Clocks
delayed sleep phase syndrome DSPS
1981 by Elliot D. Weitzman responsible for 7-10% of patient complaints of chronic insomnia, often not or misdiagnosed as mental disorder- treated with careful daily sleep practices, light therapy, dark therapy, and medications such as melatonin and modafinil (Provigil) chronic dysregulation of a person's circadian rhythm (biological clock), compared to the general population and relative to societal norms. The disorder affects the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily cycles. People with DSPD generally fall asleep some hours after midnight and have difficulty waking up in the morning (Hirshkowitz, Max (2004) Micic et al 2013 - sleep cycle longer than 24 hours no known cure Dagan 1999 - usually develops in childhood/adolescence Cleveland Clinic 2015 - Prevalence among adults, equally distributed among women and men, is approximately 0.15%, or 3 in 2,000. Prevalence among adolescents is as much as 7-16% Aoki et al 2011 - might have an unusually long circadian cycle, might have a reduced response to the resetting effect of daylight on the body clock, and/or may respond overly to the delaying effects of evening light and too little to the advancing effect of light earlier in the day Billiard 2000 - support of the increased sensitivity to evening light hypothesis, "the percentage of melatonin suppression by a bright light stimulus of 1,000 lux administered 2 hours prior to the melatonin peak has been reported to be greater in 15 DSPD patients than in 15 controls Uchiyama 1999 - sleep deprivation does not reset clock of DSPS Ascoli-Israel 2001 - DSPS runs in families Archer 2003/ Nadkarni 2005 - associated with the hPer3 (human period 3) gene
clock mutants
3-4/ 80 people Advanced sleep phase syndrome and delayed Toh et al. 2001) an autosomal dominant mutation in the human Per2 gene that inactivates a CK1ε phosphoacceptor site results in familial advanced sleep phase syndrome (FASPS) Hypophosphorylated PER proteins have a higher metabolic stability than their hyperphosphorylated counterparts, and this may lead to an increased accumulation of PER proteins. Hence, in both Tau hamsters and human FASPS subjects, threshold levels of PER complexes required for autorepression are expected to be reached faster than in the corresponding wild-type individuals. As a consequence the period length of the oscillator shortens and its phase becomes advanced (earlier in day)
describe mech circa clock regulates cell cycle timing clinical consequences of disrupting this link evidence underlying this observation (cancer progression enhanced)
Chronobiology - timing medical attention to various organisms of the body depending on the most propitious time of day for those particular organs, has shown very good results in improving the effectiveness of treatments
how does the mechanism work?
Albret and Eichele 2003; Reppert and Weaver 2002 : PER and CRY proteins form heteropolymeric complexes of unknown stoichiometry once these complexes reach critical conc in cell nucleus interact with CLOCK-BMALI heterodimer that annuls activation potential of these transcription factors. so - Cry and Per mRNAs and proteins decrease in conc once nuclear levels of CRY-PER complexes insufficent for auto-repression new cycle of Per and Cry transcription can start
Photoperiod (day length) key synchroniser of circ clock
Berson 2003 - Even visually blind mice, retina lack cone and rod photoreceptor, can still efficiently phase entrain through light sensitive ganglion cells in inner layer Hattar et al 2003/ Panda et al 2003 - only mice deficient in both classic photops and melanopsin incapable of adjusting clock to light dark cycles. - mice still rhythmic but can't phase-shift clock in response to light
two process model of sleep - molecular and neuronal processes include how does it work under: normal conditions sleep deprivation Diagram
Brobely 1980s 2 cycles regulate sleep-wake cycle. circadian rhythm, also known as Process C, the regulation of the body's internal processes and alertness levels (including the circadian drive for arousal and circadian alerting system), which is governed by the internal biological or circadian clock; sleep-wake homeostasis, or Process S, the accumulation of hypnogenic (sleep-inducing) substances in the brain, which generates a homeostatic sleep drive. SNS main mechanism that controls the timing of sleep, and is independent of the amount of preceding sleep or wakefulness. coordinated with the day-night / light-dark cycle over a 24-hour period, regulates the body's sleep patterns, feeding patterns, core body temperature, brain wave activity, cell regeneration, hormone production, and other biological activities. Even a long sleep might be ineffective (or at least inefficient) if it occurs at the "wrong" time of the circadian cycle. circadian rhythms alone are not sufficient to cause and regulate sleep. also an inbuilt propensity toward sleep-wake homeostasis, balanced against the circadian element. Sleep-wake homeostasis is an internal biochemical system that operates as a kind of timer or counter, generating a homeostatic sleep drive or pressure to sleep and regulating sleep intensity. the longer we have been awake, the stronger the desire and need to sleep becomes, and the more the likelihood of falling asleep increases; the