Lectures 1-3 Flashcards
What two overarching processes does the body clock impact
Physiological and Cellular.
What are some examples of the physiological processes that the body clock impacts? (6)
Sleep/Wake
Body Temperature
Cardiac Output
Hormone Secretion
Metabolism
Immune Response
What are some examples of the cellular processes that the body clock impacts? (6)
Cell Cycle
DNA damage repair
Energy storage/release
Detoxification
Excitability
Communication
What are the two major types of diseases that disruption of the body clock impacts?
Neurological/degenerative and Inflammatory/metabolic.
What are some examples of neurological/degenerative diseases that are associated with disruption of the body clock? (6)
Sleep Disorders
Bipolar
Schizophrenia
Alzheimer’s
Parkinson’s
Huntington’s
What are some examples of inflammatory/metabolic diseases that are associated with disruption of the body clock? (5)
Diabetes
Asthma
COPD (Chronic Obstructive Pulmonary Disease)
Arthritis
Cancer
What are some modern lifestyle influences that can disrupt the body clock?
Shift work
Inappropriate light exposure
Altered eating habits
Jet Lag
Summarise why organisms developed ways of biological timing.
There are many selective pressures that occur cyclically due to the earth and its inherent characteristics.
Thus the organisms needed to develop a system that allows them to not only adapt but thrive to these.
Therefore, it makes sense to create a system to monitor these changes.
Give examples of some of the earths cyclical selective pressures. (7)
Sunlight
Temperature
Climate
Food Availability
Predation
Social Interaction
Sexual Pressure
Give 3 examples of biological timing in organisms. (C, P, D)
Cyanobacteria - they express cyclical daily expression of a gene.
Plants - even in the dark they express their cyclical leaf movements usually present in light.
Drosophila - they have pronounced daily activity despite a lack of external timing factors; even their egg hatching has a rhythm.
Define and give an example of ultradian rhythms.
Typically <20h (hours, minutes, seconds).
Pulsatile hormone release and/or sleep stages.
Define and give an example of circadian rhythms.
Daily 20-28 hours
Body temperature and/or sleep/wake.
Define and give an example of Infradian rhythms.
Typically >28 hours.
Oestrous Cycle (also circalunar) and/or seasonal breeding (also circannual).
Define and give an example of Circalunar rhythms.
Monthly
Oestrous cycle.
Define and give an example of Circannual rhythms.
Seasonal
Seasonal Breeding.
What are the 4 major properties of a circadian clock?
It’s a self-sustained oscillation.
It drives rhythmic outputs.
It’s relevant to the environment.
It’s responsive to the environment.
Why is the circadian cycle a clock and not an hourglass?
An hour glass needs some kind of input to restart the cycle every time it ends.
A clock is self sustained and runs continually.
What does it mean that a circadian clock needs to be relevant to the environment?
It needs to be time coherent/relevant to the external environment (24 hours) sot heat the behaviour is expressed when needed.
What are zeitgebers and what does this term mean? List some examples. (5)
They are the external environmental stimuli that input the internal clocks, guiding their accuracy.
It means ‘Time Givers’.
Light, food, exercise, temperature, social interaction.
What are the 5 major key terms of circadian rhythms? What do they mean?
Period - clock speed (e.g., 24 hours for Humans).
Amplitude - magnitude difference between peak and trough.
Phase - temporal alignment relative to environment. (Can be light or another rhythm).
Entrainment - stable relationship with environmental signals (zeitgebers).
Free Running Rhythm - natural function of the clock when entrainment is removed.
What is an actogram?
An actogram is a plot that shows rhythms in biological variables throughout the day.
Traditionally, actograms describe phases of activity and rest, but they have also been used to visualize rhythms in protein phosphorylation, gene expression, and hormone secretion.
Actograms are commonly used to study the underlying circadian rhythms of animals in fields such as ecology, reproductive biology, and sleep medicine.
What is ‘double plotting’ in actograms and why is this used?
It is when you take the same actogram, lower it one level and shift it to the left of the original plot.
When dealing with shifts in cycles, at some point the time will go ‘off the edge’ and start on the other side.
By having a double plot, it allows you to see this shift over a 48 hour period compared to a 24 hour period (for example) so you can see the continual shift in a simpler way.
When are mice most active? What happens to mouses locomotor activity in a dark cycle? Why is this?
During the night (nocturnal).
It will begin to phase advance (shift to the left) due to a free running rhythm.
This is because the internal circadian rhythm of a mouse is faster than 24 hours.
Therefore, with no zeitgebers, it will begin to get up earlier and sleep later, locomoting within that period.
