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Aschoff's Rules consist of three generalized statements that were first introduced by Jürgen Aschoff based on his observations of the spontaneous frequencies (“free-running periods” according to Colin Pittendrigh) of several animal species. The circadian rhythm, which is usually driven by a circadian clock, displays endogenous and entrainable oscillation with a period of around 24 hours. The time needed for one circadian oscillation to occur under constant conditions is known as the free-running period. However, under normal conditions, the oscillation is synchronized to the local environment. This synchrony is the result of an entrainment by Zeitgeber ("time giver") signals, such as the light-dark cycle[1]. With the idea of entrainment close to the core of Aschoff’s studies[2], he proposed theories, which are now known as Aschoff’s Rules, to describe and predict the effects of different light durations (especially constant light and constant darkness conditions) and light intensities on animals' circadian behaviors.
Jürgen Aschoff
[edit]Jürgen Aschoff (January 25, 1913 – October 12, 1998) was a German physician, biologist and behavioral physiologist. Along with Colin Pittendrigh, Jürgen Aschoff is considered to be one of the pioneers of human chronobiology[3].
Life and Work
[edit]Jürgen Aschoff studied medicine at the University of Bonn, and later began his scientific career at the University of Göttingen[3]. He was inspired by and learned from Hermann Rein who then worked on thermoregulation physiology. After World War II, Aschoff lectured at the University of Würzburg. In 1952, Rein was appointed director at the new Max Planck Institute for Medical Research in Heidelberg. Aschoff followed him as a collaborator[3]. Based on his studies in humans, birds, and mice, Aschoff established that the circadian rhythm is innate in organisms[3]. Aschoff then moved to Max Planck Institute of Behavioural Physiology in Bavaria, where he built his own department dedicated to the study of biological timing, such as the effects of environmental stimuli on the endogenous circadian systems. His findings laid foundation for the field of chronobiology as he established the concept of seeing circadian rhythm as a product generated by endogenous oscillators and modulated by exogenous light-dark cycle[3]. His studies played an important role in medical field as well since the pathological implications derived from his findings helped explain many psychiatric disorders and mental illness[4]. Aschoff retired in 1983, Aschoff returned to Freiburg. After a short illness, he died at the age of 85 years[3].
History
[edit]Before the introduction of Aschoff’s Rules, scientists had already recognized the effects of constant light on the circadian behavior of animals. However, Aschoff was one of the first biologists to systematically analyze them and generalized them into widely applicable rules. The term “Aschoff's Rule” was first created by Colin S. Pittendrigh in his article published in 1960 when he summarized what is now known as Aschoff's Third Rule. In the article, he wrote:
"XII: τFR is light intensity dependent. There is evidence of a fairly strong further generalization which I propose to call Aschoff's Rule. This can be summarized by τLL > τDD in nocturnal animals; τLL < τDD in diurnal animals."[5]
(τ: endogenous free-running circadian period; FR: free-running; LL: constant light condition; DD: constant darkness condition)
The other two of Aschoff's rules were not explicitly stated by Pittendrigh in the article, but they were later included into the circadian nomenclature. The field of circadian rhythm was then not nearly as well-studied as it is right now. The introduction of Aschoff’s Rules provided an essential guideline for scientists, indicating light as the most important Zeitgeber that affects circadian rhythms.
Definition of Aschoff's Rules
[edit]Aschoff's First Rule
[edit]The endogenous free-running (FR) circadian period (tau, τ) under constant darkness condition (DD) is longer than 24 hours for diurnal animals and shorter than 24 hours for nocturnal animals[6].
Aschoff's Second Rule
[edit]Under constant light condition (LL), activity time (alpha, α) increases compared to rest time (rho, ρ) for diurnal animals and decreases for nocturnal animals. When light intensity increases, the α:ρ ratio and total amount of activity increase for diurnal animals but decrease for nocturnal animals[6].
Aschoff's Third Rule
[edit]Under constant light condition (LL), τ shortens for diurnal animals and lengthens for nocturnal animals. These effects are enhanced with increased intensity of illumination[6].
