Neurobiology of Circadian Rhythms

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1 ARC-IBRO ISN Joined Neuroscience School Behavioural Bioassays in Neuroscience: Brain and Behavior From Invertabrates To Small Mammals 4-14 December 2014 ICIPE, Nairobi KENYA Neurobiology of Circadian Rhythms Nouria Lakhdar-Ghazal, PhD Faculty of Sciences, Mohammed V University Rabat, Morocco

2 What is rhythmic in our body? Is all rhythms have the same frequency/period? What are the rhythms you know? Is a rhythm has a significance in our life If yes, what is the significance? Is the significance valuable in all environments? If yes, Why? If no, in which environment it is not valuable? Did you observed a rhythm? Did you perceived a rhythm?

3 Antiquity Birth of the rhythmicity in science Aristotle (322 before J.C.) observed the apparition of cyclic phenomenon in accordance with seasons Androsthene (325 before J.C.) : observed leaves of plants shut down during the night, but when the sun rizes, they completely open at twelve; When Sun go bed, they close. Pythagoras (480 before J.C.) confirmed that all organisms of our world, including Human, are governed by the revolution of asters...and then express rhythmicity Daily rhythms are linked to the 24 hour rotation of the earth aroud itself The milieu imposed its low to the organisms inducing the expression of rhythms

4 XVIII Century Birth of circadian rhythms in science Descartes (1664) : It is absolutely because swallows return each year in spring that they act in this view as a clocks A concept :...something in the living organism is endogenous Ortus de Mairan (1729) :...opening/closing of Mimosa plant leaves occurs even in continues darkness. Such a plant contain a clock XIX Century An endogenous rhythm generator in plants is discovered Richter (1919) : Discovered that the rhythm of locomotors activity is endogenous

5 Circadian rhythms are of endogenous nature The term circadian was introduced to identify self-sustained rhythms under constant conditions. flying squirrel (Glaucomys volans) DD, T 20 C Mink LL, T 20 C Expression under darkness Earlier activity each day Phase advanced Period of the rhythm < 24 h P.J. De Coursey, 1960 Expression under lightness Later activity each day Phase delay Period of the rhythm > 24 h D. Maurel et al, 1991

6 Circadian rhythms are of endogenous nature The endogenous nature of the human circadian system is reported by Aschoff and Wever in 1962 Rhythmicity is observed at all levels of the organism Rhythms with different periods in the same organism Human: ms: electroencephalogram S: electrocardiogram 10 s: respiratory rhythm Hours: hormones 24 hours: sleep/wake cycle; T 28 Days: ovaries activity Année Acrophases at different nychthemeral times Temporal organisation proper to each individual: unique An endogenous clock might be considered as an orchestral conductor that arranges the rhythm and synchrony of the various components in the body In Boissin & Canguilhem, Les Rythmes Du Vivant, ISBN , Nathan Ed., France

7 Rhythms of corticosteron is of circadian nature 200 ACTH (ng/l) Corticosteron 21 days 35 days ,0 1,5 0,5 0 1,5 1,0 0,5 0 1,5 1,0 0,5 0 Szavarczyk et al., J Steroid Biochem. 1983

8 What are the parameters of a circadian rhythm? ~24 h cyclic variation of a clock-induced biological function that can be synchronised to light/dark cycle; then P = exactly equal to 24 h Period: time between two identical events τ Acrophase: maximum Amplitude Middle level Bathyphase: Minimum

9 Behavioural rhythms are synchronised by light/dark cycle The rhythm of locomotors activity has the same profile in diurnal and nocturnal species Nocturnal Behaviour Diurnal Behaviour The rhythm is linked to that of corticosterone In Boissin & Canguilhem, Les Rythmes Du Vivant, ISBN , Nathan Ed., France

10 Where is the clock? Richter provides evidence pointing to the anterior hypothalamus as the location of the biological clock (1967), then the suprachiasmatic nucleus was identified as containing the principal clock by Stephan & Zuker /Moore & Eichler 1972

