Suprachaismatic nucleus (SCN) as a mammalian pacemaker

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