- Open Access
Characterization of locomotor activity circadian rhythms in athymic nude mice
© Paladino et al.; licensee BioMed Central Ltd. 2013
- Received: 6 December 2012
- Accepted: 12 January 2013
- Published: 1 February 2013
The relation between circadian dysregulation and cancer incidence and progression has become a topic of major interest over the last decade. Also, circadian timing has gained attention regarding the use of chronopharmacology-based therapeutics. Given its lack of functional T lymphocytes, due to a failure in thymus development, mice carrying the Foxn1(Δ/Δ) mutation (nude mice) have been traditionally used in studies including implantation of xenogeneic tumors. Since the immune system is able to modulate the circadian clock, we investigated if there were alterations in the circadian system of the athymic mutant mice.
General activity circadian rhythms in 2–4 month-old Foxn1(Δ/Δ) mice (from Swiss Webster background) and their corresponding wild type (WT) controls was recorded. The response of the circadian system to different manipulations (constant darkness, light pulses and shifts in the light–dark schedule) was analyzed.
Free-running periods of athymic mice and their wild type counterpart were 23.86 ± 0.03 and 23.88 ± 0.05 hours, respectively. Both strains showed similar phase delays in response to 10 or 120 minutes light pulses applied in the early subjective night and did not differ in the number of c-Fos-expressing cells in the suprachiasmatic nuclei, after a light pulse at circadian time (CT) 15. Similarly, the two groups showed no significant difference in the time needed for resynchronization after 6-hour delays or advances in the light–dark schedule. The proportion of diurnal activity, phase-angle with the zeitgeber, subjective night duration and other activity patterns were similar between the groups.
Since athymic Foxn1(Δ/Δ) mice presented no differences with the WT controls in the response of the circadian system to the experimental manipulations performed in this work, we conclude that they represent a good model in studies that combine xenograft implants with either alteration of the circadian schedules or chronopharmacological approaches to therapeutics.
Daily environmental changes have imposed a selective pressure for life on Earth, driving the development of a circadian clock mechanism for the generation and entrainment of rhythms in physiological and behavioural variables (e.g. body temperature, hormonal secretion, sleep, locomotor activity, etc.). In mammals, the master clock resides in the hypothalamic suprachiasmatic nuclei (SCN), and the principal signal that adjusts its activity is the light–dark cycle [1, 2].
A vast amount of bibliography accounts for the great number of health challenges observed in people working under circadian disruptive routines like the schedules of night- and rotating shift- working or airline workers who perform frequent transmeridian flights in which daily cues are continuously changing. Health problems associated to work-related chronodisruption include cardiovascular and gastrointestinal diseases, metabolic alterations, sleep disorders, and more importantly, elevated cancer rates [3, 4]. Indeed, the epidemiological evidence [3, 5–9] has led the WHO’s International Agency for Research on Cancer (IARC) to the declaration of shift-working as a relevant risk factor for cancer . Moreover, circadian timing might also be important for cancer therapeutics, since there is growing evidence suggesting that chronopharmacology-based chemotherapies approaches may benefit the outcome of cancer treatments and reduce drug toxicity (reviewed in ).
Although there is substantial information regarding the circadian modulation of many immunological variables [12–14], little is known about the possible effect of immune factors on the circadian system itself. Several reports suggest a possible immune feedback regulation of the circadian clock. For instance, the sleep–wake cycle (one of the most evident circadian rhythms) is modified by proinflammatory cytokines  and systemic low doses of LPS administered at circadian time (CT) 15 (CT12 corresponds to locomotor activity onset) produce a photic-like phase delay of locomotor rhythm in mice, that depend on Toll-like receptor-4 signaling [16, 17].
Foxn1(Δ/Δ) mutant –nude- mice have a specific defect in thymic development, characterized by a block in thymic epithelial cells differentiation at an intermediate progenitor stage, resulting in the production of abnormally functioning T cells . The nude mice are frequently used in cancer research because the feasibility to implant xenogeneic tumor cells (and, in particular, human tumor cells lines ). Given the increasing interest in the effects of circadian disruption on cancer biology [20–25] and the extended use of athymic mice as an useful tool for cancer studies, we aimed to characterize the circadian rhythms in nude and their corresponding control strain mice (Swiss Webster). Although the effects of the athymic mutation on some characteristics of circadian biology have been previously reported , our work extend these findings, analyzing circadian rhythmicity in constant conditions, and the response to shifts in the light/dark cycle and to light pulses. This approach results relevant to control the circadian variables in cancer-related experiments, and, in addition, these experiments assess the impact of a specific immune defect on the mammalian circadian system.
Adult (2 months old) Foxn1(Δ/Δ) mutant and wild type (WT) Swiss Webster (N:NIHS) male mice (Mus musculus) were housed in single cages under a 12:12-h light:dark photoperiod (LD, with lights on at 8 AM and light off at 8 PM) or in constant dark (DD) conditions with food and water access ad libitum. For the experiments in constant darkness, mice were transferred to DD conditions 20 days prior to the treatments. Foxn1(Δ/Δ) animals received sterile air ventilation, as well as sterile food and water. All animal experiments were carried out in accordance with the NIH Guide for the care and use of laboratory animals.
Mice were housed in individual cages equipped with infrared sensors, their locomotor activity circadian rhythm was recorded with a system designed in our laboratory and counts were collected every 5 min. Time is expressed as zeitgeber time (ZT), with ZT12 defined as the time of lights off in LD conditions, or circadian time (CT), with CT12 defined as the onset of locomotor activity in DD. Manipulation in DD conditions were performed under dim red light (<1 lux).
For light pulses experiments, mice maintained in DD were exposed to a 10 min- or 2 hour-white light pulse of 150 lux at CT15 or CT22. The onset of activity at CT12 was used as a phase reference point to calculate phase shifts.
