CASES BBS2051
Summary of cases and lectures
, CASE 01 BBS2051
WHAT IS THE CIRCADIAN CLOCK ?
Physiological processes that vary over the 24-hour day include activity, alertness, hormone secretion,
organ physiology, and gene expression. These variations are not merely passive responses to a
rhythmic environment, but instead reflect an underlying biological mechanism that can measure
time in 24-hour increments. This mechanism orchestrates physiology to achieve predictive, rather
than reactive, homeostasis. Circadian rhythms are defined as rhythms that persist with a cycle length
of approximately 24 hours(24,5 to 25 hours) in constant environmental conditions. These rhythms
are generated by a biological timing mechanism that is normally synchronized (entrained) to the 24-
hour day by environmental cues. Light is the most widely used signal for entrainment of circadian
clocks, but temperature, hormone levels, nutrient availability, and other cues can also affect
oscillations. Many cell types express the genes necessary for the transcriptional-translational
feedback loop whose molecular oscillation occurs with a ~24-hour cycle length. The circadian clock is
evolved to maximize energy expenditure by adapting to environmental changes. By anticipating the
rising and setting of the sun, the circadian system ensures that behavioral and physiological rhythms
are coordinated with the external environment.
HOW DOES THE CIRCADIAN TIMING SYSTEM WORK ?
In mammals, the central clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus.
The nuclei is located rest on each side of the third ventricle in the anterior hypothalamus, dorsal to
the optic chiasm, lateral to the third ventricle. In the SCN there are 20,000 neurons subdivided into
core and shell neurons. The SCN consists of neuronal and glial cells distributed in a ventral ‘core’
region (receiving retinal input) and a dorsal ‘shell’ region. Ventrolateral (core) neurons express
VAP/AVP and GRP and the dorsomedial (shell) neurons express VIP. All neurons express GABA.
The majority of neurons express vasoactive intestinal polypeptide (VIP). Vasopressin is released into
the brain in a circadian rhythm by neurons of the suprachiasmatic nucleus. Vasopressin released
from centrally projecting hypothalamic neurons is involved in aggression, blood pressure regulation,
and temperature regulation.
A biological timing system necessarily consists of an intrinsic clock mechanism that measures time,
an input mechanism that allows the clock to become synchronized or reset by changes in the
environment, and output pathways that lead to generation of overt rhythms such as daily changes in
locomotor activity, sleep, and hormone levels.
The mammalian circadian is composed of a hierarchy of circadian oscillators. The SCN are often
called the master circadian clock, because these nuclei (one on each side of the brain) play a key role
in coordinating oscillations in other tissues and in regulating behaviour. Many other cells and tissues
also have the capacity to display an approximately 24-hour rhythmicity. The molecular mechanism
underlying these cell-autonomous circadian oscillations is a transcriptional feedback loop. Neural
firing rate of SCNs causes Circadian effects in the body and outputs mainly to pineal gland and
hypothalamus.
,The primary input pathway to the SCN circadian clock is through retinal detection of light.
Remarkably, the retinal photoreceptors that lead to visual image formation are not needed for
circadian photoreception. Instead, a specialized population of retinal ganglion cells directly detect
light, project to the SCN, and are necessary for photic entrainment of the SCN clock.
Retinal rod and cone photoreceptors and specialized retinal ganglion cells (RGCs) that express the
photopigment melanopsin convey light information to entrain SCN clocks. These intrinsically
photosensitive RGCs project to the SCN and other brain regions, including those regulating mood,
and can even entrain SCN clocks in perceptually blind persons. Melanopsin absorbs blue light, which
is emitted by electronic devices more readily than broad-spectrum light. Artificial lighting in the
evening can delay circadian clocks, resulting in misalignment with environmental cycles and
increasing the risk of sleep disorders. The coincidence of light with the endogenous clock program in
the SCN shifts as day length varies from summer to winter months, leading to seasonal changes in
intrinsic cycles.
Pathway
1. When light enters the eye(460-480 nm wavelengths), specialized cells in the retina
expressing the photopigment melanopsin called intrinsically photosensitive retinal ganglion
cells, or ipRGCs are activated by light.
2. IpRGCs are activated indirectly via inputs from rods and cones that form images , but also
directly, by responding to light on their own.
3. When photons hit the retina, melanopsin within ipRGCs undergoes a conformational change.
This change in melanopsin causes these cells to send action potentials that travel to the SCN.
, This anatomical pathway, consisting of axon bundle of ipRGCs running within the optic nerve
is called the retinohypothalamic tract, RHT. Action potentials prompt the release of two
neurotransmitters, glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP)
into the SCN.
4. In the SCN two types of glutamate receptors, NMDA and AMPA receptors and the RACAP
receptor PAC1 play important toles in reiving light signals.
5. The binding of glutamate to an NMDA receptor opens the receptor, which causes an influx of
cations ( sodium and calcium) into the cytoplasm which in turn causes the SCN neurons to
depolarize.
6. PACAP helps amplify this depolarization by enhancing the release of glutamate onto SCN
neurons and by enhancing the magnitude of NMDA receptor-mediated currents.
7. The membrane depolarization also activates voltage-gated calcium channels, which open to
allow more calcium release. At the same time, rising intracellular calcium levels activate
ryanodine receptors on the endoplasmic reticulum, triggering the release of calcium from the
ER into the cytoplasm.
8. Calcium in the cytoplasm binds to a protein called calmodulin to form a calcium-calmodulin.
9. This complex in turn activates Calcium-calmodulin Kinase 2 which is now able to
phosphorylate CREB.
