Physiology & Behavior 128 (2014) 92–98
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Effects of light, food, and methamphetamine on the circadian activity rhythm in mice Julie S. Pendergast 1, Shin Yamazaki ⁎ Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA
H I G H L I G H T S • • • •
Food anticipatory activity phase shifts coordinately with the light–dark cycle. The phase of food anticipatory activity is delayed by methamphetamine consumption. Coupling of the SCN and MASCO is affected by exposure to restricted feeding. The outputs of the SCN, FEO and MASCO collectively drive behavior.
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Article history: Received 17 July 2013 Received in revised form 2 November 2013 Accepted 25 January 2014 Available online 11 February 2014 Keywords: FEO Restricted feeding SCN MASCO Pacemaker coupling C57BL/6J
a b s t r a c t The circadian rhythm of locomotor activity in mice is synchronized to environmental factors such as light and food availability. It is well-known that entrainment of the activity rhythm to the light–dark cycle is attained by the circadian pacemaker in the suprachiasmatic nucleus (SCN). Locomotor activity is also controlled by two extra-SCN oscillators; periodic food availability entrains the food-entrainable oscillator (FEO) and constant consumption of low-dose methamphetamine reveals the output of the methamphetamine-sensitive circadian oscillator (MASCO). In this study, we sought to investigate the relationship between the SCN, FEO, and MASCO by examining the combinatorial effects of light, food restriction, and/or methamphetamine on locomotor activity. To investigate coupling between the SCN and FEO, we tested whether food anticipatory activity, which is the output of the FEO, shifted coordinately with phase shifts of the light–dark cycle. We found that the phase of food anticipatory activity was phase-delayed or phase-advanced symmetrically with the respective shift of the light–dark cycle, suggesting that the FEO is strongly coupled to the SCN and the phase angle between the SCN and FEO is maintained during ad libitum feeding. To examine the effect of methamphetamine on the output of the FEO, we administered methamphetamine to mice undergoing restricted feeding and found that foodentrained activity was delayed by methamphetamine treatment. In addition, restricted feeding induced dissociation of the MASCO and SCN activity rhythms during short-term methamphetamine treatment, when these rhythms are typically integrated. In conclusion, our data suggest that the outputs of the SCN, FEO and MASCO collectively drive locomotor activity. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Light and food availability are periodic environmental factors that entrain circadian oscillators in mammals. Entrainment is believed to improve fitness and survival by allowing anticipation of predictable daily changes in environmental conditions and coordinating precise phasing of rhythms in behavior and physiology. ⁎ Corresponding author at: Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390–9111, USA. Tel.: +1 214 648 1830. E-mail address: [email protected] (S. Yamazaki). 1 Present address: Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
http://dx.doi.org/10.1016/j.physbeh.2014.01.021 0031-9384/© 2014 Elsevier Inc. All rights reserved.
It is well-known that light entrains the circadian pacemaker in the suprachiasmatic nucleus (SCN) through monosynaptic projections from the retina [1]. Numerous studies have also examined the effect of periodic food availability on circadian locomotor activity. When a single daily meal is provided at a fixed time of day (i.e. restricted feeding), locomotor activity increases 2 to 4 h before the scheduled feeding time [2,3]. Even though this food anticipatory activity disappears during ad libitum feeding, it reappears at the previous time of restricted feeding when rodents are subsequently food deprived, demonstrating that it is controlled by a self-sustained oscillator [2]. In addition, food anticipatory activity persists when the SCN is lesioned and displays properties of a circadian oscillator, namely a limited range of entrainment and transients following phase shifts of mealtime [4–10]. Thus, the food-
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entrainable oscillator (FEO) that controls food anticipatory activity is distinct from the SCN, although its anatomical locus is unknown [11]. Compared to the SCN and FEO, relatively few studies have examined the methamphetamine-sensitive circadian oscillator (MASCO). The MASCO-controlled wheel-running activity rhythm is observed when rats and mice are continuously administered low-dose methamphetamine [12,13]. During chronic (N30 days) methamphetamine treatment, the MASCO-controlled activity rhythm dissociates from the
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SCN-controlled activity rhythm and the MASCO rhythm also persists when the SCN is lesioned, demonstrating that the MASCO is distinct from the SCN [13–17]. Like the FEO, the anatomical locus of MASCO is unknown. This has, in part, led to speculation that the FEO and MASCO are the same oscillator (but see [18]; for discussion see [17]). The SCN is regarded as the master pacemaker because it coordinates the phases of peripheral clocks and controls rhythmic locomotor activity [19,20]. Like the SCN, the FEO and MASCO can coordinate the phases of
Fig. 1. Effect of shifting the light–dark cycle on the phase of food anticipatory activity. Double-plotted actograms of wheel-running activity (5-min bins) of wild-type mice (A, C, E: males; B, D, F: females) maintained in 18L:6D (x-axis: time in hours; y-axis: days). Darkness is outlined with black boxes and the time when food was available is indicated by gray shading (shown only on the left halves of the actograms). The mice were fed ad libitum (AL) for 2 days, and then deprived of food for 25 h. Food availability was then gradually reduced from 8 h (2 days) to 6 h (2 days) and then to 4 h (15 days) per day (RF). Mice were then fed ad libitum (ALI) for 7 days. On the third day of ad libitum feeding, the light–dark cycle was either not shifted (A, B), delayed 6 h (C, D), or advanced 6 h (E, F). Four days later, mice were food deprived (FDI) for 50 h. Then, mice were fed ad libitum (ALII) for 5 days and then food deprived (FDII) again for 48 h.
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peripheral oscillators and control locomotor activity, suggesting that they also function at the top of the hierarchy of the mammalian circadian system [19–21]. Thus, the circadian rhythm of locomotor activity is controlled not only by SCN output, but also by the output of oscillators responding to at least three distinct environmental cues—light entrains the SCN, food entrains the FEO, and methamphetamine reveals MASCO output. In this study, we sought to investigate the relationship between these oscillators by examining the combinatorial effects of light, food restriction, and/or methamphetamine on locomotor activity.
