Light Extracts

Foreword

Circadian rhythms are found in nearly every living thing on earth.They help organisms time their daily and seasonal activities so that they are synchronized to the external world and the predictable changes in the environment. These biological clocks provide a cross-cutting theme in biology and they are incredibly important. They influence everything, from the way growing

sunflowers track the sun from east to west, to the migration timing of monarch butterflies, to the morning peaks in cardiac arrest in humans.

despite the diversity of life on our planet, there are many similarities in the way in which circadian rhythms are generated and synchronized to the solar cycle. There is a molecular feedback loop—the transcription-translation feedback loop (TTFL)—that underpins all these processes, and our understanding of this molecular clockwork provides the best example to date of how genes and their protein products interact to generate complex behaviour.

A 24 hour phenomenon

1

There have been over a trillion dawns and dusks since life began some 3.8 "billion years ago. During that time the earth's daily rotation has slowed to a shade less than 24 hours-or 23 hours 56 minutes and 4 seconds to be precise. This predictable daily solar cycle results in regular and profound changes in environmental light, temperature, and food availability as day follows night. Almost all life on earth, including humans, employs an internal biological timer to anticipate these daily changes. The possession of some form of clock permits organisms to optimize physiology and behaviour in advance of the varied demands of the day/night cycle. Organisms effectively 'know' the time of day. Such internally generated daily rhythms are called 'circadian rhythms' from the Latin circa (about) and dies (day).

Efficient use of time to maximize survival almost certainly provides a large selective advantage, and consequently all organisms seem to be led By such anticipation.

2

The imposition of aniatemal temporal framework, combined with the anticipation of environmental change, makes -the possession ofacircadian timing system an essential part of an organism's biology.

However, to be biologically useful, these rhythms must be synchronized or entrained to the external environment, predominantly by the patterns of light produced t>y the earth's rotation, but also by other rhythmic changes within the environment such as temperature, food availability, rainfall and even predation. These entraining signals, or time-givers, are known as zeitgebers. The key point is that circadian rhythms ares not driven by an external cycle but are generated internally, and then entrained so that they are synchronized to the external cycle.

3

Our own daily patterns of sleeping and waking; eating and drinking, depend not just on an alarm clock nor how much exercise we have done, but fundamentally on what our internal biological clocks are instructing us to do. When left without time cues, such underground or during an Arctic Winter or in an experimental isolation chamber, our endogenous clocks still tick and attempt to drive us.

pisrupting this pattern, as happens with jet lag or shift work, leads to internal desynchrony of the circadian system and our ability to do the right thing at the right time is greatly impaired.

4

In constant conditions, such as constant light or constant darkness, and with no exposure to, entraining zeitgebers, circadian rhythms freerun. Depending on the species, the period can vary between 22 and 25 hours, although there is considerable variation

both between species and between individuals of the same species. Most humans have slightly long body clocks and freerun with a period of about 24 hours and 10 minutes.

5

Bees and flowering plants have co-evolved the synchronization of the timing of a critical daily activity.

In effect the bees have a daily appointments book for flower-visiting and they can '

remember as many as nine appointments a day. The bees turn up at a particular time, receive their food reward, and in turn help the plants cross-pollinate. Both bees and plants share a common internal representation of the solar day and they can 'tell' the time and synchronize their internal 'watches'.

6

The nectar receivers typically stay inside the dark and temperature-stable hive. They lack light and temperature time cues but still 'know' the correct time because the foragers, who are outside and are exposed to time cues, entrain the interior workers by some form of social interaction. In this case the foragers act as zeitgebers for the receivers.

Some fish species can show either diurnal or nocturnal behaviour, and shift from one to the other depending on the season and developmental stage. Such circadian plasticity is of particular importance to animals living in the polar regions. Species such as the Arctic reindeer live in regions where photoperiodic (day length) information (Chapter 8) is much reduced or even absent

for considerable periods.

These animals are exposed to continuous daylight in the summer months and darkness in the winter. During these periods the clock function that drives circadian rhythms is much reduced if not wholly absent Switching off the clock probably helps them maximize food intake. During the summer, sustained feeding off the abundance of vegetation will allow the development of food reserves in preparation for the severe winter conditions, while in winter reindeer will be able to graze whenever the harsh weather conditions permit

10

Circadian rhythms self-sustaining with a period of about 24 hours that persists under constant environmental conditions.

