Neurogenetics of food anticipation - Wiley Online Library

European Journal of Neuroscience

European Journal of Neuroscience, Vol. 30, pp. 1676–1687, 2009

doi:10.1111/j.1460-9568.2009.06962.x

REVIEW ARTICLE

Neurogenetics of food anticipation Etienne Challet,1 Jorge Mendoza,1 Hugues Dardente2 and Paul Pe´vet1 1

Centre National de la Recherche Scientifique, UPR3212 associe´ a` l’Universite´ de Strasbourg, Institut de Neurosciences Cellulaires et Inte´gratives, De´partement de Neurobiologie des Rythmes, 5 rue Blaise Pascal, 67084 Strasbourg, France and 2 Aberdeen University, School of Biological Sciences, Tillydrone Avenue, Aberdeen, Scotland, UK Keywords: circadian rhythms, clock gene mutant, food-anticipatory activity, restricted feeding

Abstract Circadian clocks enable the organisms to anticipate predictable cycling events in the environment. The mechanisms of the main circadian clock, localized in the suprachiasmatic nuclei of the hypothalamus, involve intracellular autoregulatory transcriptional loops of specific genes, called clock genes. In the suprachiasmatic clock, circadian oscillations of clock genes are primarily reset by light, thus allowing the organisms to be in phase with the light–dark cycle. Another circadian timing system is dedicated to preparing the organisms for the ongoing meal or food availability: the so-called food-entrainable system, characterized by foodanticipatory processes depending on a circadian clock whose location in the brain is not yet identified with certainty. Here we review the current knowledge on food anticipation in mice lacking clock genes or feeding-related genes. The food-entrainable clockwork in the brain is currently thought to be made of transcriptional loops partly divergent from those described in the lightentrainable suprachiasmatic nuclei. Possible confounding effects associated with behavioral screening of meal anticipation in mutant mice are also discussed.

Introduction The master circadian clock in the mammalian brain is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN clock controls the daily sleep–wake (rest–activity) cycle and adjusts the timing of a myriad of oscillators throughout the body, in both the brain and peripheral organs (Ralph et al., 1990; Herzog & Schwartz, 2002; Schibler et al., 2003). Light is the most potent synchronizer of the SCN clock (for review, see Meijer et al., 2007). In contrast, most other circadian oscillators in the brain and peripheral tissues appear quite sensitive to nutritional cues because their phase is readily synchronized by imposed meal times out of the regular phase of feeding, that is, during the usual resting period (Damiola et al., 2000; Wakamatsu et al., 2001; Angeles-Castellanos et al., 2007; Waddington Lamont et al., 2007; Feillet et al., 2008a). This demonstrates that feeding cues can override synchronizing signals from the SCN and suggests that feeding-related cues act as the dominant synchronizer for extra-SCN circadian clocks. When food availability is limited to a restricted temporal window every day at the same time (temporal restricted feeding), animals display a bout of locomotor activity prior to food presentation (for review, see Mistlberger, 1994; Stephan, 2001). Moreover, multiple physiological parameters such as body temperature and corticosterone release also rise before meal time, in phase with anticipatory behavior (Honma et al., 1984; Nelson & Halberg, 1986). Such a foodanticipatory activity is manifest not only in food-restricted adult animals (Mistlberger, 1994; Fig. 1) but also in pups nursed by the

Correspondence: Dr E. Challet, as above. E-mail: challet@inci-cnrs.unistra.fr Received 30 April 2009, revised 3 July 2009, accepted 6 July 2009

mother only for a short time every day (Caba & Gonza´lez-Mariscal, 2009). In rodents rendered arrhythmic by SCN lesions, daily restricted feeding provides temporal cues to the rest of the circadian system, thus restoring behavioral rhythmicity via circadian food-anticipatory activity (Stephan et al., 1979; Mendoza, 2007) and hormonal rhythmicity as well (Feillet et al., 2008b). Entrainment of foodanticipatory activity typically occurs when the periodicity of food access is between 23 and 29 h, well into the circadian range. Also, when the time of daily food access is abruptly changed (‘jet-lag’ of feeding schedule), food-anticipatory activity shows transient cycles misaligned to both old and new feeding times (Stephan, 2001). Such transients are typical of endogenous clocks and physical pendula and reflect the inertia within a system in transition between one phase and another. Furthermore, the fact that food-anticipatory activity can reappear at the expected time of restricted food access while the animal is fasted strengthens the notion that this behavior depends upon an endogenous time-keeping system. Taken together, these observations indicate that another clock, distinct from the SCN, drives food-anticipatory components and is synchronized by meal time (Mistlberger, 1994; Stephan, 2001). Even though its location remains to be determined, the so-called food-entrainable clock probably resides within the brain (Davidson et al., 2003). The prevalent hypothesis is that the food-entrainable circadian system is indeed a network that involves several cerebral regions (Davidson, 2006). Nonetheless, nutritional signals from the periphery are known to convey critical information on feeding state and metabolic status to the brain (King, 2005). These nutritional messages from peripheral organs would constitute synchronizing inputs to this specific timing system. Both forward (from phenotype to genotype) and reverse (from genotype to phenotype) genetics have been successful in identifying

ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd

Neurogenetics of food anticipation 1677

Fig. 1. Behavioral and physiological responses in B6CBA mice challenged with temporal restricted feeding under a light–dark cycle. (A) Daily wheel-running activity in a mouse initially fed ad libitum for 10 days and subsequently exposed to a restricted feeding (food available from midday to dark onset) for 10 days. A bout of food-anticipatory activity (FAA) was expressed prior to the time of food access. (B) Daily body temperature in a mouse initially fed ad libitum for 10 days and subsequently exposed to a restricted feeding (food available from midday to dark onset) for 10 days. A peak of thermogenesis (so-called food-anticipatory thermogenesis, or FAT) was expressed prior to the time of food access. Thermogenesis was also increased during mealtime, corresponding to the so-called dietinduced thermogenesis (DIT). Successive 24-h periods are double-plotted (48 h horizontal time scale). Nighttime, when mice were under light–dark conditions, is indicated by a black bar on the abscissa.

key genes in the molecular clockwork of the SCN and local clocks in peripheral organs (Takahashi et al., 1994, 2008). Some functional differences between clockworks have now been demonstrated, for instance between the SCN and the liver (DeBruyne et al., 2007a), raising the possibility that the various circadian clocks throughout the body might tick with a blend of both ubiquitous and tissue-specific molecular gears. Therefore, it was initially hypothesized that the molecular machinery involved in meal anticipation would rely at least in part on clock genes employed by the ‘classical’ circadian system (Pitts et al., 2003). The aim of this review is to evaluate, in light of results obtained using circadian mutant and knock-out (KO) mice, the usefulness of the neurogenetic approach in understanding the molecular mechanisms of food anticipation.