longer we have been asleep, the more the pressure to sleep dissipates, and the more the likelihood of awakening increases. when the circadian clock slackens off its alerting system and begins sleep-inducing melatonin production instead. This opens the so-called "sleep gate" (marked by the point in the diagram above where the homeostatic sleep drive is at its greatest distance above the circadian drive for arousal). The exact way in which this occurs is still not fully understood, but the recent neuronal group theory of sleep theorizes that individual groups of neurons in the brain enter into a state of sleep after a certain threshold of activity has been reached, and that, once enough groups of neurons are in this sleep state, the whole organism falls asleep. During the night, while sleep is actually being experienced, the homeostatic sleep drive rapidly dissipates, and circadian-regulated melatonin production continues. In the early morning, melatonin secretion stops and the circadian alerting system begins to increase its activity again. Eventually, the point is reached where the circadian drive for arousal begins to overcome the homeostatic sleep drive (marked by the point in the diagram above where the two curves meet), triggering awakening, and the process begins all over again. While these are the two main processes involved, there are also other neurological mechanisms at work, including the suppression and re-activation of the everyday alertness signals of wakefulness, the switching between non-REM and REM sleep, the sleep inertia effect on waking, etc.
entrainment
Daan 1998 Entrainment is the exquisite functional link between circadian oscillators and the rotation of the earth that shaped their evolution in virtually the entire living world. circadian synchronization in accordance with an outside cue Read more: http://www.marksdailyapple.com/circadian-rhythms-zeitgebers-entrainment-and-non-photic-stimuli/#ixzz47aP459zN ∆φ(φ) = τ - T (Pittendrigh, 1981a): in stable entrainment, the free-running period τ of the circadian system is corrected each day for the difference between τ and 24 h when the light falls at that particu- lar phase φ of the cycle in which a phase shift ∆φ equal to this difference is generated.
period gene
HArdin et al 1990 identified period gene required for the cyclic accumulation of its own mRNA so engaged in auto reg feedback loop A defect in the human homologue of the Drosophila "period" gene was identified as a cause of the sleep disorder FASPS (Familial advanced sleep phase syndrome), underscoring the conserved nature of the molecular circadian clock through evolution Ron Konopka and Seymour Benzer isolated the first clock mutant in Drosophila in the early 1970s and mapped the "period" gene, the first discovered genetic component of a circadian clock.
circannual
Hazlerigg 2009 biological rhythm that occurs on an annual basis, even in the abscence of environmental cues still exhibit seasonal variations in behaviour reflecting the underlying rhythm Miyazaki 2005 pupation rhythm in carpet beetles Gwinner E (2003 the urge to migrate in birds Kondo 2006 , hibernation cycles in ground squirrels Lincoln 2003 and cycles of reproductive activity and moulting in ungulates
Photoperiod and scotoperiod
In a light-dark cycle, the period of light is called the photoperiod, and the period of dark is called the scotoperiod. The length of the photoperiod can affect entrainment. Sparrows can be entrained to extremes of 1 hour of light per 24 hour cycle or 23 hours of light per 24 hour cycle (Binkley 1997). However this affects behaviour. When there is less than 6 hours of light, the sparrows are active during the photoperiod only. However when there are less than 6 hours of light, the sparrows are active in the dark in anticipation of the light (Binkley 1997).
nocturnal
In a skeleton photoperiod, with two brief light pulses 12 h apart in otherwise darkness, the activity of a nocturnal mammal—its subjective night—will be restricted to one of the two dark intervals. If one compresses this interval, at some point a phase ψ-jump will occur, as predicted from the PRC. One problem that emerged was that this compression could go much further than predicted: The observed ψ-jumps occurred at skeleton photoperiods of 18 to 20 h, not at 12 to 15 (Fig. 6). We also sometimes observed nearly complete compression of activity time in entrainment by single pulses. Jeff Elliott (1981) has later shown that this compression simultaneously entails a compression of the PRC. That means that the PRC is not a fixed property of the system but is itself modified by entrainment. Also, τ is not a fixed property. We know that there are after effects of prior entrainment: initially, after release from a 24-h regime, τ is very close to 24. Only in prolonged free runs, τ gradually reverts to its stable endogenous value. entrainment and PCR are not fixed properties of the system- vary according to zeitgeber PRCs for nocturnal animals tend to have a longer delaying portion. This is because nocturnal animals tend to freerun with a period shorter than 24 hours and need to delay to correct to a 24-hour cycle. Diurnal animals tend to have a longer advancing portion and they freerun with periods longer than 24 hours and thus need to advance their clocks to reduce the cycle to 24 hours.
