Effects of temperature on circadian clock and chronotype: an experimental study on a passerine bird

Daily schedules of many organisms, including birds, are thought to affect fitness. Timing in birds is based on circadian clocks that have a heritable period length, but fitness consequences for individuals in natural environments depend on the scheduling of entrained clocks. This chronotype, i.e., timing of an individual relative to a zeitgeber, results from interactions between the endogenous circadian clock and environmental factors, including light conditions and ambient temperature. To understand contributions of these factors to timing, we studied daily activity patterns of a captive songbird, the great tit (Parus major), under different temperature and light conditions. Birds were kept in a light (L)-dark (D) cycle (12.5?L:11.5 D) at either 8°C or 18°C with ad libitum access to food and water. We assessed chronotype and subsequently tested birds at the same temperature under constant dim light (LL(dim)) to determine period length of their circadian clock. Thermal conditions were then reversed so that period length was measured under both temperatures. We found that under constant dim light conditions individuals lengthened their free-running period at higher temperatures by 5.7?±?2.1?min (p?=?.002). Under LD, birds kept at 18°C started activity later and terminated it much earlier in the day than those kept under 8°C. Overall, chronotype was slightly earlier under higher temperature, and duration of activity was shorter. Furthermore, individuals timed their activities consistently on different days under LD and over the two test series under LL(dim) (repeatability from .38 to .60). Surprisingly, period length and chronotype did not show the correlation that had been previously found in other avian species. Our study shows that body clocks of birds are precise and repeatable, but are, nonetheless, affected by ambient temperature. (Author correspondence: marina.lehmann@uni-konstanz.de ).     

Environmental cycles regulate development time via circadian clock mediated gating of adult emergence

Background

Previous studies have implicated a role for circadian clocks in regulating pre-adult development of organisms. Among them two approaches are most notable: 1) use of insects whose clocks have different free-running periods and 2) imposition of artificial selection on either rate of development, timing of emergence or circadian period in laboratory populations. Using these two approaches, influence of clock on rate of development has been elucidated. However, the contribution of circadian clocks in determining time taken for pre-adult development has remained unclear. Here we present results of our studies aimed to understand this influence by examining populations of fruit flies carrying three different alleles of the period gene and hence having different free-running periods. We tried to achieve similarity of genetic background among the three strains while also ensuring that they harbored sufficient variation on loci other than period gene.

Results

We find that under constant conditions, flies with long period have slower development whereas in presence of light-dark cycles (LD) of various lengths, the speed of development for each genotype is influenced by whether their eclosion rhythms can entrain to them. Under LD 12:12 (T24), where all three strains entrain, they do not show any difference in time taken for emergence, whereas under LD 10:10 (T20) where long period flies do not entrain and LD 14:14 (T28) where short period flies do not entrain, they have slower and faster pre-adult development, respectively, compared to the controls. We also show that a prior stage in development namely pupation is not rhythmic though time taken for pupation is determined by both the environmental cycle and period allele.

Conclusion

We discuss how in presence of daily time cues, interaction of the cyclic environmental factors with the clock determines the position and width of the gate available for a fly to emerge (duration of time within a cycle when adult emergence can occur) resulting in an altered developmental duration from that observed under constant conditions. We also discuss the relevance of genetic background influencing this regulation.

     

Evolution of circadian rhythms in Drosophila melanogaster populations reared in constant light and dark regimes for over 330 generations