Circadian clockwork Several genes, so-called (circadian) clock genes, have been shown to play a role in circadian oscillations. Of note, identification of the first circadian gene in the mouse, i.e. Clock (circadian locomotor output cycles kaput; King et al., 1997), resulted from a forward genetic approach in which mice were screened for altered circadian behavior after large-scale random chemical mutagenesis (Vitaterna et al., 1994). Most of the other mammalian circadian genes, with the notable exception of BMAL1 (brain and muscle ARNT-like

protein 1), have been cloned by sequence homology with genes in the fruit fly. The current model of circadian oscillations in the light-entrainable SCN clock is based on autoregulatory transcriptional loops and also implements a handful of post-translational modifications (Ko & Takahashi, 2006; Dardente & Cermakian, 2007; Maywood et al., 2007; Fig. 2). In the core of these oscillatory mechanisms are two transcription factors, CLOCK and BMAL1. Both proteins belong to the bHLH ⁄ PAS family (where bHLH is basic helix–loop–helix and PAS is PER-ARNT-SIM, PER being period and SIM single-minded). CLOCK ⁄ BMAL1 heterodimers activate the transcription of other clock genes, including three Period (Per1-3) and two Cryptochrome (Cry1-2) genes via E-box sequences in their promoter. The PER and CRY proteins then form complexes that are translocated in the nucleus where they inhibit their own CLOCK ⁄ BMAL1-induced transactivation. Inactivation of PER ⁄ CRY repressor complexes targeted for ubiquitination and proteasome degradation by F-box proteins [FBXL3 and FBXL21 for the CRYs and b-TRCP (beta-transducin repeatcontaining proteins) 1-2 for the PERs] is considered a critical step for allowing a new cycle of autoregulation to ensue (Shirogane et al., 2005; Godinho et al., 2007; Siepka et al., 2007; Dardente et al., 2008; Maier et al., 2009). Phosphorylation of the PER proteins in the cytoplasm by Casein kinases Id and Ie bears several functional consequences that together contribute to their delayed nuclear translocation, hence delayed feedback effects on their own transcription

ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 30, 1676–1687

1678 E. Challet et al. repressors although they may also, in a cell type- and promoterdependent context, behave as transcriptional activators (Honma et al., 2002; Rossner et al., 2008; Dardente et al., 2009). Several clockcontrolled genes are considered to be outputs of the circadian clock responsible for the local distribution of circadian signals. In the lightentrainable SCN clock, vasopressin and D-site albumin binding protein (DBP) are clock-controlled factors regulated by the interlocked feedback loops described above (Lopez-Molina et al., 1997; Jin et al., 1999). As a nocturnal rodent species, mice exposed to a light–dark cycle show a pattern of feeding and drinking, general and wheel-running activities that is mostly restricted to the night while being mostly inactive during daytime. When released in constant darkness, mice continue to be active during the projected nighttime and rest during the projected daytime. This qualifies this rhythm as being truly circadian, that is, self-sustained as opposed to daily rhythmicity triggered by direct responses to daily events. Under constant darkness the activity onset, however, occurs each day a bit earlier (approximately 0.5 h) than the day before, defining an endogenous (free-running) period that is shorter (approximately 23.5 h) than 24 h. In rats and also in humans the endogenous (free-running) period is different from 24 h, usually slightly longer than 24 h. The implication of a candidate gene in the clockwork is classically evaluated by assessment of the free-running rhythm of locomotor activity in mice mutant or KO for this gene. Any dramatic effect on parameters such as the period or the relative strength of the rhythm, ranging from wild-type to complete arrhythmicity, is deemed suggestive of a role for this gene within the clockwork. Further characterization is nevertheless required as disruption of rhythmicity might result from distinct effects at different levels as exemplified for VPAC2-KO mice, which show arrhythmicity as a consequence of lack of coupling by the vasoactive intestinal peptide between neurons of the SCN (for review, see Vosko et al., 2007). Assuming that the food-entrainable clock uses the same clock genes as those found in the light-entrainable SCN clock, mice mutant or KO for clock genes were challenged with temporal restricted feeding. The expectation for this phenotyping of food entrainment was that foodanticipatory processes would be affected by functionally impaired clock genes. Fig. 2. (A) Current model of light-entrainable oscillations in the suprachiasmatic clock. (B) Hypothetical model of the core feedback loops in the foodentrainable clock. PER2 is thought to participate in the molecular mechanisms regulating food anticipation. Other molecular candidates are NPAS2 and CRY1 ⁄ 2. AVP, vasopressin; b-TRCP, beta-transducin repeat-containing protein; BMAL1-2, brain and muscle arylhydrocarbon receptor nuclear translocator-like proteins 1-2; CLOCK, circadian locomotor output cycles kaput; CRY, cryptochrome; DBP, D-site albumin-binding protein; FBXL, F-box protein; HIF1a, hypoxia-inducible factor 1a; NPAS2, neuronal PAS domain protein 2; PER1-2, Period proteins 1-2; REV-ERBa, reverse viral erythroblastis oncogene product a; RORa, retinoic acid receptor-related orphan receptor a.