Clock genes activated by the two PAS domain basic helix-loop helix transcription factors: = positive components of oscillator. CLOCK = transcription factor of circ oscillator BMLI1
Joseph Takahashi discovered the first mammalian 'clock gene' (CLOCK) using mice in 1994. King et al 1997 -
clock cells
Lincoln et al 2003 temporal, melatonin-controlled expression of clock genes in specific calendar cells may provide a molecular mechanism for long-term timing. The agranular secretory cells of the pars tuberalis (PT) of the pituitary gland provide a model cell-type because they express a high density of melatonin (mt1) receptors and are implicated in photoperiod/circannual regulation of prolactin secretion and the associated seasonal biological responses. Studies of seasonal breeding hamsters and sheep indicate that circadian clock gene expression in the PT is modulated by photoperiod via the melatonin signal. In the Syrian and Siberian hamster PT, the high amplitude Per1 rhythm associated with dawn is suppressed under short photoperiods, an effect that is mimicked by melatonin treatment. More extensive studies in sheep show that many clock genes (e.g. Bmal1, Clock, Per1, Per2, Cry1 and Cry2) are expressed in the PT, and their expression oscillates through the 24-h light/darkness cycle in a temporal sequence distinct from that in the hypothalamic suprachiasmatic nucleus (central circadian pacemaker). Activation of Per1 occurs in the early light phase (dawn), while activation of Cry1 occurs in the dark phase (dusk), thus photoperiod-induced changes in the relative phase of Per and Cry gene expression acting through PER/CRY protein/protein interaction provide a potential mechanism for decoding the melatonin signal and generating a long-term photoperiodic response. The current challenge is to identify other calendar cells in the central nervous system regulating long-term cycles in reproduction, body weight and other seasonal characteristics and to establish whether clock genes provide a conserved molecular mechanism for long-term timekeeping.
phase response curve
Mansbach 2014: curve describing the relationship between a stimulus such as light exposure and response i.e. shift in circadian rhythm = phase shift earlier in the day (phase advance) or later in the day (phase delay). St. Hilaire 2012 - response to one hour light exposure Light on awakening advances schedule about ¼ hour Light around bedtime delays schedule about 2 hours Daan 1998 endogenous oscillation, which runs at a frequency slightly deviating from once per 24 h, and that deviation is corrected each day by an instantaneous, abrupt phase shift in response to light: every evening at dusk and/or every morning at dawn dictated by PRS detected in the late 1950s virtually simultaneously in his own lab (Burchard, 1958; Pittendrigh, 1958) and in those of Woody Hastings (Hastings and Sweeney, 1958) and Ken Rawson (Decoursey, 1960a, 1960b) PRC model yielded highly accurate predictions for the pattern of entrainment of Drosophila eclosion rhythms by brief light pulses. The range of entrainment by different Zeitgeber periods could be predicted, and so could the phase of both the overt rhythm and the underlying oscillator. The match between prediction and observa- tion culminated when Pittendrigh used skeleton photoperiods and was able to precisely predict the so-called zone of bistability and where the oscillator would land depending on initial conditions (Pittendrigh, 1981b) Larger phase shifts can be obtained from smaller signals in nocturnal animals. For example nocturnal hamsters respond to a 15 minute light pulse, whilst diurnal house sparrows respond only to light pulses of 2-4 hours. This may be due to nocturnal animals having a greater sensitivity in detecting light, as their natural environments have only limited light (Binkley 1997).
