Circadian Rhythm Entrainment in Flies and...

INTRODUCTION

The environment is highly periodic withrespect to many of its geophysical variables,such as light–dark or temperature cycles, andso there may be implications for Darwinian fit-ness for the organism to anticipate andrespond to these monotonously regular envi-ronmental changes. It is not surprising, there-fore, that organisms can and do measureastronomical time, including daily (24 h circa-

dian), tidal (12.4 h), lunar (monthly, 28 d), andyearly (circannual) periods using biologicaltimers. These timers not only measure time,but they also generate adaptive rhythms inbehavior and physiology that have evolved inresponse to these environmental perturbations.These biological oscillators also have consider-ably longer periods than those that give rise toultrafast chemical reactions, to biochemicalrhythmicities of intermediary metabolism, andto those rhythms commonly observed in theepigenetic and genetic time domains (1).

Circadian rhythms are, thus, a fundamentaladaptation of living cells to the daily and sea-sonal fluctuation in light and temperature.

Circadian Rhythm Entrainment in Flies and Mammals

Rachel Ben-Shlomo*,1 and Charalambos P. Kyriacou2

1Department of Biology, University of Haifa–Oranim, Tivon 36006, Israel; and 2Department ofGenetics, University of Leicester, Leicester LE1 7RH, UK

ABSTRACT

Circadian rhythms are a fundamental adaptation of living cells to the daily and seasonal fluc-tuation in light and temperature. Circadian oscillations persist in constant conditions; however,they are also phase-adjusted (entrained) by day-night cycles. It is this entrainability that providesfor the proper phasing of the program, to the sequence of external changes that it has evolved toexploit. Synchronization of circadian oscillators with the outside world is achieved because light,temperature, or other external temporal cues, have acute effects on the levels of one or more of theclock’s components. The consequences are ripples through the interconnected molecular loops,leading to a stable phase realignment of the endogenous rhythm generator and the external con-ditions. This review summarized the evolving knowledge of the different types, modes, and mol-ecular processes of entrainment in flies and mammals.

Index Entries: Chronobiology; circadian rhythm; entrainment; clock genes.

* Author to whom all correspondence and reprintrequests should be addressed. E-mail: [email protected]

REVIEW ARTICLE

© Copyright 2002 by Humana Press Inc.All rights of any nature whatsoever reserved.1085-9195/02/37/141–156/$20.00

Cell Biochemistry and Biophysics 141 Volume 37, 2002

Circadian oscillations persist in constant condi-tions; however, they are also phase adjusted(entrained) by day–night cycles (2). Theendogenous circadian period for any speciesunder constant conditions is usually close to,but seldom exactly, 24 h. A simplified circadianpacemaking system contains three basic com-ponents: a central clock or pacemaker, an inputpathway, and an output pathway. The molecu-lar mechanism underlying the central clock ineukaryotes involves periodic gene expression,with RNA and protein products from these“cycling” genes defining the clock by operatingwithin molecular feedback loops to generatetheir own rhythms (3). The emerging picture isthat at least two interconnected transcriptionaland translational feedback loops, one mainlyfunctioning in a positive manner and the otherin a negative capacity, provide synchronizedpulls and pushes that generate an oscillatorwith a stable period of around 24 h (3,4).

Progress in understanding the molecularunderpinnings governing circadian rhythmshas been remarkable in the last few years(reviewed in refs. 3 and 5–10). At least eight cir-cadian-relevant clock genes: period (per), time-less (tim), cryptochrome (cry), Clock, bmall (cycle),doubletime (dbt), vrille (vri), and shaggy (sgg)have been characterized in Drosophilamelanogaster. Homologs of most of the genesinvolved in the fly clockwork have also beencloned in mammals (see reviews), but in somecases, multiple copies exist in mammals,whereas in flies there are two copies of timeless(see ref. 11). The clock or clock-candidate genesin the mouse that appear to be functionalinclude the mPer’s (mPer1, mPer2, mPer3),mClock, mBMAL1, mCry1, and mCry2. In addi-tion, the tau locus of the hamster encodes acasein kinase I epsilon (CKIε) that is homolo-gous to Drosophila DBT and, furthermore, playsa similar role in regulating PER stability in bothspecies, as well as in mice and humans (12–15).There are strong similarities between the coreclock mechanisms of Drosophila and mice, withboth composed of interlocking transcriptionaland translational feedback loops (Fig. 1).However, there are substantial differences in

the molecular details of how the loops operatebetween the two species (5).

In the mouse, only the Clock gene so far hasbeen identified in a search using forwardgenetic strategies to isolate mutations thataffect behavioral rhythms (16). The remainingclock genes were identified based on interac-tion screens with known clock components orby homology with either Drosophila counter-parts, or in the case of cryptochrome, with pho-tolyases/blue-light photoreceptors found inplants (17–27). Even the hamster tau locus (28)was eventually molecularly characterizedbased on the observation that the mutationmapped to a conserved region in the humangenome that contained the gene coding forCKIε (3,14).

ENTRAINMENT

The circadian program is subject to entrain-ment by one or more external environmentalstimuli, with light being the most important. Itis this entrainability that provides for theproper phasing of the program to the sequenceof external changes that it has evolved toexploit (2). A powerful strategy for probing thisresetting feature is based on the ability of shortpulses of the environment stimuli or otheragents to elicit phase shifts in circadian pace-maker. These perturbation experiments revealthat the direction (i.e., delay or advance) andmagnitude of a phase shift are functions of thetime in the daily cycle that the zeitgeber (timegiver) is administered (29). Plotting the aver-age phase shift as a function of time that thestimulus is applied yields a phase-responsecurve (PRC) that describes the resetting behav-ior of the clock for that particular agent (2).

Synchronization of circadian oscillators withthe outside world is achieved because light,temperature, or other external temporal cueshave acute effects on the levels of one or moreof the clock’s components. The consequencesare “ripples” through the interconnected mole-cular loops, leading to a stable phase realign-ment of the endogenous rhythm generator and

142 Ben-Shlomo and Kyriacou

Cell Biochemistry and Biophysics Volume 37, 2002

Fig. 1. Model of the core clock mechanisms of Drosophila (A) and mammals (B), with both com-posed of interlocking transcriptional and translational feedback loops.

the external conditions (3). Although light andtemperature work synergistically in nature,light is generally considered a more potententraining agent than temperature.

LIGHT RESPONSES

Light is an influential regulator of physiol-ogy and behavior. In both flies and mammals,under constant darkness, brief light exposure(typically 5–60 min) during the early subjectivenight causes phase delays, whereas exposureduring the late subjective night causes phaseadvances. Typically, light exposure during thesubjective day does not alter circadian phase(2,30). The restriction of the photic response ofthe circadian clock to the subjective nightappears to be an intrinsic property of the clock.The photic phase-response curve is qualita-tively similar among all mammalian speciesstudied, whether nocturnal or diurnal (30).

There are several steps in the entrainment ofthe circadian system (1,31). A photopigment ina receptor or receptor cell must first absorb thephotons and the light signal. This informationmust then be transduced, coded, and propa-gated to the pacemaker. Afterward, decodingprocesses take place, resulting ultimately in aphase shift of some overt rhythmic output ofthe clock. Relatively little definitive informa-tion regarding the mechanisms of circadianphotosensitivity is available (32). Over the lastfew years, there has been growing support forthe hypothesis that the photoreceptors mediat-ing circadian responses differ from the classicalphotoreceptors of the visual system.