(starting at ZT8, where ZT0 is lights on), and then fed 8 h/day for 2 days and 6 h/day for 2 days (starting at ZT8). Then mice were fed 4 h/day (ZT10–14) for 13 days. On the 14th day, food was placed in the cage at ZT10 and was not removed. On the 3rd day of ad libitum feeding, the time of lights on was either not shifted (n = 8), delayed by 6 h (n = 8), or advanced by 6 h (n = 8). After 6 days of ad libitum feeding (3 days before the shift and 3 days after the shift), mice were food deprived for 48 h (starting at 18:00 local time in all groups). Mice were then fed ad libitum for 4 days and then food deprived for 48 h (starting at 18:00 local time in all groups).
2. Materials and methods 2.1. Animals Adult male and female mice (5 to 18 weeks old) were used for all experiments. C57BL/6J mice were purchased from the Jackson Laboratory (Bar Harbor, ME, USA; Fig. 1; Fig. S1–S3 except the mice shown in Fig. S2E–H), where they were bred and group-housed in a 14-h light/ 10-h dark cycle, or C57BL/6J mice were bred and group-housed in the Vanderbilt University animal facility in 12L:12D (light intensity ~350 lx; Figs. S2E–H, S3, S4). All experiments were approved by the Institutional Animal Care and Use Committee at Vanderbilt University (M/08/096). 2.2. Recording of circadian behavior Animals were singly housed in cages (length × height × width: 33 × 17 × 14 cm) with unlimited access to a running wheel (diameter 11 cm), food, and water. The cages were placed in light-tight, ventilated boxes in 18L:6D (light intensity: 200–300 lx). Cages were changed every 3 weeks. Wheel-running activity (recorded every minute by computer) was monitored and analyzed using ClockLab (Actimetrics, Wilmette, IL, USA). Activity data were double-plotted in actograms in 5-min bins using the normalized format in ClockLab. 2.3. Restricted feeding
2.3.2. Methamphetamine treatment during restricted feeding Mice (n = 3) were maintained in 18L:6D for 78 days with ad libitum food. Mice were then fed 6 h/day (starting at ZT8, where ZT0 is lights on) for 33 days. On the 22nd day of restricted feeding, mice were given 0.005% methamphetamine in their drinking water at the same time that food was provided. Methamphetamine was administered for the remainder of the experiment. 2.3.3. Release from restricted feeding during methamphetamine treatment Mice were maintained in 18L:6D and continuously administered 0.005% methamphetamine in their drinking water for 78 days. One group of mice (n = 4; Fig. 4A–D) were fed ad libitum for the entire experiment. Another group of mice (n = 3; Fig. 4E–G; same mice as described in Section 2.3.2) were fed 6 h/day during the first 12 days of methamphetamine treatment and then fed ad libitum for the remainder of the 78 days. 2.3.4. Analysis The phase of food anticipatory activity was determined using ClockLab. During restricted feeding, activity for each mouse was averaged over 10 days of 4 h/day restricted feeding. The phase of food anticipatory activity was designated as the time when daytime activity exceeded 10 counts/min on the activity profile. During food deprivation, the phase of food anticipatory activity was defined as the time when daytime activity exceeded 10 counts/min on the activity profile of the
Mice were fed LabDiet™ 5L0D (Purina, Richmond, IN). Food was placed on the bottom of the cage and in the hopper during restricted feeding. Mice were allowed to eat as much as they desired during the time when food was available. When food was removed, the lighttight box was opened and all food was removed from the wire-top and from the bottom of the cage. When food was removed in the dark (Fig. 1E, F; Fig. S3), an infrared viewer (FIND-R-SCOPE Infrared Viewer, FJW Optical Systems, Inc., Palatine, IL) was used so that mice were not exposed to visible light. During ad libitum feeding and food deprivation, the light-tight boxes were not opened in order to avoid any external cues associated with food availability. During this time, the well-being of the mouse was monitored by assessing wheel-running data collected by computer. 2.3.1. Restricted feeding protocol during shifts of the light–dark cycle To examine the effect of shifting the light–dark cycle on the phase of food anticipatory activity, we performed experiments in 18L:6D for two reasons. First, we found in our previous studies that food anticipatory activity was more robust in long photoperiods and we wanted to provide ideal conditions for observing food anticipatory in our current experiments [22]. Second, if 6-h shifts of the light–dark cycle were performed in 12L:12D, the predicted phase of food anticipatory activity would occur during the dark phase, making it difficult to distinguish food anticipatory activity (output of the FEO) from nocturnal activity (output of the SCN). After 6-h shifts of the light–dark cycle in 18L:6D, the predicted phase of food anticipatory activity would occur during the light phase, thus permitting the distinction between FEO and SCN output. Mice were maintained in 18L:6D (lights on 03:00–21:00 local time) for 5–8 days with ad libitum food. After acclimation to the wheelrunning cage (for at least 4 days), mice were food deprived for 24 h
Fig. 2. The phase of food anticipatory activity shifts coordinately with the light–dark cycle. The mean phases (±SD) of food anticipatory activity during restricted feeding (RF) and during day 2 of food deprivation following either 1 week (FDI) or 2 weeks (FDII) of ad libitium feeding are plotted. The light–dark cycle was either not shifted (A), delayed 6 h (B), or advanced 6 h (C) prior to food deprivation. White and gray boxes show light and dark, respectively. The dotted line indicates the time of restricted feeding. The arrows indicate the predicted phase if food anticipatory activity shifted coordinately with the light–dark cycle.
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Fig. 3. Effect of methamphetamine on food-entrained activity. Double-plotted actograms of wheel-running activity (A-C) of wild-type male mice maintained in 18L:6D (light–dark cycle indicated by white and black bars, respectively, above actograms). Mice (n = 3) were fed ad libitum for 5 days and then were fed for 6 h/day for 33 days. Beginning on the 22nd day of restricted feeding, mice were given 0.005% methamphetamine (MA) in their drinking water at the same time food was provided to the mice (the start of food availability). Methamphetamine was administered for the remainder of the experiment (days when MA was administered are indicated by vertical lines on the left axis of each actogram). The time when food was available is indicated by gray shading on the left half of each actogram. D. The phase of food anticipatory activity for each mouse during restricted feeding before (RF) and during MA administration (RF + MA) is plotted. White and gray boxes show light and dark, respectively. The dotted line indicates the time of restricted feeding.
second day of food deprivation. Food anticipatory activity was absent If daytime activity did not exceed 10 counts/min. Data are plotted as mean phase of food anticipatory activity ± SD. The period of the MASCO rhythm after dissociation from the SCN-controlled activity rhythm was determined by fitting a regression line to the onset of MASCO activity (5–9 days; ClockLab).