melatonin role
Melatonin is produces by a photoperiodically controlled cycle. Its precursor seratonin is transformed to melatonin by a process that involved the enzyme N-acetyltransferase (NAT). NAT has a cycle that has an amplitude that is suppressed by constant light but freeruns in constant dark. Normally NAT and melatonin are produced at night. Altun 2006 N-acetyl-5-methoxy tryptamine involved in the entrainment (synchronization) of the circadian rhythms of physiological functions including sleep timing, blood pressure regulation, seasonal reproduction metabolite Hepatic via CYP1A2 mediated 6-hydroxylation Hardeland 2005 - pervasive and powerful antioxidant Hardeland 2010 - neuroprotective Relter et al 2001 - particular role in the protection of nuclear and mitochondrial DNA Cassone 1990 may also reduce circadian misalignment Lewy et al 1986 and reduce seasonal affective disorder. Cochrane Database 2002 - Melatonin is known to aid in reducing the effects of jet lag, especially in eastward travel, by promoting the necessary re-set of the body's sleep-wake phase. If the timing is not correct, however, it can instead delay adaption Immune system: Arushanian 2002 known that melatonin interacts with the immune system, the details of those interactions are unclear. Pohanka 2013 Anti-inflammatory effect seems to be the most relevant and most documented in the literature. Relter et al 2002 Melatonin is a poor direct antioxidant, it is, however, a highly efficient direct free radical scavenger and indirect antioxidant due to its ability to stimulate antioxidant enzymes Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. Carrillo-Vico et al 2006 In preclinical studies, melatonin may enhance cytokine production, Arendt 2005 melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behavior, coat growth and camouflage coloring in seasonal animals Until its identification in plants in 1987, melatonin thought to be animal neurohormone
Pittendrigh (Daan 1998) single instantaneous event of eclosion in Drosophila
Nonparametric entrainment (action of nature of light: , Discrete, transitions of light to darkness Phasic (Suggestive of phasic effects are the large phase shifts elicited often by very brief light pulses), PRC, Instantaneous, Twilight
how might disruption of circa clock lead to enhanced cancer progression
Paine et al 2006 New Zealand - Evening types were 2.5 times more likely to report that their general health was only poor or fair compared to morning types
ASCHOFF continuous modulation of activity in the circadian rhythms of birds, mammals, and humans
Parametric entrainment : Continuous, depen- dence of circadian period on constant light Tonic (changes in period as a result of different constant light intensities) τ = f (light intensity), Gradual Daylight entrainment Aschoff suggested that light lengthens or shortens the period of an endogenous oscillation, while at the same time it affects the average level around which this oscillation moves only above a threshold (e.g., Aschoff, 1964
Additional component
Preitner et al 2002 orphan nuclear receptor and repressor REV-ERBα interconnects circ transcription of the +ve and -ve "limbs" of the oscillator Rev-Erbα transcription is reg by same components control Per and Cry transcription (yet phase of circ Rev-Erbα mRNA accumulation differs from Per2 and Cry1 mrNA byt 9 and 11 hours so more complex mech occuring in CRY and PER autorepression.) In turns leads to rhythmic expression of Bmal1 and Clock (to lesser extent) mRNA= antiphasic to Rev-Erbα expression. i.e. Rev-Erbα transcription antiphasic to accumulation of PER and CRY However is almost in phase with Per and Cry transcription. Preitner et al 2002 data show phase of circadian transcription precedes that of circadian mRNA accumulation by about 2 hrs.
SCN experiments
Ralph et al 1990 Silver et al 1996 lesion and transplantation experiment SCN lesion animal arrhythmic regarding wheel running activity Rhythms restored by transplantation of foetal SCN tissue and period length of rescued rhythmicity depends on SCN implant of donor
cellular metabolism directly influences circ rhyhtms in CLOCK
Rutter et al 2001 in vitro the dimerisation of CLOCK with BMAL1 and/or binding of resulting heterodimers to their DNA recognition sequences (E-Boxes) = dramtically moduated by ratio of NADP(H) and NAD(P+) - high NADP(H) to NADP+ ratio facilitates occupancy of E-boxes by CLOCK-BMAL1 heterodimers while low ratios inhibit process. Gachon 2004 - exciting possibility that circ oscillators can adapt their phase to nutrient state of cell.
brain's circadian clock regulates
The core body temperature, brain wave activity, hormone production, regulation of glucose and insulin levels, urine production, cell regeneration The most important hormones affected by the circadian clock, at least insofar as they affect sleep, are melatonin (which is produced in the pineal gland in the brain, and which chemically causes drowsiness and lowers body temperature) and cortisol (produced in the adrenal gland, and used to form glucose or blood sugar and to enable anti-stress and anti-inflammatory functions in the body). Growth hormone, essential to the repair and restoration processes of the body, is also secreted during sleep, particularly during deep non-REM sleep, as are other hormones like testosterone. Thyrotropin (or thyroid-stimulating hormone), on the other hand, is actively inhibited or suppressed during sleep. However, unlike melatonin and cortisol (which are almost entirely dependent on the circadian clock, regardless of whether an individual actually sleeps or not), these hormonal effects appear to be regulated by actual sleep and not by circadian rhythms per se.
