Circadian Rhythms (II)

Below I have added some more observations from the book, as well as some links of interest.

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“Most circadian clocks make use of a sun-based mechanism as the primary synchronizing (entraining) signal to lock the internal day to the astronomical day. For the better part of four billion years, dawn and dusk has been the main zeitgeber that allows entrainment. Circadian clocks are not exactly 24 hours. So to 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 most organisms, it is important to stress that many, if not all cells within an organism possess the capacity to generate a circadian rhythm, and that these independent oscillators are regulated by a variety of different signals which, in turn, drive countless outputs […]. Colin Pittendrigh was one of the first to study entrainment, and what he found in Drosophila has been shown to be true across all organisms, including us. For example, if you keep Drosophila, or a mouse or bird, in constant darkness it will freerun. If you then expose the animal to a short pulse of light at different times the shifting (phase shifting) effects on the freerunning rhythm vary. Light pulses given when the clock ‘thinks’ it is daytime (subjective day) will have little effect on the clock. However, light falling during the first half of the subjective night causes the animal to delay the start of its activity the following day, while light exposure during the second half of the subjective night advances activity onset. Pittendrigh called this the ‘phase response curve’ […] Remarkably, the PRC of all organisms looks very similar, with light exposure around dusk and during the first half of the night causing a delay in activity the next day, while light during the second half of the night and around dawn generates an advance. The precise shape of the PRC varies between species. Some have large delays and small advances (typical of nocturnal species) while others have small delays and big advances (typical of diurnal species). Light at dawn and dusk pushes and pulls the freerunning rhythm towards an exactly 24-hour cycle. […] 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 by 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.”

“[B]irds, reptiles, amphibians, and fish (but not mammals) have ‘extra-ocular’ photoreceptors located within the pineal complex, hypothalamus, and other areas of the brain, and like the invertebrates, eye loss in many cases has little impact upon the ability of these animals to entrain. […] Mammals are strikingly different from all other vertebrates as they possess photoreceptor cells only within their eyes. Eye loss in all groups of mammals […] abolishes the capacity of these animals to entrain their circadian rhytms to the light/dark cycle. But astonishingly, the visual cells of the retina – the rods and cones – are not required for the detection of the dawn/dusk signal. There exists a third class of photoreceptors within the eye […] Studies in the late 1990s by Russell Foster and his colleagues showed that mice lacking all their rod and cone photoreceptors could still regulate their circadian rhythms to light perfectly normally. But when their eyes were covered the ability to entrain was lost […] work on the rodless/coneless mouse, along with [other] studies […], clearly demonstrated that the mammalian retina contains a small population of photosensitive retinal ganglion cells or pRGCs, which comprise approximately 1-2 per cent of all retinal ganglion cells […] Ophthalmologists now appreciate that eye loss deprives us of both vision and a proper sense of time. Furthermore, genetic diseases that result in the loss of the rods and cones and cause visual blindness, often spare the pRGCs. Under these circumstances, individuals who have their eyes but are visually blind, yet possess functional pRGCs, need to be advised to seek out sufficient light to entrain their circadian system. The realization that the eye provides us with both our sense of space and our sense of time has redefined the diagnosis, treatment, and appreciation of human blindness.”

“But where is ‘the’ circadian clock of mammals? […] [Robert] Moore and [Irving] Zucker’s work pinpointed the SCN as the likely neural locus of the light-entrainable circadian pacemaker in mammals […] and a decade later this was confirmed by definitive experiments from Michael Menaker’s laboratory undertaken at the University of Virginia. […] These experiments established the SCN as the ‘master circadian pacemaker’ of mammals. […] There are around 20,000 or so neurons in the mouse SCN, but they are not identical. Some receive light information from the pRGCs and pass this information on to other SCN neurons, while others project to the thalamus and other regions of the brain, and collectively these neurons secrete more than one hundred different neurotransmitters, neuropeptides, cytokines, and growth factors. The SCN itself is composed of several regions or clusters of neurons, which have different jobs. Furthermore, there is considerable variability in the oscillations of the individual cells, ranging from 21.25 to 26.25 hours. Although the individual cells in the SCN have their own clockwork mechanisms with varying periods, the cell autonomous oscillations in neural activity are synchronized at the system level within the SCN, providing a coherent near 24-hour signal to the rest of the mammal. […] SCN neurons exhibit a circadian rhythm of spontaneous action potentials (SAPs), with higher frequency during the daytime than the night which in turn drives many rhythmic changes by alternating stimulatory and inhibitory inputs to the appropriate target neurons in the brain and neuroendocrine systems. […] The SCN projects directly to thirty-five brain regions, mostly located in the hypothalamus, and particularly those regions of the hypothalamus that regulate hormone release. Indeed, many pituitary hormones, such as cortisol, are under tight circadian control. Furthermore, the SCN regulates the activity of the autonomous nervous system, which in turn places multiple aspects of physiology, including the sensitivity of target tissues to hormonal signals, under circadian control. In addition to these direct neuronal connections, the SCN communicates to the rest of the body using diffusible chemical signals.”

“The SCN is the master clock in mammals but it is not the only clock. There are liver clocks, muscle clocks, pancreas clocks, adipose tissue clocks, and clocks of some sort in every organ and tissue examined to date. While lesioning of the SCN disrupts global behavioural rhythms such as locomotor activity, the disruption of clock function within just the liver or lung leads to circadian disorder that is confined to the target organ. In tissue culture, liver, heart, lung, skeletal muscle, and other organ tissues such as mammary glands express circadian rhythms, but these rhythms dampen and disappear after only a few cycles. This occurs because some individual clock cells lose rhythmicity, but more commonly because the individual cellular clocks become uncoupled from each other. The cells continue to tick, but all at different phases so that an overall 24-hour rhythm within the tissue or organ is lost. The discovery that virtually all cells of the body have clocks was one of the big surprises in circadian rhythms research. […] the SCN, entrained by pRGCs, acts as a pacemaker to coordinate, but not drive, the circadian activity of billions of individual peripheral circadian oscillators throughout the tissues and organs of the body. The signalling pathways used by the SCN to phase-entrain peripheral clocks are still uncertain, but we know that the SCN does not send out trillions of separate signals around the body that target specific cellular clocks. Rather there seems to be a limited number of neuronal and humoral signals which entrain peripheral clocks that in turn time their local physiology and gene expression.”