Organisms are believed to have evolved circadian clocks as adaptations to deal with cyclic environmental changes, and therefore it has been hypothesized that evolution in constant environments would lead to regression of such clocks. However, previous studies have yielded mixed results, and evolution of circadian clocks under constant conditions has remained an unsettled topic of debate in circadian biology. In continuation of our previous studies, which reported persistence of circadian rhythms in Drosophila melanogaster populations evolving under constant light, here we intended to examine whether circadian clocks and the associated properties evolve differently under constant light and constant darkness. In this regard, we assayed activity-rest, adult emergence and oviposition rhythms of D. melanogaster populations which have been maintained for over 19 years (~330 generations) under three different light regimes – constant light (LL), light–dark cycles of 12:12 h (LD) and constant darkness (DD). We observed that while circadian rhythms in all the three behaviors persist in both LL and DD stocks with no differences in circadian period, they differed in certain aspects of the entrained rhythms when compared to controls reared in rhythmic environment (LD). Interestingly, we also observed that DD stocks have evolved significantly higher robustness or power of free-running activity-rest and adult emergence rhythms compared to LL stocks. Thus, our study, in addition to corroborating previous results of circadian clock evolution in constant light, also highlights that, contrary to the expected regression of circadian clocks, rearing in constant darkness leads to the evolution of more robust circadian clocks which may be attributed to an intrinsic adaptive advantage of circadian clocks and/or pleiotropic functions of clock genes in other traits.     

Effects of Temperature on Circadian Clock and Chronotype: An Experimental Study on a Passerine Bird

Daily schedules of many organisms, including birds, are thought to affect fitness. Timing in birds is based on circadian clocks that have a heritable period length, but fitness consequences for individuals in natural environments depend on the scheduling of entrained clocks. This chronotype, i.e., timing of an individual relative to a zeitgeber, results from interactions between the endogenous circadian clock and environmental factors, including light conditions and ambient temperature. To understand contributions of these factors to timing, we studied daily activity patterns of a captive songbird, the great tit (Parus major), under different temperature and light conditions. Birds were kept in a light (L)-dark (D) cycle (12.5?L:11.5 D) at either 8°C or 18°C with ad libitum access to food and water. We assessed chronotype and subsequently tested birds at the same temperature under constant dim light (LL_dim) to determine period length of their circadian clock. Thermal conditions were then reversed so that period length was measured under both temperatures. We found that under constant dim light conditions individuals lengthened their free-running period at higher temperatures by 5.7?±?2.1?min (p?=?.002). Under LD, birds kept at 18°C started activity later and terminated it much earlier in the day than those kept under 8°C. Overall, chronotype was slightly earlier under higher temperature, and duration of activity was shorter. Furthermore, individuals timed their activities consistently on different days under LD and over the two test series under LL_dim (repeatability from .38 to .60). Surprisingly, period length and chronotype did not show the correlation that had been previously found in other avian species. Our study shows that body clocks of birds are precise and repeatable, but are, nonetheless, affected by ambient temperature. (Author correspondence: marina.lehmann@uni-konstanz.de)     

Circadian phototransduction: phase resetting and frequency of the circadian clock of Gonyaulax cells in red light

Constant red light (RR) influences the Gonyaulax clock in several ways: (1) Phase resetting by white or blue light pulses is stronger under background RR than in constant white light (WW); (2) frequency of the rhythm is less in RR than in WW; and (3) the amplitude of the spontaneous flashing rhythm is greater in RR than in WW. The phase response curve (PRC) to 4-hr white or blue light pulses is of high amplitude (Type 0) for cells in RR, but is of lower amplitude (Type 1) for cells in WW. In all cases, the PRC is highly asymmetrical: The magnitude of advance phase resetting is far higher than that of delay resetting. Consistent with this PRC, Gonyaulax cells in RR (free-running period greater than 24 hr) will entrain to T cycles of between 21 and 26.5 hr. The bioluminescence rhythms exhibit "masking" by blue light pulses while entrained to these T cycles. The fluence response of phase resetting to light-pulse intensity is not linear or logarithmic--rather, it is discontinuous. This feature is consistent with a limit cycle interpretation of Type 0 resetting of circadian clocks. Light pulses that cause large phase shifts also shorten the subsequent free-running period. The phase angle difference between the clock and the previous LD cycle is within 2 hr of the same phase between 16 degrees C and 25 degrees C, as determined from the light PRCs at various temperatures. Several drugs that inhibit mitochondria and/or electron transport will partially inhibit the phase shift by light.     