3. Results 3.1. The phase of food anticipatory activity shifts coordinately with the light–dark cycle
of food anticipatory activity during food deprivation was advanced by 5 h (Fig. 2C; Fig. S4C: FDI: 8 of 8 mice). We next tested whether food anticipatory activity would reappear at the phase-shifted time following an additional 5 days of ad libitum feeding (ALII). We found that food anticipatory activity during food deprivation occurred at the same phase in control mice (7 of 8 mice; Fig. 2A; Fig. S4A: FDII), and was delayed 6.5 h (8 of 8 mice; Fig. 2B; Fig. S4B: FDII) or advanced 5 h (8 of 8 mice; Fig. 2C; Fig. S4C: FDII) in mice that experienced a 6 h delay or advance, respectively, of the light–dark cycle. Together, these data suggest that the FEO is stably coupled to the SCN. 3.2. Methamphetamine consumption alters food-entrained activity
Food anticipatory activity to periodic daytime meals disappears during ad libitum feeding but reappears at the same phase during subsequent food deprivation, suggesting that the FEO is coupled to the SCN [2]. We hypothesized that the phase relationship between the FEO and SCN persists during ad libitum feeding and that the FEO shifts in parallel with the SCN. To test this hypothesis, we examined whether the phase of food anticipatory activity shifted symmetrically with a phase shift of the light–dark cycle. We first performed restricted feeding, then delayed or advanced the light–dark cycle during ad libitum feeding (Figs. 1–2; Fig. S1–S4), and then measured food anticipatory activity during food deprivation. We found that all mice exhibited food anticipatory activity before mealtime during restricted feeding (RF; observed in 24 of 24 mice; Fig. 1; Fig. S1–S3). In control mice that did not experience a shift of the light–dark cycle (Fig. 1A,B; Fig. S1), food anticipatory activity occurred at the same phase during restricted feeding (Fig. 2A; Fig. S4A: RF) and food deprivation (Fig. 2A; Fig. S4A: FDI; 7 of 8 mice: the mouse in Fig. S1E did not display food anticipatory activity during FD1). Following a 6-hour phase delay of the light–dark cycle (Fig. 1C, D; Fig. S2), the phase of food anticipatory activity during food deprivation was delayed by 5 h (Fig. 2B; Fig. S4B: FDI: 8 of 8 mice). When the light–dark cycle was advanced by 6 h (Fig. 1E, F; Fig. S3), the phase
We next examined the effect of methamphetamine on the output of the FEO (Fig. 3). During restricted feeding without methamphetamine, food anticipatory activity occurred prior to food availability (Fig. 3D: RF). Upon addition of methamphetamine to the drinking water, the phase of food-entrained activity was delayed 2 h in each mouse (Fig. 3D: RF + MA). When mice were returned to ad libitum feeding, the food-entrained activity component disappeared or merged with the light-entrained activity component. 3.3. Restricted feeding induces dissociation of the SCN and MASCO Consistent with previous studies, we found that during short-term (typically b 30 days) methamphetamine treatment, the wheel-running activity rhythm was the integrated output of the SCN and MASCO [12,15,23] (Fig. 4A–D). During chronic methamphetamine consumption (typically N30 days) the MASCO rhythm dissociated from the SCNcontrolled activity rhythm and exhibited a 26.5-hour period [13,15–17] (Fig. 4B, C). To determine the effect of restricted feeding on coupling between the SCN and MASCO during short-term methamphetamine treatment,
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we continuously administered methamphetamine to mice while restricting food availability to 6 h/day for 12 days (Fig. 4E–G). Upon return to ad libitum feeding, the MASCO rhythm immediately dissociated from the SCN-controlled activity rhythm and exhibited a ~ 26-hour period (Fig. 4E: 25.9 h; Fig. 4F: 28.2 h; Fig. 4G: 24.8 h). 4. Discussion 4.1. The FEO is coupled to the SCN When rats are food deprived following an intervening period of ad libitum feeding, food anticipatory activity reappears at the previous time of entrainment to scheduled meals [2]. Food anticipatory activity does not free-run during ad libitum feeding, suggesting that the FEO is coupled to another circadian oscillator such as the SCN. In previous studies, this hypothesis was tested by shifting the light–dark cycle and then determining whether parallel shifts in food anticipatory activity occurred. While the results of these studies suggested that food anticipatory activity shifted concurrently with the light–dark cycle, the activity of rats was analyzed in 12L:12D [24,25] or 14L:10D [26], so food anticipatory activity was obscured by nocturnal activity following phase shifts of the light–dark cycle. In this study we used an optimized protocol and found that the phase of food anticipatory activity was phase-delayed or phaseadvanced coordinately with the respective shift of the light–dark cycle. These data suggest that the phase angle between the SCN and FEO is stable during ad libitum feeding. Furthermore, coupling of the FEO to the SCN is stable as the phase-shifted food anticipatory activity persisted after an additional time of 5 days of ad libitum feeding. However, our study does not preclude the possibility that the FEO is driven directly by the timing of the light–dark cycle or by the output of the retina. Future studies should examine food anticipatory activity during food deprivation in constant darkness following a shift of the light– dark cycle to demonstrate coupling of the FEO to the SCN. 4.2. The phase of food anticipatory activity is delayed by methamphetamine consumption Because the FEO and MASCO are both extra-SCN circadian oscillators whose anatomical location(s) are unknown, it has been speculated that they are the same pacemaker (but see [18]). We therefore hypothesized that methamphetamine treatment would alter the output of the FEO/ MASCO. Indeed, we found that methamphetamine administration delayed the phase of food anticipatory activity by 2 h. It is possible that methamphetamine treatment lengthens the period of the FEO/ MASCO, resulting in a delayed phase of entrainment to food availability. However, a possible confound in the experiment is that mice may drink a large amount of water (containing methamphetamine) in association with the daily scheduled meal, which could result in the increased locomotor activity observed during restricted feeding. 4.3. Coupling between the SCN and MASCO is affected by restricted feeding During short-term (b30 days) methamphetamine treatment, rats and mice express a single, free-running wheel-running activity rhythm with a period that is intermediate to the SCN and MASCO periods, suggesting that the SCN and MASCO are coupled [12,15,23]. After ~30 days of methamphetamine administration, MASCO dissociates from the SCN