In Drosophila, the ventral lateral brain neu-rons (LNvs) represent the pacemakers that con-trol circadian locomotor activity rhythms(33,34). However, autonomous clocks are alsopresent in a wide variety of peripheral tissues,and circadian oscillations can be observed inisolated organs (35,36). The circadian rhythmsof Drosophila that lack eyes still entrain to a lowlevel of light, so the fly’s canonical visual trans-duction pathway does not mediate resetting(37,38). In contrast, the cry gene, a blue-light

photoreceptor similar to bacterial photolyases,may represent the circadian light receptor inDrosophila (36,39–41). Progress in identifyingand characterizing the circadian photorecep-tion system has been made both by trackingbackward from clock components to lightreception and by identifying novel photorecep-tors (38).

In mammals, the primary circadian clock islocated within the suprachiasmatic nuclei(SCN). Clocks in the SCN do not appear to besensitive to light. In rodents, experimental evi-dence suggests that ocular photoreceptorsmediate photoentrainment (42). The eyes arelargely responsible for providing visible lightinformation to the circadian pacemakers in theSCN. The photoentrainment system is com-posed of the retina, the retinohypothalamictract, the SCN, and an indirect retinal projec-tion to the SCN by way of the intergeniculateleaflet of the lateral geniculate nucleus (7).

Two types of photoreceptive cell have beenidentified in the mammalian retina: rods,which are responsible for vision in dim lightsituations and contain the photopigmentrhodopsin, and cone photoreceptors, which areresponsible for vision in bright light conditionsand contain the photopigment opsin (7).However, circadian photoreception worksequally well without rods and cones. There isevidence for involvement of an opsin-basedpigment in the response (43). Action spectra forphase shifting the biological clock of mice andhamsters implicates photopigments basedupon opsin/retinaldehyde (42).

A secondary circadian clock has also beenreported in the mammalian retina (44–46), asreflected in cultured retinas that continuallyexpressed circadian rhythm of melatonin syn-thesis, release, and phase shifting. Althoughretinal degenerate mutant rodents entrain tolight cycles, enucleation of these animalsblocks photoentrainment (42). The subter-ranean mole rat, Spalax ehrenbergi, is totallyblind and has only minute rudiment eyesburied beneath the skin (47–49). Nevertheless,Spalax exhibits natural variability in its circa-dian locomotor activity (50) and does perceive



photoperiodic changes as reflected in mela-tonin secretion (51) and changes in thermoreg-ulation (52). It seems that in mammals there arefunctionally two distinct systems for process-ing light information within the SCN: animage-forming system, which constructs avisual representation of the environment, and anon-image-forming light-detection system,which provides information about environ-mental irradiance (42). Part of the problem inidentifying the photoreceptors that communi-cate with the SCN is that the photoentrainmentpathway is obscured by the large number ofphotoreceptors and retinal neurons devoted toimage formation (43).

Recent evidence suggests that the entrainingphotoreceptors are retinal ganglion cells (RGCs)that project to the SCN. Unlike other ganglioncells, they depolarize in response to light evenwhen all synaptic input from rods and cones areblocked. The sensitivity, spectral tuning, andslow kinetics of this light response matchedthose of the photic entrainment mechanism,suggesting that these ganglion cells may be theprimary photoreceptors (53). The visual pig-ment for this photoreceptor may be melanopsin,an opsinlike protein whose mRNA is found in asubset of mammalian RGCs (54–56). Most RGCsthat project to the SCN express melanopsin(57,58). It is present in cell bodies, dendrites, andproximal axonal segments of a subset of ratRGCs. Moreover, rat RGCs that exhibitedintrinsic photosensitivity invariably expressedmelanopsin (56). Hence, melanopsin is mostlikely the visual pigment of phototransducingRGCs that set the circadian clock and initiateother non-image-forming visual functions.

MOLECULAR BASIS OF LIGHTENTRAINMENT IN DROSOPHILA

In Drosophila, many of the cardinal clockgenes show circadian rhythms in their expres-sion. The product of one of these, TIM, is lightsensitive, and its degradation by light pulses ateither the accumulation phase in the earlynight or the decay phase in the late night per-

mits light entrainment (reviewed in ref. 59).This light-dependent degradation initiates achain of event that ultimately result in (re)syn-chronization of the clock, which is essential forfly entrainment (3,5). Degradation of TIM dur-ing its accumulation phase delays progressionof the cycle, whereas the opposite is true dur-ing its declining phase. Therefore, TIM is oneof the pacemaker elements targeted by the lightinput pathway. The sensitivity of TIM regula-tion by light has been tested in an in vitro assaywith inhibitors of the candidate proteolyticpathway (60). The data suggested that TIM isdegraded through an ubiquitin–proteasomemechanism. TIM response to light involvestyrosine phosphorylation and ubiquitination,followed by proteosomal degradation.

The blue-light photoreceptor cryptochrome(CRY) provides an important (and perhapsessential) interface between light and TIMresponses (36,39,61,62). Flies overexpressingCRY are behaviorally hypersensitive to lightpulses. It appears that in most, if not all, pace-maker cells, CRY is required for the light-induced degradation of TIM, thereby mediatingcircadian photoresponses. Light stimulatesCRY:TIM interactions, which, in turn, may trig-ger TIM degradation (40). A mutant allele ofthe cry gene (cryb) leaves the circadian oscilla-tor function intact in the central circadianpacemaker neurons but renders peripheral cir-cadian oscillators largely arrhythmic (39,63,64).However, the clock in cryb mutants is stillentrained by a light–dark cycle unless the cryb

simultaneously carry a mutation in the canoni-cal visual pathway (39,64).

Another circadian photoreceptive pathwayin flies involves an eye-specific phospholipaseC (PLC) encoded by the no receptor potential(norpA) gene (65). PLC seems to operate througha pathway independent of CRY, because fliesmutant in both genes have a poorer ability tosynchronize to light–dark-cycle shifts com-pared with single mutants, as mentioned ear-lier (39). In cryb flies, light applied during thedark period fails to induce degradation of TIMin the lateral neurons (LNs) of larval brains,and attenuated cycling of TIM is also observed

Circadian Rhythm Entrainment 145


in the light–dark cycle. This cycling is abol-ished in norpAp41:cryb double mutants (64).Thus, the general conclusion appears to be thatCRY acts as a photoreceptor in the LNs andplays a role in the TIM light-responsive kinet-ics, but in peripheral tissues, CRY appears to bea cardinal component of the central clockworks.

Finally, a hypophosphorylated mutant PERprotein, produced by creating a small internaldeletion downstream of the PAS protein–pro-tein interaction domain, displays increasedstability and low-amplitude oscillations (66).In addition to aberrant circadian periodicity,transgenic flies show altered responses to light,particularly to pulses of light in the late nightthat normally advance the phase of the rhythm.The molecular deficits underlying these behav-ioral phenotypes include an increase in proteinstability and a defect in negative feedback (66).The region of PER mutated includes the partthat physically interacts with CRY (41) andmay interact with DBT (66), so perhaps thechanges in light responses are also partly medi-ated by defective PER-CRY, or even PER-CRY-TIM-DBT interactions.

