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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
1

Neuroscience xxx (2015) xxxxxx

FOOD REWARD WITHOUT A TIMING COMPONENT DOES NOT ALTER

THE 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

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Chronobiology Unit, Groningen Institute for Evolutionary

Life Sciences, University of Groningen, Groningen, The Netherlands

AbstractCircadian clocks drive daily rhythms in physiology and behavior which allow organisms to anticipate
predictable daily changes in the environment. In most mammals, circadian rhythms result in nocturnal activity patterns
although plasticity of the circadian system allows activity
patterns to shift to dierent 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 mechanisms underlying FAA are unknown but data suggest the
involvement of the reward system and homeostatic regulation of metabolism. We previously demonstrated the isolated
eect 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 preferred time by working in a running wheel was compared with
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 sufcient to induce diurnality in nocturnal mammals. FAA
observed following timed food restriction is likely the result
of an additive eect 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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*Corresponding author.
E-mail address: vincentvandervinne@gmail.com (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, lightdark; SCN, suprachiasmatic
nucleus; TCF, timed chocolate feeding; WFC, working for chocolate
protocol; WFF, working for food protocol.
http://dx.doi.org/10.1016/j.neuroscience.2015.07.061
0306-4522/ 2015 Published by Elsevier Ltd. on behalf of IBRO.
1

INTRODUCTION

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Circadian clocks drive daily oscillations in physiology and

behavior allowing organisms to anticipate daily changes
in their environment (Pittendrigh, 1993). The main mammalian circadian oscillator in the suprachiasmatic nucleus
(SCN) is synchronized with the outside lightdark (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 nocturnal 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 temperature, 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 dierent mealtimes and are expressed in SCN-ablated
animals (Stephan et al., 1979). Together, these experiments 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 6080% 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), suggesting 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 hypothesis 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 eect is augmented by lower ambient
temperatures (van der Vinne et al., 2014). The WFF experiments thus conrm that negative energy balance per se
induces diurnality and hence negative energy balance
can partly explain diurnal activity in FAA protocols.

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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; AngelesCastellanos et al., 2008) and mice (Hsu et al., 2010).
The length and intensity of FAA, induced without challenging 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 eects 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 libitum
access 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.

EXPERIMENTAL PROCEDURES

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Animals and activity registration

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Male CBA/CaJ mice were moved from our breeding

facility (14 h10 h LD cycle) to the experimental rooms
(12 h12 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
oset 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

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custom build scripts in SciLab 5.5.0, with statistics being

performed using mixed-eects general linear models in
SAS JMP 7.0. In these statistical analyses, separate analyses were performed for each of the dependent variables
(daytime activity, onset, COG and oset) with treatment
as independent factor. Animal ID was included as a random factor to our analyses to correct for the repeated
measurement of each individual. Tukey HSD post hoc
tests were performed when applicable. Data are represented as mean SEM in graphs and text.

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Experiment 1: WFC

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The WFC protocol allowed twelve ad libitum fed, vemonth-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 xed 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
eect of timed chocolate feeding (TCF) on the activity
rhythm. Daily checks were performed around one hour
before lights o, to conrm 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.

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Experiment 2: TCF

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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 940. On days 4160
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 2930, the acute eect 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 eects 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)

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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

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

acute eects of termination of TCF were assessed by
comparing the changes in daily distribution of activity on
day 2732.

RESULTS

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Experiment 1: WFC

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

being energetically challenged, was assessed by the

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WFC protocol in mice with ad libitum access to regular

chow (Fig. 1A). Body mass increased signicantly
throughout the experiment (F14,152 = 5.884; p < 0.0001)
without changes in growth during any of the dierent
feeding regimes, showing that the mice were never
energetically challenged during the experiment. WFC
induced signicantly 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

Fig. 1. Mice remain nocturnal during working for chocolate (WFC) but diurnality is induced by timed chocolate feeding during the light phase (TCF).
(A) Representative actogram of ad libitum fed mouse undergoing WFC (day 925, hatched area) followed by TCF (day 2639, vertical line). The
daily proportion of activity occurring during the light phase is plotted in the right hand graph. (B) The proportion of activity occurring during the light
phase is unaected by WFC (day 2125) but increases signicantly during TCF (day 3539), compared to ad libitum (AL; day 48) fed mice. (C)
Total daily activity is increased during the last ve days of WFC compared to AL and TCF. *p < 0.05.

Fig. 2. Activity is phase advanced by TCF but not by WFC compared to AL. (A) Average relative activity proles during the last 5 days of AL, WFC
and TCF in 10-min bins with SEM. TCF induced a phase advance of activity. Activity was increased during the middle and late light phase and
decreased during the middle dark phase during TCF compared to AL and WFC. (B) Activity onset, center of gravity (COG) and oset were all phase
advanced by TCF but not by WFC.
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

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Fig. 3. Representative actograms showing running wheel and feeding place activity of a mouse provided with chocolate (days 928, 3140) or
additional chow (days 2930, 4160) 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 gure legend, the reader is referred to the web
version of this article.)

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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 eect of TCF was also observed when the onset,
COG and oset 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; Oset
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).

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Experiment 2: TCF

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The importance of food timing for the induction of

diurnality in mice not subjected to energetic challenges
was further studied to determine the inuence 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 dierent 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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energy balance. Neuroscience (2015), http://dx.doi.org/10.1016/j.neuroscience.2015.07.061

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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 rst
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 phaseadvanced phenotype was assessed by replacing the
chocolate reward with regular-chow pellets. The immediate eects of chocolate replacement were assessed on
experimental days 2732 (Fig. 4B). Replacement of the
chocolate reward by regular chow did not result in a
return to a nocturnal activity prole (F5,35 = 1.724,
p = 0.1548). Prolonged absence (2040 days) of TCF
during the light phase resulted in a signicant reduction in
relative daytime activity but daytime activity remained
signicantly 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 eect of food reward during the
light phase on activity timing.

Fig. 4. Daytime chocolate feeding produces a slowly reversible

increase in daytime activity. (A) The proportion of activity occurring
during the light phase was signicantly increased after 3540 days of
daytime chocolate feeding (Chocolate). Relative daytime activity
reduced signicantly after termination of chocolate feeding but did not
return to pre-test levels in mice provided with additional chow pellets
(Chow pellets; days 5660) and left undisturbed (post-test; days 76
80). (B) Relative daytime activity did not change signicantly during a
two-day interruption of daytime chocolate feeding. *p < 0.05.

DISCUSSION

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This study was designed to assess the inuence 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 sucient to induce diurnality in mice.
Previous studies assessing the inuence of timerestricted 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 studies failed to induce FAA (Abe and Rusak, 1992; Pecoraro
et al., 2002; Waddington Lamont et al., 2007). In the present 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
signicantly 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
signicantly 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 negative 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 timerestricted 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 dierent
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
inuence of time-restricted palatable food access in mice

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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

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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 dierence 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 inuences 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 unsuccessful in nding 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 hypothesis is the observation that FAA is reduced following DMH
lesioning but reappears after SCN ablation (AcostaGalvan 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 networks activated by either energetic challenges or by timed
food reward, are both capable of inducing diurnality.

343

AcknowledgmentsWe thank Jamey Scheepe, Nathasja Hartog

and Jenke Gorter for practical help during the experimental procedures. This work was partially funded an Ubbo Emmius
Fellowship (to S.J.R.).

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(Accepted 21 July 2015)

(Available online xxxx)

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

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