When are Rhabdomys’ most active? What happens to a Rhabdomys’ locomotor activity in a dark cycle? Why is this?
During the day (Diurnal).
It will begin to phase advance (shift to the left) due to a free running rhythm.
This is because the internal circadian rhythm of a Rhabdomys is faster than 24 hours.
Therefore, with no zeitgebers, it will begin to get up earlier and sleep later, locomoting within that period.
When are Degus’ most active? What happens to a Degus’ locomotor activity in a dark cycle? Why is this?
At dawn and dusk (Crepuscular).
It will begin to phase delay (shift to the right) due to a free running rhythm.
This is because the internal circadian rhythm of a Degus is slower than 24 hours.
Therefore, with no zeitgebers, it will begin to get up earlier and sleep later, locomoting within that period.
If you were to be given the actogram of an average human living their life, would you be able to discern their circadian rhythm with confidence? Why?
No.
Their life is guided by a myriad of complex zeitgebers; day light, alarm clocks, different eating times, socialising, travelling etc.
Without the absence of zeitgebers, you can’t tell with confidence the rhythm; they are entrained to the environment around them.
What is Social Jet Lag?
It is the difference in your sleep/wake between your cycle when you are working and have an external responsibility to get up and your natural time of waking on your free time (e.g., on the weekends).
Why are there seasonal changes in a humans sleep/wake cycle?
Solar time doesn’t change; solar noon is always at the same absolute time.
However, local times changes (Summer and Winter time changes).
This means that the local environment has changed, e.g., work always starts at 9am but this changes relative to solar noon with these clock changes.
Therefore, depending on the season, your sleep/wake shifts in response to these external stimuli.
How does the body adaptations of Jet Lag take effect?
Activity patterns gradually shift across time zones as you acquaint yourself with the new environment.
Why can Jet Lag be so impactful on a person?
Every aspect of your bodies’ physiology is effected by the change in time, hence it can be quite intense/strenuous to feel these effects.
What are the two axis of the circadian rhythm that external clocks set?
The time they are set on/occur on and the speed that they occur.
Describe Part 1 of the WT vs WT/tau vs tau/tau mouse experiment on the limits to entrainment.
METHODS:
- A classic light/dark cycle then dark only cycle experiment (tested circadian rhythms in both conditions).
- A WT mouse was used with a clock of ~23.7 hours.
- A tau/tau mouse was used with a clock of ~20 hours. (tau mutation causes the speeding up of internal rhythms).
- A WT/tau mouse was bred that had a clock of ~22 hours.
- Exposed each to light/dark then dark only and used actograms to see what happened.
RESULTS:
- WT mouse would be entrained in the light/dark to be active only at night.
- It would phase advance in dark only.
- tau/tau mouse would not entrain in light/dark and would free run due to its clock being to fast to phase delay.
- would free run in darkness too.
- WT/tau would entrain in light/dark, however, with an abnormal phase (waking up slightly too early and sleeping too late; was awake partially for light).
- WT/tau would free run in dark only.
THIS SHOWS:
- There is a limit to whether an animal can entrain depending on how close its internal clock is to the external stimuli.
What are the limits to entrainment?
Generally, clocks can only speed up or slow down by 2-3h per day.
The range of differences in entrainment was a function of the differences in the intrinsic period and environment and results in two different altered phases:
If the intrinsic period is faster, there is an earlier phase.
If the intrinsic period is slower, there is a later phase.
Describe Part 2 of the WT vs WT/tau vs tau/tau mouse experiment on the limits to entrainment.
METHODS:
- Researchers introduced a 50/50 split of WT to tau/tau mice in a field, wild type environment for a year.
- They left them to live life and wanted to see the effect of the tau/tau mutation and it’s prevalence in this population.
RESULTS:
- By the end of the year, natural selection had resulted in a reduction of the tau allele to only 0.2.
- This shows the intense selection against it.
- Likely due to predation, breeding (biological and temporal availability).
Where are the ‘body clocks’? How do they work (simple statement).
Individual cells across the body are clocks; most cells have them.
They work be a process of gene expression and degradation.
What is the basic process of the ACTIVATION of the molecular clock? Use the mouse as an example.
Two genes bind together, BMAL1 and CLOCK, both of which are transcriptional activators.
This means they drive the expression of genes, specifically period and cryptochrome.
The accumulation of these two genes’ RNA leads to their protein synthesis in the cytoplasm.
These two bind and dimerise, from which the dimer translocate to to the nucleus.
What is the basic process of the REPRESSION of the molecular clock? Use the mouse as an example.