MOLECULAR BASIS OF LIGHTENTRAINMENT IN MAMMALS

The molecular basis of photic entrainment inmammals is very different from the scenario inDrosophila, where photic cues evoke a rapiddecrease in the levels of TIM. The circadianoscillator in the mouse SCN is also comprised ofinteracting positive and negative transcrip-tional–translational feedback loops (4). The neg-ative feedback loop involves the dynamicregulation of three Period genes (mPer1–3) andtwo Cryptochrome genes (mCry1 and mCry2)(3,5,18,67,68). The rhythmic transcription ofmPer and mCry genes is driven by the transcrip-tion factors CLOCK and BMAL1 (also known asMOP3 and homologous to fly CYC) (18,69,70).

Unlike the scenario for Drosophila, mBmal1undergoes daily oscillations in its RNA level inantiphase to those of the mPer’s and mCry1,whereas mClk is constitutively expressed

(71,72). An additional radical departure ofmammals from Drosophila is that the mouseCRY1 and CRY2 proteins are not required forlight perception by the circadian pacemaker.The mCry genes act as components of the clockmechanism itself and have an essential role inthe oscillator by inhibiting the activity ofCLOCK: BMAL1-mediated transcription of themPer’s (4,68,73–76).

In the mouse, mPER1 levels are altered byexposure to light at night. mPer1 and mPer2 arerequired for normal photic resetting of themammalian clock, with the two genes regulat-ing opposite behavioral responses to nocturnallight (77,78). There are no alterations in theabundance of mTIM or mCRY proteins follow-ing brief light exposure (5,78). In fact, it turnsout that mTIM is not the true ortholog ofDrosophila TIM (reviewed in ref. 5), and becausethe human genome sequence does not have anortholog for clock-relevant TIM (11), mTim andits ortholog in insects, called tim2 (79) or timeout(80), are probably the descendants of the ances-tral tim gene from which the clock relevant tim(tim1) is duplicated in the insect lineage.

In humans, the gene for familial advancesleep-phase syndrome (FASPS, or “very earlyto bed and very early to rise”) is located tochromosome 2q near the telomere, to the samelocus as the hPer2 gene (15). Affected individu-als have a serine to glycine mutation within theCKIε-binding region of hPER2, which causeshypophosphorylation by CKIε in vitro. Thus, avariant in human sleep behavior can be attrib-uted to a missense mutation in a canonicalclock component. Phosphorylation of PER byCKIε promotes its degradation during the cir-cadian cycle. Deficient phosphorylation ofhPER2 in the cytoplasm could impair itsdegradation and/or accelerate its nuclear entryand thus hasten its accumulation (15).

TEMPERATURE RESPONSE

With the likely exception of light, tempera-ture is the most predominant entraining cue innature (81). Although early studies revealed



that even in poikilotherms, the free-runningperiods of circadian rhythms are essentiallystable over a wide range of constant tempera-tures, these rhythms can be phase shifted bytemperature pulses or steps and therebyentrained by daily temperature cycles. Thisthermosensitivity has been demonstrated inboth poikilotherms and homeotherms(29,82,83). However, the essential temperaturebuffering of the free-running period (after all, aclock is a clock, not a thermometer), whichdoes not imply true temperature indepen-dence, is known as “temperature compensa-tion” and has become a defining characteristicof a true clock (84).

TEMPERATURE COMPENSATION IN DROSOPHILA CLOCK GENES

The per gene has a repetitive region, whichencodes alternating pairs of threonine–glycineresidues (Thr-Gly). The Thr-Gly repeat is poly-morphic in length in natural populations (85),and alleles that encode 14, 17, 20, and 23 dipep-tide pairs make up about 99% of European vari-ants. Two major variants (Thr-Gly)17 and(Thr-Gly)20 are distributed as highly significantlatitudinal cline in Europe and North Africa(86). The Thr-Gly length variation from bothwild caught flies and transgenic individuals isrelated to the fly’s ability to maintain a circadianperiod at different temperatures (87). Natural(Thr-Gly)20 variants show an overall better tem-perature compensation than (Thr-Gly)17 vari-ants. This may explain the higher frequency ofthe (Thr-Gly)20 allele in northern population, inwhich the environment is more thermally vari-able. Furthermore, at high temperatures, the(Thr-Gly)17 variants have periods that are closerto 24 h than their (Thr-Gly)20 cousins, therebyresonating more accurately with the geophysi-cal day, and this may explain their higher fre-quencies in hotter latitudes (87). This scenarioprovides an interesting example of naturalselection at the per locus, which has been inde-pendently confirmed using statistical analysesof Thr-Gly nucleotide polymorphisms (88,89).

Mutations in various regions of the PER pro-tein will generate temperature-sensitive effectson the clock, suggesting a breakdown in tem-perature compensation (reviewed in ref. 90).Thus, at present, we do not have much insightinto the temperature compensation mecha-nism(s) and, certainly, no general model thatwithstands any scrutiny.

TEMPERATURE ENTRAINMENT IN DROSOPHILA

Measurements of the effects of short-dura-tion heat pulses on the protein and mRNAproducts from the Drosophila circadian clockgenes per and tim (29) showed that heat pulsesat all times in a daily cycle elicited a dramaticand rapid decrease in the levels of PER andTIM proteins. PER is sensitive to heat but notdirectly to light (except as a byproduct of TIMdegradation, after which PER becomes unsta-ble in the absence of TIM), indicating that indi-vidual clock components can markedly differin sensitivity to environmental stimuli. When aheat signal is administrated in the early night,it evokes a phase delay in behavioral rhythm,similar to the effect of a light signal. However,in the late night, heat-induced degradation ofPER and TIM results in little, if any, long-termperturbation in the cycle of these clock pro-teins, which is surprising, as advances mightbe expected on reducing TIM levels, as inphase shifting by light.

A thermosensitive splicing event in the 3′-untranslated region (3′-UTR) of per contributesto an earlier rise in the level of its RNA (91).This phase advance enables flies to maintaindaytime activity during seasonally cold dayswhen the day length is shortened. In this situa-tion, the effects of temperature on the rate ofPER accumulation and those of light on themetabolism of TIM are integrated, becausePER and TIM engage in functional interactionthat appears necessary for progression of thecycle (3). CRY may also contribute to thermore-ception in peripheral oscillators in Drosophila.Krishnan et al. (63) showed that CRY con-



tributes to oscillator function in an antennallymediated rhythm, even when photic input iseliminated by entraining flies to temperaturecycles. These results demonstrated a photore-ceptor-independent role for CRY and a func-tion in the temperature responsiveness ofperipheral rhythms.

TEMPERATURE COMPENSATION AND ENTRAINMENT IN MAMMALS

Despite the potent effects of temperature oncircadian rhythms in ectotherms, little work hasbeen done in endotherms. It is assumed that therelatively narrow range of temperatures experi-enced by circadian pacemakers in homeothermshas little consequence for circadian organiza-tion. This assumption fails to consider, how-ever, that the evolution of endothermy mayhave relaxed selection pressure for temperaturecompensation of pacemaker frequency and forpacemaker sensitivity to phase shifts by ther-mal stimuli (92). It is not known whether orhow thermal information can be communicatedthrough the SCN neural network, particularlybecause biological clocks such as the SCN areassumed to be temperature compensated. It isunclear whether the mammalian SCN exhibitstemperature compensation or whether it is“temperature protected” by homeostatic ther-moregulation responses controlled by the pre-optic and anterior hypothalamic area (93).

The effects of temperature on circadianrhythms have been very difficult to test inhomeothermic mammals in vivo because pace-maker temperature is homeostatically con-trolled within narrow limits. Nonetheless,partial entrainment of activity rhythms toambient temperature has been reported forsquirrel monkeys (94), rats (95), antelopeground squirrels, and Syrian hamsters (96).The effect of pulses of warm ambient tempera-ture on the phase of activity onset in rats free-running in constant light reveals phaseadvances occurring mainly in the subjectiveday and delays mainly, but not entirely, in thesubjective night. However, there were no con-

sistent relationships between changes in activ-ity levels because of the temperature pulsesand phase shifts (97).

