proteins activates the SCN.
During the day light is high and therefore SCN activity is high. (high amplitude)
The SCN releases AVP (vasopressin) and/or GABA to inhibit the PVN
(paraventricular nucleus) and melatonin production.
Clock genes
Phosphorylated CREB proteins transcribe CLOCK and BMAL1. They will dimerize in
the cytosol and once in the nucleus, they will activate the transcription of Per and
Cry. The presence of Per/Cry dimers in the cytoplasm will in its turn inhibit CLOCK
and BMAL1 production. BMAL and CLOCK also drive the CCGs (clock controlled
genes) which is 10% of the genome.
Input: Night
During the night light is low and therefore SCN activity is low. (low amplitude)
The SCN does not release AVP or GABA to inhibit the PVN, this is not inhibited and
allows melatonin production to start. The hypothalamus will secrete
norepinephrine (NE) to the Pineal gland (via cAMP) to start the conversion from
tryptophan to melatonin. Then the melatonin travels to the MT1 and MT2
receptors of the SCN to inhibit clock gene expression.
TENTAMEN 2051 Pagina 1
,allows melatonin production to start. The hypothalamus will secrete
norepinephrine (NE) to the Pineal gland (via cAMP) to start the conversion from
tryptophan to melatonin. Then the melatonin travels to the MT1 and MT2
receptors of the SCN to inhibit clock gene expression.
Clock genes
No CREB is phosphorylated, less CLOCK and BMAL1 and Per/Cry is also
downregulated. Then during the night when all levels are low the CLOCK/BMAL1
is no longer inhibited so that in the morning the concentrations are high and
Per/Cry is low.
TENTAMEN 2051 Pagina 2
, Case 2: Circadian misalignment
dinsdag 28 mei 2024 09:27
1. What happens with Circadian misalignment?
Alignment can be seen when the activity and eating period correspond to the day
period. Circadian misalignment is disruption e.g. a night shift. Night shift can also be
responsible for a social jet lag as work and nonwork activities are misaligned. The night
shift causes the SCN to become out of sync, because of changes in:
o Light
The photic entrainment can be caused by natural light due to the night/day
cycle or by electronic/artificial light. Electronic light can manipulate the normal
cycle of the SCN activity and cause phase delays/advances within the circadian
rhythm of the body. Most important is the blue light of laptops/phones/etc. They
are within the range of 460-480nmwavelength which is exactly the wavelength
most sensitive to the photopigment melanopsin. In an environment with mostly
natural light, the melatonin onset as well as the melatonin offset is earlier than
with artificial light This means that artificial light as an environmental cue causes
a phase delay within our sleep-wake cycle. Or in night shifts the presence of light
is enough to cause changes.
o Food intake (GI disruption)
The Gut Clock is disrupted and the pancreas tries to solve this by releasing more insulin,
but this is not proportional leading to higher insulin levels and more insulin resistance.
The increasing insulin levels in the blood no longer suppress tissue lipolysis, leading to
the presence of more free fatty acids in the plasma. This process in the adipose tissue
enhances insulin resistance even more. The resistance causes the glucose levels to rise
by the liver clock as due to the resistance glucose production is no longer affected by
insulin.
The SCN is a Zeitgeber for the liver, as the liver is affected by signals of:
• SNS vs. PSNS activity
• Body temperature (to indicate time)
• Glucocorticoids like cortisol can reset the clock
• Feeding time (higher activity)
Molecular level: Eating during the night causes BMAL and PER for example to inverse
(picture).
o Physical activity (muscle disruption)
Activity during the night disrupts the muscle clock leading to decreased glucose
tolerance and increased insulin resistance.
Which can eventually lead to metabolic syndrome. Metabolic health syndrome = a
group of risk factors, including central obesity, elevated blood pressure, elevated
triglycerides, elevated fasting glucose, and low high-density lipoprotein (HDL)
cholesterol, which increase the risk for cardiovascular disease and diabetes.
2. Confounding factors
Not all factors that are changed by the circadian rhythm are solely dependent
on this rhythm also other factors can play a role.
o Core body temperature: circadian but directly coupled to sleep
o Melatonin: circadian but is supressed by light at night
o Cortisol: circadian but enhanced by awakening response
o Urine volume: circadian but is influenced by sleep/wake
o Thyroid hormone: circadian but is supressed by sleep
o Growth hormone: not circadian – stimulated by sleep
o Prolactin: not circadian – stimulated by sleep (hormone involved in fertility)
So be cautious with drawing conclusions as some changes are caused by sleep
impairment or other factors.
3. Jet Lag & Melatonin
Jet lag = phase shift induced feeling of discomfort
Term introduced in 1966 (travelling was too slow before then)
Characterized by disturbed sleep
o Travelling east → difficulty falling asleep
TENTAMEN 2051 Pagina 3
maandag 27 mei 2024 10:32
1. Circadian rhythm definition
Circadian rhythm (= about, day) as it is about 24 hours due to earth rotation and changes
in light and temperature.
Other types of rhythms are:
• Tidal ~12h (sea tide high and low)
• Circadian ~24h (Day)
• Circatrignitan ~30 days (menstrual cycle)
• Circannual ~12 months (year)
To live with an internal clock has advantages as:
1) Anticipation to predicable changes is external conditions (e.g. temperature)
2) Efficient use of resources; produce offspring when circumstances are
optimal
3) Temporal segregation of incompatible processes (e.g. hibernation)
A rhythm consists of a period (full cycle (1)) with a phase (particular point in the
cycle (2)) and an amplitude (3) (the difference between peak (4) and trough (5) of
a cycle)
2. Terms you have to know
• Circadian rhythm: every 24h
• Ultradian rhythm: shorter/faster than 24h
• Infradian rhythm: longer/slower than 24h
• Diurnal rhythm: active during the day
• Nocturnal rhythm: active during the night
• Endogenous/ free running rhythm: genetically fixed biologic rhythm,
persistent in an environment without outside time cues (free running)
• Zeitgebers: ‘time-givers’ = factors that can (re)set/synchronize the
endogenous clock. They include light, exercise, temperature, sleep,
sound, social activity, melatonin or medicines)
• Entrainment: synchronized with Zeitgeber
3. How does the circadian rhythm work?
The human Central Circadian Clock is located in the suprachiasmatic nucleus
(SCN) of the hypothalamus.