(Lowrey et al., 2000; Lee et al., 2004). Adding to the robustness of the system, CLOCK ⁄ BMAL1 heterodimers drive transcription of the orphan nuclear receptors of the REV-ERB (Reverse viral erythroblastis oncogene product) and ROR (Retinoic acid receptor-related orphan receptor) families. In turn, REV-ERBa ⁄ b and RORa ⁄ b ⁄ c inhibit and activate, respectively, the rhythmic transcription of Bmal1 via two ROR response elements present in the proximal promoter (Preitner et al., 2002; Sato et al., 2004; Guillaumond et al., 2005). The bHLHOrange transcription factors DEC1 (bHLHB2, SHARP2 or STRA13) and DEC2 (bHLHB3 or SHARP1), whose rhythmic transcription is also imparted by CLOCK ⁄ BMAL1, are usually viewed as circadian

Mice lacking specific clock genes Clock Mice carrying the ClockD19 gene mutation (so-called Clock-mutant mice) were the first line of clock mutants to be phenotyped for meal anticipation. Homozygous Clock-mutant mice retain food-anticipatory activity when challenged with temporal restricted feeding, whether it is performed in a light–dark cycle or in constant darkness (Pitts et al., 2003). Another lab has confirmed this observation (Horikawa et al., 2005). The persistence of food-anticipatory activity in Clock-mutant mice is generally interpreted as evidence that CLOCK is dispensable for food-anticipatory processes (Pitts et al., 2003; Horikawa et al., 2005). It should be noted, however, that the circadian phenotype in constant darkness largely differs between ClockD19-mutant mice and Clock null-mutant () ⁄ )) mice, the former and latter being arrhythmic and rhythmic, respectively (King et al., 1997; DeBruyne et al., 2006). This probably reflects the fact that the CLOCK protein is still present in the ClockD19-mutant mice, although it lacks a 51-amino-acid stretch (corresponding to exon 19, hence the name of the mutant) and therefore behaves as a dominant-negative, while no CLOCK protein is present in the null-mutant (King et al., 1997; DeBruyne et al., 2006).


Neurogenetics of food anticipation 1679 Furthermore, the onset of food-anticipatory activity occurs earlier in Clock mutants than in wild-type mice (i.e. its duration is longer in mutants). As previously discussed (Stephan, 2003), the relatively modest phenotype of food anticipation in Clock-mutant mice does not imply that this gene plays no role in the food-entrainable clock. It may well mean that this internal deletion does not impact equally on light- and food-entrained mechanisms. Alternatively, it may reflect compensatory mechanisms or redundant function by closely related proteins. Besides CLOCK, there are several members of the bHLH ⁄ PAS family able to bind to BMAL1 to provide a positive transcriptional drive. NPAS2 (Neuronal PAS domain protein 2), a paralog of CLOCK that can dimerize with BMAL1 (Hogenesch et al., 2000; Reick et al., 2001), is indeed also expressed in the SCN, albeit at very low levels (i.e. not detectable by in situ hybridization; Dudley et al., 2003; DeBruyne et al., 2006). In homozygous Clock null-mutants, these low levels of NPAS2 appear sufficient to maintain a (mostly) normal lightentrainable clock in the SCN. Interestingly, the suprachiasmatic clock is no longer functional in Clock) ⁄ ); Npas2) ⁄ ) double-KO mice (DeBruyne et al., 2007b). Thus, before drawing a definitive conclusion on the role of CLOCK in food entrainment, it seems necessary to investigate food anticipation in Clock null-mutant (Clock) ⁄ )) mice. If this null mutant turns out to be indistinguishable from wild-type littermates, it will be of interest to investigate further a possible role for other transcription factors of the bHLH ⁄ PAS family in the foodentrainable clockwork (see below).

unchanged or reduce the duration of food-anticipatory activity (Marchant & Mistlberger, 1997). The main bout of activity preceding time of feeding may actually reflect residual rhythmic activity of the SCN clock that would be retained due to temporal restricted feeding and synchronized to feeding time. Similar patterns of food synchronization (i.e. with the main SCN-controlled pattern of activity preceding meal time) have already been described for wild-type mice and rats in constant darkness (Marchant & Mistlberger, 1997; Caldelas et al., 2005). Therefore, SCN lesions are necessary to assess whether the unusually prolonged activity prior to feeding time in Bmal1) ⁄ ) mice is real food-anticipatory activity independent of any SCN control.

Npas2 NPAS2 (also called MOP4) forms transcriptionally active heterodimers with either BMAL1 or BMAL2 (Hogenesch et al., 1998, 2000; Dardente et al., 2007). The lack of NPAS2 expression prevents daily variations in other clock genes in the forebrain, indicating that NPAS2 can act as a clock component therein (Reick et al., 2001) in addition to its role in the SCN (DeBruyne et al., 2007b). In response to temporal restricted feeding, mice KO for Npas2 display delayed food-anticipatory activity, eat less and lose weight compared to their wild-type littermates (Dudley et al., 2003). These alterations have been interpreted as indicating that NPAS2 plays a role in adaptability to limited temporal food availability. Due to the possible redundancy between CLOCK and NPAS2, it would also be informative to challenge Clock) ⁄ ); Npas2) ⁄ ) double-KO mice with restricted feeding.

Bmal1 It is rare that a single clock gene KO leads to major disruptions in the circadian rhythm of rest and activity. This robustness and resilience to genetic perturbations probably reflects redundancy in the molecular mechanism of the light-entrainable clock within the SCN. An exception to that rule might be the clock gene Bmal1, also known as MOP3 (Member of PAS superfamily No 3): Bmal1 null-mutant () ⁄ )) mice are arrhythmic as soon as they are transferred to constant darkness (Bunger et al., 2000; McDearmon et al., 2006). When challenged with temporal restricted feeding, Bmal1) ⁄ ) mice were first described as lacking food-anticipatory increases in locomotor activity and body temperature, those mice being actually torpid before the expected time of food access, that is, when food-restricted wild-type mice would display food anticipation (Fuller et al., 2008). Several shortcomings in that study have been detailed elsewhere (Mistlberger et al., 2009a). Three other datasets from independent laboratories show that food-anticipatory activity is maintained in Bmal1) ⁄ ) mice when the final duration of limited temporal food access is reached through a gradual narrowing of the time window over several days (Mistlberger et al., 2008; Pendergast et al., 2009; Storch & Weitz, 2009). It is noteworthy that, under constant darkness, the behavioral activity expressed by Bmal1) ⁄ ) mice before food access is much longer (up to approximately 12 h in Storch & Weitz, 2009 and at least 6 h in Mistlberger et al., 2008; Pendergast et al., 2009) than the regular food-anticipatory activity (approximately 2–3 h) of wild-type individuals. Also in Bmal1) ⁄ ) mice, daily onsets of food-anticipatory activity appear quite unstable. Therefore, expression of food-anticipatory activity is clearly affected in these KO mice, mimicking to some extent the phenotype of Clock mutants (Pitts et al., 2003). The prolonged activity of Bmal1) ⁄ ) mice before meal time is unlikely to be related to an unmasking effect of suprachiasmatic dysfunction on the expression of food-anticipatory activity because bilateral complete lesions of the mouse SCN clock either leave