12

The ubiquity of circadian clocks and rhythms speaks to their importance. They play a key role in a vast array of philological processes, including sleep/wake cycles, sexual behaviour and reproduction, thermoregulation, and metabolic control such as energy intake/expenditure, glucose metabolism, lipid metabolism, and food and water intake. Such innate timing mechanisms have been a feature of life on this planet since the first cyanobacteria and their production of oxygen began to shape the future planet billions of years ago. Circadian rhythms not only have a large impact upon us, but when they are disrupted our overall health and well-being can be severely affected.

Time of day matters

perhaps the most obvious and profound of our 24-hour rhythms is the cycle of activity and sleep Koenneberg's studies have developed the notion of an individual individuals as either larks, owls, or neither. For example, using the original classification schemes about 10-15 per cent of us are morning people, or larks, starting our days early. Another 10-15 per cent or so are owls, who find rising early very difficult and go to bed late. Roenneberg has shown that there is a spectrum of chronotypes ranging from extreme early types, who sleep (without social obligations) from 20.00 to 04.00, to extreme late types, who sleep from 04.00 to 12.00 noon.

The chronotype becomes later by four minutes for every longitude degree from east to west, the same time that the sun takes to cross one longitude. The MCTQ data have shown that many of us live timetables, one enforced by the weekday alarm clock on work days, and the other more aligned to our internal circadian time, involving 'sleeping in' at the weekend. To align sleep and wake times with social obligations, 80 per cent of the population uses an alarm clock on workdays, and a growing number of people use sleep medication at night and stimulants to drive wakefulness during the day.

19

The difference between alarm-clock-driven wake times and natural wake times on free days has been termed by Roenneberg social jet lag'

determining individual chronotypes can be used to mitigate social jet lag and some of the disruptive effects of shift working. Evening-type individuals report better tolerance for night work (e.g. better work performance and higher job satisfaction) than morning-type individuals. But social jet lag is associated with increased health risks. Independent of social background or region, the number of smokers in the population inc of alcohol and caffeine increases, along with increased levels of depression.

20

Senior teachers in their fifties will generally be

generally be at their best first thing in the morning, but their students will invariably be ill-prepared by their circadian system to learn. This finding may explain why there is a widespread belief that demanding subjects such as mathematics and science should be taught early in the school day while other, possibly less demanding topics such as physical education, art, and music, should be taught later in the day. The senior teachers and not the students determine the timetable and the tacit assumption for well over a century has been that students are most alert in the morning and the most important and intellectually demanding subjects should naturally be taught during this time. This assumption is wrong.

24

When timing goes wrong

Sleep and circadian rhythm disruption (SCRD) is almost always associated with poor health.

Jet lag

Jet lag is the most obvious example of what can happen when the circadian system is disrupted and environmental and internal

time are not properly aligned. Crossing more than three time zones in a jet aircraft uncouples these rhythms from the natural light/dark cycle and from each other. The various rhythms exhibit 'internal desynchrony' so metaphorically speaking the and the heart is still in San Francisco. It is even worse in space. Astronauts in orbit on the International Space Station may see sixteen dawns and dusks in 24 hours, so it is no wonder that sleeping tablets are the most frequently used medication in space.

27

Lemmers concluded that to be at the top of your game you need at least two weeks to recover from time zone transitions of 6 hours or more.

Horses also suffer from jet lag. Like humans, their performance suffers for a or more after the flight, and trainers try to decrease the effects of jet lag by changing both feeding times and exercise schedules destination. The horses are also exposed to bright early morning light prior to an eastward journey as this helps to advance the body clock. Likewise, evening light is beneficial for horses travelling westward which will delay the clock.

28

Shift work

The misalignments that occur as a result of the occasionaJ trans-meridian flight are transient. Shift working represents a chronic misalignment Shift workers try to sleep during the day* but sleep is usually shorter and of poorer quality than when sleep occurs at night. They then work during the night at a time when the circadian system has prepared the body for sleep, and alertness and performance are low. In effect, they work when they are sleepy

and sleep when they are not. Irrespective of how many years shift -workers have been on a permanent night shift, nearly all (-97 per cent) night shift workers do not adjust to the nocturnal regime but are still synchronized to a diurnal rhythm because of light exposure.

Artificial light in the office or factory is dim compared to environmental light. Shortly after dawn natural light is some fifty times brighter than the 300 to 400 lux experienced in the workplace, and by noon natural light can be 250 times brighter. After leaving the night shift, an individual will usually experience bright natural light and the circadian system will always lock onto the brighter light signal as daytime and align internal biology to the diurnal state. In one study by Charles Czeisler and his team at Harvard University, night shift workers were exposed to 2,000 lux in the workplace and then completely shielded from any natural light during the day. jjnder these circumstances they became nocturnal. This, of course, is not a practical solution for most night shift workers.

