Perfect Timing

Anyone who wants to be successful in life should know their priorities and be in the right place at the right time. Today, such wisdom is often taught in management training courses, yet humans have carried the prerequisites for it within us for millions of years: It is our internal clock that gets us out of bed in the morning, guides us through every day from cradle to grave, and ensures the necessary rest periods at night.

Not only do our sleep-wake cycle and seasonal adaptations depend on this internal clock, but also learning and memory, as well as nearly all physiological daily rhythms such as fluctuations in blood pressure, heart rate, Hormone levels, respiratory rate, and even blood clotting.

In fact, there is no single internal clock. Instead, a highly complex, hierarchical system of interconnected timers, pacemakers, and correction mechanisms governs our time. It consists of specific regions of the nervous system, specialized cells, hormones, neurotransmitters, proteins, and nucleic acids. Ultimately, every single cell has its very own internal clock. “We have a veritable clock shop,” explains Gregor Eichele, who heads the “Genes and Behavior” department at the Max Planck Institute for Biophysical Chemistry in Göttingen.

The nervous system’s primary timekeeping mechanism is surprisingly small: the Suprachiasmatic nucleus (SCN), located on both sides of the brain, is part of the Hypothalamus and sits above the crossing of the optic nerves. It contains only about 50,000 neurons – less than three millionths of the total number of our 65 billion nerve cells. Among these are the circadian pacemaker neurons. A defining feature is the strong fluctuations between day and night in the frequency of their spontaneous discharges. Both the excitatory and inhibitory signals for a robust daily rhythm arise from the temporally coordinated activity with which sodium and potassium ions flow through the membranes of the pacemaker neurons, and from the specific change in ionic conductance during action potentials. The pacemaker neurons in the SCN are not only necessary but also sufficient to drive the circadian rhythm. Furthermore, they counteract deviations from the 24-hour day-night rhythm and synchronize our activities with the rotating earth.

In fact, the human circadian clock would actually have a rhythm of just under 25 hours, as is known from experiments with volunteers who lived in uniformly lit rooms for several weeks. It is thanks to the SCN’s synchronization with real daylight that these subjects quickly regained their rhythm after the experiment ended. Thus, even in the age of artificial lighting, the SCN prevents us from losing our sense of time and turning into zombies after a night of partying.

But how does information about the length of the day reach the SCN? Unsurprisingly, the Eye plays a crucial role in this process. Located in the Retina between the Cones and Rods are specialized Ganglion cells (RGCs), which, alongside the cones and rods, form a third class of Retinal Photoreceptors. They are equipped with the Photopigment melanopsin, which allows them to detect incoming light. The fibers of the RGCs then run to the SCN and other brain regions – including those that regulate mood. Even in people who have gone blind due to damage to the visual cortex, this adjustment of the internal clock functions via the pathway from the RGCs to the SCN – as long as the retina and the nerve pathways extending from it remain intact.

However, nature did not anticipate the invention of artificial light by humans, and in particular of cell phones, tablets, and similar devices. These emit – similar to normal daylight – abundant blue light, to which melanopsin reacts sensitively. The problem: In the evening, the internal clock is particularly sensitive to light effects. If electronic devices are not turned off in the evening, there is a risk of the internal clock being delayed, and the risk of sleep disorders increases.
 

hronobiologists have learned a great deal from dissecting these circuits. However, it is primarily molecular biologists who have discovered what makes the clock tick. They found that an approximately 24-hour cycle also runs inside most of the cells in our bodies. Although this has been studied primarily in fruit flies and mice, and the details as well as the naming of the components differ in part between the various experimental organisms, the structure of this clockwork is apparently very similar throughout the animal kingdom and is even found in the single-celled baker’s yeast.

This periodicity is achieved through the principle of negative feedback: A “clock gene” is read by the cell’s machinery, and messenger RNA (mRNA) is produced from this information, which in turn is translated into a specific protein. During the day, this CLOCK protein activates another clock Gene called “per” (for period). The corresponding per-mRNA is thus used to synthesize the PER protein. Together with other tissue-specific proteins, the PER protein forms a complex that binds to the CLOCK protein and thereby blocks it. The result is that no new per-mRNA is produced, the remaining PER protein gradually breaks down, and the blockage of the CLOCK protein is thus lifted. The cycle then begins anew.

In detail, this system is far more complex: with its fluctuating concentrations, different binding partners, and through equilibrium reactions with other cellular components, PER can, for example, indirectly sense the cell’s energy supply, influence metabolism, or modulate stress responses.

Although the SCN acts as the highest control authority regulating the timing of bodily functions, most organs and tissues can maintain their own rhythm independently thanks to the clock/per system, as can be observed in isolated liver, lung, or kidney cells in culture dishes.