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and distinct MASCO-controlled and SCN-controlled activity rhythms are observed [13,15–17]. One possible explanation for these observations is that methamphetamine lengthens the period of MASCO so that over time it is no longer able to entrain to the 24-h light–dark cycle, resulting in relative coordination or dissociation of the MASCO-controlled rhythm from the SCN-controlled rhythm. Consistent with this proposed mechanism, Tataroglu et al. (2006) reported gradual lengthening of the MASCO-controlled activity rhythm in SCN-lesioned mice during longterm methamphetamine treatment. However, in our previous study, we did not consistently observe lengthening of the MASCO-controlled activity rhythm in SCN-lesioned mice [27]. An alternative explanation is that methamphetamine changes the coupling strength between the SCN and MASCO, resulting in dissociation of the two rhythms. We found that restricted feeding at the onset of methamphetamine treatment induced desynchronization of the MASCO rhythm from the SCN rhythm immediately upon release to ad libitum feeding. Thus, restricted feeding may induce changes in MASCO or in the relationship between the SCN and MASCO that mimics chronic methamphetamine treatment. We speculate that restricted feeding increases the amplitude of MASCO (or FEO if they are the same oscillator) and/or changes the coupling strength between the MASCO and SCN. Additionally, if the FEO and MASCO are the same oscillator, then daytime restricted feeding could establish an unusual phase relationship between the FEO/MASCO and the SCN, which may cause their dissociation. A caveat of this explanation is that there is no evidence that the phase angle between the SCN and the FEO is changed during daytime restricted feeding. Unfortunately, it is impossible to measure the phase of the FEO because its anatomical location is unknown. 5. Conclusions The mammalian circadian system is composed of a hierarchical network of pacemakers. The SCN, FEO, and MASCO can coordinate the phases of peripheral oscillators demonstrating that they function at the top of the hierarchy [19,21]. Thus, while the SCN is often considered as the master controller of locomotor activity rhythms, our data suggest that the outputs of the SCN, FEO and MASCO collectively drive behavior. Conceptually, this organization of ascendant pacemakers would allow the organism to integrate distinct environmental inputs—light and food (and perhaps reward-related stimuli) and phase its behavior and physiology accordingly. Acknowledgements This research was supported by a National Science Foundation grant IOS-1146908 to SY. We thank Dr. Gisele A. Oda for insightful discussion of the data. The authors declare no conflicts of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.physbeh.2014.01.021. References [1] Foster RG, Hankins MW. Circadian vision. Curr Biol 2007;17:R746–51. [2] Mistlberger RE. Circadian food-anticipatory activity: formal models and physiological mechanisms. Neurosci Biobehav Rev 1994;18:171–95. [3] Richter CP. Animal behavior and internal drives. Q Rev Biol 1927;2:307–42.
Fig. 4. Dissociation of the MASCO rhythm from the SCN rhythm following restricted feeding. Double-plotted actograms of wheel-running activity (5-min bins) of wild-type mice (A–D: females; E–G: males) maintained in 18L:6D (light and dark indicated by white and black bars, respectively, above actograms) and administered 0.005% methamphetamine (MA; indicated by vertical lines) for the entire experiment (x-axis: time in hours; y-axis: days). In A–D, mice were fed ad libitum. In E–G, mice were fed 6 h/day with MA for 12 days (these are the same mice as shown in Fig. 3) and then fed ad libitum (with continuous MA administration). Arrows indicate the day of dissociation of the MASCO rhythm from the SCN rhythm (no dissociation in A, D). The time of food availability is shown in gray shading and cage changes are indicated by white asterisks on the left halves of the actograms. The time of darkness is outlined on the left halves of the actograms. In all actograms, the first day shown is the first day of MA treatment. Fifty-three days of data are shown in all actograms. The data shown in A–D are from [17].
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[4] Bolles RC, deLorge J. The rat's adjustment to a-diurnal feeding cycles. J Comp Physiol Psychol 1962;55:760–2. [5] Bolles RC, Stokes LW. Rat's anticipation of diurnal and a-diurnal feeding. J Comp Physiol Psychol 1965;60:290–4. [6] Stephan FK. Phase shifts of circadian rhythms in activity entrained to food access. Physiol Behav 1984;32:663–71. [7] Stephan FK. Resetting of a feeding-entrainable circadian clock in the rat. Physiol Behav 1992;52:985–95. [8] Stephan FK, Swann JM, Sisk CL. Anticipation of 24-hr feeding schedules in rats with lesions of the suprachiasmatic nucleus. Behav Neural Biol 1979;25:346–63. [9] Stephan FK, Swann JM, Sisk CL. Entrainment of circadian rhythms by feeding schedules in rats with suprachiasmatic lesions. Behav Neural Biol 1979;25:545–54. [10] Marchant EG, Mistlberger RE. Anticipation and entrainment to feeding time in intact and SCN-ablated C57BL/6j mice. Brain Res 1997;765:273–82. [11] Stephan FK. The “other” circadian system: food as a Zeitgeber. J Biol Rhythms 2002;17:284–92. [12] Tataroglu O, Davidson AJ, Benvenuto LJ, Menaker M. The methamphetaminesensitive circadian oscillator (MASCO) in mice. J Biol Rhythms 2006;21:185–94. [13] Honma K, Honma S, Hiroshige T. Disorganization of the rat activity rhythm by chronic treatment with methamphetamine. Physiol Behav 1986;38:687–95. [14] Honma K, Honma S, Hiroshige T. Activity rhythms in the circadian domain appear in suprachiasmatic nuclei lesioned rats given methamphetamine. Physiol Behav 1987;40:767–74. [15] Masubuchi S, Honma S, Abe H, Ishizaki K, Namihira M, Ikeda M, et al. Clock genes outside the suprachiasmatic nucleus involved in manifestation of locomotor activity rhythm in rats. Eur J Neurosci 2000;12:4206–14. [16] Cuesta M, Aungier J, Morton AJ. The methamphetamine-sensitive circadian oscillator is dysfunctional in a transgenic mouse model of Huntington's disease. Neurobiol Dis 2011;45:145–55.