11 Distribution of neurotransmitters in SCN The neurochemical nature of cells divides the SCN in functional subdivisions Vasopressine (VP) 2100/GABA Angiotensine II, Met-Enkephaline SCN dorso-médial Somatostatine/GABA shell VIP 1100/GABA Calretine, Neurotensine GRP 500/GABA core SCN ventro-latéral Optic Chiasma Glu

12 Neurotransmitters can be determined by different methods of immunocytochemistry Abrahamson & Moore, Brain res; 2001 Welsh et al., Annual Review of Physiology, 2010 Mohawk & Takahashi, Trens Neuroscience,2011

13 Molecular basis of circadian rhythmicity SCN CRY PER VP mrna CRY PER PER Retina CRY BMAL1 CLOCK - + Ebox Ebox Ebox Ebox Ebox Clock Bmal1 Per1-2 Cry1-2 Dec1-2 Rev-erb ROR RORE - + DEC ROR REV-ERB Circadian Outputs VIP mrna GRP mrna Dardente et al., Brain Res, 2002

14 SCN controls circadian expression of physiological and behavioural functions Free running activities Central/Peripheral Clocks

15 Molecular basis of circadian rhythmicity : clock genes The principal genes of rhythmicity are clock, bmal1, per 1-3, cry 1 and 2, caseine kinase The rhythmicity is founded on positive and negative retrocontrols. Clock and Bmal1 codes for the synthesis of CLOCK and BMAL1 proteins ClOCK and BMAL1 constitute an heterodimer that activates the rhythmic expression of per 1-3 and cry 1-2 genes PER 2 can stimulate the transcription of bmal1 gene in BMAL 1 protein which dimerise with CLOCK which reactivates per/cry gene transcription CRY 1 and 2 proteins inhibits per and cry gene transcription via CLOCK and BMAL1 heterodimere

16 Modulation by environmental input, effects of light pineal gland SCN NPV IML retina Circadian rhythms SCG

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18 Modulation by environmental input, effects of light Golombek & Rosenstein, Physiology Review, 2010

19 Signal transduction mechanisms involved in circadian entrainment Golombek & Rosenstein, Physiology Review, 2010

20 Modulation by environmental input, effects of light Circadian entrainment represents an adaptation of organisms to their environment Challet, Chronobiology International, 2009 Golombek & Rosenstein, Physiology Review 2010i

21 Hormonal rhythms are synchronised by light-dark cycle Kalsbeek et al. 1999; 2000

22 VP rhythmically expressed in circadian pattern 3V VP Ventro-latéral «retino recipient» VIP GRP Optic Chiasma Kalsbeek et al. 1999; 2000

23 Synchronized circadian information reaches other brain structures to control circadian expression of physiological functions VP rhythm Hormonal rhythms Kalsbeek et al. 1999; 2000

24 Mel Rhythm is Inverse to that of Vasopressin

25 Is VP involved in the inhibition of melatonin synthesis during the day? VP release in the PVN Collection of Melatonin from pineal Kalsbeek et al. 1999; 2000

26 Is VP involved in the inhibition of melatonin synthesis during the day? Control 1 Vasopressin Control +1 Kalsbeek et al. 1999; 2000

27 VP infused in PVN during the nightime does not affect melatonin rhythm VP cells of the SCN co-synthesize GABA Pineal Melatonin rhythm SCG Light Retina RHT PVN SCN VP GABA

28 Is GABA involved in the inhibition of melatonin synthesis during the day? Light pulse during the nightime decreases melatonin Kalsbeek et al. 1999; 2000

29 Is GABA involved in the inhibition of melatonin synthesis during the day? Muscimol, a GABA agonist decreases melatonin when infused during the nightime Mélatonine Noradrénaline Kalsbeek et al. 1999; 2000

30 Is GABA involved in the inhibition of melatonin synthesis during the day? Biccuculine, blocks the light-induced decrease of melatonin Kalsbeek et al. 1999; 2000

31 Is GABA involved in the inhibition of melatonin synthesis during the day? Circadien rhythm of GABA is inversely correlated to that of melatonin Kalsbeek et al. 1999; 2000

32 Corticosterone PVN - VP - GABA Pineal Melatonine + SCN Glut/NMDA

33 PERSPECTIVES