Clocks, sleep and the rhythms of life
Lecture 1: introduction to biological timekeeping
Mammalian physiology is rhythmic.
• Have times of peak performance and highest risk of heart attack for example
• Circadian rhythm disruption often linked to disease
• Modern lifestyles often oppose our natural clocks/rhythms e.g. chronic shift work, sleep
deprivation, altered eating habits, jet lag.
Evolution of biological timing:
• We live in an extremely rhythmic environment: earth
• Day/night, seasonal rhythm, food availability etc. all act as selective pressure for the evolution
of biological timing
• Everything from cyanobacteria (daily RNA synthesis fluctuation) to mammals (activity over the
day) have oscillating rhythms of some sort.
• So, timers are a universal and fundamental feature of biological processes
Rhythms of life:
• Circadian = daily, 20-28hours
• Ultradian= shorter than 20hour cycles e.g. pulsatile hormone release
• Infradian = >28 hour cycle
• Circalunar = monthly
• Circannual = seasonal
Properties of a circadian clock
• Has to be environmental responsive
• has to have self-sustained oscillation
• needs to drive rhythmic output
• ha to be relevant to environment e.g. operate over 24 hour period
Some terms:
• period = clock speed (peak to peak time), is species specific e.g. human clock has a period of
24.5 hours
• amplitude = magnitude of difference between peak and trough of the clock
• Phase = temporal alignment relative to environment e.g. you rise 1 hour after sunrise so the
phase is +1. Phase is relative to a fixed point.
• Entrainment= there is a stable relationship with environmental signal. The entraining signal is
called a zeitgeber. E.g. light
• Free running = natural function of clock with no entrainment by zeitgebers
,Light:
• Dominant zeitgeber for mammals an many other organisms
• Re-setting of the clock in mammals depends on retinal input to the suprachiasmatic nucleus
Wheel running in hamsters provides great example of circadian clock:
• Animal physiology is temporally organised- animals rarely active uniformly across night and
day
• Hamsters run at night, they’re nocturnal. Oscillations persist even if the light is left on all the
Time
Actogram:
• Days on y-axis
• Time in hours on x-axis
• Activity may slope to the right or left in the absence of the zeitgeber which is due to the
natural clock being more or less than 24 hours in period
Clock shifting in response to light:
,• Direction of clock shift depends on the phase of circadian clock, e.g. difference between
natural internal clock and the actual light stimuli given to the animals
• Direction of phase shift will depend on what will most quickly correct the rhythm.
• Phase response curve = resetting of the clock
Destruction of SCN → loss of behavioural rhythmicity in animals
Levels of clock properties:
• Molecular and cellular: there are molecular components that keep time
• Anatomical: cells/tissues that dictate time
• Physiological level: oscillating processes, signals to subordinate processes, acts as readout
of the clock
Mammalian circadian system:
• Both photic and non- photic influences
• Light is the dominant cue
• SCN is the master clock of the body
• SCN is paired nucleus structure on either side of the 3rd ventricle
• No SCN = arrhythmic animal
• SCN transplant imparts donor clock time on recipient
• Rhythms observed in SCN clock gene expression, neuronal activity and neuropeptide release
• SCN highest activity in day, least at night
Circadian clocks are actually found in virtually every cell and organ of the body
• Not just unique to SCN
• These clocks are critical to cellular and organ function, beyond just activity/rest
• Clocks all over the body are synchronised by the SCN
• Via hormonal signals e.g. melatonin, cortisol
, The molecular clock
• Basic elements of the molecular clock are preserved across organisms
• Two master positive regulators: proteins CLOCK and BMAL1, t drive transcription of period
(per) and cryptochrome (cry)
• Per and cry mRNA accumulates in the cytosol
• After translation, they dimerise (forming PER/CRY dimers
• They relocate to the nucleus and inhibit CLOCK and BMAL1 = simple negative feedback loop
• This cycle gives us a 24 hour clock
Components of a circadian clock:
• are all transcription factors
• also act outside of the clock e.g. act on non-clock genes
• they drive expression of non-clock genes rhythmically so are clock-controlled
• can act directly via E-box, RORE, D-box sites or indirectly by chromatin remodelling
Anatomy of the circadian system:
• in any given tissue, expression of >10-15% of the transcriptome is under direct
circadian Control
• 20% of hepatic proteome cycles
• 40%of all transcribed genes are under circadian control (40% of gene expression
oscillates
• rhythmically)
• Circadian disruption: caused by mutation, aging or disease.
• Mental health, inflammation, ND disease and cancer all linked to look disruption.
