Light
is detected exclusively by the retina, in large part by intrinsically
photosensitive retinal ganglion cells (ipRGCs) which express the non-visual
opsin, melanopsin. Neural signals from these cells are conveyed to the SCN via
the retino-hypothalamic tract (RHT). Thereby, the phase of the SCN clock is
indirectly reset in response to light, and in turn, timing information is
relayed to the network of peripheral clocks via a complex combination of
blood-borne signals, feeding-fasting rhythms and core body temperature changes. Within
the same genus, the circadian system is significantly more sensitive to light in
shade-dwelling species than in those species adapted to live in more brightly
illuminated areas.
Cytologically,
the SCN contain both neurons and astroglia with an estimated ratio of 7–8:1 in
the rat SCN. The SCN are bilobed, situated on either side of the ventral floor
of the third ventricle in the periventricular zone of the anterior
hypothalamus. In the adult laboratory rat, they are ~0.7 to 1 mm in length.
Physiologically, four key features define circadian timekeeping in the nocturnal
rodent SCN:
(1) The SCN exhibits daily changes in the uptake of 2-deoxyglucose,
a marker of metabolic activity.
(2) electrophysiological recordings show that
SCN neurons of nocturnal rodents are spontaneously active and intrinsically
generate ~24 h rhythms in the frequency of action potential (AP) discharge.
(3)
The 24 h variation in electrical activity does not depend on ‘network’
properties as dissociated SCN neurons isolated in culture also vary daily
discharge of AP firing.
(4) SCN neuronal clocks are predisposed to synchronise
their activity with another, and intercellular communication is necessary for
this process.
SCN
input –
1) The retinohypothalamic tract (RHT) is a monosynaptic pathway from
melanopsin-containing retinal ganglion cells to the SCN,
2)
The geniculohypothalamic tract (GHT) mostly innervates the ventral and central
aspects of the rodent SCN and originates from neurons in the intergeniculate
leaflet (IGL) of the visual thalamus,
3)
The median raphe (MR) innervates the ventral and central SCN aspects, and the
neurotransmitter serotonin (5-hydroxytryptophan or 5-HT) is the characteristic
neurochemical of this pathway.
In
the SCN, the terminations of the RHT, GHT, and MR pathways overlap,
particularly in the ventral aspects. Perhaps unsurprisingly, activation of
non-photic pathways can limit the resetting effects of light pulses, while
acute light exposure can reduce or eliminate shifts to non-photic stimuli.
Thus, SCN neurons actively integrate photic and non-photic cues to shape the
phase of the molecular clock and the entrainment of the circadian system to the
external world.
Visualisation
of gene expression by in situ hybridisation indicates that not all regions of
the SCN rhythmically express clock genes at the same phase or perhaps at all.
While the SCN as a whole functions as the mammalian brain’s master circadian
clock, intra-SCN timekeeping is heterogeneous with some areas appearing to lead
daily changes in molecular clock activity, while others follow.
Neurochemically,
all SCN neurons contain GABA, but they can, to an extent, be distinguished by
the neuropeptides that they synthesise. The prominent neuropeptides contained
in SCN neurons include vasoactive intestinal polypeptide (VIP),
gastrin-releasing peptide (GRP), and arginine vasopressin (AVP).
The
peptide prokineticin-2 (PK2) is synthesised in the mouse SCN and is implicated
in conveying circadian information to the rest of the brain. Levels of PK2 mRNA
in the SCN vary across the light-dark and circadian cycles.
Most
of our current knowledge of the biological timekeeping mechanisms in mammals
arises from laboratory investigations focused on nocturnal rodent models, but
studies in diurnal species are much more limited. Comparative analysis of
diurnal species from different taxonomic groups is necessary to identify
convergent adaptations that are common to a diurnal niche and therefore more
likely to be shared by most diurnal species, including humans.
A
fundamental property of the circadian system is the PRC which describes the
resetting effects of light on the SCN clock. As stated earlier, the shifting
effects of light on the SCN clock depend on the time of day when light is
applied. With pulses of light given during the night, the pattern of PRC
appears to be quite similar across a wide range of diurnal and nocturnal
species.
The
typical organisation of the SCN into ‘core’ and ‘shell’ described in nocturnal
species seems to be present in some but not all diurnal species.
Patterns
of Per1 and Per2 expression, with high levels during the light phase and low
levels at night, have been found in all diurnal rodent species studied so far.
Summary
and Questions of Interests
· SCN neurons
exhibit intrinsic circadian variation in molecular, metabolic, and
electrophysiological characteristics.
· Regional
differences in neurochemical and timekeeping characteristics in the SCN are
pronounced in some species.
· SCN molecular
clock does not appear to differ between nocturnal and diurnal species.
· What processes
and mechanisms make an animal diurnal?
· How do SCN output
signals influence activity in specific target areas?
· Why are ‘core’
and ‘shell’ compartments more discernable in some species and not others?
· What are the
mechanisms underlying temporal niche switching within the same species?
Circadian
phase markers
Unlike
nonhuman models, scientists do not have direct access to the SCN in humans and
instead use marker rhythms driven by the SCN to indicate phase, amplitude, and
period of the circadian clock.
The
most commonly used circadian marker rhythm in humans is the melatonin rhythm.
Melatonin is easily measured in saliva, blood, and urine. Two other commonly
used circadian marker rhythms in humans are body temperature and cortisol.
Accurate
assessment of circadian period in sighted humans requires assessment in the
absence of external synchronizers, or under tightly controlled exposure to
synchronizers, which ensures their even distribution with respect to circadian phase.
Biological
Timekeeping: Cloks, Rhythms & Behavior, edited by Vinod Kumar, Springer
2017