Summary
[edit]When chronobiologists talk about Aschoff’s Rules, they most commonly talk about Aschoff’s Third Rule, while Aschoff’s Second Rule is often referred to as the “Circadian Rule”[7]. However, all three statements in Aschoff’s Rules play extremely important parts in the study of chronobiology and are applied as the fundamental and generalized rules in many chronobiologists’ research[3]. Below is a table that summarizes characteristics of the three rules in diurnal and nocturnal animals.
Table 1: Characteristics of Aschoff's Rules in diurnal and nocturnal animals[6]
| Aschoff’s Rules | Diurnal Animals (Light-active) | Nocturnal Animals (Dark-active) |
|---|---|---|
| First Rule | τDD > 24 h | τDD < 24 h |
| Second Rule | α increases under LL α:ρ ratio and total amount of activity increase with increased light intensity αLL > ρLL |
α decreases under LL α:ρ ratio and total amount of activity decrease with increased light intensity αLL < ρLL |
| Third Rule | τLL < τDD | τLL > τDD |
Models of Entrainment
[edit]When approaching the entrainment of circadian rhythm with light-dark cycle, Aschoff and Pittendrigh based their experiments on different models. Aschoff’s Rules are related to the model of parametric entrainment, indicating continuous or tonic phase changes. Aschoff put emphasis on the parametric dependence of circadian period on constant light. However, Pittendrigh started with the model of nonparametric entrainment, which assumed discrete or phasic phase changes. He paid attention to the transition between light and darkness. This distinction between their approaches attributed to the systems they studied: Pittendrigh studied the single instantaneous event of eclosion in Drosophila, while Aschoff studied the continuous modulation of activity in the circadian rhythms of birds, mammals, and humans[2].
The nonparametric theory is now more widely accepted by researchers[8]. The nonparametric phase response curve (PRC), which was derived from the effects of single brief light pulses, has become a standard textbook concept in the field of chronobiology[2].
Violations and Exceptions of Aschoff’s Rules
[edit]As with most rules, there are exceptions in Aschoff’s Rules. Since Aschoff’s Rules were proposed and widely used for reference in the field of chronobiology, scientists have discovered violations of these rules in many species.
Aschoff stated in his follow-up research published in 1979 that, although most species seemed to correspond to Aschoff’s Rules, he discovered “a bimodal [decreasing-then-increasing] dependence of τ on ILL [light intensity under constant light condition] could be characteristic for at least some species of night-active mammals”. He also discovered that different from the uniform τ characteristics obtained from night-active mammals and light-active birds, some of the light-active species of mammal actually show large differences in the dependence of τ on ILL. These discoveries show violations of Aschoff’s Third Rule.[9]
Violations Specific to Arthropods
[edit]Apart from certain species of mammals, violations and exceptions of Aschoff’s Rules are more often observed among arthropods[7].
Violation of Aschoff’s First Rule
[edit]- In onion flies, Delia antiqua, τDD changes with age. Their τDD is shorter than 24 hours until 14–20 days after adult eclosion; thereafter, it becomes longer than 24 hours[10].
Violation of Aschoff’s Second Rule
[edit]- In the nocturnal beetle, Tenebrio molitor, a positive correlation between the α:ρ ratio and light intensity was observed, although τ increased when the beetle was transferred from DD to LL, which corresponded to Aschoff’s Third Rule.[11]
Violation of Aschoff’s Third Rule
[edit]- In cockroaches, no obvious correlation was observed between τ and the intensity of illumination (in LL).[12]
- In V. currens, no systematic change of τ was observed when the intensity was raised from 0.1 to 700 lux.[13]
- In the mainly light-active dung beetle, Geotrupes sylvaticus, τ lengthened in LL.[14]
Genetic Aspects of Aschoff’s First Rule
[edit]Although there has been research in the various physiological, molecular, or anatomical mechanisms motivating Aschoff’s Rules, scientific experiments have indirectly supported Aschoff’s First Rule. Studies with nocturnal rodents have demonstrated light’s role in decelerating the circadian oscillator: constant light seems to shorten a nocturnal animal’s period and is believed to increase the period in diurnal animals.
Recent experiments have indicated a genetic influence in animals’ reaction to constant light conditions.