Ruby et al. (92) also assessed temperaturecompensation and the effects of heat pulses onrhythm phase in the SCN of rats. In their work,phase delays and advances were observed dur-ing early and late subjective night, respectively,and no phase shifts were obtained during themid subjective day, in a manner similar to lightpulses. The phase-response curve for heatpulses is found to be similar to ones obtainwith light pulses for behavioral rhythms. Thus,the circadian pacemaker period in the rat SCNis temperature compensated over a physiolog-ical range of temperatures. The effects of heatpulses on pacemaker phase do not requireaction-potential-dependent neurotransmitterrelease nor are they the result of increased cel-lular metabolism associated with changes inaction-potential frequency during heat pulse.Heat pulses may have phase shifted rhythmsby directly altering transcriptional or transla-tional events in SCN pacemaker cells (92).

Whole-cell patch clamp recordings of neu-rons in the SCN from rat brain slices have beenanalyzed for changes in spontaneous synapticactivity during changes in temperature (98)and have revealed that in many SCN neurons,temperature affects the frequency of inhibitorypostsynaptic potential and current. An increasein frequency with warming and a decrease infrequency during cooling made several SCNneurons temperature insensitive, allowingthese neurons to maintain a relatively constantfiring rate during changes in temperature. Thistemperature-adjusted change in synaptic fre-quency can provide a mechanism of tempera-ture compensation (98).

OLFACTORY RESPONSES

Olfaction is essential for food acquisition,social interactions, and predator avoidance.Thus, circadian regulation of olfactory systemcould have profound effects on the behavior oforganisms that rely on this sensory modality. In



Drosophila, circadian oscillations in per expres-sion occur in chemosensory cells of the anten-nae, even when the antennae are excised andmaintained in isolated organ culture (35).Olfactory stimuli cause a robust circadianrhythm in electrophysiological responses. Theserhythms are observed in wild-type flies duringlight–dark cycles and in constant darkness, butare abolished in per or tim-null mutant flies(per01 and tim01), which lack rhythms in adultemergence and locomotor activity (99).

There is evidence to suggest that olfactoryand circadian systems are linked functionallyand that olfactory stimuli can modulate circa-dian rhythms in mammals. Furthermore, olfac-tory bulb removal in the diurnal rodent Octodondegus inhibits socially facilitated but not photicre-entrainment in females and significantlydelays photic reentrainment rates in males(100,101). Olfactory stimulation of free-runningrhythms and photic resetting in rats reveals thatbrief exposure to cedar wood essence has noaffect on either free-running rhythms or Fosexpression in the SCN. However, when pre-sented in combination with light, the odor dra-matically enhanced light-induced phase shiftsand Fos expression (102). These findings, show-ing that clock resetting by light can be facili-tated by olfactory stimulation, point to amechanism by which olfactory cues can modu-late entrainment of circadian rhythms.

The spiny mice of the genus Acomys are com-mon murids inhabiting the arid part of Israel.Two species, the common spiny mouse, A.cahirinus, and the golden spiny mouse, A. rus-satus, coexist in the extreme arid and hot partof the Arava Rift Valley (103). The coexistenceof these two species is through competitiveexclusion of A. russatus from nocturnal activityby A. cahirinus, which is nocturnal. Removal ofA. cahirinus from the common habitat, or keep-ing A. russatus alone under laboratory condi-tions, resulted in a change in its pattern ofactivity, which becomes nocturnal (103–105).Haim and Fluxman (106) have shown thatintroducing heterospecific chemical signalsreleased by A. cahirinus urine have an impacton the onset of activity of A. russatus, as well as

on the daily body temperature and oxygenconsumption rhythms. The response to chemi-cal signals is immediate and causes phaseshifts in the consecutive night (Haim, personalcommunication).

The ways in which chemical stimuli affectthe circadian system are not yet clear. Themammalian olfactory system recognizes a vastrange of molecules that represent vital infor-mation about an animal’s environment, includ-ing the locality of prey and predators, thesexual, hormonal, and reproductive state ofmating partners, and the level of aggression inrivals. New evidence suggests that there areseveral subpopulations of sensory neurons inthe nose that project to different areas in theforebrain. Strikingly, evidence is now emergingthat several of these neuronal subpopulationsemploy distinct second-messenger cascades totransduce chemical stimuli (107). Of particularinterest is how each of these groups of neuronsencodes chemosensory information and whatthe consequences of the anatomical segrega-tion of these subsystems for odor-dependentbehavior might be.

SOCIAL RESPONSES

Repeated social interactions at the same timeof the day can entrain activity rhythms inmammals. Phase shifts in free-running activityin male golden hamsters often occur when theyestablish a new territory or home after a cagechange. Similar shifts also often occur afterpairs of animals interact with each other forhalf an hour (108). When these events takeplace during the middle of the subjective day,they produce phase advances; when late in thesubjective night, they produce phase delays.The effect of social interactions and of otherdisturbances may be mediated through anoscillator whose phase depends on generalarousal (108).

The effect of social cues and daily distur-bances on the circadian locomotor activity ofOctodon degus were assessed by housing femalesin free-running conditions with an entrained



female partner (“donor”) in a cage on either sideof a mesh barrier (109). Most tested animalsshowed partial entrainment and an alteredphase of activity onset. Thus, social informationin the absence of light was found to be sufficientfor partial entrainment and for changes in thephase of the free-running rhythm.

In humans, social cues acting through thesleep–wake cycle may be important in entrain-ment. Bright light is an important human zeit-geber to which humans receive inadequate andsporadic exposure. Social cues, although lesspowerful, may be an important form ofentrainment for contemporary humans andalso serve to augment the effects of availablebright light (110). Recent findings suggest thatsocial entrainment works via an oscillator thatis not the one that controls temperature andmelatonin rhythms (111).

BEHAVIORAL RESETTING OF THE CIRCADIAN CLOCK

In mammals, nonphotic behavioral cues canentrain the principal oscillator of the SCN, trig-gering phase advances during the subjectiveday, when the clock is insensitive to light.Resetting by behavioral cues is a rapid event,and the SCN oscillator adopts a new phasewithin 1–2 h of presentation of the stimulus(112,113). Given this sensitivity of the SCNclock to nonphotic resetting, it has been predi-cated that if mPer genes do encode state vari-ables of the core oscillator (i.e., elements thatdefine, rather than simply reflect, circadianphase), they should be acutely sensitive to non-photic cues (114). Moreover, that such cuesadvance the clock during the subjective daywhen expression of these genes is high andprotein levels are rising leads to a further pre-diction: Advances are achieved by rapid sup-pression of the genes and/or their proteinproducts, thereby accelerating the spontaneouscycle to a new phase encoded by lower levelsof mRNA or protein (115).

In mice, expression of mPer1 and mPer2 inthe SCN is rhythmic and acutely upregulated

by light. Nonphotic resetting of the mam-malian clock acutely downregulates thesegenes (i.e., is associated with acute suppressionof mPer1 and mPer2 in the SCN). Moreover, itreveals a molecular target for the convergentbut opposing actions of environmental andbehavioral stimuli that regulate circadian timeand thus offers an integrative explanation forcircadian entrainment (115).