Cry1 and Cry2 Mutant mice lacking either Cry1 or Cry2 show altered circadian rhythmicity (i.e. significant changes in the endogenous period). The double Cry1) ⁄ );Cry2) ⁄ ) KO mice become arrhythmic when transferred to constant darkness due to a severely blunted SCN clockwork (Van der Horst et al., 1999; Vitaterna et al., 1999). These findings together with an analysis of clock gene oscillations reveal that Cry1 and Cry2 are central components of the light-entrainable clock. Double Cry1) ⁄ );Cry2) ⁄ ) KO mice challenged with restricted feeding express delayed and unstable food-anticipatory activity under a light– dark cycle or constant darkness. Interestingly, clearer reduction in food-anticipatory activity is apparent in these double-mutants when the SCN clock is lesioned (Iijima et al., 2005). Nevertheless, these data show that Cry1 and Cry2 may be involved to some extent in the food-entrainable clock.

Per1 and Per2 Because they are major molecular components of the SCN circadian clock, are readily induced by light therein and are also induced by multiple chemical and physical cues in other tissues and cell lines, it is thought that Per1 and Per2 provide a molecular conduit through which clockwork resetting can be achieved (Albrecht et al., 1997, 2001; Shigeyoshi et al., 1997; Balsalobre et al., 2000; Hamada et al., 2004). For these reasons, Per1 and Per2 genes could be involved in the adaptation to limited food availability. Accordingly, mice KO for Per1 (Per1Brdm1, considered a null-mutant allele; described in Zheng et al., 2001) have been studied during restricted feeding. Young adult homozygous Per1Brdm1 mice show food-anticipatory activity at levels close to those of wild-type littermates (Feillet et al., 2006). These results were initially interpreted as meaning that food-entrainable


1680 E. Challet et al. oscillations do not depend on PER1. Older (middle-aged) homozygous Per1Brdm1 mice, however, show a marked reduction in behavioral meal anticipation, indicating a possible role for PER1 (J. Mendoza, U. Albrecht and E. Challet, unpublished observations). Interestingly, Per2Brdm1-mutant mice (an in-frame deletion mutant that lacks most of the PAS domain; targeting construct described in Zheng et al., 1999) do not express any food-anticipatory components of wheel-running activity, general activity or body temperature (Feillet et al., 2006). This lack of anticipation is independent of lighting conditions (i.e. exposure to light–dark cycle, constant darkness or constant light does not change the response) and severity of food restriction (i.e. no meal anticipation was observed under either temporal restricted feeding or hypocaloric feeding that result in no or significant body mass loss, respectively). In contrast to this strong phenotype in Per2Brdm1-mutant mice, no obvious alteration of behavioral food anticipation has been reported in the Per2ldc strain, considered to be a null-mutant allele (Storch & Weitz, 2009; generation of the Per2ldc strain described in Bae et al., 2001). Such a striking difference might be due to redundant function by paralog genes and ⁄ or compensatory developmental mechanisms present in mice bearing loss-of-function mutations that would be absent in mice bearing point mutations or genes with only short deletion (see review in Takahashi et al., 2008). This possibility is substantiated by, for instance, the fact that Npas2 is drastically overexpressed in the liver of the Clock-KO mice (DeBruyne et al., 2006), while it is expressed at similar levels in the liver of the Clockmutant mice (Noshiro et al., 2005). Although speculative, if a similar scenario is applied to Per2 it is plausible that the mutant PER2 protein expressed in Per2Brdm1-mutant mice would not be completely dysfunctional and may therefore not elicit compensatory mechanisms during development. In contrast, the total lack of PER2 or the presence of only a very short N-terminal peptide in the null-mutant mice could be compensated for by closely related PAS proteins (PER1 or PER3?). Active compensatory mechanisms have already been shown following multiple knock-downs in the clockwork of immortalized human cells (Baggs et al., 2009). In middle-aged double Per1Brdm1; Per2Brdm1-mutant mice, apparent behavioral anticipation of food access is hardly observable, if at all, under a light–dark cycle compared to wild-type littermates. Moreover, in constant darkness double Per1Brdm1; Per2Brdm1-mutant mice challenged with restricted feeding did not show a specific and stable increase in locomotor activity during the 2–3 h before meal time, as typically expressed in food-restricted wild-type mice (J. Mendoza, U. Albrecht and E. Challet, unpublished observations). On the other hand, double Per1ldc; Per2ldc mice apparently display regular (if not increased?) food anticipation (Storch & Weitz, 2009). It cannot fully be excluded that removing Per1 may partially rescue the Per2Brdm1mutant phenotype. Such an unexpected phenotypic rescue has for instance been observed in the arrhythmic Per2Brdm1-mutant, which recovers rhythmicity when the Cry2 gene is also knocked out (Oster et al., 2002). Alternatively, the observed behavior may eventually result from direct responses to metabolic or physiological changes triggered by food restriction. As discussed below, further behavioral and nutritional tests (persistence, T-cycles, transient cycles after changes in feeding time and ⁄ or SCN lesion) will be necessary to solve this issue.