[17] Pendergast JS, Oda GA, Niswender KD, Yamazaki S. Period determination in the food-entrainable and methamphetamine-sensitive circadian oscillator(s). Proc Natl Acad Sci U S A 2012;109:14218–23. [18] Jansen HT, Sergeeva A, Stark G, Sorg BA. Circadian discrimination of reward: evidence for simultaneous yet separable food- and drug-entrained rhythms in the rat. Chronobiol Int 2012;29:454–68. [19] Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, et al. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci U S A 2004;101:5339–46. [20] Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 2000;288:682–5. [21] Pezuk P, Mohawk JA, Yoshikawa T, Sellix MT, Menaker M. Circadian organization is governed by extra-SCN pacemakers. J Biol Rhythms 2010;25:432–41. [22] Pendergast JS, Nakamura W, Friday RC, Hatanaka F, Takumi T, Yamazaki S. Robust food anticipatory activity in BMAL1-deficient mice. PLoS One 2009;4:e4860. [23] Honma S, Honma K, Hiroshige T. Methamphetamine effects on rat circadian clock depend on actograph. Physiol Behav 1991;49:787–95. [24] Stephan FK. Coupling between feeding- and light-entrainable circadian pacemakers in the rat. Physiol Behav 1986;38:537–44. [25] Ottenweller JE, Tapp WN, Natelson BH. Phase-shifting the light–dark cycle resets the food-entrainable circadian pacemaker. Am J Physiol 1990;258:R994-1000. [26] Rosenwasser AM, Pelchat RJ, Adler NT. Memory for feeding time: possible dependence on coupled circadian oscillators. Physiol Behav 1984;32:25–30. [27] Pendergast JS, Niswender KD, Yamazaki S. The complex relationship between the light-entrainable and methamphetamine-sensitive circadian oscillators: evidence from behavioral studies of Period-mutant mice. Eur J Neurosci 2014 http:// dx.doi.org/10.1111/ejn.12309 [Epub ahead of print] [in press].
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Physiology & Behavior journal homepage: www.elsevier.com/locate/phb
Effects of light, food, and methamphetamine on the circadian activity rhythm in mice Julie S. Pendergast 1, Shin Yamazaki ⁎ Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA
H I G H L I G H T S • • • •
Food anticipatory activity phase shifts coordinately with the light–dark cycle. The phase of food anticipatory activity is delayed by methamphetamine consumption. Coupling of the SCN and MASCO is affected by exposure to restricted feeding. The outputs of the SCN, FEO and MASCO collectively drive behavior.
a r t i c l e
i n f o
Article history: Received 17 July 2013 Received in revised form 2 November 2013 Accepted 25 January 2014 Available online 11 February 2014 Keywords: FEO Restricted feeding SCN MASCO Pacemaker coupling C57BL/6J
a b s t r a c t The circadian rhythm of locomotor activity in mice is synchronized to environmental factors such as light and food availability. It is well-known that entrainment of the activity rhythm to the light–dark cycle is attained by the circadian pacemaker in the suprachiasmatic nucleus (SCN). Locomotor activity is also controlled by two extra-SCN oscillators; periodic food availability entrains the food-entrainable oscillator (FEO) and constant consumption of low-dose methamphetamine reveals the output of the methamphetamine-sensitive circadian oscillator (MASCO). In this study, we sought to investigate the relationship between the SCN, FEO, and MASCO by examining the combinatorial effects of light, food restriction, and/or methamphetamine on locomotor activity. To investigate coupling between the SCN and FEO, we tested whether food anticipatory activity, which is the output of the FEO, shifted coordinately with phase shifts of the light–dark cycle. We found that the phase of food anticipatory activity was phase-delayed or phase-advanced symmetrically with the respective shift of the light–dark cycle, suggesting that the FEO is strongly coupled to the SCN and the phase angle between the SCN and FEO is maintained during ad libitum feeding. To examine the effect of methamphetamine on the output of the FEO, we administered methamphetamine to mice undergoing restricted feeding and found that foodentrained activity was delayed by methamphetamine treatment. In addition, restricted feeding induced dissociation of the MASCO and SCN activity rhythms during short-term methamphetamine treatment, when these rhythms are typically integrated. In conclusion, our data suggest that the outputs of the SCN, FEO and MASCO collectively drive locomotor activity. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Light and food availability are periodic environmental factors that entrain circadian oscillators in mammals. Entrainment is believed to improve fitness and survival by allowing anticipation of predictable daily changes in environmental conditions and coordinating precise phasing of rhythms in behavior and physiology. ⁎ Corresponding author at: Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390–9111, USA. Tel.: +1 214 648 1830. E-mail address: [email protected] (S. Yamazaki). 1 Present address: Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
http://dx.doi.org/10.1016/j.physbeh.2014.01.021 0031-9384/© 2014 Elsevier Inc. All rights reserved.