Possible Evidence for Shift Work Schedules in the Media Workers of the Ant Species Camponotus compressus

The locomotor activity rhythm of the media workers of the ant species Camponotus compressus was monitored under constant conditions of the laboratory to understand the role of circadian clocks in social organization. The locomotor activity rhythm of most ants entrained to a 24 h light/dark (12:12 h; LD) cycle and free-ran under constant darkness (DD) with circadian periodicities. Under entrained conditions about 75% of media workers displayed nocturnal activity patterns, and the rest showed diurnal activity patterns. In free-running conditions these ants displayed three types of activity patterns (turn-around). The free-running period (τ) of the locomotor activity rhythm of some ants (10 out of 21) showed period lengthening, and those of a few (6 out of 21) showed period shortening, whereas the locomotor activity rhythm of the rest of the ants (5 out of 21) underwent large phase shifts. Interestingly, the pre-turn-around τ of those ants that showed nocturnal activity patterns during earlier LD entrainment was shorter than 24 h, which became greater than 24 h after 6–9 days of free-run in DD. On the other hand, the pre-turn-around τ of those ants, which exhibited diurnal patterns during earlier LD entrainment, was greater than 24 h, which became shorter than 24 h after 6–9 days of free-run in DD. The patterns of activity under LD cycles and the turn-around of activity patterns in DD regime suggest that these ants are shift workers in their respective colonies, and they probably use their circadian clocks for this purpose. Circadian plasticity thus appears to be a general strategy of the media workers of the ant species C. compressus to cope with the challenges arising due to their roles in the colony constantly exposed to a fluctuating environment.     

Possible evidence for shift work schedules in the media workers of the ant species Camponotus compressus

The locomotor activity rhythm of the media workers of the ant species Camponotus compressus was monitored under constant conditions of the laboratory to understand the role of circadian clocks in social organization. The locomotor activity rhythm of most ants entrained to a 24 h light/dark (12:12 h; LD) cycle and free-ran under constant darkness (DD) with circadian periodicities. Under entrained conditions about 75% of media workers displayed nocturnal activity patterns, and the rest showed diurnal activity patterns. In free-running conditions these ants displayed three types of activity patterns (turn-around). The free-running period (τ) of the locomotor activity rhythm of some ants (10 out of 21) showed period lengthening, and those of a few (6 out of 21) showed period shortening, whereas the locomotor activity rhythm of the rest of the ants (5 out of 21) underwent large phase shifts. Interestingly, the pre-turn-around τ of those ants that showed nocturnal activity patterns during earlier LD entrainment was shorter than 24 h, which became greater than 24 h after 6-9 days of free-run in DD. On the other hand, the pre-turn-around τ of those ants, which exhibited diurnal patterns during earlier LD entrainment, was greater than 24 h, which became shorter than 24 h after 6-9 days of free-run in DD. The patterns of activity under LD cycles and the turn-around of activity patterns in DD regime suggest that these ants are shift workers in their respective colonies, and they probably use their circadian clocks for this purpose. Circadian plasticity thus appears to be a general strategy of the media workers of the ant species C. compressus to cope with the challenges arising due to their roles in the colony constantly exposed to a fluctuating environment.     