Model for the food-entrainable clockwork Even if this view has been recently challenged (Storch & Weitz, 2009), our working hypothesis is that at least NPAS2, PER2 and CRY1-2

play some role in behavioral food anticipation. Probably neither CLOCK nor BMAL1 are crucial candidates for generating foodentrainable oscillations, although they can modulate expression of these oscillations. Overall, the available results suggest that the foodentrainable clockwork in the brain relies on transcriptional loops partly different from those of the SCN clock. This interpretation is in accordance with other functional differences (e.g. differential sensitivity to deuteriation; Mistlberger et al., 2001). Thus, it might be that other genes of the bHLH-PAS family substitute for CLOCK ⁄ BMAL1 to transactivate expression of Pers and Crys. NPAS2 is a prime candidate because it is expressed in various extra-SCN brain regions and heterodimerizes with BMAL1 and BMAL2. Bmal2 (also known as MOP9) is a Bmal1 paralog expressed in the brain and the BMAL2 protein can dimerize with CLOCK or NPAS2 to transactivate (clock) genes (Hogenesch et al., 2000; Dardente et al., 2007). Despite its expression within the SCN (Hogenesch et al., 2000; Okano et al., 2001) BMAL2 does not appear to functionally compensate for BMAL1 deficiency in the SCN clock of Bmal1) ⁄ ) mice, otherwise these mice would maintain circadian rhythmicity. Nevertheless, it cannot be excluded that BMAL2 would play a role in the foodentrainable circadian system (Fig. 2). Knock-outs or mutants for Bmal2 will now be required to test this hypothesis further. Besides BMAL2, other members of the bHLH-PAS family such as HIF1a (hypoxia-inducible factor 1a, also known as MOP1) are putative circadian regulators of food-entrainable oscillators. Of note, HIF1a can interact not only with BMAL1 and CLOCK (Hogenesch et al., 1998; Ghorbel et al., 2003) but also with BMAL2 (Hogenesch et al., 2000). Interestingly, some target genes transactivated by HIF1a include those encoding for glucose transporters (Dery et al., 2005; Mobasheri et al., 2005) that are important for glucose sensing (Peńicaud et al., 2002). As mentioned above, only a few clock genes have been considered within the framework of food anticipation. In particular, the involvement of important components of the current model for molecular clockwork, such as Rev-Erba ⁄ b and Rora ⁄ b ⁄ c, remains to be investigated. These genes belong to the orphan nuclear receptor superfamily that encode for negative and positive regulators of transcription, respectively. On the one hand, as mentioned earlier, REV-ERB and ROR proteins are involved in the circadian clockwork (Preitner et al., 2002; Sato et al., 2004; Guillaumond et al., 2005). On the other hand, these transcription factors are intracellular sensors for circulating lipids and liposoluble hormones, and also participate in diverse pathways of lipid and carbohydrate metabolism in liver, skeletal muscle and adipose tissues (Duez & Staels, 2008). REV-ERBs and RORs are thus involved in the circadian control of cellular metabolism (Yang et al., 2006; Teboul et al., 2008) and further investigations are needed to explore their putative role in the context of the food-entrainable clockwork. Furthermore, it is worth highlighting that bHLH ⁄ PAS transcriptional regulators act as metabolic sensors capable of detecting hypoxia, redox or hypoglycaemia (Rutter et al., 2001; Kewley et al., 2004). The broad repertoire of molecular interactions between these proteins makes them ideal candidates for extensive cross-talk and integration between various signalling pathways (for review, see Gu et al., 2000).Their possible links as transcriptional activators for orphan nuclear receptors (some of them being metabolic sensors) have also to be considered. Whether these properties have physiological relevance in all brain cells or only in more specialized subpopulations is not known yet. Incidentally, the modulating effect of redox state, at least in cultured SCN cells, is not salient (Wise & Shear, 2004). Needless to say, progress in the identification of brain regions critical for meal anticipation would be welcome to help better


Neurogenetics of food anticipation 1681 understand the underlying clockwork (e.g. self-sustained properties, temporal patterns of clock gene expression, synchronizing cues etc). Moreover, not all brain clocks outside the suprachiasmatic nuclei share the same molecular oscillations (for review, see Guilding & Piggins, 2007; Mendoza & Challet, 2009). Therefore, it is also conceivable that the different oscillatory structures underlying the food-entrainable network use slightly different clockworks, a hypothesis that, if correct, would add another level of complexity.

Mice lacking specific feeding-related genes Food intake and energy metabolism are regulated within the brain by a network of discrete nuclei in the mediobasal hypothalamus and brainstem. Briefly, the mediobasal hypothalamus, including the arcuate and ventromedial hypothalamic nuclei, receives and integrates blood-borne nutritional signals from peripheral organs. Among these signals are metabolic cues (plasma glucose, free fatty acids), orexigenic cues mediated by circulating ghrelin synthesized in the stomach, and anorexigenic cues mediated by circulating leptin from fat tissues, insulin from pancreas or intestinal gluco-incretin hormones (Peńicaud et al., 2002; King, 2005). Genetically obese Zucker ( fa ⁄ fa) rats have a missense mutation in the leptin receptor gene (Cusin et al., 1996). Because obese Zucker rats display greater food-anticipatory activity than do wild-type littermates (Mistlberger & Marchant, 1999), leptin receptor signalling is dispensable (albeit negative regulator?) for food-anticipatory processes. Ghrelin receptor-KO mice express reduced food-anticipatory activity, suggesting that ghrelin modulates food-anticipatory activity (LeSauter et al., 2009). In the arcuate nuclei, several neuropeptides have opposite actions on food intake: neuropeptide Y and Agouti-related peptide (AgRP) have potent orexigenic effects while a-melanocyte stimulating hormone (a-MSH) and cocain- and amphetamine-related transcript (CART) are anorexigenic. Depending on their role, release of these peptides will be activated or inhibited by peripheral signals of satiety or hunger, respectively. Release from nerve terminals of neuropeptide Y, AgRP, a-MSH and CART in targets of the arcuate nuclei, such as ventromedial hypothalamic nuclei (also sensitive to circulating leptin and glucose as the arcuate nuclei are), paraventricular hypothalamic nuclei and lateral hypothalamic areas, will then modulate food intake and energy balance (Dietrich & Horvath, 2009). Of note, paraventricular hypothalamic nuclei produce two anorexigenic peptides, thyrotropin-releasing hormone and corticotrophin-releasing hormone, while the lateral and perifornical hypothalamic areas produce three orexigenic peptides, orexins A and B (also named hypocretins 1 and 2) and melaninconcentrating hormone (MCH). Surprisingly, only a few rodent strains mutant for these feedingrelated neuropeptides have been phenotyped for meal anticipation. To our knowledge, anticipation responses to timed meals have not been investigated yet in mice mutant for neuropeptide Y or its receptors. Chemical lesion of the arcuate nucleus leads to enhanced expression of food-anticipatory behavior (Mistlberger & Antle, 1999). Such a lesion destroyed neurons expressing neuropeptide Y, but probably also affected expression of AgRP, a-MSH and CART in the arcuate region. Further investigations are thus needed to assess possible involvement of neuropeptide Y and other arcuate neuropeptides in the regulation of food anticipation. Genetic ablation of orexin-producing neurons in mice leads to a reduction in food-anticipatory activity and wakefulness during meal anticipation (Akiyama et al., 2004; Mieda et al., 2004), suggesting