ENTRAINMENT BY FOOD

Restricted feeding schedules in mammalsentrain behavioral and physiological circadianrhythms, which depend on a food-entrainableoscillator. Anticipation of daily water or foodaccess in rodents is regulated by nonphoticallyentrainable circadian oscillators located out-side of the SCN. Ablation of the SCN does noteliminate anticipatory activity in experimentalanimals, but eliminates the free-running com-ponent of the rhythms (116–118). Ttransgenicrats whose tissues express luciferase in vitroindicated that although rhythmicity in the SCNremained phase locked to the light–dark cycle,restricted feeding rapidly entrained the liver,shifting its rhythm by 10 h within 2 d (119).Feeding time has been shown to be the domi-nant zeitgeber for rhythmic gene expression intissues such as the liver, pancreas, kidney, andheart (119–122). The peaks of mPer1, mPer2, D-site-binding protein (Dbp), and cholesterol 7 alpha-hydroxylase mRNA in the liver were advanced6–12 h after 6 d of restricted feeding, whereasthose in SCN were unaffected. The advance ofmPer expression in the liver by restricted feed-ing was still observed in SCN-lesioned mice(121). In the livers and kidneys of mice (noc-turnal) with intact glucocorticoid signaling,daytime feeding affects the expression of mPer1more dramatically than that of other circadiangenes. Thus, although the steady-state phasesof mPer1 and Dbp mRNA accumulation arenearly identical, they are transiently differentat the onset of daytime feeding (120,122). Itseems that the entrainment mechanism wouldhave to be specific to peripheral oscillators,



because feeding time does not impinge on thephase entrainment of central SCN pacemaker(119,120,122).

CONCLUDING REMARKS

Synchronization of circadian oscillators withthe outside world is achieved because light orother external temporal cues, have acute effectson the levels of one or more of the clock’s com-ponents (3). Light can be described mostly as anupregulator of the circadian system. EvenDrosophila TIM, which degrades on exposure tolight, by virtue of its negative feedback on itself,will upregulate tim transcription. In mammals,however, although some of the clock genes areaffected by light, as of now, a TIM-like equiva-lent has not been found. Preliminary microar-ray analysis in our laboratory, in which wemonitored gene expression differences from thebrains of mice that were exposed to 1-h lightpulses, reveals that about 5% of the genes onthe array altered their expression (Ben-Shlomoet al., unpublished data). More than 100 tran-scripts showed acute downregulation shortlyafter the light stimulus. This type of complexityalso emerges from the study of circadian pho-toperception, in the way that overt rhythmsthroughout an organism are synchronized toentraining light–dark cycles, temperature, orother nonphotic cues (9,115).

REFERENCES

1. Edmunds, L. N. (1988) Cellular and MolecularBases of Biological Clocks, Springer-Verlag, NewYork.

2. Pittenbrigh, C. S. (1981) Circadian systems:entrainment, in Handbook of BehavioralNeurobiology (Ashoff, J., ed.), Plenum, NewYork, pp. 95–124.

3. Edery, I. (2000) Circadian rhythms in a nut-shell. Physiol. Genom. 3, 59–74.

4. Shearman, L. P., Sriram, S., Weaver, D. R.,Maywood, E. S., Chaves, I., Zeng, B., et al.(2000) Interacting molecular loops in the mam-malian circadian clock. Science 288, 1013–1019.

5. Reppert, S. M. and Weaver, D. R. (2000)Comparing clockworks: mouse versus fly. J.Biol. Rhythms 15, 357–364.

6. King, D. P. and Takahashi, J. S. (2000)Molecular genetics of circadian rhythms inmammals. Annu. Rev. Neurosci. 23, 713–742.

7. Lowrey, P. L. and Takahashi, J.S (2000)Genetics of the mammalian circadian system:photic entrainment, circadian pacemakermechanisms, and posttranslational regulation.Annu. Rev. Genet. 34, 533–562.

8. Williams, J. A. and Sehgal, A. (2001) Molecularcomponents of the circadian system inDrosophila. Annu. Rev. Physiol. 63, 729–755.

9. Devlin, P. F. and Kay, S. A. (2001) Circadianphotoperception. Ann. Rev. Physiol. 63, 677–694.

10. Young, M. W. and S. A. Kay. (2001) Time zones:a comparative genetics of circadian clocks.Nat. Rev. Genet. 2, 702–715.

11. Clayton, J. D., Kyriacou, C. P., and Reppert, S.M. (2001) Keeping time with the humangenome. Nature 409, 829–831.

12. Kloss, B., Price, J. L., Saez, L., Blau, J.,Rothenfluh, A., Wesley, C. S., et al. (1998) TheDrosophila clock gene double-time encodes aprotein closely related to human casein kinaseIepsilon. Cell 94, 97–107.

13. Price, J. L., Blau, J., Rothenfluh, A., Abodeely,M., Kloss, B., and Young, M. W. (1998) Double-time is a novel Drosophila clock gene that regu-lates PERIOD protein accumulation. Cell 94,83–95.

14. Lowrey, P. L., Shimomura, K., Antoch, M. P.,Yamazaki, S., Zemenides, P. D., Ralph, M. R. etal. (2000) Positional syntetnic cloning andfunctional characterization of the mammaliancircadian mutation tau. Science 288, 483–492.

15. Toh, K. L., Jones, C. R., He, Y., Eide, E. J., Hinz,W. A., Virshup, D. M., et al. (2001) An hPer2phosphorylation site mutation in familialadvanced sleep phase syndrome. Science 291,1040–1043.

16. Vitaterna, M. H., King, D. P., Chang, A. M.,Kornhauser, J. M., Lowrey, P. L., McDonald, J.D., et al. (1994) Mutagenesis and mapping of amouse gene, Clock, essential for circadianbehavior. Science 264, 719–725.

17. Albrecht, U., Sun, Z. S., Eichele, G., and Lee, C.C. (1997) A differential response of two puta-tive mammalian circadian regulators, mper1and mper2, to light. Cell 91, 1055–1064.

18. Gekakis, N., Staknis, D., Nguyen, H. B., Davis,F. C., Wilsbacher, L. D., King, D. P., et al. (1998)



Role of the CLOCK protein in the mammaliancircadian mechanism. Science 280, 1564–1569.

19. Hsu, D. S., Zhao, X., Zhao, S., Kazantsev, A.,Wang, R. P., Todo, T., et al. (1996) Putativehuman blue-light photoreceptors hCRY1 andhCRY2 are flavoproteins. Biochemistry 35,13,871–13,877.

20. Koike, N., Hida, A., Nimano, R., Hirose, M.,Sakaki, Y., and Tei, H. (1998) Identification of themammalian homologues of the Drosophila time-less gene, Timeless1. FEBS Lett. 441, 427–431.

21. Sangoram, A. M., Saez, L., Antoch, M. P.,Gekakis, N., Staknis, D., Whiteley, A., et al.(1998) Mammalian circadian autoregulatoryloop: a timeless ortholog and mPer1 interactand negatively regulate CLOCK-BMAL1-induced transcription. Neuron 21, 1101–1113.

22. Sun, Z. S., Albrecht, U., Zhuchenko, O., Bailey,J., Eichele, G., and Lee, C. C. (1997) RIGUI, aputative mammalian ortholog of Drosophilaperiod gene. Cell 91, 1043–1053.

23. Takumi, T., Matsubara, C., Shigeyoshi, Y.,Taguchi, K., Yagita, K., Maebayashi, Y., et al.(1998) A new mammalian period gene pre-dominantly expressed in the suprachiasmaticnucleus. Genes Cells 3, 167–176.

