Food Reward Without a Timing Component Does Not Alter the Timing of Activity Under Positive Energy Balance

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Please cite this article in press as: van der Vinne V et al. Food reward without a timing component does not alter the timing of activity under positive

energy balance. Neuroscience (2015), http://dx.doi.org/10.1016/j.neuroscience.2015.07.061

NSC 16458 No. of Pages 6

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Neuroscience xxx (2015) xxx–xxx

FOOD REWARD WITHOUT A TIMING COMPONENT DOES NOT ALTERTHE TIMING OF ACTIVITY UNDER POSITIVE ENERGY BALANCE

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V. VAN DER VINNE, *� J. AKKERMAN, G. D. LANTING,S. J. RIEDE AND R. A. HUT

Chronobiology Unit, Groningen Institute for Evolutionary

Life Sciences, University of Groningen, Groningen, The Netherlands
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Abstract—Circadian clocks drive daily rhythms in physiol-

ogy and behavior which allow organisms to anticipate

predictable daily changes in the environment. In most mam-

mals, circadian rhythms result in nocturnal activity patterns

although plasticity of the circadian system allows activity

patterns to shift to different times of day. Such plasticity is

seen when food access is restricted to a few hours during

the resting (light) phase resulting in food anticipatory activity

(FAA) in the hours preceding food availability. The mecha-

nisms underlying FAA are unknown but data suggest the

involvement of the reward system and homeostatic regula-

tion of metabolism.We previously demonstrated the isolated

effect of metabolism by inducing diurnality in response to

energetic challenges. Here the importance of reward timing

in inducing daytime activity is assessed. The daily activity

distribution of mice earning palatable chocolate at their pre-

ferred time byworking in a runningwheel was comparedwith

that of mice receiving a timed palatable meal at noon. Mice

working for chocolate (WFC) without being energetically

challenged increased their total daily activity but this did

not result in a shift to diurnality. Providing a chocolate meal

at noon each day increased daytime activity, identifying food

timing as a factor capable of altering the daily distribution of

activity and rest. These results show that timing of food

reward and energetic challenges are both independently suf-

ficient to induce diurnality in nocturnal mammals. FAA

observed following timed food restriction is likely the result

of an additive effect of distinct regulatory pathways activated

by energetic challenges and food reward. � 2015 Published

by Elsevier Ltd. on behalf of IBRO.

Key words: activity rhythm, circadian thermo-energetics,

food entrainable oscillator, nocturnality, palatable food.

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http://dx.doi.org/10.1016/j.neuroscience.2015.07.0610306-4522/� 2015 Published by Elsevier Ltd. on behalf of IBRO.

*Corresponding author.

E-mail address: [email protected] (V. van der Vinne).� Present address: Department of Neurobiology, University of

Massachusetts Medical School, Worcester, MA, USA.Abbreviations: CTE, circadian thermo-energetics hypothesis; COG,center of gravity; ExT, external time; FAA, food anticipatory activity;FEO, food entrainable oscillator; LD, light–dark; SCN, suprachiasmaticnucleus; TCF, timed chocolate feeding; WFC, working for chocolateprotocol; WFF, working for food protocol.

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INTRODUCTION

Circadian clocks drive daily oscillations in physiology and

behavior allowing organisms to anticipate daily changes

in their environment (Pittendrigh, 1993). The main mam-

malian circadian oscillator in the suprachiasmatic nucleus

(SCN) is synchronized with the outside light–dark (LD)

cycle by light input from the eye (Reppert and Weaver,

2002). The SCN uses neuronal and endocrine pathways

to orchestrate rhythmicity throughout the brain and

peripheral tissues (Dibner et al., 2010), leading to noctur-

nal activity patterns in most small mammals.

Plasticity in circadian organization allows for adaptation

to changes in the temporal organization of the environment

(Hut et al., 2012). Such plasticity can be observed when

access to food is restricted to a limited time during the light

phase (Mistlberger, 1994; Stephan, 2002). Food restriction

during the light phase results in food anticipatory activity

(FAA) accompanied by phase changes in body tempera-

ture, corticosterone (Mistlberger, 1994; Stephan, 2002)

and liver rhythms (Stokkan et al., 2001), while the SCN

remains phase locked to the LD cycle (Stokkan et al.,

2001). FAA-related activity bouts persist during periods of

complete food deprivation, show transients when entraining

to different mealtimes and are expressed in SCN-ablated

animals (Stephan et al., 1979). Together, these experi-

ments show that FAA is driven by a SCN-independent ‘food

entrainable oscillator’ (FEO).