SCRD, of the sort experienced by night shift workers, can lead an increased risk of serious health conditions (Table 1). Short-term SCRD for a few days can have a big impact upon emotion and cognition, whereas longer term SCRD over years has been shown to increase the risk of cancer and cardiovascular disease.

correlations are so strong that shift work is now officially classified as 'probably carcinogenic [Group 2A]' by the World Health Organization.

study of over 3,000 people in southern France found that those who had worked some type of extended night shift work for ten or more years had much lower overall cognitive and memory scores than those who had never worked on the night shift.

30

Shift working and jet lag are excellent reminders that human existence is embedded within a dynamic 24-hour world. Until the 19th century, society was still largely agricultural and most people spent much of their time outdoors and lived their lives according to the natural day/night cycle. With increased industrialization, cheap electric light, and an increasingly 24/7 society, individuals have been detached from the solar cycle and the temporal order provided by the circadian system has been lost or diluted. The generations since the beginning of the 20th century have been living through a time of'Great Circadian Disruption', and it is now becoming clear that this headlong rush into modernity, without a second thought to our biology, is having profound effects upon our health.

37

SCRD in mental illness

SAD is a mood disorder in which individuals experience depressive symptoms in the winter but have normal mental health throughout the rest of the year. SAD was first described in a 1984 paper by Norman Rosenthal and colleagues at the National Institute of Mental Health. Light therapy either before or during the depressive episode can either eliminate or reduce many of the symptoms of winter SAD. Light therapy using a light box exposes an individual to more than 2,000 lux, compared to normal domestic light levels of around 300 lux. Also exposure to

normal domestic light levels of around 300 lux. Also exposure to sunlight by spending more time outside has shown to be effective, There are two favoured explanations for this action of light. The first suggests that supplementary light acts to entrain the circadian system in the winter months and so prevents internal desynchrony and the drift into SCRP; the second suggests that supplementary light will by some means increase serotonin levels throughout the brain, and elevated levels of serotonin are associated with feelings of well-being and happiness while low levels are linked to depression.

43

In combination with light and/or melatonin, social cues can also be useful in regulating the circadian/sleep system. Timed activities can influence daily patterns of light exposure and modify the timing of behaviour by associative learning and reinforcement. Meal timing, for example, can act as a strong stimulus for the synchronization of peripheral circadian rhythms in animals and humans, and could prove valuable when incorporated into cognitive behavioural therapy (CBT) paradigms. One key, but clinically unrecognized, element of CBT is to increase 'zeitgeber’ strength' by timing appropriate light exposure or meal times to the appropriate time of day (circadian phase).

Developing better pharmacological, light, and CBT treatments for light, and CBT treatments for SCRD will have a global impact the economics of health care, and at an individual level improve the quality of life for countless patients and their caregivers.

45

Shedding Light on the clock

To be of any value a clock must be set to local time. If you were a resident of Greenwich in London during the 19th century you would have set your clock by a visual time signal from the observatory in the form of a Time Ball' on a tower that was dropped at precisely 13.00 every day. The first time ball was erected at Portsmouth, England, in 1829 by its inventor Robert \Vauchope, a captain in the Royal Navy. However, when radio time signals were introduced in Britain from 1924, time balls became obsolete and many were demolished in the 1920s. Nowadays you would use the talking clock or the time on your smartphone, signals that originate from an atomic clock so accurate that if it had been started nearly 14 billion years ago at the Big Bang it would have only lost a second or two by now.

Most circadian clocks make use of a sun-based mechanism as primary synchronizing (entraining) signal to lock the internal to the astronomical day. For the better part of four billion dawn and dusk has been the main zeitgeber that allows entrainment Circadian clocks are not exactly 24 hours. So prevent daily patterns of activity and rest from drifting (freerunning) over time, light acts rather like the winder on a mechanical watch. If the clock is a few minutes fast or slow, turning the winder sets the clock back to the correct time. Although light is the critical zeitgeber for much behaviour, and provides the overarching time signal for the circadian system of organisms, it is important to stress that many, if not all cells within an organism possess the capacity to generate a circadian and that these independent oscillators are regulated by a ariety of different signals which, in turn, drive countless outputs

Light at dawn and dusk pushes and pulls the freerunning rhythm S- towards an exactly 24-hour cycle. In addition, the PRC also explains how activity is appropriately aligned to the expanding contracting dawn/dusk signal across the seasons in non-equatorial zones.