24. Takumi, T., Taguchi, K., Miyake, S., Sakakida,Y., Takshima, N., Matsubara, C., et al. (1998) Alight-independent oscillatory gene mPer3 inmouse SCN and OVLT. EMBO J. 17, 4753–4759.

25. Takumi, T., Nagamine, Y., Miyake, S.,Matsubara, C., Taguchi, K., Takekida, S., et al.(1999) A mammalian ortholog of Drosophilatimeless, highly expressed in SCN and retina,forms a complex with mPER1. Genes Cells 4,67–75.

26. Zylka, M. J., Shearman, P. L., Weaver, D. R.,and Reppert, S. M. (1998) Three periodhomologs in mammals: differential lightresponses in the suprachiasmatic circadianclock and oscillating transcripts outside ofbrain. Neuron 20, 1103–1110.

27. Zylka, M. J., Shearman, P. L., Levine, J. D., Jin,X., Weaver, D. R., and Reppert, S. M. (1998)Molecular analysis of mammalian timeless.Neuron 21, 1115–1122.

28. Ralph, M. R. and Menaker, M. (1998) A muta-tion of the circadian system in golden ham-sters. Science 241, 1225–1227.

29. Sidote, D., Majercak, J., Parikh, V., and Edery, I.(1998) Differential effects of light and heat onthe Drosophila circadian clock proteins PERand TIM. Mol. Cell. Biol. 18, 2004–2013.

30. Rea, M. A. (1998) Photic entrainment of circa-dian rhythms in rodents. Chronobiol. Int. 15,395–423.

31. Eskin, A. (1979) Circadian system of theAplysia eye: properties of the pacemaker andmechanisms of its entrainment. Fed. Proc. 38,2573–2579.

32. Lucas, R. J. and Foster, R. G. (1999)Photoentrainment in mammals: a role of cryp-tochrome? J. Biol. Rhythms 14, 4–10.

33. Helfrich-Foster, C. (1998) Robust circadianrhythmicity of Drosophila melanogaster requiresthe presence of lateral neurons: a brain behav-ioral study of dusconnected mutants. J. Comp.Physiol. 182, 435–453.

34. Kaneko, M. (1998) Neural substrates ofDrosophila rhythms revealed by mutants andmolecular manipulations. Curr. Opin. Neurobiol.8, 652–658.

35. Plautz, J. D., Kaneko, M., Hall, J. C., and Kay,S. A. (1997) Independent photoreceptive circa-dian clock throughout Drosophila. Science 278,1632–1635.

36. Emery, P., So, W. V., Kaneko, M., Hall, J. C., andRosbash, M. (1998) CRY, a Drosophila clock andlight-regulated cryptochrome, is a major con-tributor to circadian rhythm resetting and pho-tosensitivity. Cell 95, 669–679.

37. Wheeler, D. A., Hamblen-Coyle, M. J., Dushay,M. S., and Hall, J. C. (1993) Behavior inlight–dark cycles of Drosophila mutants thatare arrythmic, blind, or both. J. Biol. Rhythms 8,67–94.

38. Van Gelder, R. N. (1998) Circadian rhythms:eyes of the clock. Curr. Biol. 8, R798–R801.

39. Stanewsky, R., Kaneko, M., Emery, P., Beretta,B., Wagner-Smith, K., Kay, S. A., et al. (1998)The cryb-mutation identifies cryptochrome as acircadian photoreceptor in Drosophila. Cell 95,681–692.

40. Ceriani, M. F., Darlington, T. K. Stakins, D.,Mas, P., Petti, A. A., Weitz, C. J., et al. (1999)Light-dependent sequestration of TIMELESSby CRYPTOCHROME. Science 285, 553–556.

41. Rosato, E., Codd, V., Mazzota, G., Piccin, A.,Zordan, M., Costa, R., et al. (2001) Light-dependent interaction between Drosophila CRYand the clock protein PER mediated by the car-boxy terminus of CRY. Curr. Biol. 11, 909–917.

42. Foster, R. G. (1998) Sheding light on the bio-logical clock. Neuron 20, 829–832.

43. Von Schantz, M., Provencio, I., and Foster, R.G. (2000) Recent developments in circadian



photoreception: more than meet the eye.Invest. Ophthalmol. Vis. Sci. 41, 1605–1607.

44. Tosini, G. and Menaker, M. (1996) Circadianrhythms in cultured mammalian retina. Science272, 419–421.

45. Tosini, G. and Menaker, M. (1998) The clock inthe mouse retina: melatonin synthesis and pho-toreceptor degeneration. Brain Res. 789, 221–228.

46. Herzog, E. D. and Block, G. D. (1999) Keeping aneye on retinal clocks. Chronol. Int. 16, 229–247.

47. Nevo, E. (1991) Evolutionary theory andprocesses of active speciation and adaptive radi-ation in subterranean mole rats, Spalax ehrenbergisuperspecies, in Israel. Evol. Biol. 25, 1–125.

48. Cooper, H. M., Herbin, M., and Nevo, E. (1993)Ocular regression conceals adaptive progres-sion of the visual system in a blind subter-ranean mammal. Nature 361, 156–159.

49. Cooper, H. M., Herbin, M., and Nevo, E. (1993)Visual system of a naturally microphthalmicmammal: the blind mole rat, Spalax ehrenbergi.J. Comp. Neurol. 328, 313–350.

50. Ben-Shlomo, R., Ritte, U., and Nevo, E. (1995).Activity pattern and rhythm in the subter-ranean mole rat superspecies Spalax ehrenbergi.Behav. Genet. 25, 239–245.

51. Ben-Shlomo, R., Nevo, E., Ritte, U., Steinlechner,S., and Klante, G. (1996). 6-Sulphatoxymelatoninsecretion in different locomotor activity types ofthe blind mole rat Spalax ehrenbergi. J. Pineal Res.21, 243–250.

52. Haim, A., Heth, G., Pratt, H., and Nevo, E.(1983) Photoperiodic effects on thermoregula-tion in a “blind” subterranean mammal. J. Exp.Biol. 107, 59–64.

53. Berson, D. M., Dunn, F. A., and Takao, M.(2002) Phototransduction by retinal ganglioncells that set the circadian clock. Science 295,1070–1073.

54. Provencio, I., Rodriguez, I. R., Jiang, G., Hayes,W. P., Moreira, E. F., and Rollag, M. D. (2000) Anovel human opsin in the inner retina. J.Neurosci. 20, 600–605.

55. Provencio, I., Rollag, M. D., and Castrucci, A.M. (2002) Photoreceptive net in the mam-malian retina. This mesh of cells may explainhow some blind mice can still tell day fromnight. Nature 415, 493.

56. Hattar, S., Liao, H. W., Takao, M., Berson, D.M., and Yau, K. W. (2002) Melanopsin-contain-ing retinal ganglion cells: architecture, projec-tions, and intrinsic photosensitivity. Science295, 1065–1070.

57. Gooley, J. J., Lu, J., Chou, T. C., Scammell, T. E.,and Saper, C. B. (2001) Melanopsin in cells oforigin of the retinohypothalamic tract. Nat.Neurosci. 4, 1165.

58. Hannibal, J., Hindersson, P., Knudsen, S. M.,Georg, B., and Fahrenkrug, J. (2002) The pho-topigment melanopsin is exclusively present inpituitary adenylate cyclase-activating polypep-tide-containing retinal ganglion cells of theretinohypothalamic tract. J. Neurosci. 22, RC191.