Effect of Behavioural Feedback on Circadian Clocks of the Nocturnal Field Mouse Mus booduga

The effect of 'novel running wheels' on circadian clocks of the nocturnal field mouse Mus booduga was investigated during free-running and entrained conditions. In order to find out whether daily access to novel running wheels can entrain the locomotor activity rhythms experimental animals (n = 6) were provided with 'novel running wheels' at a fixed time of the day. The control animals (n = 5) were handled similar to the experimental animals but were not given access to novel running wheels. The results show that daily access to novel running wheels entrained the free-running locomotor activity rhythm of these mice. The post-entrainment free-running period (τ) of the experimental animals was significantly shorter than the pre-entrainment τ, whereas the pre- and post-treatment τ of the control animals did not differ significantly. In separate set of experiments, the effect of access to novel running wheels on the rate of re-entrainment was studied after a 6 h phase advance/delay in 24 h (12:12 h) light/dark (LD) cycles. Experimental animals were given access to novel running wheels for 3-h, 1 h after the 'lights-off' only on the first day of the 'new LD cycles'. Experimental animals took fewer cycles to re-entrain to 6-h phase advanced LD cycles compared to the control animals. After a phase delay in the LD cycles by 6h, the experimental animals took more number of cycles to re-entrain compared to the control animals. These results thus suggest that access to novel running wheel can act as a Zeitgeber for the circadian clocks of the nocturnal mouse M. booduga, and can also modify the rates of re-entrainment to phase shifted LD cycles, in a time-dependent manner.     

Circadian rhythm of locomotor activity in the Japanese honeybee, Apis cerana japonica

Abstract.  To reveal circadian characteristics and entrainment mechanisms in the Japanese honeybee Apis cerana japonica , the locomotor-activity rhythm of foragers is investigated under programmed light and temperature conditions. After entrainment to an LD 12 : 12 h photoperiodic regime, free-running rhythms are released in constant dark (DD) or light (LL) conditions with different free-running periods. Under the LD 12 : 12 h regime, activity offset occurs approximately 0.4 h after lights-off transition, assigned to circadian time (Ct) 12.4 h. The phase of activity onset, peak and offset, and activity duration depends on the photoperiodic regimes. The circadian rhythm can be entrained to a 24-h period by exposure to submultiple cycles of LD 6 : 6 h, as if the locomotive rhythm is entrained to LD 18 : 6 h. Phase shifts of delay and advance are observed when perturbing single light pulses are presented during free-running under DD conditions. Temperature compensation of the free-running period is demonstrated under DD and LL conditions. Steady-state entrainment of the locomotor rhythm is achieved with square-wave temperature cycles of 10 °C amplitude, but a 5 °C amplitude fails to entrain.     

Changes in the phase response curve of the circadian clock to a phase-shifting stimulus.

Experiments were conducted in hamsters to determine whether the phase response curve (PRC) to injections of the short-acting benzodiazepine triazolam is a fixed or a labile property of the circadian clock. The results indicated that (1) both the shape and the amplitude of the PRC to triazolam generated on the first day of transfer from a light-dark cycle (LD 14:10) to constant darkness (DD) (i.e., PRCLD) were different from those of the PRC generated after many days in DD (PRCDD); and (2) the phase-shifting effects of triazolam on the activity rhythms of hamsters transferred from LD 14:10 or 12:12 to DD changed dramatically within the first 8-9 days spent in DD. In an attempt to accelerate the resynchronization of the circadian clock of hamsters subjected to an 8-hr advance in the LD cycle, triazolam was given to the animals at a time selected on the basis of the characteristics of PRCLD. The activity rhythms of five of eight triazolam-treated animals were resynchronized to the new LD cycle within 2-4 days after the shift, whereas those of most of the control animals were resynchronized 21-29 days after the shift. These findings suggest that attempts to use pharmacological or nonpharmacological tools to phase-shift circadian clocks under entrained conditions should take into account information derived from PRCs generated at the time of transition from entrained to free-running conditions.     

