1. Disrupting circadian rhythms can have consequences When external cues change, we have to re- adjust 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

7. Figure 1: Control of melatonin secretion. Photic information is conveyed to the suprachiasmatic nuclei (SCN), principally through the retino- hypothalamic 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.

8. Melatonin biosynthetic pathway

9. 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 Triggers synthesis of N-acetyltransferase (NAT) (NAT) is enzyme that triggers the conversion of serotonin to melatonin Cyclic AMP Serotonin NAT Beta Noradrenergic Receptor Pinal Gland Pinealocytes melatonin Circuitry

10. Neural Pathway controlling melatonin release

11. Melatonin acts as an endogenous synchronizer.

12. 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

13. Circadian rhythms are generated by cells in the hypothalamic suprachiasmatic nucleus (SCN), location of THE biological clock in the mammalian brain

15. Circadian timing system Circadian pacemaker Entrainment inputs- RHT, GHT etc SCN efferent pathways SCN and circadian rhythms From Zigmond et al Fundamental Neuroscience, AP 1999

20. 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).