Time-restricted feeding protocols used to induce FAA

typically reduce daily food intake to 60–80% of ad libitum

levels to motivate animals to eat during their rest phase.

Increasing the severity of food deprivation also increases

FAA (Mendoza et al., 2005b; Gallardo et al., 2014), sug-

gesting that negative energy balance per se might be able

to induce diurnal activity in otherwise nocturnal mammals

(Hut et al., 2011, 2012). This idea was made explicit in

the circadian thermo-energetics (CTE) hypothesis, which

predicted that energetically challenged animals become

day active, because diurnality is associated with reduced

daily energy expenditure under natural conditions (Hut

et al., 2012; van der Vinne et al., 2014). The CTE hypothe-

sis was tested in a protocol where mice were energetically

challenged by letting them work for food (WFF; Hut et al.,

2011). High ‘workloads’ (i.e. running long distances to

obtain a food pellet) indeed induce diurnality in mice (Hut

et al., 2011) and this effect is augmented by lower ambient

temperatures (van der Vinne et al., 2014). The WFF exper-

iments thus confirm that negative energy balance per seinduces diurnality and hence negative energy balance

can partly explain diurnal activity in FAA protocols.

http://dx.doi.org/10.1016/j.neuroscience.2015.07.061

mailto:[email protected]



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The argument above does not rule out the timing of

food availability as an important factor in inducing FAA.

Providing a palatable chocolate meal during the light

phase in animals with ad libitum access to regular chow

can induce FAA in rats (Mistlberger and Rusak, 1987;

Mendoza et al., 2005a; Verwey et al., 2007; Angeles-

Castellanos et al., 2008) and mice (Hsu et al., 2010).

The length and intensity of FAA, induced without chal-

lenging animals energetically, is reduced in comparison

to the FAA observed when all food access is restricted

to the light phase (Mendoza et al., 2005a; Verwey et al.,

2007; Angeles-Castellanos et al., 2008). Taken together,

these data show that the FEO controlled expression of

FAA is induced by effects of food timing combined with

negative energy balance. This suggests that both the

reward system and homeostatic regulation of metabolism

are involved in the expression of the FEO.

To test whether the reward system is also involved in

WFF-induced diurnality, we developed the ‘working for

chocolate’ (WFC) protocol in which mice with ad libitumaccess to regular chow can obtain a palatable chocolate

reward at all times of day by running in a wheel. The

daily distribution of activity observed during the WFC

protocol was compared to that of mice receiving a

chocolate reward in the middle of the light phase to

assess the importance of reward timing in re-organizing

the daily activity pattern. We expect that in the absence

of energetic challenges, daytime activity can be induced

by reward timing but not when reward timing is absent

in the WFC protocol. Furthermore, the long-term impact

of a palatable meal on the daily distribution of activity

was assessed by monitoring the daily activity pattern

after termination of daytime chocolate feeding.
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EXPERIMENTAL PROCEDURES

Animals and activity registration

Male CBA/CaJ mice were moved from our breeding

facility (14 h–10 h LD cycle) to the experimental rooms

(12 h–12 h LD cycle) at least one week before the start

of experiments. Mice were housed individually in

standard macrolon cages (15 � 32 � 13 cm) equipped

with a running wheel on a sawdust bedding (Lignocel

hygienic animal bedding, Rettenmaier, Rosenberg,

Germany) on experimental day 0. Standard chow food

(AM II diet rodent chow 10 mm, 17.3 kJ/g, Arie Blok,

Woerden, The Netherlands) and water were provided

ad libitum throughout the experiments. Procedures were

approved by the Animal Experimentation Committee of

the University of Groningen (DEC 5454).

Running wheel activity and activity around the feeding

place (only Experiment 2) were recorded in two-minute

bins and split in daily intervals starting at lights on

(external time (ExT) six). Activity during the light phase

was divided by the total daily activity to calculate the

percentage of daytime activity. Daily activity onset and

offset were calculated as the intersections of a short

(10 min) and a long running average (24 h; Hut et al.,

1999). Daily center of gravity (COG) was calculated as

the time of day where total activity in the preceding and

following 8 h was equal. Analyses were performed using

Please cite this article in press as: van der Vinne V et al. Food reward without

energy balance. Neuroscience (2015), http://dx.doi.org/10.1016/j.neuroscience

custom build scripts in SciLab 5.5.0, with statistics being

performed using mixed-effects general linear models in

SAS JMP 7.0. In these statistical analyses, separate anal-

yses were performed for each of the dependent variables

(daytime activity, onset, COG and offset) with treatment

as independent factor. Animal ID was included as a ran-

dom factor to our analyses to correct for the repeated

measurement of each individual. Tukey HSD post hoc

tests were performed when applicable. Data are repre-

sented as mean ± SEM in graphs and text.