Summary of cases and lectures
, CASE 01 BBS2051
WHAT IS THE CIRCADIAN CLOCK ?
Physiological processes that vary over the 24-hour day include activity, alertness, hormone secretion,
organ physiology, and gene expression. These variations are not merely passive responses to a
rhythmic environment, but instead reflect an underlying biological mechanism that can measure
time in 24-hour increments. This mechanism orchestrates physiology to achieve predictive, rather
than reactive, homeostasis. Circadian rhythms are defined as rhythms that persist with a cycle length
of approximately 24 hours(24,5 to 25 hours) in constant environmental conditions. These rhythms
are generated by a biological timing mechanism that is normally synchronized (entrained) to the 24-
hour day by environmental cues. Light is the most widely used signal for entrainment of circadian
clocks, but temperature, hormone levels, nutrient availability, and other cues can also affect
oscillations. Many cell types express the genes necessary for the transcriptional-translational
feedback loop whose molecular oscillation occurs with a ~24-hour cycle length. The circadian clock is
evolved to maximize energy expenditure by adapting to environmental changes. By anticipating the
rising and setting of the sun, the circadian system ensures that behavioral and physiological rhythms
are coordinated with the external environment.
HOW DOES THE CIRCADIAN TIMING SYSTEM WORK ?
In mammals, the central clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus.
The nuclei is located rest on each side of the third ventricle in the anterior hypothalamus, dorsal to
the optic chiasm, lateral to the third ventricle. In the SCN there are 20,000 neurons subdivided into
core and shell neurons. The SCN consists of neuronal and glial cells distributed in a ventral ‘core’
region (receiving retinal input) and a dorsal ‘shell’ region. Ventrolateral (core) neurons express
VAP/AVP and GRP and the dorsomedial (shell) neurons express VIP. All neurons express GABA.
The majority of neurons express vasoactive intestinal polypeptide (VIP). Vasopressin is released into
the brain in a circadian rhythm by neurons of the suprachiasmatic nucleus. Vasopressin released
from centrally projecting hypothalamic neurons is involved in aggression, blood pressure regulation,
and temperature regulation.
A biological timing system necessarily consists of an intrinsic clock mechanism that measures time,
an input mechanism that allows the clock to become synchronized or reset by changes in the
environment, and output pathways that lead to generation of overt rhythms such as daily changes in
locomotor activity, sleep, and hormone levels.
The mammalian circadian is composed of a hierarchy of circadian oscillators. The SCN are often
called the master circadian clock, because these nuclei (one on each side of the brain) play a key role
in coordinating oscillations in other tissues and in regulating behaviour. Many other cells and tissues
also have the capacity to display an approximately 24-hour rhythmicity. The molecular mechanism
underlying these cell-autonomous circadian oscillations is a transcriptional feedback loop. Neural
firing rate of SCNs causes Circadian effects in the body and outputs mainly to pineal gland and
hypothalamus.
,The primary input pathway to the SCN circadian clock is through retinal detection of light.
Remarkably, the retinal photoreceptors that lead to visual image formation are not needed for
circadian photoreception. Instead, a specialized population of retinal ganglion cells directly detect
light, project to the SCN, and are necessary for photic entrainment of the SCN clock.
Retinal rod and cone photoreceptors and specialized retinal ganglion cells (RGCs) that express the
photopigment melanopsin convey light information to entrain SCN clocks. These intrinsically
photosensitive RGCs project to the SCN and other brain regions, including those regulating mood,
and can even entrain SCN clocks in perceptually blind persons. Melanopsin absorbs blue light, which
is emitted by electronic devices more readily than broad-spectrum light. Artificial lighting in the
evening can delay circadian clocks, resulting in misalignment with environmental cycles and
increasing the risk of sleep disorders. The coincidence of light with the endogenous clock program in
the SCN shifts as day length varies from summer to winter months, leading to seasonal changes in
intrinsic cycles.
Pathway
1. When light enters the eye(460-480 nm wavelengths), specialized cells in the retina
expressing the photopigment melanopsin called intrinsically photosensitive retinal ganglion
cells, or ipRGCs are activated by light.
2. IpRGCs are activated indirectly via inputs from rods and cones that form images , but also
directly, by responding to light on their own.
3. When photons hit the retina, melanopsin within ipRGCs undergoes a conformational change.
This change in melanopsin causes these cells to send action potentials that travel to the SCN.
, This anatomical pathway, consisting of axon bundle of ipRGCs running within the optic nerve
is called the retinohypothalamic tract, RHT. Action potentials prompt the release of two
neurotransmitters, glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP)
into the SCN.
4. In the SCN two types of glutamate receptors, NMDA and AMPA receptors and the RACAP
receptor PAC1 play important toles in reiving light signals.
5. The binding of glutamate to an NMDA receptor opens the receptor, which causes an influx of
cations ( sodium and calcium) into the cytoplasm which in turn causes the SCN neurons to
depolarize.
6. PACAP helps amplify this depolarization by enhancing the release of glutamate onto SCN
neurons and by enhancing the magnitude of NMDA receptor-mediated currents.
7. The membrane depolarization also activates voltage-gated calcium channels, which open to
allow more calcium release. At the same time, rising intracellular calcium levels activate
ryanodine receptors on the endoplasmic reticulum, triggering the release of calcium from the
ER into the cytoplasm.
8. Calcium in the cytoplasm binds to a protein called calmodulin to form a calcium-calmodulin.
9. This complex in turn activates Calcium-calmodulin Kinase 2 which is now able to
phosphorylate CREB.