49

Meerkats, larks, Owls, bees

Light can act directly to modify behaviour. In nocturnal rodents such as mice, light encourages these animals to seek shelter, reduce activity, and even sleep, while in diurnal species light promotes alertness and vigilance. So circadian patterns of activity are not only entrained by dawn and dusk but also driven directly t>y light itself. This direct effect of light on activity has been called 'masking', and combines with the predictive action of the circadian system to restrict activity to that period of the light/dark cycle to which the organism has evolved and is optimally adapted.

53

But where is 'the* circadian clock of mammals He narrowed it down to somewhere deep in the brain, and almost certainly within hypothal^ l970s, Robert Moore and Irving Zucker independently found seemed to be 'the clock'. Knowing that circadian rhythms entrained by the light/dark cycle they considered structures the hypothalamus that received a direct retinal input. The SUPRACHIASMATIC nucleus, or SCN, is a pair of small nuclei located the base of the hypothalamus that sit either side of the third VENTRICLE just above the point where the optic nerves enter the in—the optic chiasma.

The behaviours of rats are strongly regulated by their circaddan rhythms, not least feeding rhythms. demonstrating the existence of an SCN-independent food-entrainable oscillator (FEO). Many organs seem to possess an FEO. A key mechanism food acts as a zeitgeber on these FEOs seems to involve release of hormones including leptin and ghrelin.

FEO - food

In addition to light and food, there are yet more zeitgebers such AS physical exercise and temperature. single bout of physical exercise at nught was demonstrated to phase-delay thecircadian rhythms, while scheduled physical exercise during the waking period can help achieve stable entrainment. Periodic temperature cycles wit.li periods around 24 hours, even with a temperature range of 1-2°C, can entrain all ectothermic (poikilothermic) organisms (insects, fish, reptiles etc.), but have very little or no impact upon. homeotherms such as birds and mammals. Although isolated and maintained in culture, mammalian cells can be entrained to a temperature cycle. Temperature changes probably act directly on the clocks of ectotherms and mammalian cells in culture by altering membrane properties, ion homeostasis, calcium influx, other signal cascades, and in this regard resemble some of the signalling pathways activated by light

Clearly the early mammalian model of a hierarchical circadian system with the SCN alone dictating circadian rhythmicity was far too simplistic. The circadian timing system is turning out to be a complex and highly sophisticated method of handling an organism's temporal alignment with both its external and internal environment. In parallel with this new understanding circadian system is organized, there has been equally remarkable progress in the understanding of how a single cell can generate an endogenous 24-hour circadian oscillation that can be regulated by external zeitgebers.

106

Seasons of life

Some 4.5 billion years ago, the nascent and still condensing earth was in an almighty collision with another proto planet. The bang ejected a moon-sized chunk and our planet's spin axis was tilted with respect to the plane of its orbit about the sun to an angle of 23.5°. That is one explanation for the tilt. There are others.

Photoperiod is the dominant source of information to time seasonal biology in species that live at mid-latitudes. Those living in environments where day length information is limited (e.g. at the equator where day length is close to 12 hours all year round, or in the high Arctic with its 24-hour summers and 24-hour winters), or have lifestyles that make day length unreliable or temporarily inaccessible (e.g. during migration and hibernation), use another timing system. These species rely on a clock with a period of about one year. Until the recent past, the changing seasons influenced human biology, with indications of annual cycles of reproduction, immune function, disease, and death. Since the electric light, air conditioning, central heating, and globalized food production, humans have become progressively isolated from seasonal changes in temperature, food, and photoperiod in the industrialized nations, Nevertheless, the seasons continue to have effects on our lives. The activity of almost a quarter of our genes (5,136 out of 22,822 genes some more active in winter and others more active in summer. It is not just our genes-much of our biology, including the composition of our blood and fat tissue, changes across the seasons. While we do not know if these changes result from some photoperiodic and/or circannual timer, or are simply driven by the environment, it does raise the possibility that although seasonal rhythms in humans have been largely masked by social forces, they may yet turn out to be important contributors to our physiology and even disease.

129

We will probably never know the real reason why circadian timing systems evolved, but what we do know is that a timing system of sg some sort seems to have been hardwired into the genome a very longtime ago. The world in which clocks evolved is profoundly % different from the one in which we live today. Even as recently as the patterns driven by the solar day. It has been said that we IV
humans are prepared for a world that no longer exists. Our world lacks clear 24-hour patterns. The profound changes in light, temperature, and food availability in nature are all masked by our 24/7 society. With such ancient biological systems embedded Avithin our biology, we are going to have to learn much more about how eircadian systems work, develop, and control physiology and behaviour if we are to achieve health and productivity in our brave new 24/7 world.