that orexin neurons contribute to the regulation of food-anticipatory activity. This implication is probably specific to anticipatory activity and arousal because orexin-KO mice show reduced food-anticipatory motor activity, while anticipatory body temperature is similar to that in wild-type mice (Kaur et al., 2008). Specific damage to orexin neurons can be induced by intrahypothalamic injections of an immunotoxin directed against orexin neurons. To some extent, this treatment will lead to destruction of orexin neurons, as it would produce a conditional ablation of these neurons in adult rodents. In rats, however, the destruction of orexin-producing neurons does not impair food-anticipatory components, either of food cup activity or of drinking behavior (Mistlberger et al., 2003), in keeping with the lack of effect after chemical lesion of the lateral hypothalamus in rats (Mistlberger & Rusak, 1988). Besides species differences, further work would thus be beneficial to clarify the role of the orexin system in meal anticipation. The putative involvement of the MCH system in food anticipation has been investigated by studying mice deficient for the MCH1 receptor. Mchr1) ⁄ ) mice display food-anticipatory activity indistinguishable from that in wild-type mice, suggesting that MCH does not play an essential role in that circadian behavior (Zhou et al., 2005). The MSH system mediates its actions on ingestive behavior and energy metabolism via two melanocortin receptors, MCR3 and MCR4. Interestingly, food-anticipatory activity and wakefulness are reduced in Mcr3) ⁄ ) mice (Sutton et al., 2008).

Possible confounding effects When phenotyping mutant mice for meal anticipation, one should clearly define what is meant by food-anticipatory activity. In wild-type mice, food-anticipatory activity typically begins 2–3 h before food access and drops when the meal starts. It takes only 3–4 days of restricted feeding to see the first signs of food-anticipatory activity and this becomes fairly stable in the next few days. As discussed later, there are several possibilities, especially in mutant mice, that can lead to misinterpretations of apparent ‘food-anticipatory’ behaviors. Even minor procedural differences can influence the expression of foodanticipatory activity in mice (e.g. housing conditions; de Groot & Rusak, 2004). Furthermore, one should always bear in mind that, due to putative pleiotropic effects of genes, their mutation may produce altered phenotypes not directly linked to their expected role (i.e. circadian rhythmicity in the case of clock genes), but whose alterations can interfere with expression of food-anticipatory variables.

Measured parameters Behavioral anticipation of food access can be recorded by various means. A commonly used parameter is wheel-running activity but this has the disadvantage of being rewarding in itself (de Visser et al., 2007). Other possibilities include general cage activity assessed by an intraperitoneal transmitter and infrared motion sensor, both devices being considered equivalent for phenotyping food anticipation (Mistlberger et al., 2009b). Motor activity directed at a food bin has also been used (Mistlberger & Rusak, 1988; Davidson et al., 2000) but, in some instances, this behavior can be dissociated from foodanticipatory activity (e.g. Mistlberger & Rusak, 1988). Food-anticipatory processes are not limited to behavioral anticipation of meal time, even if this is the most studied parameter. Other anticipatory physiological (e.g. core temperature), hormonal (e.g. corticosterone) or metabolic (e.g. free fatty acids) parameters can be considered clock hands of the food-entrainable circadian system.


1682 E. Challet et al. However, because these processes are regulated by different downstream pathways, altered expression in one single output parameter does not necessarily imply impaired function in the clockwork itself. Differential effects on outputs, as exemplified above by the unaffected food-anticipatory body temperature concomitant with a blunted anticipatory activity in orexin-KO mice (Kaur et al., 2008), clearly suggest that the affected pathways are efferent to the food-entrainable clockwork and, in that case, specific to behavioral activity and arousal. Thus, it is advisable to investigate at the same time several foodanticipatory components for a given genotype.

Circadian entrainment vs. Associated learning or hourglass Food-anticipatory activity in rats and mice has long been conceptualized as the output of a self-sustained food-entrainable clock that does not rely on associated learning or hourglass measurement (Mistlberger, 1994; Stephan, 2001). These features have been demonstrated in wildtype animals. Our point here is that these possibilities have to be tested in clock-mutant mice that may use compensatory clues to maintain apparent ‘food-anticipatory’ behaviors. For instance, wild-type mice exposed to food access at midday will express food-anticipatory activity during the 2–3 h prior to feeding time. If mutant mice start to run as soon as lights are on (e.g. at 06.00 h) until feeding time, this sustained activity lasting 6 h might have nothing to do with foodanticipatory activity, even if expressed before food access. In that case, the mice may use the time of light onset as an external time-giving cue so that they ‘remember’ that they will be fed 6 h after that signal. To check this eventuality, it would be important to test food anticipation in mice of the same genotype under constant darkness where they would then lose the time cue associated with lights on. Food-anticipatory activity is well-known not to be simply triggered after a certain time lag (e.g. when depletion of energy stores reaches a given threshold), indicating that the food-entrainable system is probably not an hourglass (interval timer). Again, this is true in wild-type animals but merits checking in the studied mutant mice that may become more (or less) sensitive to peripheral metabolic cues. This test can be done by modifying the circadian periodicity of food access (T-cycles). Even when the SCN clock is thought to be altered in clock-mutant or KO mice, there might be interferences with expression of foodanticipatory processes. The SCN in mice can be synchronized to restricted feeding schedules under light–dark cycle or constant darkness (Abe et al., 1989; Marchant & Mistlberger, 1997; Castillo et al., 2004; Mendoza et al., 2005). When a nocturnal activity (i.e. controlled by the SCN clock) is still expressed it may become difficult to distinguish between food-entrainable activity per se and a drift in the nocturnal activity towards the time of feeding. In mutant mice arrhythmic in constant darkness, daily rhythmicity induced by restricted feeding may trigger some behavioral outputs from a subset of newly coupled cells in the light-entrainable clock. In that case, the apparent food-anticipatory activity is expected to be distinct in terms of duration, intensity and stability from that expressed in wild-type littermates. Thus, to circumvent a potential bias due to indirect effects on the SCN, it seems important to assess food-anticipatory processes in mutant mice with bilateral SCN lesions, as done in double Cry1) ⁄ );Cry2) ⁄ ) mice (Iijima et al., 2005). Also, clock mutations may alter the sensitivity to synchronizing cues. In the case of Per1Brdm1- and Per2Brdm1-mutant mice, the altered responses to light have been used to support the notion of a role for these genes in photic resetting of the SCN (Albrecht et al., 2001). Altered synchronization has also been observed in Clock-mutant mice in response to photic cues, interpreted as a result of reduced amplitude

of the SCN oscillations (Vitaterna et al., 2006). In the same vein, the Clock mutation also modifies the synchronizing effects of nonphotic, including metabolic, cues on the SCN clock (Challet et al., 2000). It is thus possible that resetting properties of the food-entrainable clock are changed by mutations of clock genes as well.

