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SLEEP AND TEMPERATURE REGULATION

The involvement of Cry1 and Cry2 genes in the regulation of the circadian body temperature rhythm in mice

¹Department of Integrative Physiology, School of Human Sciences, Waseda University, Tokorozawa, Saitama; ²Department of Physiology, School of Allied Health Sciences, Faculty of Medicine, Osaka University Suita, Osaka; ³Clock Cell Biology Research Group, National Institute of Advanced Industrial Science and Technology, Institute for Biological Resources and Functions, Tsukuba, Ibaraki; and ⁴Department of Physiology, School of Sports Sciences, Waseda University, Tokorozawa, Saitama, Japan

Submitted 15 June 2004 ; accepted in final form 20 August 2004

	ABSTRACT

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The criptochrome genes (Cry1 and Cry2) are involved in the molecular mechanism that controls the circadian clock, and mice lacking these genes (Cry1^–/–/Cry2^–/–) are behaviorally arrhythmic. It has been speculated that the circadian clock modulates the characteristics of thermoregulation, resulting in body temperature (T_b) rhythm. However, there is no direct evidence proving this speculation. We show here that T_b and heat production in Cry1^–/–/Cry2^–/– mice are arrhythmic under constant darkness. In contrast, both rhythms occur under a light-dark cycle and/or periodical food restriction linked with spontaneous activity and/or eating, although they are not robust as those in wild-type mice. The relationship between heat production and T_b in Cry1^–/–/Cry2^–/– mice is linear and identical under any conditions, indicating that their T_b rhythm is determined by heat production rhythm associated with activity and eating. However, T_b in wild-type mice is maintained at a relatively higher level in the active phase than the inactive phase regardless of the heat production level. These results indicate that the thermoregulatory responses are modulated according to the circadian phase, and the Cry genes are involved in this mechanism.

circadian clock; thermoregulation; metabolism

The suprachiasmatic nucleus (SCN) in the hypothalamus is the master clock of the circadian rhythm. Lesions of the SCN have been used to indicate that the circadian clock is associated with several physiological rhythms. Although these lesions also abolish the T_b rhythm in rodents (1, 11, 21, 24, 31, 32, 36), this finding may not indicate that the circadian clock regulates the T_b rhythm. It has been reported that behavioral or physiological responses such as locomotor activity, eating, and the secretion of several hormones accompany changes in heat production and T_b (23, 28, 29, 37, 38). Thus it could be interpreted that a lack of these rhythms in the presence of SCN lesions (1, 3, 16, 24, 36) abolishes the T_b rhythm with the heat production rhythm. We previously reported that the T_b rhythm was maintained in fasted rats; however, heat production and its circadian amplitude decreased (25). These results may indicate that, despite the strong influence of food intake on heat production rhythm, the circadian T_b rhythm is regulated independently of heat production.

Recent studies clarified the core molecular mechanisms of the circadian clock (8, 10, 18), which consists of autoregulatory transcription-translation loops with a periodicity of 24 h. Moreover, the mechanism is situated in the central and peripheral tissues (4, 5, 9). The absence of this mechanism may abolish all internal rhythms, although it remains unclear yet how the molecular mechanism governs actual physiological and behavioral rhythms.

Cryptochromes are photoactive pigments for light entrainment of the circadian rhythm in plants and Drosophila and play a key role in the molecular feedback loop (14, 22, 35, 39) in mammals. The mice lacking the cryptochromes 1 and 2 genes (Cry1 and Cry2) lose periodicity in wheel-running behavior (39) as well as electrophysiological activity in the SCN cells under constant darkness (DD) (6). However, interestingly, lights have a masking effect on the behavior: the wheel-running activity is suppressed in the lights, and a light-dark (LD) cycle results in the display of the daily rhythmicity.

