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Disrupting circadian rhythms can have
consequences
• When external cues change, we have to readjust our internal clock (and cycles)
• Jet lag…adaptation: easier when flying in a
westerly direction…phase delay…
• Take ~3 days to adjust to a 12 hr time shift
• Shift work: accident prone times
– Chernobyl / truck collisions (1am- 4am)
– Doctors, nurses, policeman must cope
– Melatonin
Figure 1: Control of melatonin secretion. Photic
information is conveyed to the suprachiasmatic
nuclei (SCN), principally through the retinohypothalamic tract (RHT), where it synchronizes
the activity of the circadian oscillator to exactly
24 h. Neuronal efferent pathways from the SCN
directly distribute circadian information to
different brain areas, including the pineal gland,
that generates the melatonin rhythm. The neural
route for environmental lighting control of
melatonin secretion, after relay in the
paraventricular nuclei (PVT), includes the
intermediolateral column of the thoracic chord
grey (ILC) and the superior cervical ganglion
(SCG). The generated melatonin rhythm might
be used by the SCN to distribute its rhythmic
information. Melatonin can feed back at the
level of the SCN, as well as the retina itself. A
melatonin-driven circadian rhythm of sensitivity
to melatonin may exist in the structure(s)
involved in seasonality. Reprinted from Sleep
Medicine Reviews, Cardinali D, Pevet P, 1998,
2, 175–190. Basic aspects of melatonin action.
Melatonin biosynthetic pathway
Circuitry
Synthesis of Melatonin
The synthesis of melatonin is
initiated by activation of beta
NE receptors of pinealocytes.
This causes the synthesis of
cyclic AMP which
Pinal
Gland
Beta Noradrenergic
Receptor
Cyclic
AMP Serotonin
Pinealocytes
NAT
Triggers synthesis of
N-acetyltransferase (NAT)
(NAT) is enzyme that triggers
the conversion of serotonin
to melatonin
melatonin
Neural Pathway controlling melatonin release
Melatonin acts as an endogenous synchronizer.
Relationship of
plasma melatonin to
other major
circadian rhythms.
Note the close
correspondence
between the core
temperature nadir
and the melatonin
peak. Sleep
propensity closely
follows the
melatonin rhythm.
Reproduced from
Rajaratnam SMW
and Arendt J.
Lancet 358:999-1005,
2001 by permission
Circadian rhythms are generated by cells in the hypothalamic
suprachiasmatic nucleus (SCN),
location of THE biological clock in the mammalian brain
SCN and circadian rhythms
Circadian timing system
• Circadian pacemaker
• Entrainment inputs- RHT, GHT etc
• SCN efferent pathways
From Zigmond et al Fundamental Neuroscience, AP 1999
Fig. 2: Schematic summary of brain regions and circuits influenced by intrinsically photosensitive retinal ganglion cells
(ipRGCs). The ipRGCs and their axons are shown in dark blue, their principal targets in red. Projections of ipRGCs to the
suprachiasmatic nucleus (SCN) form the bulk of the retinohypothalamic tract and contribute to photic entrainment of the
circadian clock. The orange pathway with green nuclei shows a polysynaptic circuit that originates in the SCN and photically
regulates melatonin release by the pineal gland (P) through its sympathetic innervation. Synaptic links in this pathway include
the paraventricular nucleus (PVN) of the hypothalamus, the intermediolateral nucleus (IML) of the spinal cord and the superior
cervical ganglion (SCG). Another direct target of ipRGCs is the olivary pretectal nucleus (OPN), a crucial link in the circuit
underlying the pupillary light reflex, shown in light blue (fibers) and purple (nuclei). Synapses in this parasympathetic circuit are
found at the Edinger–Westphal nucleus (EW), the ciliary ganglion (CG) and the iris muscles (I). Other targets of ipRGCs
include two components of the lateral geniculate nucleus of the thalamus, the ventral division (LGNv) and the intergeniculate
leaflet (IGL).