Homeostatic vs. Circadian regulation When food-anticipatory processes are not observed under temporal restricted feeding (with a daily time window of food access long enough to prevent body mass loss), it could be interesting to investigate what occurs under more severe conditions (i.e. conditions leading to a body mass loss) such as hypocaloric feeding, which has quite potent synchronizing effects (Challet et al., 1997; Mendoza et al., 2007). Under both conditions of food shortage, Per2Brdm1mutant mice do not anticipate daily meals (Feillet et al., 2006), indicating that the lack of anticipation in this strain is not due to secondary effects, such as deep torpor or hypothermia that would preclude arousal at the right time. When no or reduced anticipation is found in mutant mice during a restricted feeding paradigm that clearly appears harmful for them (Dudley et al., 2003; Fuller et al., 2008), it would be appropriate to repeat the experiment in less metabolically challenging conditions (e.g. with a longer daily access to food). This has been done with a progressive reduction in the duration of food access for Bmal1) ⁄ ) mice which then display recurrent behavioral activity before feeding time (Mistlberger et al., 2008; Pendergast et al., 2009; Storch & Weitz, 2009). Conversely, under conditions of positive energy balance, dietinduced obesity is known to alter anticipation of food access (Persons et al., 1993). Therefore, in mutant or transgenic mice thought to have increased adiposity (e.g. orexin ⁄ ataxin-3 and Mcr3r) ⁄ ); see Hara et al., 2001; and Sutton et al., 2008, respectively), the circadian responses to meal anticipation evoked above might have been modified indirectly due to altered lipid metabolism. Because nutritional messages from peripheral organs would constitute synchronizing inputs to the cerebral food-entrainable timing system, it is relevant to investigate possible alterations of plasma metabolites and hormonal cues in mutant mice. For instance, mice that do not express Bmal1 specifically in the liver show metabolic abnormalities, even under conditions of ad libitum food (Lamia et al., 2008).

Fasting test One of the strong arguments for a food-entrainable clock is the reappearance of a bout of food-anticipatory activity in food-deprived animals at the previous time of restricted food access. Historically, this demonstration has been done in rats. Because rats and mice largely differ in terms of fat stores and metabolic rate, what is tolerable for rats may not be appropriate for mice. Indeed, rats can cope with food deprivation over several days before showing a fasting-induced rise in daytime locomotor activity (Challet et al., 1995, 1996). By contrast, mice can display fasting-induced hyperactivity as soon as after only a single day of food deprivation (Challet et al., 1999; Pendergast et al., 2009), which may totally override any putative reappearance of foodanticipatory activity. Furthermore, even in mice that have not been previously challenged with restricted feeding, the fasting-induced rise in activity is not clearly distinguishable from the expected reappearance of food-anticipatory activity (Fig. 3). In our opinion, it is advisable not to systematically use the fasting test (if possible, for no longer than 1 day) in mice and to avoid it in skinny mutant mice.


Neurogenetics of food anticipation 1683 decrease the ability to anticipate meal time, independently of circadian mechanisms. Exposure to constant light has been shown to maintain circadian rhythmicity in several clock-mutant mice that would otherwise be arrhythmic under constant darkness (Spoelstra et al., 2002; Abraham et al., 2006). Moreover, in wild-type rats rendered arrhythmic by a prolonged exposure to constant illumination, daily restricted feeding is able to restore clock gene oscillation in the suprachiasmatic clock (Lamont et al., 2005). Thus, constant light could be a suitable condition under which to obtain more insights into the foodentrainable system.

Cognitive deficits A number of mutations in clock genes have been correlated with impaired learning abilities (e.g. Npas2) ⁄ ) and Cry1) ⁄ );Cry2) ⁄ ) mice; Garcia et al., 2000; Van der Zee et al., 2008; respectively) or altered behavioral responses (e.g. Clock-mutant mice; Easton et al., 2003). Any cognitive or emotional defect has to be taken into account as a potential confounding effect when interpreting food-anticipatory data. Hypoactivity of a clock-mutant strain during food anticipation might be due to depressive-like behavior instead of involvement in foodentrainable mechanisms.

Genetic background

Fig. 3. Behavioral responses in C57BL ⁄ 6·129Sv mice challenged with temporal restricted feeding under a light–dark cycle and ⁄ or food deprivation in constant darkness. (A) Daily wheel-running activity in a mouse initially fed ad libitum for 2 weeks and then exposed to a restricted feeding (food available 4 h after lights on until lights off) for 3 weeks under a light–dark cycle. A bout of food-anticipatory activity (FAA) was expressed prior to the time of food access. Thereafter, the mouse was transferred to constant darkness and fed ad libitum for 4 weeks until being challenged with a 2-day fasting period. A bout of locomotor activity was expressed in late subjective afternoon (corresponding more or less to FAA under conditions of restricted feeding). (B) Daily wheelrunning activity in a mouse fed ad libitum for 5 weeks under a light–dark cycle and transferred to constant darkness for 4 weeks until being challenged with a 2-day fasting period. A fasting-induced rise in activity is visible during the usual inactive period. This fasting-induced rise in diurnal activity is not clearly distinguishable from the so-called reappearance of food-anticipatory activity shown by the mouse in panel A. Successive 24-h periods are double-plotted (48 h horizontal time scale). Nighttime, when mice were under light–dark conditions, is indicated by a black bar on the abscissa.