It is well-known that light entrains the circadian pacemaker in the suprachiasmatic nucleus (SCN) through monosynaptic projections from the retina [1]. Numerous studies have also examined the effect of periodic food availability on circadian locomotor activity. When a single daily meal is provided at a fixed time of day (i.e. restricted feeding), locomotor activity increases 2 to 4 h before the scheduled feeding time [2,3]. Even though this food anticipatory activity disappears during ad libitum feeding, it reappears at the previous time of restricted feeding when rodents are subsequently food deprived, demonstrating that it is controlled by a self-sustained oscillator [2]. In addition, food anticipatory activity persists when the SCN is lesioned and displays properties of a circadian oscillator, namely a limited range of entrainment and transients following phase shifts of mealtime [4–10]. Thus, the food-
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entrainable oscillator (FEO) that controls food anticipatory activity is distinct from the SCN, although its anatomical locus is unknown [11]. Compared to the SCN and FEO, relatively few studies have examined the methamphetamine-sensitive circadian oscillator (MASCO). The MASCO-controlled wheel-running activity rhythm is observed when rats and mice are continuously administered low-dose methamphetamine [12,13]. During chronic (N30 days) methamphetamine treatment, the MASCO-controlled activity rhythm dissociates from the
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SCN-controlled activity rhythm and the MASCO rhythm also persists when the SCN is lesioned, demonstrating that the MASCO is distinct from the SCN [13–17]. Like the FEO, the anatomical locus of MASCO is unknown. This has, in part, led to speculation that the FEO and MASCO are the same oscillator (but see [18]; for discussion see [17]). The SCN is regarded as the master pacemaker because it coordinates the phases of peripheral clocks and controls rhythmic locomotor activity [19,20]. Like the SCN, the FEO and MASCO can coordinate the phases of
Fig. 1. Effect of shifting the light–dark cycle on the phase of food anticipatory activity. Double-plotted actograms of wheel-running activity (5-min bins) of wild-type mice (A, C, E: males; B, D, F: females) maintained in 18L:6D (x-axis: time in hours; y-axis: days). Darkness is outlined with black boxes and the time when food was available is indicated by gray shading (shown only on the left halves of the actograms). The mice were fed ad libitum (AL) for 2 days, and then deprived of food for 25 h. Food availability was then gradually reduced from 8 h (2 days) to 6 h (2 days) and then to 4 h (15 days) per day (RF). Mice were then fed ad libitum (ALI) for 7 days. On the third day of ad libitum feeding, the light–dark cycle was either not shifted (A, B), delayed 6 h (C, D), or advanced 6 h (E, F). Four days later, mice were food deprived (FDI) for 50 h. Then, mice were fed ad libitum (ALII) for 5 days and then food deprived (FDII) again for 48 h.
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peripheral oscillators and control locomotor activity, suggesting that they also function at the top of the hierarchy of the mammalian circadian system [19–21]. Thus, the circadian rhythm of locomotor activity is controlled not only by SCN output, but also by the output of oscillators responding to at least three distinct environmental cues—light entrains the SCN, food entrains the FEO, and methamphetamine reveals MASCO output. In this study, we sought to investigate the relationship between these oscillators by examining the combinatorial effects of light, food restriction, and/or methamphetamine on locomotor activity.
(starting at ZT8, where ZT0 is lights on), and then fed 8 h/day for 2 days and 6 h/day for 2 days (starting at ZT8). Then mice were fed 4 h/day (ZT10–14) for 13 days. On the 14th day, food was placed in the cage at ZT10 and was not removed. On the 3rd day of ad libitum feeding, the time of lights on was either not shifted (n = 8), delayed by 6 h (n = 8), or advanced by 6 h (n = 8). After 6 days of ad libitum feeding (3 days before the shift and 3 days after the shift), mice were food deprived for 48 h (starting at 18:00 local time in all groups). Mice were then fed ad libitum for 4 days and then food deprived for 48 h (starting at 18:00 local time in all groups).
2. Materials and methods 2.1. Animals Adult male and female mice (5 to 18 weeks old) were used for all experiments. C57BL/6J mice were purchased from the Jackson Laboratory (Bar Harbor, ME, USA; Fig. 1; Fig. S1–S3 except the mice shown in Fig. S2E–H), where they were bred and group-housed in a 14-h light/ 10-h dark cycle, or C57BL/6J mice were bred and group-housed in the Vanderbilt University animal facility in 12L:12D (light intensity ~350 lx; Figs. S2E–H, S3, S4). All experiments were approved by the Institutional Animal Care and Use Committee at Vanderbilt University (M/08/096). 2.2. Recording of circadian behavior Animals were singly housed in cages (length × height × width: 33 × 17 × 14 cm) with unlimited access to a running wheel (diameter 11 cm), food, and water. The cages were placed in light-tight, ventilated boxes in 18L:6D (light intensity: 200–300 lx). Cages were changed every 3 weeks. Wheel-running activity (recorded every minute by computer) was monitored and analyzed using ClockLab (Actimetrics, Wilmette, IL, USA). Activity data were double-plotted in actograms in 5-min bins using the normalized format in ClockLab. 2.3. Restricted feeding
2.3.2. Methamphetamine treatment during restricted feeding Mice (n = 3) were maintained in 18L:6D for 78 days with ad libitum food. Mice were then fed 6 h/day (starting at ZT8, where ZT0 is lights on) for 33 days. On the 22nd day of restricted feeding, mice were given 0.005% methamphetamine in their drinking water at the same time that food was provided. Methamphetamine was administered for the remainder of the experiment. 2.3.3. Release from restricted feeding during methamphetamine treatment Mice were maintained in 18L:6D and continuously administered 0.005% methamphetamine in their drinking water for 78 days. One group of mice (n = 4; Fig. 4A–D) were fed ad libitum for the entire experiment. Another group of mice (n = 3; Fig. 4E–G; same mice as described in Section 2.3.2) were fed 6 h/day during the first 12 days of methamphetamine treatment and then fed ad libitum for the remainder of the 78 days. 2.3.4. Analysis The phase of food anticipatory activity was determined using ClockLab. During restricted feeding, activity for each mouse was averaged over 10 days of 4 h/day restricted feeding. The phase of food anticipatory activity was designated as the time when daytime activity exceeded 10 counts/min on the activity profile. During food deprivation, the phase of food anticipatory activity was defined as the time when daytime activity exceeded 10 counts/min on the activity profile of the
Mice were fed LabDiet™ 5L0D (Purina, Richmond, IN). Food was placed on the bottom of the cage and in the hopper during restricted feeding. Mice were allowed to eat as much as they desired during the time when food was available. When food was removed, the lighttight box was opened and all food was removed from the wire-top and from the bottom of the cage. When food was removed in the dark (Fig. 1E, F; Fig. S3), an infrared viewer (FIND-R-SCOPE Infrared Viewer, FJW Optical Systems, Inc., Palatine, IL) was used so that mice were not exposed to visible light. During ad libitum feeding and food deprivation, the light-tight boxes were not opened in order to avoid any external cues associated with food availability. During this time, the well-being of the mouse was monitored by assessing wheel-running data collected by computer. 2.3.1. Restricted feeding protocol during shifts of the light–dark cycle To examine the effect of shifting the light–dark cycle on the phase of food anticipatory activity, we performed experiments in 18L:6D for two reasons. First, we found in our previous studies that food anticipatory activity was more robust in long photoperiods and we wanted to provide ideal conditions for observing food anticipatory in our current experiments [22]. Second, if 6-h shifts of the light–dark cycle were performed in 12L:12D, the predicted phase of food anticipatory activity would occur during the dark phase, making it difficult to distinguish food anticipatory activity (output of the FEO) from nocturnal activity (output of the SCN). After 6-h shifts of the light–dark cycle in 18L:6D, the predicted phase of food anticipatory activity would occur during the light phase, thus permitting the distinction between FEO and SCN output. Mice were maintained in 18L:6D (lights on 03:00–21:00 local time) for 5–8 days with ad libitum food. After acclimation to the wheelrunning cage (for at least 4 days), mice were food deprived for 24 h
Fig. 2. The phase of food anticipatory activity shifts coordinately with the light–dark cycle. The mean phases (±SD) of food anticipatory activity during restricted feeding (RF) and during day 2 of food deprivation following either 1 week (FDI) or 2 weeks (FDII) of ad libitium feeding are plotted. The light–dark cycle was either not shifted (A), delayed 6 h (B), or advanced 6 h (C) prior to food deprivation. White and gray boxes show light and dark, respectively. The dotted line indicates the time of restricted feeding. The arrows indicate the predicted phase if food anticipatory activity shifted coordinately with the light–dark cycle.