• Influences behaviour, hormones, physiological processes
Lecture 1: introduction to biological timekeeping
Mammalian physiology is rhythmic.
• Have times of peak performance and highest risk of heart attack for example
• Circadian rhythm disruption often linked to disease
• Modern lifestyles often oppose our natural clocks/rhythms e.g. chronic shift work, sleep
deprivation, altered eating habits, jet lag.
Evolution of biological timing:
• We live in an extremely rhythmic environment: earth
• Day/night, seasonal rhythm, food availability etc. all act as selective pressure for the evolution
of biological timing
• Everything from cyanobacteria (daily RNA synthesis fluctuation) to mammals (activity over the
day) have oscillating rhythms of some sort.
• So, timers are a universal and fundamental feature of biological processes
Rhythms of life:
• Circadian = daily, 20-28hours
• Ultradian= shorter than 20hour cycles e.g. pulsatile hormone release
• Infradian = >28 hour cycle
• Circalunar = monthly
• Circannual = seasonal
Properties of a circadian clock
• Has to be environmental responsive
• has to have self-sustained oscillation
• needs to drive rhythmic output
• ha to be relevant to environment e.g. operate over 24 hour period
Some terms:
• period = clock speed (peak to peak time), is species specific e.g. human clock has a period of
24.5 hours
• amplitude = magnitude of difference between peak and trough of the clock
• Phase = temporal alignment relative to environment e.g. you rise 1 hour after sunrise so the
phase is +1. Phase is relative to a fixed point.
• Entrainment= there is a stable relationship with environmental signal. The entraining signal is
called a zeitgeber. E.g. light
• Free running = natural function of clock with no entrainment by zeitgebers
,Light:
• Dominant zeitgeber for mammals an many other organisms
• Re-setting of the clock in mammals depends on retinal input to the suprachiasmatic nucleus
Wheel running in hamsters provides great example of circadian clock:
• Animal physiology is temporally organised- animals rarely active uniformly across night and
day
• Hamsters run at night, they’re nocturnal. Oscillations persist even if the light is left on all the
Time
Actogram:
• Days on y-axis
• Time in hours on x-axis
• Activity may slope to the right or left in the absence of the zeitgeber which is due to the
natural clock being more or less than 24 hours in period
Clock shifting in response to light:
,• Direction of clock shift depends on the phase of circadian clock, e.g. difference between
natural internal clock and the actual light stimuli given to the animals
• Direction of phase shift will depend on what will most quickly correct the rhythm.
• Phase response curve = resetting of the clock
Destruction of SCN → loss of behavioural rhythmicity in animals
Levels of clock properties:
• Molecular and cellular: there are molecular components that keep time
• Anatomical: cells/tissues that dictate time
• Physiological level: oscillating processes, signals to subordinate processes, acts as readout
of the clock
Mammalian circadian system:
• Both photic and non- photic influences
• Light is the dominant cue
• SCN is the master clock of the body
• SCN is paired nucleus structure on either side of the 3rd ventricle
• No SCN = arrhythmic animal
• SCN transplant imparts donor clock time on recipient
• Rhythms observed in SCN clock gene expression, neuronal activity and neuropeptide release
• SCN highest activity in day, least at night
Circadian clocks are actually found in virtually every cell and organ of the body
• Not just unique to SCN
• These clocks are critical to cellular and organ function, beyond just activity/rest
• Clocks all over the body are synchronised by the SCN
• Via hormonal signals e.g. melatonin, cortisol
, The molecular clock
• Basic elements of the molecular clock are preserved across organisms
• Two master positive regulators: proteins CLOCK and BMAL1, t drive transcription of period
(per) and cryptochrome (cry)
• Per and cry mRNA accumulates in the cytosol
• After translation, they dimerise (forming PER/CRY dimers
• They relocate to the nucleus and inhibit CLOCK and BMAL1 = simple negative feedback loop
• This cycle gives us a 24 hour clock
Components of a circadian clock:
• are all transcription factors
• also act outside of the clock e.g. act on non-clock genes
• they drive expression of non-clock genes rhythmically so are clock-controlled
• can act directly via E-box, RORE, D-box sites or indirectly by chromatin remodelling
Anatomy of the circadian system:
• in any given tissue, expression of >10-15% of the transcriptome is under direct
circadian Control
• 20% of hepatic proteome cycles
• 40%of all transcribed genes are under circadian control (40% of gene expression
oscillates
• rhythmically)
• Circadian disruption: caused by mutation, aging or disease.
• Mental health, inflammation, ND disease and cancer all linked to look disruption.
• Influences behaviour, hormones, physiological processes