In the present study, we hypothesized that the core mechanism involved in the T_b rhythm would be regulated by the molecular mechanisms of the circadian clock. Moreover, the T_b rhythm would be controlled independently of heat production. To test this hypothesis, we compared a daily change in T_b in the knockout mice of Cry1 and Cry2 (Cry1^–/–/Cry2^–/–) with wild-type mice in three different conditions: 1) the DD with ad libitum feeding (i.e., in a constant condition) and the LD with 2) ad libitum feeding and 3) restricted feeding during the dark phase (i.e., in the presence of factors modulating heat production). We surmised that, in the knockout mice, the T_b rhythms would appear in the presence of factors modulating heat production. Moreover, the relationship between T_b and heat production would be similar in all the conditions in the knockout mice but not in wild-type mice.

	METHODS

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Animals. Wild-type mice (n = 5, C57BL/6) and Cry1^–/–/Cry2^–/– mice (n = 5, C57BL/6 background) were used for the experiments. The mice in both groups were male, 24–44 wk old, and weighed between 26 and 35 g. Normally, mice were individually housed in a plastic cage (16 x 26 x 13 cm) with water and food available ad libitum. The ambient temperature was 26°C, and the lighting cycle was 12 h light (300 lx at eye level, lights on at 0700) and 12 h complete darkness. All procedures in this study were approved by the Institutional Animal Care and Use Committee, Faculty of Medicine, Osaka University.

Surgery. A radio transmitter device used to measure T_b and spontaneous activity (17 x 10 x 8 mm; Physiotel, model TA10TA-F40, DataScience, St. Paul, MN) was implanted in the abdominal cavity by sterile technique under general anesthesia induced by intraperitoneal injection of pentobarbital sodium (5.0 mg/100 g body wt). Lignocain jelly (Astrazeneca, Tokyo) was applied to the wound, and penicillin G (1,000 U, Meiji Pharmaceutical, Tokyo, Japan) was intramuscularly injected to minimize postsurgical pain and infection. T_b and spontaneous activity were monitored throughout the experiment. Spontaneous activity was estimated by the change in intensity of the telemetry signal. The signals passed through a receiver board (model CTR86, DataScience) underneath the cage and were stored in a personal computer every 5 min. The mice were allowed to recover for at least 4 wk before the experiments. Wild-type mice usually took 2 wk before showing clear circadian T_b and activity rhythms.

Indirect calorimetry. To measure metabolic heat production, a mouse was transferred at 1300 to a Plexiglas metabolic box (17 x 17 x 17 cm) attached to an airflow system with a constant flow rate of 500 ml/min. The ambient temperature in the metabolic box was monitored and kept at 26.0 ± 0.2°C. The difference in oxygen tension between the inlet and outlet was continuously monitored by an electrochemical oxygen analyzer (model LCJ-700, Toray, Tokyo), and the data were stored in a personal computer at 10-s intervals. Oxygen consumption rate (O₂, indirect calorimetry) was calculated as the product of the difference in oxygen tension and flow rate divided by the 0.75 power of body weight (Brody-Kleiber formula) and corrected to conditions of standard temperature (0°C), pressure (760 mmHg), and dry. In addition, we familiarized the mice with the system by placing them in the box several times during the recovery period after surgery. Body weight was measured before and after each trial. Normal daily food intake was not different between wild-type and Cry1^–/–/Cry2^–/– mice (Student's t-test, P < 0.05).

Experimental protocols. T_b and spontaneous activity of wild-type and Cry1^–/–/Cry2^–/– mice in a cage were continuously measured by telemetry (n = 5 in each group). To examine the effect of lighting on T_b and spontaneous activity, mice were exposed to DD for 3 days after 12:12-h light-dark (LD, lights on at 0700). Before DD exposure, the two groups were exposed to LD for at least 10 days.

We placed the same mice separately in a semiclosed Plexiglas chamber for 3 days at least 1 wk after the first experiment and continuously measured their oxygen consumption rate (O₂, i.e., metabolic heat production) by indirect calorimetry together with T_b and spontaneous activity. This was repeated three times under different conditions with at least a 1-wk interval: 1) DD with ad libitum feeding, 2) LD with ad libitum feeding, and 3) LD with food restriction. The food restriction protocol was aimed at enhancing the eating rhythm. Ordinary chow was given at 1900, the end of light period, at 70–80% of the normal daily intake. We verified that both Cry1^–/–/Cry2^–/– and wild-type mice finished eating 10–12 h after the appearance of chow in the food-restriction regimen, which induced a fed-fasting rhythm.

