Chronobiology

Presentation on Chronobiology and Circadian rhythm, presented at CME on 18 th March 2022, KIMS & RF

1. Chronobiology Sleep CME 18 th March 2022 Dr. Donthu Raj Kiran DNB, MSc Psychology, PGDMLE Asst Prof, Psychiatry, KIMS & RF

2. roadmap What is chronobiology Circadian rhythm Functions Different levels of functioning Clinical implications Deregulation & implications

3. chronobiology Greek work ‘ chronos ’ meaning “time” & ‘biology’ meaning “science of life”. Studies variation of timing and duration of biological activity in living organisms which occur for many essential biological processes. Vast areas of application: anatomy, physiology, genetics, molecular biology, psychology, reproduction, epigenetics etc… Different processes: Animals: eating, mating, hibernating, migration etc. Plants: leaf movements, photosynthetic reactions etc. Microbial organisms: bacterial circadian rhythm

4. History French scientist first observed circadian cycle in 18 th century in movement of plant leaves. Carl Linneaeus designed a “flower clock” based on the time of the day when the flowers open. 1960 symposium at cold spring harbor lab, laid the groundwork for chronobiology . Franz Halberg coined the word circadian & considered to be “father of American chronobiology .”

5. Different cycles Infradian rhythm: cycles which are longer than 24 hrs. Ultradian rhythm: cycles which shoter than 24 hrs (90 min REM cycle, 3 hr cycle of GH production). Tidal rhythm: roughly 12.4 hr transition from high to low tide and back, observed in marine life. Lunar rhythm: follows lunar month (29.5 days). Gene oscillations: particular genes are expressed more during certain hours of the day than during other hours.

6. There are innumerable biological rhythms discovered, which range from milliseconds to several years. Focus is restricted to rhythms that match predictable environmental cycles: tides, days, lunar months and years. These have an endogenous clock that can stably synchronize to specific rhythmic environmental signal (‘ Zeigebers ’). But these clocks are self sustained; i.e. they continue to cycle internally with a period close to the environmental period even in absence of zeitgeber .

7. Anthropological links… Mammals are descendants of day-active, land-roaming reptiles. Evolution wise, there were two ways to reduce resource competition: conquer the air-space or be active at night. Former evolved the birds and the latter the mammals. No matter whether they later in evolution became day-active again (e.g., humans) or conquered the air-space (e.g., bats), all mammals originally went through the “nocturnal bottleneck”. In that respect, clocks are not only timers but also the equivalent of a compass within a structured, repetitive and therefore highly predictable temporal space. Foster Russell and Kreitzman Leon, The Rhythms of Life: The Biological Clocks That Control the Daily Lives of Every Living Thing London: Profile, 2004 Foster Russell G., Leon Kreitzman Circadian Rhythms: A Very Short Introduction Oxford University Press, Oxford, 2017, pp 143

8. Circadian rhythm Best studied rhythm in chronobiology is circadian rhythm. ‘Circa’ latin word for “around” and ‘dies’ meaning “approximately a day”. Function: anticipate, synchronise , coordinate and being on time for specific resources. Ex: prepares body physiology for transition from sleep to wake, by creating internal ‘day’ of a 24 hr biochemical clock.

9. Functions Anticipates and plans ahead without the need to consult external clocks. Coordinates different functions of physiology in cells, tissues and organs within the structure of 24 hr. Synchronizes organs performing different tasks at different times of day, some relate to outside world (e.g., to light-dark, warm-cold) others to our behaviour (e.g., wake-sleep, feed-fast). Physiology of body ranging from transcription and translation via transmitter and hormone excretion, to modulating metabolic and cognitive functions.

10. Organ systems involved Involves: immune, reproductive, gastrointestinal, skeletal, endocrine, renal and cardio vascular. Central clock  SCN. Secondary/ peripheral oscillators: heart, liver, kidneys, lungs etc.. Although independent, these are synchronized with SCN and other factors like temperature, meal timings and external cues.

11. Relation with sleep Sleep allows body to engage in circadian rhythms in the body. This initiates: Build up of energy  metabolic processes. Neuronal remodelling synaptic function, memory consolidation & assimilation of complex motor systems. + Circadian rhythm  -- RAS in brainstem  + sleep. Sleep regulation  balance between internal sleep homeostasis (process S) & external circadian drive (process C).