Locomotor activity rhythm in four wrasse species under varying light conditions

Under controlled laboratory conditions, the locomotor activity rhythms of four species of wrasses (Suezichthys gracilis, Thalassoma cupido, Labroides dimidiatus andCirrhilabrus temminckii) were individually examined using an actograph with infra-red photo-electric switches in a dark room at temperatures of 21.3–24.3°C, for 7 to 14 days. The locomotor activity ofS. gracilis occurred mostly during the light period under a light-dark cycle regimen (LD 12:12; 06:00-18:00 light, 18:00-06:00 dark). The locomotor activity commenced at the beginning of the light period and continued until a little before the beginning of dark period. The diel activity rhythm of this species synchronizes with LD. Under constant illumination (LL) this species shows distinct free-running activity rhythms varying in length from 23 hrs. 39 min. to 23 hrs. 47 min. Therefore,S. gracilis appears to have a circadian rhythm under LL. However, in constant darkness (DD), the activity of this species was greatly suppressed. All the fish showed no activity rhythms in DD conditions. After DD, the fish showed the diel activity rhythm with the resumption of LD, but this activity began shortly after the beginning of light period. The fish required several days to synchronize with the activity in the light period. Therefore,S. gracilis appeared to continue the circadian rhythm under DD. InT. cupido, the locomotor activity commenced somewhat earlier than the beginning of the light period and continued until the beginning of the dark period under LD. The diel activity rhythm of this species synchronizes with LD. Under LL, four of the five specimens of this species tested showed free-running activity rhythms for the first 5 days or longer varying in length from 22 hrs. 54 min. to 23 hrs. 39 min. Although the activity of this species was suppressed under DD, two of five fish showed free-running activity rhythms throughout the experimental period. The lengths of such free-running periods were from 23 hrs. 38 min. to 23 hrs. 50 min. under DD. Therefore, it was ascertained thatT. cupido has a circadian rhythm. InL. dimidiatus, the locomotor activity rhythm under LD resembled that observed inT. cupido. The diel activity rhythm of this species synchronizes with LD. Under LL, four of seven of this species showed free-running activity rhythms throughout the experimental period. The lengths of such free-running periods were from 23 hrs. 07 min. to 25 hrs. 48 min. Although the activity of this species was suppressed under DD, three of five fish showed free-running activity rhythms throughout the experimental period. The lengths of such free-running periods were from 23 hrs. 36 min. to 23 hrs. 41 min. under DD. Therefore, it was ascertained thatL. dimidiatus has a circadian rhythm. Almost all locomotor activity of C.temminckii occurred during the light period under LD. The diel activity rhythm of this species coincides with LD. Under LL, two of four of this species showed free-running activity rhythms throughout the experimental period. The lengths of such free-running periods were from 23 hrs. 32 min. to 23 hrs. 45 min. Although the activity of this species was suppressed under DD, one of the four fish showed free-running activity rhythms throughout the experimental period. The length of the free-running period was 23 hrs. 21 min. under DD. Therefore,C. temminckii appeared to have a circadian rhythm. According to field observations,S. gracilis burrows and lies in the sandy bottom whileT. cupido, L. dimidiatus, andC. temminckii hide and rest in spaces among piles of boulders or in crevices of rocks during the night. It seems that the differences in nocturnal behavior among the four species of wrasses mentioned above are closely related to the intensity of endogenous factors in their locomotor activity rhythms.     

Circadian clock functioning is linked to acute stress reactivity in rats

At least two major physiological systems are involved in the adaptation of the organism to environmental challenges: the circadian system and the stress reaction. This study addressed the possibility that interindividual differences in stress sensitivity and in the functioning of the circadian system are related. At 2 months of age, corticosterone secretion in response to a 20-min restraint stress was assessed in 9 Sprague-Dawley rats for which running wheel activity was recorded as a rhythmic behavioral marker of the circadian clock. Two weeks later, the adaptive response of the circadian system to an abrupt shift in the light:dark (LD) cycle was assessed in those rats using a jet-lag paradigm. Finally, after resynchronization to the new LD cycle, rats were transferred to constant darkness to assess the free-running period of their circadian rhythm of running-wheel activity. Results indicate that stress-induced corticosterone secretion was (1) positively correlated with the number of days to resynchronize the circadian activity rhythm to the new LD cycle, and with the value of its free-running period, and (2) negatively correlated with the intensity of daily locomotor activity. Those data, emphasizing the interactions between the stress response of an organism and the functioning of its circadian system, could explain interindividual differences in humans' susceptibility to shift work or other circadian-related disorders.     