phase angle
There can be a difference between the entraining cycle and the entrained rhythm. This difference can be measured by selecting a point in the entraining cycle (e.g. light on), and a phase reference point in the resulting rhythm (e.g. the onset of a particular activity). The difference between these two points is known as the phase angle. The phase angle is a function of photoperiod, for example it may be greater at LD 1:23 than at LD 4:20 (i.e. there may be a greater time between say light on and the start of activity at a shorter photoperiod). In humans the phase angle difference can be seen between the natural lights on i.e. dawn, and waking up phase-delaying effects of indoor electric lights Mongrain 2004 A shorter phase angle between habitual wake time and underlying circadian rhythms has been reported in evening types (E types) compared to morning-types Phase angles were defined as the interval between phase markers and averaged wake time Later circadian phase was associated with a shorter phase angle. Crowley 2014 Phase angles were the time durations from (dim light melatonin onset) DLMO to weekday sleep onset and offset times
Secondary/ PEripheral biological clocks - salves to master clock
Throughout the body, such as in the liver, heart, pancreas, kidneys, lungs, intestines, and even in the skin and lymphocytes, all of which show natural daily oscillations. These organs are largely entrained independently by factors like the timing of meals, ambient temperatures, etc, rather than by the light-dark cycle, but the central coordination and synchronization of these secondary body clocks is still carried out by the suprachiasmatic nuclei. The main circadian system in the SCN in turn receives multiple feedbacks from these various organs, in a complex system of reciprocal interactions Almost every cell has a clock. Pacemakers are specialized tissues responsive to environmental cues. They send neural or chemical signals to other (peripheral) clocks in the body. Pacemaker cells (unlike the cells of peripheral oscillators) can cycle indefinitely in isolation, Pacemakers in invertebrates reside in the eyes, optic lobes, or in the brain. Pacemakers in vertebrates are suprachiasmatic nuclei (SCN) located in the hypothalamus on the base of the brain, the pineal organ, and the retina of the eye. In mammals the SCN is the only pacemaker.
Banananas and Mosquitoes
Trinidad 1940, Colin Pittendrigh mosquitoes would close (hatch) at most moist time of day (3.3 hrs after sun comes up) which persisted on dry days = internal clock At this time though people didn't think we had an internal clock thought as light came up we started.
advantages of measuring day length
advantageous for animals to predict, and not merely react to changes in the environment. only biological timekeepers can anticipate environ change not those with external cues Along with synchronization to the outside world (external synchronization), biological clocks also synchronize events within the body (internal synchronization), e.g,. ensure that time of hormone release coincides with the time when the hormone receptor is available at the cell membrane of the target tissue, etc i.e. Harmer et al 2002 - plants circ clock allows production of photosystem 1 and 2 components already before sunrise so photosynth can commence as soon as light available. Gachon et al 2004 Nocturnal rodent can anticipate dusk in underground habitat does not have to forage periodically to examine when sunset - therefore reducing exposre to predation = selective advantage to those animals with a circ mech. Berman-Frank et al. 2001 temporal separation of chemically incompatible reactions is another important function of biological timing systems. Cyanobacteria (Synechococcus elongatus), in which nearly all genes are transcribed in a circadian fashion, can perform both nitrogen fixation and photosynthesis. If these processes were conducted simultaneously, the oxygen generated by photosynthesis would poison the nitrogenase, and nitrogen fixation would be inefficient. Bondy and Naderi 1994)Some important biochemical reactions can produce harmful side products, and it would be advantageous to limit such activities to a time window during which they are needed. For example, cytochrome p450 enzymes in hepatic detoxification. Another function of the biological clock is to put a time-stamp on memories, i.e., it functions as cognitive organ of time-perception. If an event happens to an animal that impacts its potential fitness, the animal will remember not only what happened and where, but also when (time of day). Continuously Consulted Clocks are used for sun-compass orientation and navigation, e.g., in migratory birds and in honeybees (time-sense). As the Sun moves across the horizon over the course of a day, animals that orient using the Sun as a reference point use the internal clock to compensate for the Sun's movement.
Yoo et al 2004
although only recently found out peripheral clocks also self-sustained like SCN still slave to master clock as while circ gene expression persists in peripheral organs of SCN-lesioned mice, their phases not coordinated.
