We have seen that chronotype has a genetic basis, and that it changes significantly with age. We have also seen how tightly chronotype is coupled to the light environment. Here we will exam the role that light plays in human entrainment, and how it is responsible for different chronotypes. In the lecture on entrainment and circadian formalisms, I have introduced you to the phase response curve, the PRC. From internal midnight to internal noon, light pulses advance the circadian clock while they delay the rhythm in the second half of the 24 hour day. This paradigm has been extremely useful in explaining light entrainment in the laboratory, especially in animals that show a robust, free running rhythm in constant darkness. And this is exactly the protocol the PRC was developed for. Let an animal run free in constant darkness. Expose it to a single light pulse. Let the free running rhythm establish a new steady state and then measure the difference in phase that this specific light pulse has produced. The example shown here is a nocturnal animal that is active at night and sleeps during the day. The bars represent the daily activity [INAUDIBLE]. If the light pulse is given at the end of the internal light, in this case at the end of the activity pouch, the rhythm advances. That is, the activity onsets are earlier after the light pulse intervention. If the light pulse is given at the end of the day, in this case, at the beginning of the nocturnal activity then the rhythm that is the activity onsets are later after the light pulse intervention. A complete set of such experiments, when many pulses have been presented at different internal times, gives rise to a PRC. Each point of the PRC is therefore the result of a single light pulse given in constant darkness. With its effect evaluated after several days when the free-running rhythm has gone back to a steady state. As you will see, these isolated pulses are extremely difficult to apply to real-world conditions. But it also can be quite a challenge to interpret a given PRC. Let us look at the different possibilities that are represented by a PRC. The red dot could represent the results of a short light pulse, or of a much longer one. The time plotted on the x-axis could refer to the onset of the pulse, as in the first three examples. Or to its midpoint. Or even to the time when the light was switched off. To interpret the effect of different light changes and count it throughout a day, we would have to know all the phase response codes for each pulse duration and for each intensity. Because every time the quality of a light pulse changes, we have establish a new PRC for exactly those light pulse qualities. In addition, we would have difficulties to wait until the rhythm reaches a steady state, in conditions, since there are no constant conditions in the noisy real world. In view of the real light world, it seem impractical to explain entrainment based on the PRC. This holds especially for day active organisms, like we are. Who are around and about all day exposed to a very noisy light profiles. Entrainment is successful when the length of the internal day, tao equals the length of the environmental day, T. So, the role of light in entrainment is to adjust the length of the internal day to that of the external day. We will borrow the PRC concept and modify it so that it can cope with a noisy light world. We know from the PRC experiments that in response to light, the clock advances in the first half of the internal day and delays in the second half of the day. Let us therefore assume that light during the first half of the day compresses the internal day and that light in the second half of the day expands the internal day. The result is a circadian integrated response characteristic or CiRC for short. The advantage of the CiRC is that light exposures are integrated from when the light comes on to when the lights have turned off. This allows to accommodate any given light profile. Let's start with a noisy light profile that is typical for a human. And let us assume that the individual has the following response characteristic. The actual effect of light at any given internal time can be calculated by multiplying, the light intensity with the CiRC. This can be visualized by overlapping the CiRC with the profile. The actual result of this multiplication looks like this. The weighted profile predicts that this person has a relatively slow clock that has to be compressed every day, more than it has to be expanded. The compression portion therefore has a larger integral than the expansion portion. Let us now apply the CiRC to the different chronotypes shown earlier on in this lecture. Let us first assume a person whose circadian clock produces days that are about 24 hours long. In this case, the internal day should neither be compressed nor expanded by light because this would jeopardize entrainment. But how can this task be accomplished in view of the fact that we are exposed to both compressing and expanding light over the course of a 24 hour day? The task turns out to be fairly simple. If the environment provides both darkness and light so that the clock can fine tune it's position between these states. If tau = T, then internal and external midnight coincide and so do internal and external noon. If this is the case, the intergral in the compression region before noon, here shown in blue, has the same interval as the expansion region in the afternoon, here shown in red. Since the two areas are equal, they cancel each other out. So that the internal day remains to be 24 hours despite of progressions through both compressing and expanding exit light. Internal midday, here represented by the triangle, stays at external noon. Now let's look at another example. Someone who produces internal days that are longer than 24 hours. In this case, the blue compression region should be larger than the red expansion region in order to have a net compression effect that makes the long internal day equal to the relatively shorter 24 hour day of the environment. To achieve this situation, the clock's internal time has to be later than the external time. This phase relationship exposes more of the compression region and less of the expansion region to the right. Internal midday is reached after her external noon, which is typical for later chronotypes. Finally, we look at a subject whose circadian clock produces an internal day that is shorter than 24 hours. In this case, the blue compression region has to be smaller than the red expansion region. To achieve this situation, the clock's internal time has to be earlier than the external time in order to hide more of the compression region in the dark and expose more of the expansion region to the light. Internal midday is reached before external noon, which is typical for early chronotypes. These examples prove that people whose clocks produce internal days longer or shorter than external days have to be different chronotypes. Otherwise they would not be able to synchronize with a 24 hour day. Now you know how important light is for the entrainment of the circadian clock, but also how important it is to be a certain chronotype. Only then different people able to synchronize to the 24 hour day. I will now discuss why chronotype by the chronotype distribution you have seen at the beginning of this lecture is so wide. Why extreme types are up to 12 hours apart from the extreme late types. The width of this distribution is probably relatively recent in our history. I will try to explain this with another short movie. Before industrialization, most of us worked a lot outside during the day, where light intenses are up to 1,000 fold higher than in buildings. We then moved progressively into cities, where houses prevent lights to get into the windows of other houses, and where we predominantly live inside. Electricity also enables us to be active, and expose ourselves to light long after the sun has set. These drastic behavioural changes led to a significant reduction in sight given strength. Less light during the day and more light at night. Here you see the CiRCs, again, that we used earlier to explain why early chronotypes had to be early and why late chronotypes had to be late in order to stably entrain. Let's see what happens when we increase the zeitgeber strength. Due to the fact that CiRC were not centered on midday, but either positioned slightly to the left or to the right, the increase in zeitgeber strength has different effects on the blue compression and the red expansion time. Now the finely tune proportion between compression and expansion is not correct anymore and would result in unstableentrainment for both example chronotypes. But light entrainment easily compensates for this mismatch by simply moving both chronotypes more to the center until the necessary proportions are re-established. The conclusion from this little theoretical demonstration is that chronotype distributions becomes wider the weaker the zeitgeber and narrower the stronger the zeitgeber. By using questionnaires, we cannot actually measure the zeitgeber strength in our subjects. But we have added a question in the MCT queue that allows an estimation. We asked people how much time they spend outside during the day without a roof above their head. This graph shows the answers to this question on the x-axis. And the average chronotype on the y-axis. With early at the top and late at the bottom. One can clearly see that with increasing outside light exposure people's chronotypes become early. In the first lecture of this course we looked at rhythmic changes across seasons. And we have seen how important day length or photo period are for biology. In those regions of the globe that experience significant changes in photo period, the mid sleep times also show a seasonal variation. During winter, when we experience more darkness and spend even more time inside, our chronotypes become later and advance again during the second half of the winter and spring. [SOUND]