Input: Light
Specialized ganglion cells contain the photopigments melanopsin and when light
enters the cells are activated and the signal travels down the retinohypothalamic
tract (RHT). Then Glutamate (via CaMK) or PACAP (via cAMP and PKA) activate
the phosphorylation of CREB proteins. These phosphorylated CREB proteins will
transcribe clock genes and produce clock proteins. The presence of the clock
proteins activates the SCN.
During the day light is high and therefore SCN activity is high. (high amplitude)
The SCN releases AVP (vasopressin) and/or GABA to inhibit the PVN
(paraventricular nucleus) and melatonin production.
Clock genes
Phosphorylated CREB proteins transcribe CLOCK and BMAL1. They will dimerize in
the cytosol and once in the nucleus, they will activate the transcription of Per and
Cry. The presence of Per/Cry dimers in the cytoplasm will in its turn inhibit CLOCK
and BMAL1 production. BMAL and CLOCK also drive the CCGs (clock controlled
genes) which is 10% of the genome.
Input: Night
During the night light is low and therefore SCN activity is low. (low amplitude)
The SCN does not release AVP or GABA to inhibit the PVN, this is not inhibited and
allows melatonin production to start. The hypothalamus will secrete
norepinephrine (NE) to the Pineal gland (via cAMP) to start the conversion from
tryptophan to melatonin. Then the melatonin travels to the MT1 and MT2
receptors of the SCN to inhibit clock gene expression.
TENTAMEN 2051 Pagina 1
,allows melatonin production to start. The hypothalamus will secrete
norepinephrine (NE) to the Pineal gland (via cAMP) to start the conversion from
tryptophan to melatonin. Then the melatonin travels to the MT1 and MT2
receptors of the SCN to inhibit clock gene expression.
Clock genes
No CREB is phosphorylated, less CLOCK and BMAL1 and Per/Cry is also
downregulated. Then during the night when all levels are low the CLOCK/BMAL1
is no longer inhibited so that in the morning the concentrations are high and
Per/Cry is low.
TENTAMEN 2051 Pagina 2
, Case 2: Circadian misalignment
dinsdag 28 mei 2024 09:27
1. What happens with Circadian misalignment?
Alignment can be seen when the activity and eating period correspond to the day
period. Circadian misalignment is disruption e.g. a night shift. Night shift can also be
responsible for a social jet lag as work and nonwork activities are misaligned. The night
shift causes the SCN to become out of sync, because of changes in:
o Light
The photic entrainment can be caused by natural light due to the night/day
cycle or by electronic/artificial light. Electronic light can manipulate the normal
cycle of the SCN activity and cause phase delays/advances within the circadian
rhythm of the body. Most important is the blue light of laptops/phones/etc. They
are within the range of 460-480nmwavelength which is exactly the wavelength
most sensitive to the photopigment melanopsin. In an environment with mostly
natural light, the melatonin onset as well as the melatonin offset is earlier than
with artificial light This means that artificial light as an environmental cue causes
a phase delay within our sleep-wake cycle. Or in night shifts the presence of light
is enough to cause changes.
o Food intake (GI disruption)
The Gut Clock is disrupted and the pancreas tries to solve this by releasing more insulin,
but this is not proportional leading to higher insulin levels and more insulin resistance.
The increasing insulin levels in the blood no longer suppress tissue lipolysis, leading to
the presence of more free fatty acids in the plasma. This process in the adipose tissue
enhances insulin resistance even more. The resistance causes the glucose levels to rise
by the liver clock as due to the resistance glucose production is no longer affected by
insulin.
The SCN is a Zeitgeber for the liver, as the liver is affected by signals of:
• SNS vs. PSNS activity
• Body temperature (to indicate time)
• Glucocorticoids like cortisol can reset the clock
• Feeding time (higher activity)
Molecular level: Eating during the night causes BMAL and PER for example to inverse
(picture).
o Physical activity (muscle disruption)
Activity during the night disrupts the muscle clock leading to decreased glucose
tolerance and increased insulin resistance.
Which can eventually lead to metabolic syndrome. Metabolic health syndrome = a
group of risk factors, including central obesity, elevated blood pressure, elevated
triglycerides, elevated fasting glucose, and low high-density lipoprotein (HDL)
cholesterol, which increase the risk for cardiovascular disease and diabetes.
2. Confounding factors
Not all factors that are changed by the circadian rhythm are solely dependent
on this rhythm also other factors can play a role.
o Core body temperature: circadian but directly coupled to sleep
o Melatonin: circadian but is supressed by light at night
o Cortisol: circadian but enhanced by awakening response
o Urine volume: circadian but is influenced by sleep/wake
o Thyroid hormone: circadian but is supressed by sleep
o Growth hormone: not circadian – stimulated by sleep
o Prolactin: not circadian – stimulated by sleep (hormone involved in fertility)
So be cautious with drawing conclusions as some changes are caused by sleep
impairment or other factors.
3. Jet Lag & Melatonin
Jet lag = phase shift induced feeling of discomfort
Term introduced in 1966 (travelling was too slow before then)
Characterized by disturbed sleep
o Travelling east → difficulty falling asleep
TENTAMEN 2051 Pagina 3