The Period and Cryptochrome dimer translocate to the nucleus and then inhibit the action of BMAL1 and CLOCK.
This leads to their transcription of period and cryptochrome RNA, so per and cry decrease.
This leads to a reduction in per and cry proteins, thus leading to the lack of inhibitory action from them.
From which the cycle can start again at activation.
How long does the cycle of activation and degradation in the molecular clock take? Why is this salient?
It takes roughly 24 hours and is responsible for a lot of the rhythms in cell function, hence it is the basis of the circadian cycle.
What is extraordinary about the molecular clocks appearance between organisms?
There are many unique examples of where it evolved separately, showing its fundamental nature to biology on this planet; if it developed many times independently then it must be crucial.
E.g.:
Cyanobacterial clock
Insect Clock
Fungal Clock
Mammalian Clock.
Under what circumstances might organisms not have a biological clock?
If they live in environments where there are no reliable zeitgebers to provide info on the cycles occurring.
E.g., living underground, living in the arctic circle.
Give 3 examples of animals without functioning biological clocks. Why is this the case?
Svalbard Ptarmigan, Svalbard Reindeer - both of these live in the artic circle in which there is either no sunset or no sunrise, hence there is no consistent light stimulus to entrain a cycle to.
The Somalian Cave Fish lives in complete darkness in water in caves, even in the presence of light dark cycles it doesn’t entrain.
Each of these do have a clock but mutations present in it mean that they don’t function.
What keeps all these clocks in line with the environment? Where is it located?
The Suprachiasmatic Nucleus (SCN) in the hypothalamus.
It’s located above the optic chiasm, where the optic nerves cross within the Retino-Hypothalamic tract.
What are some mechanisms that the SCN uses to control the clocks across the body?
Neural signals, hormonal signals, cortisol.
It also acts indirectly on activity, feeding and body temperature.
What are the two main factors that dictate the impact of light on the circadian rhythm?
Timing of Light
Availability of Light
What is photoentrainment?
The fact that the circadian system is tuned to ensure robust alignment to the environmental light/dark cycle.
Outline the effect of time that which light is presented in a nocturnal rodents cycle and why.
Light introduced in the early part of the night:
There is a phase delay in the cycle because the circadian system will compute that the day lasted longer than it had expected; it should wait later for night to come and it to be active.
Light introduced in the late part of the night:
There is a phase advance in the cycle because the circadian system will compute that the night was shorter than expected; it should wake up earlier and sleep earlier to avoid being awake in the day.
What is a phase response curve (PRC)?
It is used to show the relationship between circadian time and the phase shift (in hours) elicited by an external stimulus such as light.
This can be used to show us what effect the stimulus has on the shifting of the circadian cycle (whether it be phase advance or delay) and where any ‘dead zones’ are.
What is a dead zone in a PRC?
It is a period of circadian time in an animals cycle in which introduction of a zeitgeber will not cause a phase shift of any kind.
What are the differences in phase shifts in mice and hamsters? Why?
Mice often show much larger delays and smaller advances.
This is because they have a fast running clock, thus they need to delay more often.
Hamsters often show much larger advances and smaller delays.
This is because they have a slow running clock, thus it needs to advance more often.
What can the multiple difference in availability of light between midday and midnight be?
Ambient illumination can be a billion (10^9) times higher at midday than midnight.
Describe the study into the effect of the intensity of light on hamster activity rhythms.
METHODS:
- Hamster wheel running in constant conditions.
- Light pulses applied during late subjective night at varying intensities starting from dim and increasing sequentially to bright light.
- Wanted to see the impact on activity onset changes post light introduction.
RESULTS:
- When it was dim, nothing happened to the animals.
- As it gets brighter you start to see a phase advance.
- At the highest intensity of light you saw the largest phase advance.
Therefore, the brighter the light, the larger the advance.
What did plotting the results of “The effect of the intensity of light on hamster activity rhythms.” show us that was an important finding?
When plotting the Log(Photons) you can see that phase advances track the increase of available light very closely.
This is an important finding because it didn’t align with out previous understanding.
So we now know that circadian photoentrainment relies upon accurate quantitative measurement of environmental light.
What was the problem of using retinal photoreceptors (rods and cones) to explain the mechanism underlying photoentrainment?
Given that circadian photoentrainment relies upon accurate quantitative measurement of environmental light, the rods and cones are not sufficient to supply this information.
Rods are fully saturated at very low levels of light.
Cones are responsible for day time colour vision and have a mechanism to actively adapt their sensitivity to the available light.
Thus neither of them can provide a holistic measurement of the relative light levels between night and day time.