59. Young, M. W. (1998) The molecular control ofcircadian behavioral rhythms and theirentrainment in Drosophila. Annu. Rev. Biochem.67, 135–152.

60. Naidoo, N., Song, W., Hunter-Ensor, M., andSehgal, A. (1999) A role for the proteasome inthe light response of the timeless clock protein.Science 285, 1737–1741.

61. Emery, P., Stanewsky, R., Helfrich-Foster, C.,Emery-Le, M., Hall, J. C., and Rosbach, M.(2000) Drosophila CRY is a deep brain circadianphotoreceptor. Neuron 26, 493–504.

62. Emery, P., Stanewsky, R., Hall, J. C., andRosbach, M. (2000) A unique circadian-rhythmphotoreceptor. Nature 404, 456–457.

63. Krishnan, B., Levine, J., Kathlea, M., Lynch, S.,Dowse, H. B., Funes, P., et al. (2001) A new rolefor cryptochrome in a Drosophila circadianoscillator. Nature 411, 313–316.

64. Ivanchenko, M., Stanewsky, R., andGiebultowicz, J. M. (2001) Circadian photore-ception in Drosophila: function of cryp-tochrome in peripheral and central clock. J.Biol. Rhythms 16, 205–215.

65. Kim, S., McKay, R. R., Miller, K., andShortridge, R. D. (1995) Multiple subtype ofphospholipase C are encoded by the nonpAgene of Drosophila melanogaster. J. Biol. Chem.270, 14,376–14,382.

66. Schotland, P., Hunter-Ensor, M., Lawrence, T.,and Seghal, A. (2000) Altered entrainment andfeedback loop function affected by a mutantperiod protein. J. Neurosci. 20, 958–968.

67. Jin, X., Shearman, L. P., Weaver, D. R., Zylka,M. J., de Vries, G. J., and Reppert, S. M. (1999)A molecular mechanism regulating circadianrhythmic output from the suprachiasmatic cir-cadian clock. Cell 96, 57–68.

68. Kume, K., Zylka, M. J., Sriram, S., Shearman, L.P., Weaver, D. R., Jin, X., et al. (1999) mCRY1and mCRY2 are essential components of thenegative limb of the circadian clock feedbackloop. Cell 98, 193–205.



69. Hogenecsh, J. B., Gu, Y. Z., Jain, S., and Bradfield,C. A. (1998) The basic-helix-loop-helix-PASorphan MOP3 forms transcriptionally activecomplexes with circadian and hypoxia factors.Proc. Natl. Acad. Sci. USA 95, 5474–5479.

70. Takahata, S., Sogawa, K., Kobayashi, A., Ema,M., Mimura, J., Ozaki, N., et al. (1998)Transcriptionally active heterodimer forma-tion of an Arnt-like PAS protein, Arnt3, withHIF-1a, HLF and clock. Bichem. Biophys. Res.Commun. 248, 789–794.

71. Honma, S., Ikeda, M., Abe, H., Tanahashi, Y.,Namihira, M., Honma, K., et al. (1998)Circadian oscillation of BMAL1, a partner of amammalian clock gene Clock, in rat suprachi-asmatic nucleus. Biochem. Biophys. Res.Commun. 250, 83–87.

72. Oishi, K., Fukui, H., and Ishida, N. (2000)Rhythmic expression of BMAL1 mRNA isaltered in Clock mutant mice: differential reg-ulation in the suprachiasmatic nucleus andperipheral tissues. Biochem. Biophys. Res.Commun. 268, 164–171.

73. Griffin, E. R., Jr, Stakins, D., and Weitz, C. J.(1999) Light-independent role of CRY1 andCRY2 in the mammalian circadian clock.Science 286, 768–771.

74. Okamura, H., Miyake, S., Sumi, Y., Yamaguchi,S., Yasui, A., Muijtjens, M., et al. (1999) Photicinduction of mPer1 and mPer2 in cry-deficientmice lacking a biological clock. Science 286,2531–2534.

75. van der Horst, G. T., Muijtjens, M., Kobayashi,K., Takano, R., Kanno, S., Takao, M., et al.(1999) Mammalian Cry1 and Cry2 are essentialfor maintenance of circadian rhythm. Nature398, 627–630.

76. Vitaterna, M. H., Selby, C. P., Todo, T., Niwa, T.,Thompson, C., Fruechte, E. M., et al. (1999)Differential regulation of mammalian periodgenes and circadian rhythmicity by cryp-tochromes 1 and 2. Proc. Natl. Acad. Sci. USA96, 12,114–12,119.

77. Albrecht, U., Zheng, B., Larkin, D., Sun, Z. S.,and Lee, C. C. (2001) mPer1 and mPer2 areessential for normal resetting of the circadianclock. J. Biol. Rhythms 16, 100–104.

78. Field, M. D., Maywood, E. S., Obrien, J. A.,Weaver, D. R., Reppert, S. M., and Hastings, M.H. (2000) Analysis of clock proteins in mouseSCN demonstrates phylogenetic divergence ofthe circadian clockwork and resetting mecha-nisms. Neuron 25, 437–447.

79. Benna, C., Scannapieco, P., Piccin, A., Sandelli,F., Zordan, M., Kyriacou, C. P., et al. (2000) Asecond timeless gene in Drosophila sharesgreater sequence similarity with mammaliantim. Curr. Biol. 10, R512–R513.

80. Gotter, A. L., Manganaro, T., Weaver, D. R.,Kolakowski, L. F., Jr., Possidente, B., Sriram, S.,et al. (2000) A time-less function for mousetimeless. Nat. Neurosci. 3, 755–756.

81. Hasting, J. W., Rusak, B., and Boulos, Z. (1991)Circadian rhythms: the physiology of biologi-cal timing, in Neural and Integrative AnimalPhysiology (Prosser, C. L. ed.), Wiley–Liss, NewYork, pp. 435–546.

82. Tokura, H. and Aschoff, J. (1983) Effects oftemperature on the circadian rhythm of pig-tailed macaques Macaca nemestrina. Am. J.Physiol. 245, R800–R804.

83. Zimmerman, W. F., Pittendrigh, C. S., andPavlidis, T. (1968) Temperature compensationof the circadian oscillation in Drosophilapseudoobscura and its entrainment by tempera-ture cycles. J. Insect Physiol. 14, 669–684.

84. Bruce, V. and Pittendeigh, C. S. (1956)Temperature independence in a unicellular“clock” Proc. Natl. Acad. Sci. USA 42, 676–682.

85. Costa, R., Peixoto, A. A., Thackeray, J. T.,Dalglish, R., and Kyriacou, C. P. (1991) Lengthpolymorphism in the Threonine–Glycine-encoding repeat region of the period gene inDrosophila. J. Mole. Evol. 32, 238–246.

86. Costa, R., Peixoto, A. A. Barbujani, G., andKyriacou, C. P. (1992) A latitudinal cline in aDrosophila clock gene. Proc. R. Soc. Lond. B 250,43–49.

87. Sawyer, L. A., Hennessy, J. M., Peixoto, A. A.,Rosato, E., Parkinson, H., Costa, R., et al.(1997) Natural variation in a Drosophila clockgene and temperature compensation. Science278, 2117–2120.

88. Rosato, E., Peixoto, A. A., Gallippi, A.,Kyriacou, C. P., and Costa, R. (1996) Mutationalmechanisms, phylogeny, and evolution of arepetitive region within a clock gene ofDrosophila melanogaster. J. Mol. Evol. 42, 392–408.