Heritable circadian period length in a wild bird population

Timing is essential, but circadian clocks, which play a crucial role in timekeeping, are almost unaddressed in evolutionary ecology. A key property of circadian clocks is their free-running period length (τ), i.e. the time taken for a full cycle under constant conditions. Under laboratory conditions, concordance of τ with the ambient light–dark cycle confers major fitness benefits, but little is known about period length and its implications in natural populations. We therefore studied natural variation of circadian traits in a songbird, the great tit (Parus major), by recording locomotor activity of 98 hand-raised, wild-derived individuals. We found, unexpectedly, that the free-running period of this diurnal species was significantly shorter than 24 h in constant dim light. We furthermore demonstrate, to our knowledge for the first time in a wild vertebrate, ample genetic variation and high heritability (h² = 0.86 ± 0.24), implying that period length is potentially malleable by micro-evolutionary change. The observed, short period length may be a consequence of sexual selection, as offspring from extra-pair matings had significantly shorter free-running periods than their half-siblings from within-pair matings. These findings position circadian clocks in the ‘real world’ and underscore the value of using chronobiological approaches in evolutionary ecology. Evolutionary ecologists study variation and its fitness consequences, but often have difficulties relating behavioural variation to physiological mechanisms. The findings presented here open the possibility that properties of internal, circadian clocks affect performance in traits that are relevant to fitness and sexual selection.     

Effects of photoperiod on rat motor activity rhythm at the lower limit of entrainment

The experiment described here studied the rat motor activity pattern as a function of the photoperiod of circadian light-dark cycles in the limits of entrainment (22-and 23-h periods). In most cases, the overt rhythm showed 2 circadian components: 1 that followed the external LD cycle and a 2nd rhythm that was free run. The expression of these components was directly dependent on the photoperiod, and there was a gradual transition in the manifestation of 1 or the other. The component with a period equal to that of the external cycle was more manifested under long photoperiods, while the other 1 was more expressed during short photoperiods. Also, the period of the free-running component was longer under T22 than T23. For each period, the free-running component was longer under a longer photoperiod. At first sight, the presence of these 2 components in most of the rats might appear to be due to the fact that in the limits of entrainment, some rats do not entrain and thus show a free-running rhythm plus masking. However, the gradation observed in the different patterns of the overt motor activity rhythm, especially those patterns related to the different balance between the 2 components and the length of the period of the free-running component under LD as a function of the photoperiod, suggests that the circadian system can be functionally dissociated.     

Cyclic presence and absence of conspecifics alters circadian clock phase but does not entrain the locomotor activity rhythm of the fruit fly Drosophila melanogaster

Circadian clocks use a wide range of environmental cues, including cycles of light, temperature, food, and social interactions, to fine-tune rhythms in behavior and physiology. Although social cues have been shown to influence circadian clocks of a variety of organisms including the fruit fly Drosophila melanogaster, their mechanism of action is still unclear. Here, the authors report the results of their study aimed at investigating if daily cycles of presence and absence (PA) of conspecific male visitors are able to entrain the circadian locomotor activity rhythm of male hosts living under constant darkness (DD). The results suggest that PA cycles may not be able to entrain circadian locomotor activity rhythms of Drosophila. The outcome does not change when male hosts are presented with female visitors, suggesting that PA cycles of either sex may not be effective in bringing about stable entrainment of circadian clocks in D. melanogaster. However, in hosts whose clock phase has already been set by light/dark (LD) cycles, daily PA cycles of visitors can cause measurable change in the phase of subsequent free-running rhythms, provided that their circadian clocks are labile. Thus, the findings of this study suggest that D. melanogaster males may not be using cyclic social cues as their primary zeitgeber (time cue) for entrainment of circadian clocks, although social cues are capable of altering the phase of their circadian rhythms.     