“As in Drosophilia […], the mouse clockwork also comprises three transcriptional-translational feedback loops with multiple interacting components. […] [T]he generation of a robust circadian rhythm that can be entrained by the environment is achieved via multiple elements, including the rate of transcription, translation, protein complex assembly, phosphorylation, other post-translation modification events, movement into the nucleus, transcriptional inhibition, and protein degradation. […] [A] complex arrangement is needed because from the moment a gene is switched on, transcription and translation usually takes two hours at most. As a result, substantial delays must be imposed at different stages to produce a near 24-hour oscillation. […] Although the molecular players may differ from Drosophilia and mice, and indeed even between different insects, the underlying principles apply across the spectrum of animal life. […] In fungi, plants, and cyanobacteria the clock genes are all different from each other and different again from the animal clock genes, suggesting that clocks evolved independently in the great evolutionary lineages of life on earth. Despite these differences, all these clocks are based upon a fundamental TTFL.”

“Circadian entrainment is surprisingly slow, taking several days to adjust to an advanced or delayed light/dark cycle. In most mammals, including jet-lagged humans, behavioural shifts are limited to approximately one hour (one time zone) per day. […] Changed levels of PER1 and PER2 act to shift the molecular clockwork, advancing the clock at dawn and delaying the clock at dusk. However, per mRNA and PER protein levels fall rapidly even if the animal remains exposed to light. As a result, the effects of light on the molecular clock are limited and entrainment is a gradual process requiring repeated shifting stimuli over multiple days. This phenomenon explains why we get jet lag: the clock cannot move immediately to a new dawn/dusk cycle because there is a ‘brake’ on the effects of light on the clock. […] The mechanism that provides this molecular brake is the production of SLK1 protein. […] Experiments on mice in which SLK1 has been suppressed show very rapid entrainment to simulated jet-lag.”

“We spend approximately 36 per cent of our entire lives asleep, and while asleep we do not eat, drink, or knowingly pass on our genes. This suggests that this aspect of our 24-hour behaviour provides us with something of huge value. If we are deprived of sleep, the sleep drive becomes so powerful that it can only be satisfied by sleep. […] Almost all life shows a 24-hour pattern of activity and rest, as we live on a planet that revolves once every 24 hours causing profound changes in light, temperature, and food availability. […] Life seems to have made an evolutionary ‘decision’ to be active at a specific part of the day/night cycle, and a species specialized to be active during the day will be far less effective at night. Conversely, nocturnal animals that are beautifully adapted to move around and hunt under dim or no light fail miserably during the day. […] no species can operate with the same effectiveness across the 24-hour light/dark environment. Species are adapted to a particular temporal niche just as they are to a physical niche. Activity at the wrong time often means death. […] Sleep may be the suspension of most physical activity, but a huge amount of essential physiology occurs during this time. Many diverse processes associated with the restoration and rebuilding of metabolic pathways are known to be up-regulated during sleep […] During sleep the body performs a broad range of essential ‘housekeeping’ functions without which performance and health during the active phase deteriorates rapidly. But these housekeeping functions would not be why sleep evolved in the first place. […] Evolution has allocated these key activities to the most appropriate time of day. […] In short, sleep has probably evolved as a species-specific response to a 24-hour world in which light, temperature, and food availability change dramatically. Sleep is a period of physical inactivity when individuals avoid movement within an environment to which they are poorly adapted, while using this time to undertake essential housekeeping functions demanded by their biology.”

“Sleep propensity in humans is closely correlated with the melatonin profile but this may be correlation and not causation. Indeed, individuals who do not produce melatonin (e.g. tetraplegic individuals, people on beta-blockers, or pinealectomized patients) still exhibit circadian sleep/wake rhythms with only very minor detectable changes. Another correlation between melatonin and sleep relates to levels of alertness. When melatonin is suppressed by light at night alertness levels increase, suggesting that melatonin and sleep propensity are directly connected. However, increases in alertness occur before a significant drop in blood melatonin. Furthermore, increased light during the day will also improve alertness when melatonin levels are already low. These findings suggest that melatonin is not a direct mediator of alertness and hence sleepiness. Taking synthetic melatonin or synthetic analogues of melatonin produces a mild sleepiness in about 70 per cent of people, especially when no natural melatonin is being released. The mechanism whereby melatonin produces mild sedation remains unclear.”

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Links:

Teleost multiple tissue (tmt) opsin.
Melanopsin.
Suprachiasmatic nucleus.
Neuromedin S.
Food-entrainable circadian oscillators in the brain.
John Harrison. Seymour Benzer. Ronald Konopka. Jeffrey C. Hall. Michael Rosbash. Michael W. Young.
Circadian Oscillators: Around the Transcription-Translation Feedback Loop and on to Output.
Period (gene). Timeless (gene). CLOCK. Cycle (gene). Doubletime (gene). Cryptochrome. Vrille Gene.
Basic helix-loop-helix.
The clockwork orange Drosophila protein functions as both an activator and a repressor of clock gene expression.
RAR-related orphan receptor. RAR-related orphan receptor alpha.
BHLHE41.
The two-process model of sleep regulation: a reappraisal.