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Fig. 3. Effect of methamphetamine on food-entrained activity. Double-plotted actograms of wheel-running activity (A-C) of wild-type male mice maintained in 18L:6D (light–dark cycle indicated by white and black bars, respectively, above actograms). Mice (n = 3) were fed ad libitum for 5 days and then were fed for 6 h/day for 33 days. Beginning on the 22nd day of restricted feeding, mice were given 0.005% methamphetamine (MA) in their drinking water at the same time food was provided to the mice (the start of food availability). Methamphetamine was administered for the remainder of the experiment (days when MA was administered are indicated by vertical lines on the left axis of each actogram). The time when food was available is indicated by gray shading on the left half of each actogram. D. The phase of food anticipatory activity for each mouse during restricted feeding before (RF) and during MA administration (RF + MA) is plotted. White and gray boxes show light and dark, respectively. The dotted line indicates the time of restricted feeding.
second day of food deprivation. Food anticipatory activity was absent If daytime activity did not exceed 10 counts/min. Data are plotted as mean phase of food anticipatory activity ± SD. The period of the MASCO rhythm after dissociation from the SCN-controlled activity rhythm was determined by fitting a regression line to the onset of MASCO activity (5–9 days; ClockLab).
3. Results 3.1. The phase of food anticipatory activity shifts coordinately with the light–dark cycle
of food anticipatory activity during food deprivation was advanced by 5 h (Fig. 2C; Fig. S4C: FDI: 8 of 8 mice). We next tested whether food anticipatory activity would reappear at the phase-shifted time following an additional 5 days of ad libitum feeding (ALII). We found that food anticipatory activity during food deprivation occurred at the same phase in control mice (7 of 8 mice; Fig. 2A; Fig. S4A: FDII), and was delayed 6.5 h (8 of 8 mice; Fig. 2B; Fig. S4B: FDII) or advanced 5 h (8 of 8 mice; Fig. 2C; Fig. S4C: FDII) in mice that experienced a 6 h delay or advance, respectively, of the light–dark cycle. Together, these data suggest that the FEO is stably coupled to the SCN. 3.2. Methamphetamine consumption alters food-entrained activity
Food anticipatory activity to periodic daytime meals disappears during ad libitum feeding but reappears at the same phase during subsequent food deprivation, suggesting that the FEO is coupled to the SCN [2]. We hypothesized that the phase relationship between the FEO and SCN persists during ad libitum feeding and that the FEO shifts in parallel with the SCN. To test this hypothesis, we examined whether the phase of food anticipatory activity shifted symmetrically with a phase shift of the light–dark cycle. We first performed restricted feeding, then delayed or advanced the light–dark cycle during ad libitum feeding (Figs. 1–2; Fig. S1–S4), and then measured food anticipatory activity during food deprivation. We found that all mice exhibited food anticipatory activity before mealtime during restricted feeding (RF; observed in 24 of 24 mice; Fig. 1; Fig. S1–S3). In control mice that did not experience a shift of the light–dark cycle (Fig. 1A,B; Fig. S1), food anticipatory activity occurred at the same phase during restricted feeding (Fig. 2A; Fig. S4A: RF) and food deprivation (Fig. 2A; Fig. S4A: FDI; 7 of 8 mice: the mouse in Fig. S1E did not display food anticipatory activity during FD1). Following a 6-hour phase delay of the light–dark cycle (Fig. 1C, D; Fig. S2), the phase of food anticipatory activity during food deprivation was delayed by 5 h (Fig. 2B; Fig. S4B: FDI: 8 of 8 mice). When the light–dark cycle was advanced by 6 h (Fig. 1E, F; Fig. S3), the phase
We next examined the effect of methamphetamine on the output of the FEO (Fig. 3). During restricted feeding without methamphetamine, food anticipatory activity occurred prior to food availability (Fig. 3D: RF). Upon addition of methamphetamine to the drinking water, the phase of food-entrained activity was delayed 2 h in each mouse (Fig. 3D: RF + MA). When mice were returned to ad libitum feeding, the food-entrained activity component disappeared or merged with the light-entrained activity component. 3.3. Restricted feeding induces dissociation of the SCN and MASCO Consistent with previous studies, we found that during short-term (typically b 30 days) methamphetamine treatment, the wheel-running activity rhythm was the integrated output of the SCN and MASCO [12,15,23] (Fig. 4A–D). During chronic methamphetamine consumption (typically N30 days) the MASCO rhythm dissociated from the SCNcontrolled activity rhythm and exhibited a 26.5-hour period [13,15–17] (Fig. 4B, C). To determine the effect of restricted feeding on coupling between the SCN and MASCO during short-term methamphetamine treatment,
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we continuously administered methamphetamine to mice while restricting food availability to 6 h/day for 12 days (Fig. 4E–G). Upon return to ad libitum feeding, the MASCO rhythm immediately dissociated from the SCN-controlled activity rhythm and exhibited a ~ 26-hour period (Fig. 4E: 25.9 h; Fig. 4F: 28.2 h; Fig. 4G: 24.8 h). 4. Discussion 4.1. The FEO is coupled to the SCN When rats are food deprived following an intervening period of ad libitum feeding, food anticipatory activity reappears at the previous time of entrainment to scheduled meals [2]. Food anticipatory activity does not free-run during ad libitum feeding, suggesting that the FEO is coupled to another circadian oscillator such as the SCN. In previous studies, this hypothesis was tested by shifting the light–dark cycle and then determining whether parallel shifts in food anticipatory activity occurred. While the results of these studies suggested that food anticipatory activity shifted concurrently with the light–dark cycle, the activity of rats was analyzed in 12L:12D [24,25] or 14L:10D [26], so food anticipatory activity was obscured by nocturnal activity following phase shifts of the light–dark cycle. In this study we used an optimized protocol and found that the phase of food anticipatory activity was phase-delayed or phaseadvanced