Posttranslational mechanisms such as protein phosphorylation also play important roles in generating oscillations of approximately 24 h
casein kinase 1ε (CK1ε), initially identified as an essential Drosophila clock component (Price et al. 1998), CK1ε phosphorylates PER, CRY, and BMAL1 proteins (Eide et al. 2002; Eide and Virshup 2001; Lee et al. 2004), (Lowrey et al. 2000) hypomorphic Ck1εmutant alleles (dubbed Tau) cause a dramatic shortening of the period length in hamsters In Drosophila, casein kinase II (CKII) also phosphorylates PER and thereby enhances the repressing activity of this protein (Lin et al. 2002; Nawathean and Rosbash 2004). Gachon et al 2004 - Given the sequence similarities of mammalian and insect PER and CKII proteins, we consider it likely that mammalian CKII also participates in the modulation of PER activity in the mammalian system
define photoperiodism discuss importance of night length, "counter mechanism in initiation and termination of insect seasonal photoperiodic phenomenon
changes in the length of the day photoperiodism, the physiological reaction of organisms to the length of day or night, is vital to both plants and animals, and the circadian system plays a role in the measurement and interpretation of day length Only at the equator are the day lengths approximately LD 12:12 dvantage for organisms to be able to anticipate seasonal changes, so that environmental conditions are most suitable, e.g. breeding in spring or summer to take advantage of warmer temperatures, producing flowers at the right time of year to attract pollinators, change fur colour to camouflage against predators or migrate to avoid the harsher conditions of winter. Most seasonal events are triggered by a photoperiod of a certain length = critical day length/ critical photoperiod length of the critical photoperiod varies not only between species but also between the same species at different latitudes. For example the butterfly Acronycta rumicis has a critical day length of 15 hours at 45�N, but a critical day length of 18 hours at 50�N. Most critical photoperiods are between 10 and 14 hours of light (Binkley 1997). With some organisms an action will be triggered when the photoperiod falls below the critical photoperiod (short day), whilst in others an action will not occur until the photoperiod had passed the length of the critical photoperiod (long day). Hence these two terms can be used to categorise organisms by photoperiodicity � short day plants will flower when the photoperiod falls below the critical day length; long day plants will flower then the photoperiod is longer than the critical day length. These effects can be replicated in the laboratory, making it possible to determine the exact length of a photoperiod required to initiate a certain rhythm. Some organisms have rhythms that are not affected by photoperiod. Often other factors will have an effect instead e.g. temperature. Often reproduction is triggered by a critical photoperiod. In many male animals, testis size is affected by photoperiod. In both hamsters and some birds for example the testes are small in short days (i.e. in winter) but grow dramatically in long days (Anand 2002). In the case of hamsters the critical photoperiod is 12.5 hours. When the photoperiod drops below this, the testes reduce in size and stop producing sperm. When the photoperiod is longer than 12.5 hours, the testes enlarge (testicular recrudescence). Female hamsters have a similar critical day length so that the breeding cycle of both sexes coincide. The photoperiodic control of reproduction may be due to the hormone melatonin. This is produced by the pineal gland. Melatonin inhibits reproduction by blocking the hormone prolactin, which is a gonad stimulating hormone. Repression of prolactin causes gonad regression.
Yamaguchi et al 2003 - shown most neurones contain circ oscillators.
circ expression of luciferase reporter gene under control of mouse Per1 promoter in neurons of SCN in tissue culture -
Drosophilia Melanogaster
clock genes have orthologs in mammals
negative components of genetic circuitry in mam circ molecular oscillator Gachon et al 2004
encode for repressors: cryptochrome 1 (Cry1) cryptochrome 2 (Cry2) period 1 (Per1) period 2 (Per2)
zeitgeber
exogenous cue that synchronizes our internal clock. - such as blue light from a computer Aschoff - "time-giver" photic information (like blue light) non-photic information (like temperature, social cues, food availability, to name a few) act as zeitgebers with the ability to entrain due to daily and seasonal changes, temperature cues are less precise. Never the less some organisms e.g. lizards can entrain to temperature cycles with a change of less than 1�C per cycle (Binkley 1997). Whist some of these may reinforce each other e.g. light and temperature generated by the sun, the Zeitgebers may also give competing signals to the same rhythm. These are called conflicting Zeitgebers (Binkley1997) Damiola et al 2000/ Stokkan et al 2001 - showed feeing time entrains phase of peripheral oscillators feeding nocturnal rodents during day for week or longer gradually inverses phase of circ gene expression liver, pancreas, heart, skeletal muscle, kidney and lung. Day time feeding uncouples phases of circ SCN gene expression and peripheral clocks as importantly feeding time little influence on phase of circ gene expression. Le Minh et al 2001 - as soon as food offered ad libitum SCN rapidly reestablishes dominance and resynchronises periperhal clocks to normal nocturnal mode. - this more direct route is speculated to be via glucocorticoid signalling.
negative feed back loop higher eukaryotes
genetic interactions result in an interlocked feedback loop of gene products resulting in periodic fluctuations that the cells of the body interpret as a specific time of the day. Hardin et al 1990 Dros 'period' protein required for cyclic accumulation of its own mRNA - own autoreg negative feeback loop Gachon et al 2004 - -ve feedback loops of clock gene expression in all genetic model systems i.e. cyanobacteria, neurospora, plants and mammals.