Lighting conditions Light conditions can impact on the levels of locomotor activity. In particular, light exposure reduces or suppresses motor activity in nocturnal rodents (Redlin, 2001). Therefore, in mutant mice exposed under a light–dark cycle, low food-anticipatory activity during the daytime may actually reflect an increased masking effect of light. In this case, a complementary investigation in constant darkness could be informative, although the ‘nocturnal’ activity controlled by the SCN, either free-running or synchronized to feeding time, may become superimposed on the food-anticipatory activity, thus precluding reliable quantitative estimation. Furthermore, exposure to constant darkness in mice may activate lipolysis and favor torpor (Zhang et al., 2006), which could in turn

Last but not least, the genetic background in mice deeply influences various parameters of circadian rhythmicity. For instance, a wide strain-dependent diversity has been shown for the free-running rhythm of locomotor activity controlled by the SCN clock (Mayeda & Hofstetter, 1999; Tankersley et al., 2002; Siepka & Takahashi, 2005) and its responsiveness to light (Schwartz & Zimmerman, 1990) or timed feeding as well (Abe et al., 1989). Indeed, there are numerous examples of how genetic background impacts on circadian behavior. For instance, depending on the genetic background in which the Clock mutation is established, mice can become either fattier (Turek et al., 2005) or leaner than wild-type littermates (Oishi et al., 2006). As discussed previously, the Per2ldc-mutant mice are arrhythmic (Bae et al., 2001). However, when established in a different genetic background, the mice are perfectly rhythmic (Xu et al., 2007). There are also discrepancies between the circadian phenotype, which ranges from virtually unaffected to complete arrhythmicity, of the three different Per1-KO strains that have been generated (Bae et al., 2001; Cermakian et al., 2001; Zheng et al., 2001). A difference in the genetic background appears a plausible explanation although differences in the targeting constructs themselves might also be invoked. Indeed, apart from possible complications arising from the genetic background issue, the phenotype of circadian mutant mice has to be scrutinized, also taking into account how the strain has been generated (random mutagenesis, gene targeting KO) and what this implies in terms of mRNA and protein expression (truncated protein probably retaining interaction with some partners while losing the ability to interact with others, no protein at all, only a short peptide present…). Although further experiments will be needed to conclude so, differences in the targeting construct could well explain in part why we found that food-anticipatory behavior is missing in Per2Brdm1 while it is retained in Per2ldc. A putative effect of genetic background can be ruled out in this case as Storch & Weitz (2009) were careful to establish the Per2ldc mutation in the same mixed C57BL ⁄ 6·129Sv background. Surprisingly enough, wild-type mice of this mixed


1684 E. Challet et al. genetic background display robust and consistent food-anticipatory activity in our hands (Feillet et al., 2006) while food anticipation for this mouse strain is considered weak or undetectable in another study (Storch & Weitz, 2009). As a conclusion, it seems safe to say that great caution is required in the interpretation of the circadian phenotypes observed for food anticipation as they might be modulated, modified or disturbed by several methodological and technical variables, some of which are not readily controlled.

D-site albumin-binding protein; FBXL, F-box protein; HIF, hypoxia-inducible factor; KO, knock-out; MCH, melanin-concentrating hormone; MCR, melanocortin receptor; MOP, member of PAS superfamily; NPAS, neuronal PAS domain protein; PAS, PER-ARNT-SIM; PER, Period; REV-ERB, reverse viral erythroblastis oncogene product; ROR, retinoic acid receptor-related orphan receptor; SCN, suprachiasmatic nuclei; SIM, single-minded; a-MSH, a-melanocyte stimulating hormone; b-TRCP, beta-transducin repeat-containing protein.

References Future directions of research First of all, it will be necessary to pursue phenotyping meal anticipation in mutant mice for other known clock genes (e.g. Reverbs, Rors, Bmal2, Dec1-2) or closely related genes (e.g. Hif1a). Moreover, anticipation of feeding time could also be studied in mice bearing brain-specific KO of clock genes. This strategy would avoid any secondary effect due to altered peripheral defects. Alternatively, it would be interesting to restore altered food-anticipatory activity in clock-mutant mice by viral gene transfer. This elegant approach has already been used in that context to try to restore food anticipation in Bmal1) ⁄ ) mice (Fuller et al., 2008; for a critique of the presented data, see Mistlberger et al., 2009a). Other promising methods include in vivo knock-down of clock gene expression by RNA interference. Besides molecular mechanisms underlying oscillations and identification of key brain structures, comprehension of the food-entrainable clock will not be possible without clarifying how it is reset by feeding cues. Concerning the light-entrainable clock, both Per1 and Per2 genes play an important role in photic resetting (Albrecht et al., 1997, 2001; Shigeyoshi et al., 1997; Akiyama et al., 1999; Yan et al., 1999; Yan & Silver, 2002). In contrast, genes mediating synchronization of the food-entrainable clock are not identified yet. To provide insights on these resetting mechanisms, we propose to expose clock-mutant mice to abrupt changes in the time of daily food access (‘jet-lag’ of feeding schedule) for determining the rate of re-entrainment. Our hypothesis is that impaired re-entrainment of transient food-anticipatory activity to a new feeding schedule may reflect an involvement of the mutated gene in food resetting. As we have discussed in this review, it seems that the foodentrainable clockwork in the brain relies on transcriptional loops partly different from those described in the light-entrainable SCN clock. To get a more detailed picture of the molecular underpinnings of the foodentrainable clock, it is now required that the behavioral screening be extended to additional clock-mutant strains. Additionally, the development of refined murine models with brain-specific conditional KO along with targeted knock-down approaches aiming at various cerebral regions should help to localize the still elusive neural substrate(s) of the food-entrainable clock.

Acknowledgements We thank Julien Delezie and Dr Mireille Masson-Pe´vet for constructive comments. Our studies were supported by grants from Centre National de la Recherche Scientifique (E.C. and P.P.) and Agence Nationale pour la Recherche ‘Jeunes Chercheurs ⁄ Jeunes Chercheuses’ (E.C. and J.M.).

Abbreviations AgRP, Agouti-related peptide; ARNT, arylhydrocarbon receptor nuclear translocator; bHLH, basic helix–loop–helix; BMAL1 or -2, brain and muscle ARNT-like protein 1 or 2; CART, cocain- and amphetamine-related transcript; CLOCK, circadian locomotor output cycles kaput; CRY, cryptochrome; DBP,

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