12. How is it formed in humans? Development of the circadian system occurs postnatally . At birth, neonates have an immature functioning system. Fetus is not subjected to external stimuli so minimal deviations occur, but after birth, perception of day-night differences begin. In first 4 months, newborn experiences physiological changes and this establishes the 24 hr circadian rhythm. Core body temperature deviations, reveal the establishment of circadian rhythm.  Melatonin (starts 3mon)  critical to the permanent establishment of circadian rhythms. Cortisol (8wks – 9mon)  key indicator of a properly functioning circadian rhythm. Rivkees SA. The Development of Circadian Rhythms: From Animals To Humans. Sleep Med Clin . 2007 Sep 01;2(3):331-341.

13. Macro level Circadian master clock/ pacemaker: Supra Chiasmatic Nucleus (SCN). Receives light information from eye and produces strong rhythmic signal to convey internal time of day to rest of body. Peripheral clocks: cellular clocks outside of SCN. Hence, circadian program is not localized but all cells contain molecular clocks.

14. Environmental light-dark cycle act as the zeitgebers for SCN. Neuronal & Humoral outputs act as internal zeitgebers for all cellular clocks throughout the body. Some organs like liver uses feeding signals directly. In birds & reptiles, pineal gland is responsible for coordinating the outside world with the cellular and organ clocks of the body.

15. Cellular level Circadian rhythm uses positive and negative molecular feedback loops as a mechanism to regulate their expression. Identified clock genes are: BMAL1/2, CLOCK, CRY1/2 and PER1/ 2/ 3; which regulate and control transcription and translation. Expression of clock genes influences signaling pathways which allows the cells to identify the time of day and perform appropriate function. Phosphorylation of clock proteins leads to degradation to keep the 24-hour cycle in sync.

16. Gene level

17. Clinical implications Biological clock adapts our physiology to different phases of day. It regulates critical functions: behaviour , hormone levels, sleep, body temperature and metabolism. If temporary mismatch occurs between internal biological clock and external environment  well being is affected. Chronic misalignment between lifestyle and rhythm  increases risk for various diseases.

18. Chronotypes Natural inclination of body to sleep at a certain time. Based on this: early bird or night owl. Distinction has genetic component, longer allele on PER gene  morningness .

19. Dysrhythmia Linked with lifestyle/ routines: frequent flying, changing shifts & exposure to irregular light-dark conditions. Jet lag: Short term: fatigue & GI disturbances Long term: disrupts spatial cognition and hippocampal neurogenesis . Dysrhythmia : increases risk of mental illness, cardiovascular and metabolic diseases.

20. Sleep disruption Insufficient & poor sleep  increase risk of metabolic disorder & outcomes. Alters sleeping energy expenditure & affects substrate oxidation  increases risk of obesity. Light at night  sleep disruption increases risk: cardiovascular disease, dysregulation of immune system, stress, memory deficits and depression. These external factors alter genetic expression  SNP marker, MEIS1 locus and Neuronal NO Synthase (NOS1). These in turn disrupt: functions of PER, casein kinase & PRNP genes.

21. Obesity & DM Environmental/ external factors mediated disruption of sleep  alters hormonal release  reduce leptin and induces DM. Irregular light-dark cycles  alters expression of genes  affects insulin receptor substrate & glucose transporter 2.

22. Bone health Affected not only by food, lifestyle; but also disruptions in sleep & circadian rhythm. Circadian rhythm is indicated by daily rhythm in bone turnover markers and existence of clock genes. Clock gene knock out models  altered skeletal phenotypes. Repeated sleep restriction  arrested bone remodelling .

23. Heart

24. Skin ca

25. Mealtimes Should be in line with the biological clock- a process that regulates sleep-wake cycle. Analyzed 4,642 diabetes people from National Health and Nutrition Examination survey. Reduced the chances of dying from heart disease.

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28. Take home message In short, circadian rhythm plays an important role in most of our biological processes without our conscious understanding. Research is emerging on various interactions of rhythm with various body functions. In our modern lifestyle, care should be taken to keep our circadian rhythm in sync with the environment.