Statistics. The circadian period of each parameter was estimated with the chi-square periodogram (34). The mean, amplitude, and peak phase of the circadian rhythm were estimated by cosinor rhythmometry (26). Regression analysis was conducted by the least-squares method. Differences among means were analyzed by the Student's t-test or ANOVA with repeated measurement. Post hoc testing to verify significance for a specific period was conducted using the Newman-Keuls procedure. The null hypothesis was rejected at P < 0.05.

	RESULTS

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T_b rhythm during a light-dark cycle and under constant darkness. Both T_b and activity rhythms in wild-type mice were robust (Fig. 1, A and B), and their circadian period () was both 24.0 ± 0.1 under the LD condition and 23.9 ± 0.1 under the DD condition (the chi-square periodogram, P < 0.0013 in each condition; means ± SE, n = 5).

View larger version (66K): [in this window] [in a new window]   Fig. 1. Examples of 6-day changes in body temperature (Tb) and spontaneous activity of a wild-type mouse (A and B, respectively) and Cry1–/–/Cry2–/– mouse (C and D, respectively). The lighting condition was a 12:12-h light-dark cycle (LD, lights on at 0700) for the first 3 days followed by constant darkness (DD) for the remaining period. Mice were placed under the LD condition for at least 10 days before DD exposure. Changes in both Tb and activity in the 2 groups were rhythmic under the LD condition although Cry1–/–/Cry2–/– mice additionally showed oscillations with shorter periods of 3–4 h. However, Tb and activity were arrhythmic in Cry1–/–/Cry2–/– mice under the DD condition.

Heat production and T_b in light-dark and/or fed-fasting cycles. Wild-type mice showed robust circadian rhythms for O₂ and T_b during each trial (Fig. 2, A and B; the chi-square periodogram, P < 0.0073, = 23.9 ± 0.2 under the DD condition and 24.0 ± 0.1 in the 2 trials under the LD condition, n = 5). The mean, amplitude, and peak phase of T_b rhythm under the LD condition with ad libitum feeding remained similar as those under the DD condition (Table 1; ANOVA, P > 0.05). Significant differences were found in the T_b and O₂ rhythms between ad libitum feeding and food-restriction days (ANOVA, F = 7.122 and 6.450, P < 0.05). The activity rhythm was unchanged throughout the three trials.

View larger version (32K): [in this window] [in a new window]   Fig. 2. Daily changes in oxygen consumption rate (O2, A and C) and Tb (B and D) on the last day of ad libitum feeding under the DD condition, ad libitum feeding under the LD condition, and food restriction under the LD condition. Each data point is a mean (±SE) of 5 mice for 30 min. For better assessment, the data corresponding to each hour are presented. Zeitgeber time (ZT) 0 and circadian time (CT) 0 denote the time the lights were turned on under the LD condition and the corresponding time under the DD condition. The O2 and Tb changes in wild-type mice were rhythmic for the 3 trials ( = 23.9 ± 0.2 and 24.0 ± 0.1 under the DD and LD conditions, respectively). In Cry1–/–/Cry2–/– mice, the changes were arrhythmic under the DD condition. However, they became rhythmic ( = 24.0 ± 0.3) under the LD condition. On the food restriction day, the means for the Tb and O2 rhythms in both groups were smaller and the amplitudes were greater than those on the ad libitum feeding day.

View this table: [in this window] [in a new window]   Table 1. Cosinor rhythmometry for daily changes in Tb, O2, and spontaneous activity