Experiment 1: WFC

The WFC protocol allowed twelve ad libitum fed, five-

month-old mice to additionally earn 45-mg chocolate

pellets (Dustless Precision Pellets�, Sucrose, Chocolate

Flavor) by running in a wheel. The workload, the number

of revolutions needed to obtain a chocolate pellet, started

at 500 revs/pellet on day nine and was increased in steps

of 20 revs/pellet daily to 700 revs/pellet, where it was kept

stable (resulting in 37.3 ± 3.5 chocolate pellets per day).

This workload was chosen because it resulted in a

chocolate intake that was approximately twice the intake

observed when chocolate was provided at a fixed time,

ensuring that the lack of a phase shift during WFC was

not a result of lowered chocolate intake. The timing of the

chocolate reward in the WFC protocol was computer

controlled and the mice thus received their food reward

each time they reached the workload threshold. Reward

timing thus depended solely on the spontaneous activity

rhythm of the mice. After the WFC protocol (day 26 until

the end), each mouse was provided with 20 pellets daily

at the middle of the light phase (ExT 12) to assess the

effect of timed chocolate feeding (TCF) on the activity

rhythm. Daily checks were performed around one hour

before lights off, to confirm that all chocolate pellets had

been consumed. The daily distribution of activity was

compared for the last 5 days preceding WFC (AL), the

last 5 days of WFC (WFC) and the last 5 days of timed

chocolate feeding.

Experiment 2: TCF

Eight mice (1.5-month-old) were provided with 20 pellets

for two hours, starting at the middle of the light phase

(ExT 12). Food was given in a bowl without opening the

cage and remaining pellets were removed after two

hours to assess the number of pellets eaten. Chocolate

pellets were provided on days 9–40. On days 41–60

chocolate was replaced by chow pellets provided

between ExT 12 and 14, followed by 20 days of

undisturbed ad libitum feeding with only regular chow.

On experimental days 29–30, the acute effect of

termination of daily TCF was assessed by providing

mice with chow pellets between ExT 12 and 14.

Anticipatory activity around the feeding location was

assessed by measuring general locomotor activity using

a passive infrared detector placed directly above the

feeding place. The effects of TCF were assessed

between the last 5 days preceding TCF (pre test), the

last 5 days of TCF (Chocolate), the last 5 days of daily

provisioning of additional chow pellets (Chow pellets)

a timing component does not alter the timing of activity under positive

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and the last 5 days without disturbance (post test). The

acute effects of termination of TCF were assessed by

comparing the changes in daily distribution of activity on

day 27–32.

RESULTS

Experiment 1: WFC

The effect of a food reward on timing of activity, without

being energetically challenged, was assessed by the

Fig. 2. Activity is phase advanced by TCF but not by WFC compared to AL. (

and TCF in 10-min bins with SEM. TCF induced a phase advance of activit

decreased during the middle dark phase during TCF compared to AL and WF

advanced by TCF but not by WFC.

Fig. 1. Mice remain nocturnal during working for chocolate (WFC) but diurnal

(A) Representative actogram of ad libitum fed mouse undergoing WFC (day

daily proportion of activity occurring during the light phase is plotted in the rig

phase is unaffected by WFC (day 21–25) but increases significantly during T

Total daily activity is increased during the last five days of WFC compared t



WFC protocol in mice with ad libitum access to regular

chow (Fig. 1A). Body mass increased significantly

throughout the experiment (F14,152 = 5.884; p< 0.0001)

without changes in growth during any of the different

feeding regimes, showing that the mice were never

energetically challenged during the experiment. WFC

induced significantly higher daily activity levels

(compared to no chocolate meal (AL) or TCF;

F2,175 = 48.66, p< 0.0001; Fig. 1C) without changing

the timing of activity. Timing of activity was only altered

A) Average relative activity profiles during the last 5 days of AL, WFC

y. Activity was increased during the middle and late light phase and

C. (B) Activity onset, center of gravity (COG) and offset were all phase

ity is induced by timed chocolate feeding during the light phase (TCF).

