The paired suprachiasmatic nuclei (SCN) of the hypothalamus is the primary biological clock regulating circadian rhythms in mammals. The SCN generates coherent circadian oscillations through internal coupling of individual neurons that each express self-sustained circadian rhythms. The circadian clock consists of a core oscillator, output pathways, and feedback loops that allow it to maintain roughly 24-hour periods across different temperatures, known as temperature compensation.

1. Circadian Clock in Mammals Nikolai I. Kononenko Department of General Physiology of Nervous System, Bogomoletz Institute of Physiology, Kiev, Ukraine

2. INTRODUCTION As a consequence of the Earth’s rotation about its axis approximately every 24 hours, most organisms on our planet are subjected to fluctuations of light and temperature. A diverse range of species, from cyanobacteria to humans, developed endogenous biological clocks that allow for the anticipation of these daily variations. Thus, our internal physiology and function are fundamentally intertwined with this geophysical cycle.

3. The mammalian circadian timing system Hypothalamus The paired suprachiasmatic nuclei (SCN) of the hypothalamus is the primary biological clock regulating circadian rhythms in mammals. It has been show by lesion of these nuclei, destroying circadian behavior, with subsequent its restoration by implantation of SCN from donor animal. Retino-hypothalamic tract

4. Coronal and horizontal slices of suprachiasmatic nuclei Retino-hypothalamic glutamate tract ~ 700 

5. Suprachiasmatic nuclei of the mouse 1 mm

6. SCN neurons of the mouse at infrared differential interference contrast microscopy 100  m

7. Multiple-unit activity (MUA) from the rat SCN in vitro . from ~100 SCN neurons

8. 1. The paired suprachiasmatic nuclei (SCN) of the hypothalamus is the primary biological clock regulating circadian rhythms in mammals

9. Multielectrode array dish (MED) Hz 0 1 2 3 4 5 (Days) 1 min 1 mm

10. Activity of dispersed SCN neurons in MED and MUA of SCN in slice preparation Firing rate (Hz)

11. Individual SCN neurons express self-sustained circadian oscillations. As a result of internal coupling, the SCN generates a coherent output signal

12. Three main components of clock: a) oscillator, b) gear, and c) hands or digitals

13. Circadian-clock core Messenger Membrane target Hz

14. Minimal mammalian circadian clockwork model (circadian oscillator) From Scheper et al., J Neurosci 1999 The delay and nonlinearity in the protein production and the cooperativity in the negative feedback were found to be necessary and sufficient to generate robust circadian oscillations Period Period Period*

15. Temperature compensation The effect of changes in temperature on the rate of most biochemical reactions is measured by a Q 10 value, which is defined as the ratio of the rate of a given process at one temperature to the rate at a temperature 10°C lower. Q 10 = V t /V t-10 o C for known biochemical reaction 2 < Q 10 < 3 , for period of circadian rhythms Q 10 ~1

16. Light production in fireflies is due to a type of chemical reaction called bioluminescence . This process occurs in specialised light-emitting organs , usually on a firefly's lower abdomen. The enzyme luciferase acts on the luciferin , in the presence of magnesium ions, ATP , and oxygen to produce light. Genes coding for these substances have been inserted into many different organisms Firefly

17. Circadian rhythms of PER2::LUC bioluminescence recorded from knock-in mouse SCN neurons in dispersed culture From D.K.Welsh et al., Annu. Rev. Physiol. , 2010

18. Activity of dispersed SCN neurons in MED and MUA of SCN in slice preparation Firing rate (Hz)

19. Circadian rhythms of PER2::LUC bioluminescence recorded from mouse SCN neurons in slice preparation

20. 1. Nothing is known about messenger(s) between circadian-clock core and membrane target(s) responsible for circadian peaks of firing rate 2. Nature of membrane target(s) responsible for circadian peaks of firing rate enigmatic and contradictory

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