Circadian experts have shown lots of interest in inbred mice, which are variants of the Genus Mus. When exposed to constant dim red light (low intensity red light ranging from 620-750 nm) versus LL, inbred strains of mice exhibited varying circadian oscillations. Mice with the shortest free-running in dim red light exhibited the greatest period increase after immediate exposure to bright light[15]. These varied circadian reactions to the two conditions suggest an underlying genetic component in these mice’s ability to perceive light. This indicates that the mice have different levels of mClock gene expression: differences that explain the varied expression of Aschoff’s First Rule in inbred mice strains.
Specific Genes involved in Aschoff’s First Rule
[edit]Table 2: Genetic Evidence of Aschoff’s First Rule in Mice[15]
| Gene | General Function | Function in Mice |
|---|---|---|
| Period2 (Per2) | Per2 codes for PER2 protein in mammals Expressed in SCN (primary circadian pacemaker for mammals) Assists in coding for circadian clock to regulate activity levels/metabolism/behavior |
In LL PER2 protein levels are altered LL → Per2 rhythmic LL → PER2 protein elevated and arrhythmic in SCN DD → Per2 rhythmic DD → PER2 protein levels rhythmic |
| Clock Gene (mClock) | First mouse circadian mutation | Mutant mClock → lengthened period in free-running mice Mutant mClock → arrhythmic |
In the mammals, many Clock genes that support Aschoff’s First Rule demonstrate circadian oscillations. This oscillating gene pattern is also demonstrated in Drosophila melanogaster. The D. melanogaster Clock genes and their mammalian analogs are displayed in Table 3 below.
Table 3: Mammalian Circadian Genes vs. Drosophila Circadian Genes[16]
| Mammalian (mouse) Gene | D. melanogaster | Characteristics of Mutant |
|---|---|---|
| Clock | dClock | Longer period Constant conditions → Loss of rhythmicity |
| mPer1 | Period | Lower amplitude/shortened period/loss of rhythm |
| mPer2 | Period | Shorter period/loss of rhythm |
| mPer3 | Period | Modest shortening of period |
| CKEє | Doubletime | Shortened period in mutant hamsters |
| mCry1/mCry2 | dCry | mCry1 knockout → shorter period mCry2 knockout → longer period mCry1/mCry2 double knockout → arrhythmic |
| Bmal1 | Cycle | Loss of rhythm |
Mammalian Anatomical Components Contributing to Aschoff’s First Rule
[edit]Light reaches the mammalian circadian clock through the retinohypothalamic tract (RHT) pathway as demonstrated in Diagram 1. This photic neural input pathway is sufficient for entrainment [17] originates at the melatonin containing ipRGCs (intrinsically photosensitive retinal ganglion cells). The ipRGCs axons in the retina use the optic nerve to directly project to the mammalian master clock, the suprachiasmatic nuclei (SCN). The SCN then uses this information to entrain the mammalian biological clock utilizing both the information form the ipRGCs and environmental cues (light, dark, and day length).
During the entrainment process, rods and cones are not necessary: mice can entrain to light-dark cycles without these photoreceptors. Therefore, under LL, free-running mice without rods and cones exhibit a normal lengthening of their period as long as they express the melanopsin photopigment in their retinal ganglion cells.
Research has validated that Melanopsin is sufficient for the transfer of photic information to the SCN for entrainment. During a melanopsin knockout under LL, free-running mice express a reduced lengthening in their period. This evidence suggests that melanopsin actively participates in the effects explained in Aschoff’s First Rule.
In mammals, another crucial structure influences circadian rhythms: the intergeniculate leaflet (IGL). The IGL works with the SCN to receive retinal inputs and send information back to the SCN. Lesioning the IGL on free-running hamsters (not mice) in LL mitigates the lengthening period effects suggesting that the IGL is necessary for an increase in free-running hamsters experiencing LL[18].