9–25, hatched area) followed by TCF (day 26–39, vertical line). The

ht hand graph. (B) The proportion of activity occurring during the light

CF (day 35–39), compared to ad libitum (AL; day 4–8) fed mice. (C)

o AL and TCF. *p< 0.05.


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Fig. 3. Representative actograms showing running wheel and feeding place activity of a mouse provided with chocolate (days 9–28, 31–40) or

additional chow (days 29–30, 41–60) for two hours during the light phase. Chocolate feeding during the day advanced the main activity bout but did

not induce food anticipatory activity in either running wheel or feeding place activity. The daily proportion of total activity occurring during the light

phase is plotted to the right of each actogram. The total number of consumed chocolate (purple/black) and chow (green/gray) pellets eaten during

the 2-h interval is shown in the middle graph. (For interpretation of the references to color in this figure legend, the reader is referred to the web

version of this article.)



29 July 2015

when a chocolate reward was provided in the middle of

the light phase (F2,162.1 = 222.1, p< 0.0001; Fig. 1B).

The percentage of activity occurring during the light

phase in mice undergoing AL (22.2 ± 4.1%) and WFC

(21.6 ± 4.8%) was indistinguishable from that observed

in undisturbed ad libitum fed mice (van der Vinne et al.,

2014).

The effect of TCF was also observed when the onset,

COG and offset of activity were used as phase markers of

the activity rhythm. Compared to days without access to

chocolate, WFC did not induce a phase shift in these

three phase markers while TCF produced a phase

advance of the activity rhythm (Onset: F2,165 = 23.21,

p< 0.0001; COG: F2,164 = 135.2, p< 0.0001; Offset

F2,166 = 62.25, p< 0.0001; Fig. 2B). Analysis of the

distribution of activity in 10-min bins showed increased



activity during the middle and late light phase and a

decrease during the middle of the dark phase during

TCF compared to AL and WFC (Fig. 2A).

Experiment 2: TCF

The importance of food timing for the induction of

diurnality in mice not subjected to energetic challenges

was further studied to determine the influence of

prolonged daytime food reward on diurnality. Body mass

increases throughout the experiment showed that the

mice maintained a positive energy balance

(F8,56 = 67.31; p< 0.0001) without changes in growth

between the different feeding regimes. Chocolate pellets

were provided in a 2-h interval during the light phase

and feeder approaches were measured using a passive


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infrared detector placed directly above the feeding cup.

These measurements did not reveal a separate FAA

bout in any of the eight mice preceding the

administration of chocolate (Fig. 3). The obtained

reward increased from 6.0 ± 1.0 pellets/day in the first

5 days to 16.8 ± 0.8 pellets/day in the last 5 days of

chocolate feeding.

The importance of continued exposure to timed feeding

during the light phase for the maintenance of the phase-

advanced phenotype was assessed by replacing the

chocolate reward with regular-chow pellets. The imme-

diate effects of chocolate replacement were assessed on

experimental days 27–32 (Fig. 4B). Replacement of the

chocolate reward by regular chow did not result in a

return to a nocturnal activity profile (F5,35 = 1.724,

p=0.1548). Prolonged absence (20–40 days) of TCF

during the light phase resulted in a significant reduction in

relative daytime activity but daytime activity remained

significantly increased compared to the pre-test period

(F3,149 = 63.72, p< 0.0001; Fig. 4A). Surprisingly, the

fraction of activity occurring during the light phase stayed

nearly the same between experimental days 60 and 80,

showing a long-lasting effect of food reward during the

light phase on activity timing.
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Fig. 4. Daytime chocolate feeding produces a slowly reversible

increase in daytime activity. (A) The proportion of activity occurring

during the light phase was significantly increased after 35–40 days of

daytime chocolate feeding (Chocolate). Relative daytime activity

reduced significantly after termination of chocolate feeding but did not

return to pre-test levels in mice provided with additional chow pellets

(Chow pellets; days 56–60) and left undisturbed (post-test; days 76–

80). (B) Relative daytime activity did not change significantly during a

two-day interruption of daytime chocolate feeding. *p< 0.05.