\transcriptome profiling studies
have unveiled two other important aspects of the circadian timing system. First, different circadian transcripts within one tissue can accumulate with many different phases, secondly, most circadian genes are expressed in a tissue-specific manner. properties are physiologically relevant. different phases are required for the temporal separation of biochemically incompatible processes (e.g., glycogen synthesis and degradation), and cell type-specific circadian gene expression is in keeping with the concept that different tissues must control the timing of different functions
chronotype
in sleep research and sleep science as applied to humans, chronotype refers to the people's regular rising and bedtimes. Some people are morning larks and rise early and are more active in the morning. Others are night owls in zoology refers to the time of the sleep and regular activities of an animal. Nocturnal animals are active at night, for instance. Humans are diurnal - active in the day and at sleep at night Chronotype behavior isn't seen in just sleep times, but in level of activity and vigilance during waking periods, and even body temperature, serum cortisol levels, and blood pressure. Duffy et al 2001 morning larks experience an earlier circadian rhythm temperature peak than night owls so it is apparent that the entire cycle is shifted - fundamental property of the circadian pacemaker is correlated with the behavioral trait of morningness-eveningness.
common phase markers to measure circa rhythm
melatonin secretion by the pineal gland -Its onset in dim light, dim-light melatonin onset (DLMO Hardeland 2006), at about 21:00 (9 p.m.) can be measured in the blood or the saliva. Its major metabolite can also be measured in morning urine core body temperature plasma level of cortisol.
shift work
much dimmer illumination of artificial lights is not usually sufficient to trigger this reset of the circadian clock, which is why night shift workers never really fully adapt to their unnatural sleep patterns
temperature define
not reliable as cue as day-night cycle however Brown et al 2002 have shown body temperature oscillations, recorded by telemetry in the intraperitoneal cavity of mice and simulated in the cell culture medium by a computer-directed incubator, can sustain previously induced cyclic gene expression - i.e. temp not most important timing cue for peripheral clocks they probably contribute to synchronisation of these time keepers. temperature is compensated - i.e. within physiological temp range the period length changes very little if temp increased or decreased. Dunlap 1999 - Q10 - (ratio between rates measured for chemical reaction at two temperatures differing by 10degrees within physiological range ) is nearly 1 or the circ period length. Temp compensation important for fish and reptiles to anticipate daytime irrespective of ambient temp. Izumo et al 2003 - even mammalian circ oscillators = temp compensated. Gachon 2004 - may be that temp-dependent changes in accumulation of clock components may be compensated by temp-dependent interactions between them.
light-dark cycle
predictable, regular, reliable, precise more than temperature. because planet tilted 23.5 degrees - seasons predictable. as annual change of day light length and daily change to light and dark. Circadian rhythm set to light dark cycle term coined by Franz Halberg in the late 1950s. Animals, including humans, kept in total darkness for extended periods eventually function with a freerunning rhythm. Their sleep cycle is pushed back or forward each "day", depending on whether their "day", their endogenous period, is shorter or longer than 24 hours Norwegian researchers at the University of Tromso have shown that some Arctic animals (ptarmigan, reindeer) show circadian rhythms only in the parts of the year that have daily sunrises and sunsets. In one study of reindeer, animals at 70 degrees North showed circadian rhythms in the autumn, winter, and spring, but not in the summer. Reindeer at 78 degrees North showed such rhythms only in autumn and spring. The researchers suspect that other Arctic animals as well may not show circadian rhythms in the constant light of summer and the constant dark of winter. acts as an external cue to resynchronise or entrain the timing of biological rhythms, and to prevent small timing errors from accumulating
animals and plants evolved under?