coordinately with the respective shift of the light–dark cycle. These data suggest that the phase angle between the SCN and FEO is stable during ad libitum feeding. Furthermore, coupling of the FEO to the SCN is stable as the phase-shifted food anticipatory activity persisted after an additional time of 5 days of ad libitum feeding. However, our study does not preclude the possibility that the FEO is driven directly by the timing of the light–dark cycle or by the output of the retina. Future studies should examine food anticipatory activity during food deprivation in constant darkness following a shift of the light– dark cycle to demonstrate coupling of the FEO to the SCN. 4.2. The phase of food anticipatory activity is delayed by methamphetamine consumption Because the FEO and MASCO are both extra-SCN circadian oscillators whose anatomical location(s) are unknown, it has been speculated that they are the same pacemaker (but see [18]). We therefore hypothesized that methamphetamine treatment would alter the output of the FEO/ MASCO. Indeed, we found that methamphetamine administration delayed the phase of food anticipatory activity by 2 h. It is possible that methamphetamine treatment lengthens the period of the FEO/ MASCO, resulting in a delayed phase of entrainment to food availability. However, a possible confound in the experiment is that mice may drink a large amount of water (containing methamphetamine) in association with the daily scheduled meal, which could result in the increased locomotor activity observed during restricted feeding. 4.3. Coupling between the SCN and MASCO is affected by restricted feeding During short-term (b30 days) methamphetamine treatment, rats and mice express a single, free-running wheel-running activity rhythm with a period that is intermediate to the SCN and MASCO periods, suggesting that the SCN and MASCO are coupled [12,15,23]. After ~30 days of methamphetamine administration, MASCO dissociates from the SCN
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and distinct MASCO-controlled and SCN-controlled activity rhythms are observed [13,15–17]. One possible explanation for these observations is that methamphetamine lengthens the period of MASCO so that over time it is no longer able to entrain to the 24-h light–dark cycle, resulting in relative coordination or dissociation of the MASCO-controlled rhythm from the SCN-controlled rhythm. Consistent with this proposed mechanism, Tataroglu et al. (2006) reported gradual lengthening of the MASCO-controlled activity rhythm in SCN-lesioned mice during longterm methamphetamine treatment. However, in our previous study, we did not consistently observe lengthening of the MASCO-controlled activity rhythm in SCN-lesioned mice [27]. An alternative explanation is that methamphetamine changes the coupling strength between the SCN and MASCO, resulting in dissociation of the two rhythms. We found that restricted feeding at the onset of methamphetamine treatment induced desynchronization of the MASCO rhythm from the SCN rhythm immediately upon release to ad libitum feeding. Thus, restricted feeding may induce changes in MASCO or in the relationship between the SCN and MASCO that mimics chronic methamphetamine treatment. We speculate that restricted feeding increases the amplitude of MASCO (or FEO if they are the same oscillator) and/or changes the coupling strength between the MASCO and SCN. Additionally, if the FEO and MASCO are the same oscillator, then daytime restricted feeding could establish an unusual phase relationship between the FEO/MASCO and the SCN, which may cause their dissociation. A caveat of this explanation is that there is no evidence that the phase angle between the SCN and the FEO is changed during daytime restricted feeding. Unfortunately, it is impossible to measure the phase of the FEO because its anatomical location is unknown. 5. Conclusions The mammalian circadian system is composed of a hierarchical network of pacemakers. The SCN, FEO, and MASCO can coordinate the phases of peripheral oscillators demonstrating that they function at the top of the hierarchy [19,21]. Thus, while the SCN is often considered as the master controller of locomotor activity rhythms, our data suggest that the outputs of the SCN, FEO and MASCO collectively drive behavior. Conceptually, this organization of ascendant pacemakers would allow the organism to integrate distinct environmental inputs—light and food (and perhaps reward-related stimuli) and phase its behavior and physiology accordingly. Acknowledgements This research was supported by a National Science Foundation grant IOS-1146908 to SY. We thank Dr. Gisele A. Oda for insightful discussion of the data. The authors declare no conflicts of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.physbeh.2014.01.021. References [1] Foster RG, Hankins MW. Circadian vision. Curr Biol 2007;17:R746–51. [2] Mistlberger RE. Circadian food-anticipatory activity: formal models and physiological mechanisms. Neurosci Biobehav Rev 1994;18:171–95. [3] Richter CP. Animal behavior and internal drives. Q Rev Biol 1927;2:307–42.
Fig. 4. Dissociation of the MASCO rhythm from the SCN rhythm following restricted feeding. Double-plotted actograms of wheel-running activity (5-min bins) of wild-type mice (A–D: females; E–G: males) maintained in 18L:6D (light and dark indicated by white and black bars, respectively, above actograms) and administered 0.005% methamphetamine (MA; indicated by vertical lines) for the entire experiment (x-axis: time in hours; y-axis: days). In A–D, mice were fed ad libitum. In E–G, mice were fed 6 h/day with MA for 12 days (these are the same mice as shown in Fig. 3) and then fed ad libitum (with continuous MA administration). Arrows indicate the day of dissociation of the MASCO rhythm from the SCN rhythm (no dissociation in A, D). The time of food availability is shown in gray shading and cage changes are indicated by white asterisks on the left halves of the actograms. The time of darkness is outlined on the left halves of the actograms. In all actograms, the first day shown is the first day of MA treatment. Fifty-three days of data are shown in all actograms. The data shown in A–D are from [17].
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