Relationship between metabolic heat production and T_b. We assessed the relationship between O₂ and T_b in each mouse (Table 2). Each value was averaged for 30 min. Regression analysis was carried separately on the data for active [circadian time (CT) or ZT 12–24] and inactive (CT or ZT 0–12) phases in wild-type mice and the corresponding periods in Cry1^–/–/Cry2^–/– mice. All analyses showed significance. We used regression analysis for the averaged O₂ and T_b of each group to make further comparisons (Fig. 3), because all regressions within the same trial, period, and group showed a similar tendency: the slopes and intercepts were within the 95% confidence limits for the averaged O₂ and T_b. We hypothesized that if heat production was the sole determinant of circadian T_b rhythm, these regressions would be identical regardless of trial, circadian phase, and group. To test this, we first built a model equation fitted to all the data in the three trials within the same phase and group (see APPENDIX). Model equations were created for all possible relationships among the three trials: model A) all three regressions were similar; model B) all were different; and model C) two were similar. We calculated the Akaike information criterion (AIC) (Ref. 2) and selected the model with the lowest AIC as the most suitable one. In wild-type mice, the AIC in model A was the lowest in both phases (AIC = –117.87 and –90.50 in CT or ZT 12–24 and CT or ZT 0–12, respectively). Model A had the lowest AIC in both phases in the knockout mice (–271.01 and –204.82 in CT or ZT 12–24, and CT or ZT 0–12, respectively, in contrast to –242.62 and –182.11 in model B). Thus the data could be roughly separated into four groups: those at CT or ZT 12–24 and CT or ZT 0–12 in Cry1^–/–/Cry2^–/– and wild-type mice, respectively. Then, we applied a similar analysis to the four data groups simultaneously to evaluate the influence of the differences between mice groups and circadian phases on T_b. Here, the model indicated that the two regressions in wild-type mice were different, and those in the knockout mice were similar, showing the lowest AIC [–664.04 in contrast to –531.71 in the model where all regressions were similar (model A)]. These results are summarized in Fig. 4.

View this table: [in this window] [in a new window]   Table 2. Slopes and intercepts of the regression lines for O2 and Tb

View larger version (22K): [in this window] [in a new window]   Fig. 3. Relationship between metabolic heat production (O2) and Tb for the 3 trials in wild-type mice (A) and Cry1–/–/Cry2–/– (B). Values are means (±SE) of 5 mice for 30 min, and the data corresponding to each hour are used for this illustration. Regression lines were applied for the averaged values in each group. The regression analysis for each mouse is also summarized in Table 2.

View larger version (20K): [in this window] [in a new window]   Fig. 4. Summary of the model analyses of the relationship between metabolic heat production (O2) and Tb. Data are separated into 3 groups: active phase data on wild-type mice, inactive phase data on wild-type mice, and all the data on Cry1–/–/Cry2–/– mice. Each regression line is drawn within the range of O2 and Tb.

	DISCUSSION

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The model analysis for wild-type mice (Figs. 3A and 4) showed that two factors, i.e., the O₂ and circadian phase, independently determined T_b. However, the circadian phase would be a dominant factor determining the T_b rhythm in wild-type mice. The first reason is that T_b was kept higher in the active phase than the inactive phase regardless of the O₂ level. The second reason is that the regression slopes for O₂ and T_b in both phases were smaller than those for Cry1^–/–/Cry2^–/– mice (Student's t-test, P < 0.01). In other words, wild-type mice could maintain their T_b within a narrower range than the knockout mice over the same variation of O₂ in each phase. Thus the T_b rhythm in wild-type animals is not a simple by-product of the heat production rhythm but a regulated phenomenon by the factor of circadian phase.

In contrast to wild-type mice, the model analysis for the relationship between O₂ and T_b (Figs. 3B and 4) indicates that heat production predominantly determines T_b in Cry1^–/–/Cry2^–/– mice. Because the relationship was similar in all the trials, the factors of lighting, feeding, and phase themselves should have no specific effect on T_b (i.e., heat production determines T_b). Moreover, there was also a linear relationship between spontaneous activity and O₂ in the knockout mice under the ad libitum feeding condition during DD or LD (the regression analysis, R² = 0.51 and 0.59, respectively, P < 0.05), which indicates that their T_b is linked with spontaneous activity. Although the food restriction regimen had no additional effect on the activity rhythm, both the heat production and T_b rhythms became robust (Fig. 2). The means for the rhythms were smaller during the food restriction than ad libitum feeding; however, the amplitudes were greater (Table 1). These results show a suppression of heat production during the food deprivation. It is well known that fasting is a strong stimulus decreasing heat production (25, 27). Moreover, we previously suggested that eating rhythm is a potent stimulus generating heat production rhythm in normal rats (25). Thus eating is another factor modulating T_b in the knockout mice.