Modeling the differential fitness of cyanobacterial strains whose circadian oscillators have different free-running periods: comparing the mutual inhibition and substrate depletion hypotheses

In a recent experimental study, Ouyang et al. (1998, Proc. Natl. Acad. Sci. U.S.A.95, 8660-8664) have shown that, in direct competition, cyanobacterial strains whose circadian clocks have free-running periods (FRPs) which match the period of an imposed light/dark (LD) cycle exclude strains whose FRPs are out of resonance with the LD cycle. These differences in competitive fitness are observed despite the lack of measurable differences in monoculture growth rates between the strains. Here we show that the experimental results are consistent with a mathematical model in which cells rhythmically produce a metabolic inhibitor to which they display a sensitivity modulated by their circadian rhythm. We argue that models in which there is a circadian modulation of nutrient uptake kinetics cannot account for the results of these experiments. We discuss possible experiments to further characterize this phenomenon. The experimental protocol we propose can be used to distinguish between mutual inhibition and substrate depletion as underlying causes of the competitive advantage of circadian resonance.     

Egg-laying rhythm in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

Extensive research has been carried out to understand how circadian clocks regulate various physiological processes in organisms. The discovery of clock genes and the molecular clockwork has helped researchers to understand the possible role of these genes in regulating various metabolic processes. In Drosophila melanogaster, many studies have shown that the basic architecture of circadian clocks is multi-oscillatory. In nature, different neuronal subgroups in the brain of D. melanogaster have been demonstrated to control different circadian behavioural rhythms or different aspects of the same circadian rhythm. Among the circadian phenomena that have been studied so far in Drosophila, the egg-laying rhythm is unique, and relatively less explored. Unlike most other circadian rhythms, the egg-laying rhythm is rhythmic under constant light conditions, and the endogenous or free-running period of the rhythm is greater than those of most other rhythms. Although the clock genes and neurons required for the persistence of adult emergence and activity/rest rhythms have been studied extensively, those underlying the circadian egg-laying rhythm still remain largely unknown. In this review, we discuss our current understanding of the circadian egg-laying rhythm in D. melanogaster, and the possible molecular and physiological mechanisms that control the rhythmic output of the egg-laying process.     

Amplitude of circadian oscillations entrained by 24-h light-dark cycles

An intriguing property of circadian clocks is that their free-running period is not exactly 24h. Using models for circadian rhythms in Neurospora and Drosophila, we determine how the entrainment of these rhythms is affected by the free-running period and by the amplitude of the external light-dark cycle. We first consider the model for Neurospora, in which light acts by inducing the expression of a clock gene. We show that the amplitude of the oscillations of the clock protein entrained by light-dark cycles is maximized when the free-running period is smaller than 24h. Moreover, if the amplitude of the light-dark cycle is very strong, complex oscillations occur when the free-running period is close to 24h. In the model for circadian rhythms in Drosophila, light acts by enhancing the degradation of a clock protein. We show that while the amplitude of circadian oscillations entrained by light-dark cycles is also maximized if the free-running period is smaller than 24h, the range of entrainment is centered around 24h in this model. We discuss the physiological relevance of these results in regard to the setting of the free-running period of the circadian clock.     

Network medicine

To more effectively target complex diseases like cancer, diabetes and schizophrenia, we may need to rethink our strategies for drug development and the selection of molecular targets for pharmacological treatments. Here, we discuss the potential use of protein signaling networks as the targets for new therapeutic intervention. We argue that by targeting the architecture of aberrant signaling networks associated with cancer and other diseases new therapeutic strategies can be implemented. Transforming medicine into a network driven endeavour will require quantitative measurements of cell signaling processes; we will describe how this may be performed and combined with new algorithms to predict the trajectories taken by a cellular system either in time or through disease states. We term this approach, network medicine.