Welcome to a video tutorial on Mammalian Molecular Entrainment to Light and Networks.
This tutorial was produced by Adreanne Rivera, Cheyenne Schloffman, and Maria Villalon Landeros
under the guidance of Drs. Benjamin Sheredos, Karen Tonsfeldt, Takako Noguchi and Susan Golden
and narrated by Maria Villalon Landeros.
The suprachiasmatic nucleus, or SCN, in the hypothalamus, functions as the central pacemaker
in mammals.
The SCN can generate stable circadian rhythms by itself, as well as synchronize its rhythm
to the light/ dark cycle of the environment, and control the circadian rhythms of rest
of the body.
In this video tutorial, we explain the molecular signaling pathways that transmit light information
from the eyes to the SCN.
When light enters the eye, specialized cells
in the retina, expressing the photopigment melanopsin, and called intrinsically photosensitive
retinal ganglion cells, or ipRGCs, are activated by light.
ipRGCs are activated indirectly via inputs from rods and cones that form images, but
also directly, by responding to light on their own.
To learn more please watch this video tutorial…
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 an axon bundle of ipRGCs running within the optic
nerve is called the retinohypothalamic tract, or RHT.
Some ipRGCs terminate at SCN neurons.
Only a sub-region of the SCN, called the SCN core, receives input directly from ipRGC.
Action potentials prompt the release of two neurotransmitters, glutamate and
pituitary adenylate cyclase-activating polypeptide, or PACAP, onto SCN.
In the SCN, two types of glutamate receptors, NMDA and AMPA receptors, and the PACAP receptor,
PAC1, play important roles in receiving light signals.
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 neuron to depolarize.
PACAP helps amplify this depolarization by enhancing the release of glutamate onto SCN
neurons, and by enhancing the magnitude of NMDA receptor-mediated currents.
The membrane depolarization activates voltage-gated calcium channels, which open to allow more
into the cell.
At the same time, rising intracellular calcium levels activate ryanodine receptors on the
endoplasmic reticulum, triggering the release of calcium from the endoplasmic reticulum
into the cytoplasm.
Calcium in the cytoplasm binds to a protein called calmodulin to form a calcium-calmodulin
complex.
This complex in turn activates Calcium-Calmodulin Kinase II, or CaMK II, which is now able to
phosphorylate Cyclic-AMP Response Element Binding Protein, also referred to as CREB.
Phosphorylated CREB acts as a transcription factor by binding to the Cyclic AMP Response
Element, or CRE, in the promoter regions of the Per1, and Per2 genes, which encode central
components of the mammalian circadian clock.
Through this process, light drives the transcription of Per1 and Per2, which can shift the molecular
clock depending on the time of day.
This process allows the SCN core neurons to receive and process light information and
initiate synchronization of the entire SCN to the external light/dark environment.
After receiving light input, it is the job of SCN core neurons to communicate with other
SCN neurons, called SCN shell neurons, which will then synchronize the clocks of the rest
of the body.
As the core SCN neurons are activated or depolarized, action potentials are generated that travel
down axons and trigger the release of VIP and GABA.
VIP is released into the synaptic cleft and binds to VIP receptors on the membrane of
the SCN shell neuron.
VIP receptors are members of the family of G-protein coupled receptors.
When VIP binds to the receptor, VPAC2, it causes the activation of the G-alpha-S subunit
of a G protein.
Activated G-alpha-S in turn activates the enzyme adenylyl cyclase, which converts ATP
into cyclic AMP.
Cyclic AMP then activates an enzyme called protein kinase A or PKA,
which travels to the nucleus where it phosphorylates CREB.
Although the kinase that carries out the phosphorylation is different than in the SCN core cells, the
effect on CREB is the same.
Activated CREB binds to the CRE sites of the Per and Cry gene promoters and induces transcription
The induced clock genes, PER and CRY, adjust the phase of the transcription-translation
feedback loop of the cell.
In summary, when light stimulates the ipRGCs, glutamate and PACAP initiate a Calcium/CREB
signaling cascade that activates expression of PER1 and PER2 in the SCN core neurons.
Subsequently, the SCN core neurons release VIP and GABA onto the SCN shell neurons and
initiate a CREB signaling cascade, activating PER and CRY expression.
This process couples the oscillations in SCN core and shell neurons, allows the SCN to
synchronize to light/dark cycle.
The SCN, in turn, entrains clocks of rest of the body through many processes including
autonomic nervous system, hormone release, body temperature, and metabolism.
We hope you found this video helpful.
For more information on circadian biology,
please visit the UCSD BioClock Studio website (ccb.ucsd.edu/the-bioclock-studio).
Thanks for watching!