Circadian rhythm refers to biological cycles that occur over approximately 24 hours. These rhythms are regulated by molecular feedback loops in clock genes and proteins that influence cellular functions and synchronize organs. Disruption of circadian rhythms through irregular sleep/wake cycles, jet lag, or light exposure at night has been linked to increased risk of metabolic, cardiovascular, and mental health conditions. Maintaining circadian alignment through regular sleep/wake and meal times may help reduce disease risk.

1. CHRONOBIOLOGY
Sleep CME
18th 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
18th 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. Period gene  PER protein
Timeless gene  TIM protein
(help PER to enter nucleus)
Doubletime gene  DBT
protein (delayed accumulation
of PER in nucleus)

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. HEART

25. SKIN CA

26. 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.

27. PD

28. AD

29. 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.