89. Rosato, E., Piccin, A., and Kyriacou, C. P.(1997) Circadian rhythms: from behaviour tomolecules. BioEssays 19, 1075–1082.

90. Hall, J. C. (1997) Circadian pacemakers blow-ing hot and cold—but they’re clocks, not ther-mometers. Cell 90, 9–12.

91. Majercak, J., Sidote, D., Hardin, P. E., andEdery, I. (1999) How a circadian clock adapts



to seasonal decreases in temperature and daylength. Neuron 24, 219–230.

92. Ruby, N. F., Burns, D. E., and Heller, C. (1999)Circadian rhythms in the suprachiasmaticnucleus are temperature-compensated andphase-shifted by heat pulses in vitro. J.Neurosci. 19, 8630–8636.

93. Boulnat, J. A. (1996) Hypothalamic neurons reg-ulating body temperature, in Handbook ofPhysiology, Section 4, Volume 1, EnvironmentalPhysiology (Fregly, M. J. and Blatteis, C. M., eds.),Oxford University Press, Oxford, pp. 105–126.

94. Aschoff, J. and Tokura, H. (1986) Circadian activ-ity rhythms in squirrel monkeys: entrainment bytemperature cycles. J. Biol. Rhythms 1, 91–99.

95. Francis, A. J. and Coleman, G. J. (1988) Theeffect of ambient temperature cycles upon cir-cadian running and drinking activity in maleand female laboratory rats. Physiol. Behav. 43,471–477.

96. Pohl, H. (1998) Temperature cycles as zeitge-ber for the circadian clock of two burrowingrodents, the normothermic antelope groundsquirrel and the heterothermic Syrian hamster.Biol. Rhythm Res. 29, 311–325.

97. Francis, A. J. and Coleman, G. J. (1997) Phaseresponse curves to ambient temperaturepulses in rats. Physiol. Behav. 62, 1211–1217.

98. Burgoon, P. W. and Boulant, J. A. (1998)Synaptic inhibition: its role in suprachiasmaticnucleus normal thermosensitivity and temper-ature compensation in the rat. J. Physiol. 512,793–807.

99. Krishnan, B., Dryer, S. E., and Hardin, P. H.(1999) Circadian rhytms in olfactory responsesof Drosophila melanogaster. Nature 400, 375–378.

100. Goel, N. and Lee, T. M. (1997a) Olfactory bul-bectomy impedes social but not photic reen-trainment of circadian rhythms in femaleOctodon degus. J. Biol. Rhythms 12, 362–370.

101. Goel, N., Lee, T. M., and Pieper, D. R. (1998)Removal of the olfactory bulb delays photicreentrainment of circadian activity rhythmsand modifies the reproductive axis in maleOctodon degus. Brain Res. 792, 229–236.

102. Amir, S., Cain, S., Sullivan, J., Robinson, B.,and Stewart, J. (1999) Olfactory stimulationenhances light-induced phase shifts in free-running activity rhythms and Fos expressionin the suprachiasmatic nucleus. Neuroscience92, 1165–1170.

103. Shkolnik, A. (1971) Diurnal activity in a smalldesert rodent. Int. J. Biometeorol. 15, 115–120.

104. Rubal, A., Choshniak, I., and Haim, A. (1992)Daily rhythms of metabolic rate and body tem-perature of two murids from extremely differ-ent habitat. Chronobiol. Int. 9, 341–349.

105. Haim, A. and Rozenfeld, F. M. (1993) Temporalsegregation in coexisting Acomys species: therole of odour. Physiol. Behav. 54, 1159–1161.

106. Haim, A. and Fluxman, S. (1996) DailyRhythms of metabolic rates: role of chemicalsignals in coexistence of spiny mice of thegenus Acomys. J. Chem. Ecol. 22, 223–229.

107. Zufall, F. and Munger, S. D. (2001) From odorand pheromone transduction to the organiza-tion of the sense of smell. Trends Neurosci. 24,191–193.

108. Mrosovsky, N. (1988) Phase response curves forsocial entrainment. J. Comp. Physiol. A 162, 35–46.

109. Goel, N. and Lee, T. M. (1997b) Social cuesmodulate free-running circadian activityrhythms in the diurnal rodent, Octodon degus.Am. J. Physiol. 273, R797–R804.

110. Elmore, S. K., Betrus, P. A., and Burr, R. (1994)Light, social zeitgebers, and the sleep–wakecycle in the entrainment of human circadianrhythms. Res. Nurs. Health 17, 471–478.

111. Nakao, M., Yamamoto, K., Nakamura, K.,Katayama, N., and Yamamoto, M. (2001) A cir-cadian system model with feedback of cross-correlation between sleep-wake rhythm andoscillator. Psychiatry Clin. Neurosci. 55, 295–297.

112. Mead, S., Ebling, F. J. P., Maywood, E. S., Humby,T., Herbert, J., and Hastings, M. H. (1992) A non-photic stimulus causes instantaneous phaseadvances of the light-entrainable circadian oscil-lator of the Syrian hamster but does not inducethe expression of c-fos in the suprachiasmaticnuclei. J. Neurosci. 12, 2516–2522.

113. Mrosovsky, N. (1993) Tau changes after singlenonphotic events. Chronobiol. Int. 10, 271–276.

114. Hastings, M. H., Duffield, G. E., Smith, E. J. D.,Maywood, E. S., and Ebling, F. J. P. (1998)Entrainment of the circadian system of mam-mals by nonphotic cues. Chronobiol. Int. 15,425–445.

115. Maywood, E. S., Mrosovsky, N., Field, M. D.,and Hastings, M. H. (1999) Rapid down-regu-lation of mammalian Period genes duringbehavioral resetting of the circadian clock.Proc. Natl. Acad. Sci. USA 96, 15,211–15,216.

116. Abe, H. and Rusak, B. (1992) Anticipatoryactivity and entrainment of circadian rhythmsin Syrian hamsters exposed to restricted palat-able diets. Am. J. Physiol. 263, R116–R124.



117. Mistlberger, R. E. (1993) Circadian propertiesof anticipatory activity to restricted wateraccess in suprachiasmatic-ablated hamsters.Am. J. Physiol. 264, R22–R29.

118. Stephan, F. K. (1997) Calories affect zeitgeberproperties of the feeding entrained circadianoscillator. Physiol. Behav. 62, 995–1002.

119. Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y.,and Menaker, M. (2001) Entrainment of the cir-cadian clock in the liver by feeding. Science 291,490–493.

120. Damiola, F., Le Minh, N., Preitner, N.,Kornmann, B., Fleury-Olela, F., and Schibler,

U. (2000) Restricted feeding uncouples circa-dian oscillators in peripheral tissues from thecentral pacemaker in the suprachiasmaticnucleus. Genes Dev. 14, 2950–2961.

121. Hara, R., Wan, K., Wakamatsu, H., Aida, R.,Moriya, T., Akiyama, M., et al. (2001)Restricted feeding entrains liver clock withoutparticipation of the suprachiasmatic nucleus.Genes Cells 6, 269–278.

122. Le Minh, N., Damiola, F., Tronche, F., Schutz, G.,and Schibler, U. (2001) Glucocorticoid hormonesinhibit food-induced phase-shifting of periph-eral circadian oscillators. EMBO J. 20, 7128–7136.



Date post:	01-Aug-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

Circadian Rhythm Entrainment in Flies and...

Documents