rhythmic light-dark conditions. bacteria to humans except cave animals and deep sea organisms - evolved to mimic 24 hour oscillation photoperiodism the response of an organism to seasonal changes in day length. Since a relatively recent ancestor of all mammals was a nocturnal burrowing insectivore-like creature, it is likely that some mammals evolved diurnality comparatively recently and retained a nocturnal response to light intensity
cyanobacteria current model of circ clock how does it question the classical transcription translation model of clock function
simplest known circadian clock is that of the prokaryotic cyanobacteria. Recent research has demonstrated that the circadian clock of Synecohococcus elongatus can be reconstituted in vitro with just the three proteins of their central oscillator. This clock has been shown to sustain a 22 hour rhythm over several days upon the addition of ATP Previous explanations of the prokaryotic circadian timekeeper were dependent upon a DNA transcription / translation feedback mechanism, and although this has not been shown to be the case, it is still believed to hold true for eukaryotic organisms. Indeed, although the circadian systems of eukaryotes and prokaryotes have the same basic architecture: input - central oscillator - output, they do not share any homology. This implies probable independent origins
circadian (about a day in latin) rhythms -
to be considered a circadian rhythm must be: 24 hour period, endogenous (persists in constant condition), entrainable (rhythm can be reset by exposure to external stimuli) and exhibit temperature compensation Czeisler et al. at Harvard found the range for normal, healthy adults of all ages to be quite narrow: 24 hours and 11 minutes plus or minus 16 minutes. The "clock" resets itself daily to the 24-hour cycle of the Earth's rotation. Circadian rhythms are believed to have originated in the earliest cells (with photosensitive proteins) to provide protection for replicating DNA, from high ultraviolet radiation during day-time - so replication relegated to the dark. The fungus Neurospora retains this clock-regulated mechanism. molecular circadian clock can function within a single cell; i.e., it is cell-autonomous. At the same time, different cells may communicate with each other resulting in a synchronized output of electrical signaling. These may interface with endocrine glands of the brain to result in periodic release of hormones. The receptors for these hormones may be located far across the body and synchronize the peripheral clocks of various organs rhythmicity appears to be as important in regulating and coordinating internal metabolic processes suggested by the maintenance (heritability) of circadian rhythms in fruit flies after several hundred generations in constant laboratory conditions, as well as in creatures in constant darkness in the wild, and by the experimental elimination of behavioural but not physiological circadian rhythms in quail. Paine et al 2006 morningness/eveningness preference is largely independent of ethnicity, gender, and socioeconomic position, indicating that it is a stable characteristic that may be better explained by endogenous factor
SNS
two small groups of neurons located in the ventral hypothalamus an area of the brain just above where the optic nerves from the eyes cross. = suprachiasmatic nucleus Lesser circadian pacemakers with their own 24-hour cycles, sometimes called slave oscillators, have also been located in the eyes, pineal gland, liver, intestines, and other organs, but the SCN is said to synchronize them, employing over 20,000 neurons in the process. The SCN receives input via three main pathways: the retino-hypothalamic tract, which directly delivers photic (light-derived) information; the geniculo-hypothalamic tract, which indirectly delivers photic information; and the raphe-hypothalamic tract, which uses serotonin to deliver non-photic information to the SCN SCN tells the pineal gland to secrete melatonin. Several studies have indicated that pineal melatonin feeds back on SCN rhythmicity to modulate circadian patterns of activity and other processes individual neurons that make up the SCN have been found to exhibit a near-24-hour rhythm of activity, suggesting that the clock mechanism actually works on a sub-cellular level. When dissociated from the SCN, the individual cells follow their own intrinsic 24-hour rhythms, but, when incorporated into the SCN, they all fire in synchrony Destruction of the SCN results in the complete absence of a regular sleepÐwake rhythm hrough the eyes. The retina of the eye contains "classical" photoreceptors ("rods" and "cones"), which are used for conventional vision. But the retina also contains specialized ganglion cells which are directly photosensitive contain the photopigment melanopsin and cryptochrome and their signals follow a pathway called the retinohypothalamic tract, leading to the SCN where they help in the entrainment of this master circadian clock. If cells from the SCN are removed and cultured, they maintain their own rhythm in the absence of external cues. the SCN also sends out an alerting pulse throughout the day (sometimes referred to as the circadian alerting system) which counteracts the increasing homeostatic sleep pressure. These alerting pulses from the SCN reach their peak about 2-3 hours before one's habitual bedtime (sometimes referred to as the "wake maintenance zone"), which serves to offset the homeostatic drive that has been continually accumulating throughout waking hours, allowing for continued alertness late into the evening. As the evening progresses, though, the SCN's alerting pulses start to weaken, melatonin production in the pineal gland increases (also under the direction of the SCN), and the "sleep gate" (also known as the primary sleepiness zone or sleep onset zone) opens, and the urge to sleep increases dramatically.
Liu et al 1997 shown most neurones contain circ oscillators.
with circ firing in individual hamster SCN neurones - all show circ fluctuations in eletrical activity, their periods vary between cells - yet avg period length correspond to period length of locomotor activity of donor Hence in vivo SCN neurons must be coupled to synchronise their molecular oscillators.