It makes perfect sense that many internal organs, as well as muscles, adipose tissue, and blood vessels, have a certain degree of independence from the SCN. This allows them to better adapt to changing environmental influences throughout the day thanks to their own molecular clocks. For example, a rising body temperature prepares us for the day even before we wake up, and in the morning, the stress Hormone Cortisol is released in greater quantities. This increases both physical and mental performance.

If necessary, these oscillations are fine-tuned by the SCN to maintain a 24-hour rhythm. There are evidently many cross-connections between the systems, though the details have not yet been fully explored. Only recently was a fast data pathway discovered, thanks to which the so-called mitral cells in the brain’s olfactory center register rhythmic changes in blood vessels caused by the heartbeat. Because more of these “heartbeat sensors” are distributed throughout the entire brain, researchers led by Luna Jammal Salahmeh at the Zoological Institute of the University of Regensburg speculate that they have found an interface here through which the heartbeat could directly influence our thoughts.

Neurons located beneath the skull in the Neocortex exhibit a completely different rhythm. Cells from different regions can work together, revealing this in the form of “brain waves” that can be visualized using an electroencephalogram (EEG). Since the 1920s, the EEG has therefore become an important research tool, and it is now also used to diagnose neurological and psychiatric disorders. 

Generally, the following waveforms are distinguished, sorted by the level of activity:

• Gamma waves with a frequency between 30–100 oscillations per second (hertz) during states of concentration or learning,
Beta waves ranging from 12 to 30 hertz, which are generated during normal wakefulness, Alpha waves at 8 to 13 hertz when the subject lies relaxed with their eyes closed,
• theta waves at 4 to 7 hertz, which are generated during dreaming but also indicate memory-related activity, as well as
• delta waves at less than 1 to 4 hertz, which occur during deep sleep.

Between wakefulness and sleep, these brain waves alternate in a fairly clear and consistent pattern. The curves in the EEG, which are still rather “restless” before falling asleep, appear to gradually calm down in the first hour of sleep. The muscles and eyes relax, heart rate, blood pressure, and body temperature drop, and characteristic slow waves with high amplitude can be seen in the EEG – hence the term “slow wave.”

After the sleeper remains at the lowest point of this decline for about half an hour, the EEG waves also gradually become faster again. Similar to when waking up, the eyes begin to move, which has given this sleep phase the name REM sleep (Rapid Eye Movement). The muscles remain paralyzed, but significant variability in heart rate, blood pressure, and body temperature indicates that a dream phase is now taking place. This first dream phase lasts about 10 to 15 minutes, during which men, incidentally, often experience an erection.

These alternating cycles of deep sleep and REM sleep typically repeat about four more times during the rest of the night. As the night progresses, the deep Sleep phases generally become shorter and the REM phases longer until waking. So we already know quite a lot about this phenomenon – though it is still not entirely clear what this phase is actually for!

Without an internal clock, it would be impossible to adapt our lives to daily and seasonal fluctuations. Less obvious, but just as important for survival, is another type of time measurement that the nervous system handles: It recognizes which events occur more or less simultaneously. It constructs a “before” and an “after” from the signals of the sensory organs and distinguishes random occurrences from those linked as cause and effect.

Behind this lies one of evolution’s most ingenious “inventions”: the mechanism of synaptic integration. Put very simply, this helps us recognize what belongs together. Most neurons in the nervous system receive thousands of signals via their synapses and integrate them in such a way that a single output signal is produced: the Action potential Every second, the brain performs billions of such calculations. Signals sent by a single Neuron within a short period of time can be summed up just as easily as those originating from different nerve cells and arriving (almost) at the same time ▸ Communication of Cells. However, these stimuli are only transmitted if a certain threshold is exceeded. For example, events registered almost simultaneously by different sensory organs – such as a flash of lightning and the subsequent thunder, or a fall on the knee and the ensuing pain – can be “linked together.”

If the stimuli occur at too great a distance from one another or are not strong enough, they are “filtered out”: they apparently have nothing to do with one another. They are as insignificant as our hairstyle during a thunderstorm or the fact that we fell on a Tuesday. The situation is quite different when one experiences the same combination of stimuli multiple times. The nervous system can “adapt” to this by storing the experience and adjusting its reactions to it – in short: by learning.

Scientists researching our internal clock have now uncovered much of the inner workings and begun to understand their complex interplay. In doing so, they have gained unexpected insights that point far beyond the mechanistic. Their answers now even touch on philosophical questions regarding the nature of time. And they can also answer the mundane question of practical value with a clear conscience. After all, it was their work that laid the foundation for a better understanding and for future therapies of many neurological-psychiatric as well as organic diseases in which the internal clock has gone out of sync (see box). 

Further reading

• Wilhelm, Klaus. Chronobiology: internal clocks in synch . Max-Plack-Gesellschaft (online). URL:  https://www.mpg.de/10785637/chronobiology  [Stand 25.3.2024]