Table 4: Key Anatomical Components and Lesion Effects[19]
| Anatomical Component | Function | Lesion Effects |
|---|---|---|
| RHT | Photic neural input pathway Important for mammalian circadian rhythms Origin = ipRGCs |
Lesion in LD → loss of entrainment RHT is necessary for entrainment |
| SCN | Light information transported here through RHT Functions as a master circadian oscillator Center for circadian rhythmicity[20] |
Arrhythmicity |
| IGL | Receives retinal inputs and sends information to SCN | Lesion in LL → reduced lengthening effects on period in free-running hamsters (not mice) |
| ipRGCs | Transmit light signals to brain areas Help control circadian rhythms and pupil reflex |
N/A |
References
[edit]- ^ Golombek, D.A., Rosenstein, R.E. (2010) “Physiology of circadian entrainment.“ Physiol Rev. 90(3):1063-102. doi: 10.1152/physrev.00009.2009. PMID 20664079
- ^ a b c Daan, Serge. (1998) "Colin Pittendrigh, Jürgen Aschoff, and the Natural Entrainment of Circadian Systems." The Colin S. Pittendrigh Lecture.
- ^ a b c d e f g Daan S, Gwinner E (1998). "Jürgen Aschoff (1913–1998)". Nature. 396 (6710): 418. doi:10.1038/24750. PMID 9853745
- ^ Eastwood, M. R.; A. M. Peter (1988). "Epidemiology and seasonal affective disorder". Psychological Medicine. 18 (4): 799–806. doi:10.1017/S0033291700009727. PMID 3078047
- ^ Pittendrigh, C.S. (1960) "Circadian rhythms and the circadian organization of living systems". Cold Spring Harb Symp Quant Biol 25:159–184. PMID 13736116
- ^ a b c d Stillman, Bruce (2007). "Clocks and Rhythms." Cold Spring Harbor: CSHL Press. p. 513.
- ^ a b Saunders, D.S. (2002). Insect clocks (3rd ed.). Elsevier. ISBN 9780444504074.
- ^ Roenneberg, T., Hut, R., Daan, S., Merrow, M. (2010) “Entrainment concepts revisited.” J Biol Rhythms. 25(5):329-39. doi: 10.1177/0748730410379082. PMID 20876813
- ^ Aschoff, J. (1979) "Influences of internal and external factors on the period measured in constant conditions". Z. Tierpsychol. 49: 225-249. PMID 386643
- ^ Watari, Yasuhiko, Arai, Tetsuo (1999). “Effect of Dim Light on Locomotor Activity Rhythm in the Onion fly, Delia antiqua”. Zoological Science. 16(4): 603-609
- ^ Lohmann, M. (1964) "Der einfluss von Beleuchtungsstarke und Temparatur auf die Tagesperiodische Laufaktivitat des Mehlkafers, Tenebrio molitor L". Z vergl Physiol. 49, 341-389.
- ^ Roberts, S. K. de F. (1960) "Circadian activity in cockroaches. I. The freerunning rhythm in steady-state". J. cell. Comp. Physiol. 55, 99-110. PMID 14437836
- ^ Rensing, L. (1961) "Aktivitatsperiodik des Wasserlaufers Velia currens F". Z. vergl. Physiol. 44, 292-322.
- ^ Geisler, M. (1961) "Untersuchungen zur Tagesperiodik des Mistkafers Geotrupes silvaticus Panz". Z.Tierpsychol. 18, 389-420.
- ^ a b Possidente B., Hegmann JP. (1982) "Gene differences modify Aschoff's rule in mice". Physiol Behav. 28(1):199-200. PMID 7200614
- ^ Vitaterna, M.H. (2001) "Overview of circadian rhythm". Alcohol Research and Health. 25(2), 85-93.
- ^ Johnson, R.F., Moore, R.Y., Morin, L.P.(1988) "Loss of entrainment and anatomical plasticity after lesions of the hamster retinohypothalamic tract". Brain Res. 60(2):297-313. PMID 2465060
- ^ Joshua J. Gooley, Clifford B. Saper. (2011) “Anatomy of the Mammalian Circadian System” Principles and Practice of Sleep Medicine (Fifth Edition), 376-389.
- ^ Johnson, R.F., et al. (1988) “Loss of Entrainment and Anatomical Plasticity after Lesions of the Hamster Retinohypothalamic Tract.” Brain Research. 460(2):297-313. PMID 2465060
- ^ Kwon, Ilmin, et al. (2011) “Mammalian Molecular Clocks.” Experimental Neurobiology. 20(1): 18–28. PMID 22110358