DISCUSSION

This study was designed to assess the influence of food

timing on the daily distribution of activity in the absence

of energetic challenges. The lack of a phase shift of

activity during WFC shows that an endogenously driven

shift to diurnality as observed during WFF (Hut et al.,

2011; van der Vinne et al., 2014) requires an energetic

challenge and cannot be induced by elevated activity

levels or the rewarding aspects of food. Although mice

increased the number of revolutions to obtain more

chocolate, these elevated activity levels did not change

the phase of the daily rhythm of activity and rest. Timing

of a palatable chocolate meal during the light phase did

however induce a phase shift in the daily timing of activity

in the absence of energetic challenges. These results

show that daytime food reward, independent of energetic

challenges, is sufficient to induce diurnality in mice.

Previous studies assessing the influence of time-

restricted palatable food access showed that the

intensity of FAA is typically lower than that observed in

response to timed food restriction (Mistlberger and

Rusak, 1987; Mendoza et al., 2005a; Verwey et al.,

2007; Angeles-Castellanos et al., 2008), while other stud-

ies failed to induce FAA (Abe and Rusak, 1992; Pecoraro

et al., 2002; Waddington Lamont et al., 2007). In the pre-

sent study, all 20 mice subjected to TCF showed a shifted

daily activity pattern although the behavioral changes

were smaller than those observed during timed food

restriction and WFF experiments (van der Vinne et al.,

2014), illustrating the importance of the metabolic state

of an animal in shaping the daily distribution of activity

(Hsu et al., 2010; van der Vinne et al., 2014).

The current study produced prolonged changes in the

daily distribution of activity and rest after daily chocolate

exposure was stopped. Although mice became

significantly less day active over the 40-day extinction

period, mice were substantially more day active during

the post-test period than pre-test. Compared to previous

measurements of the day activity observed in

undisturbed ad libitum fed mice in our laboratory (van

der Vinne et al., 2014), post-test daytime activity was also

significantly increased. Continued activity around the time

of feeding following a return to ad libitum feeding has

been reported previously (Abe and Rusak, 1992), but

not for the prolonged period seen in the present study.

The absence of energetic constraints or a reduced nega-

tive masking response in our mice might possibly provide

an explanation for the prolonged daytime activity. Overall,

the present study shows that our mice responded to time-

restricted palatable food access by robustly altering the

daily distribution of activity and rest.

The behavioral changes induced by timed palatable

food access in this study were qualitatively different

compared to the FAA observed in previous studies in

rats. Whereas the time-restricted feeding in rats induced

a separate FAA activity bout (Mistlberger and Rusak,

1987; Mendoza et al., 2005a; Verwey et al., 2007;

Angeles-Castellanos et al., 2008), our mice responded

to a timed daytime chocolate reward by phase advancing

the entire active phase. Previous studies assessing the

influence of time-restricted palatable food access in mice


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29 July 2015

and hamsters did also not report a separate FAA activity

bout during the light phase (Abe and Rusak, 1992; Hsu

et al., 2010; Mendoza et al., 2010). Overall, these results

indicate a possible species difference between rats and

other rodents in their response to the weak timing signal

provided by time-restricted palatable food access, with

rats being more likely to split their total daily activity into

multiple activity bouts.

FAA induced by time-restricted feeding protocols is

likely the result of the combined influences of the

energetic challenges and daytime food reward that

occur during these protocols (Challet and Mendoza,

2010). Assuming that these two driving forces underlying

FAA are located in anatomically distinct locations may

explain why a large number of studies have been unsuc-

cessful in finding a single locus for the FEO (reviewed in

Davidson, 2009). This leads to the suggestion that the

FEO is comprised of a dispersed network of clocks

(Davidson, 2009; Verwey and Amir, 2009; Mistlberger,

2011; Blum et al., 2012). In line with this network hypoth-

esis is the observation that FAA is reduced following DMH

lesioning but reappears after SCN ablation (Acosta-

Galvan et al., 2011). Our results show that mice exposed

to the WFC protocol did not become diurnal while the

same mice shifted their active phase in response to

TCF. Because WFC simulates the rewarding aspect of

food in the previously used WFF protocol (Hut et al.,

2011; van der Vinne et al., 2014) without challenging mice

energetically, we conclude that distinct regulatory net-

works activated by either energetic challenges or by timed

food reward, are both capable of inducing diurnality.
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Acknowledgments—We thank Jamey Scheepe, Nathasja Hartog

and Jenke Gorter for practical help during the experimental pro-

cedures. This work was partially funded an Ubbo Emmius

Fellowship (to S.J.R.).

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(Accepted 21 July 2015)(Available online xxxx)


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