Homeothermic animals control T_b by balancing heat loss and heat production. For example, an activation of heat loss responses results in a negative heat balance, decreasing T_b until the heat balance is equilibrated again. Because this model shows that the influence of heat production on the circadian T_b rhythm is small, the difference in heat loss between the active and inactive phases may determine the T_b rhythm. Several studies may support this conclusion: the circadian T_b rhythm persists in completely bed-rested (13) humans, fasting humans and rats (7, 25), and hibernating squirrels (32), in which the amplitude of heat production rhythm disappears or is attenuated. Circadian changes in nonthermoregulatory factors that affect heat loss, such as the basal tone of the sympathetic nerve, may be involved in the T_b rhythm in part. However, the difference in the regression slope for heat production and T_b between wild-type and the knockout mice (Fig. 4) indicates modulation of the thermoregulatory responses of heat loss in the presence of the circadian clock.

Refinetti (30) reported that there was a heat balance rhythm with a 180-degree phase difference from the T_b rhythm; however, the amplitude was small. The results clearly show that the rhythm of heat balance is not a factor determining the T_b rhythm and also support our data that the heat production rhythm was not a prime mechanism involved in the T_b rhythm. Moreover, we speculate that the heat balance is mostly equilibrated throughout the day (i.e., the influence of heat production on T_b is reduced by heat loss responses), except for the dawn and sunset when T_b increases and decreases. This is also confirmed by the present data that the regression slope for heat production and T_b in each phase was smaller in wild-type than Cry1^–/–/Cry2^–/– mice.

Mice lacking the Clock gene, another key regulator of the circadian molecular loop, also lose activity and T_b rhythm under the DD condition (17, 33, 40). This result would indicate that Cry1/Cry2 genes are not specifically responsible for circadian T_b rhythm. The activity of the circadian clock should be regular to generate the T_b rhythm. However, it remains unclear how the molecular mechanisms of the circadian clock modulate neural and/or humoral signals, which regulate the thermoregulatory responses.

In conclusion, the thermoregulatory responses change according to the circadian phase, which is an important mechanism involved in circadian T_b rhythm. In contrast, Cry1^–/–/Cry2^–/– mice lack this change. We surmise that the circadian clock controls the thermoregulatory system to maintain the T_b rhythm.

	APPENDIX

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Model Analysis for Relationship Between O₂ and T_b.

The equation fitted to the O₂-T_b data points was built as follows:

where X and Y are O₂ and the estimated T_b, respectively; n is the number in the data group separated by the trial and/or circadian phase; a_n and b_n denote the regression intercept and slope for the nth group, respectively; d_n is a dummy variable with a value of either 1 or 0: d_n = 1 when applying the model equation to the nth group, and d_n = 0 otherwise. We built the models using as many assumptions as possible by modifying the above equation. For example, five models can be built for the three trials in each phase in each group of mice by assuming that model A) all the regressions are similar, a₁ = a₂ = a₃ and b₁ = b₂ = b₃; model B) any regression is different, a₁ a₁ a₃ and b₁ b₂ b₃; and models C1–C3) two regressions are similar, a₁ = a₂ a₃ and b₁ = b₂ b₃; or a₁ a₂ = a₃ and b₁ b₂ = b₃; or a₁ = a₃ a₂ and b₁ = b₃ b₂, respectively. Then, the AIC for each model is calculated as n'ln(SSE/n) + 2p, where n', SSE, and p are the observed number of data, sum of square error of the model equation, and the number of parameters in the equation, respectively. If the assumption is not adequate, the AIC of the model equation will increase.

	GRANTS

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This study was partially supported by the Ministry of Education, Science, and Culture of Japan, Grants-in-Aid for Scientific Research, No. 14570058.

	ACKNOWLEDGMENTS

 
We thank Drs. Y. Ohno and T. Nakamura for valuable suggestions in the model analysis.

	FOOTNOTES

 

Address for reprint requests and other correspondence: K. Nagashima, Dept. of Integrative Physiology, School of Human Sciences, Waseda Univ., Mikajima 2–579-15, Tokorozawa, Saitama 359–1192, Japan (E-mail: k-nagashima{at}waseda.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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