Abrupt 6-h advances in the LD schedule were achieved by advancing the time of lights-on and shortening of the dark phase. Conversely, abrupt 6-h delays in the LD schedule were achieved by delaying the time of lights-on, and lengthening the dark phase.
Mice were deeply anaesthetized with a cocktail containing ketamine (150 mg/kg) and xylazine (10 mg/kg) 60 min after light pulse at CT15 and perfused intracardially with 4% paraformaldehyde in 0.01 M phosphate buffer. Brains were carefully removed, post-fixed overnight, cryoprotected in sucrose 30% in 0.01 M PBS for 24 h and 25 μm thick coronal sections were cut with a freezing microtome and collected in 0.01 M PBS. Free floating slices were blocked with 5% non-fatty milk in PBS contained 0.4% Triton X-100 and incubated with primary antisera raised in rabbit against c-Fos (Santa Cruz Biotechnology, 1:2000) diluted in the same solution, for 48 hs at 4°C. Sections were then treated using the avidin–biotin method with a Vectastain Elite Universal kit containing a biotinylated universal secondary antibody, avidin and biotilylated horseradish peroxidase (Vector Laboratories, Burlingame, CA) and Vector-VIP peroxidase substrate (SK-4600). Image analysis and cell counting was performed using ImageJ software, as described previously .
All circadian parameters were calculated using El Temps program (Antoni Díez Noguera, University of Barcelona). For phase angle (ψ) calculation and phase shifts analysis, individual waveforms were performed using 15 consecutive days in LD or DD condition. Activity onsets were defined as the moment in which the activity curve is on top of the mean line of each individual waveform. ψ was calculated as the difference between the activity onset in LD conditions and the time of lights off.
In order to improve the visualization and analysis of the activity patterns we computed an hourly activity profile, in which we plotted mean locomotion for each hour (or circadian hour) relative to average activity counts. These individual hourly waveforms were used for the analysis of activity distribution both in LD and DD conditions. Also, an average waveform for each animal group was calculated using these individual waveforms.
The activity distribution over the day in LD conditions was analyzed in four different intervals: ZT12-23, ZT23-3, ZT3-10 and ZT10-12 (see results). The contribution of each interval to total activity was calculated by performing hourly waveform analysis of the relative activity for each individual animal, and measuring the area under the curve for each interval. The ratio between this area and the total area under the curve of the waveform, expressed as a percentage, was used for further comparisons.
Resynchronization to a new LD cycle, after 6-hour phase shifts of the time of lights off, was considered fully accomplished when activity onset took place at the new time of lights off ±15 minutes. We calculated the number of days (transients) required to resynchronize for each animal.
In DD conditions, free-running activity periods (τ) were determined by Chi-square periodograms. Duration of the subjective night (α), was calculated by performing an hourly waveform analysis of the relative activity data for each animal in DD (using the corresponding τ), and measuring the time length covered by the portion of the curve on top of the mean of activity. Conversely, ρ (duration of the subjective day) was calculated as the time length covered by the portion of the curve under the mean of activity. The percentage of total activity occurring during α was calculated as the percentage of the area under the curve of the waveform analysis occurring within the α interval.
Phase shifts were calculated as follows: individual waveforms of the ten previous days to the light pulse and of ten days after the light pulse (excluding the 2 cycles immediately after the pulse) were obtained; the time at which the activity curve crossed the mean line of each waveform was defined as the activity onset and used as phase marker of the rhythm prior and after the pulse. Phase shifts were calculated as the difference between the two onsets.
Data are presented as mean ± SEM. Differences between the two groups were analyzed by unpaired Student’s t test or the non-parametric Mann Whitney test, accordingly. P values of 0.05 or less were considered to be statistically significant.
Free running period and general activity pattern in nude mice
Activity patterns in LD conditions
(mean ± SEM)
(mean ± SEM)
8.7 ± 6.3
8.1 ± 3.1
64.54 ± 3.43
65.68 ± 6.82
12.37 ± 2.17
14.81 ± 4.00
13.49 ± 1.69
10.22 ± 1.75
8.11 ± 1.13
6.85 ± 1.71
Activity patterns in DD conditions
23.86 ± 0.03
23.88 ± 0.05
8.7 ± 0.6
10.8 ± 1.5
36.5 ± 2.4
45.4 ± 6.3
% Area (α)
66.1 ± 3.5
79.9 ± 3.7
0.58 ± 0.06
0.98 ± 0.27
Characterization of circadian responses to light in nude mice
Studies using xenogeneic tumor implantation in athymic immune-deficient mice are becoming a useful tool for understanding both the importance of circadian dysregulation as a factor that potentiates tumor progression and the benefits of timed cancer therapies [29–31]. Therefore, a circadian characterization of nude mice results necessary to fully comprehend the results of such experimental approaches. A previous report by Beau et al. (1990) has described the patterns of circadian locomotor activity under LD conditions, analyzing 3 days of recording. In the present study, we extend those results, analyzing circadian rhythms in constant conditions, the response to light pulses and the resynchronization to light–dark cycles shifts.
Our results show that general activity characteristics (ψ and activity distribution over different ZT intervals) in athymic mice were not different from their WT control. Presence of anticipatory behavior was seen in approximately 50% of the WT mice, evidenced by a sharp bout of activity occurring 1–2 hours before the time of lights off (ZT10-12). However, the percentage of total activity occurring within this interval did not differ between athymic and control mice, probably due to the presence of irregular diurnal activity also during this interval in the nude mice. An important activity bout was found in both WT and mutant mice, occurring in an interval ranging from ZT23 to ZT3. In a previous report showing an activity waveform for WT Swiss Webster mice, this activity bout was also found in the first hours of the light phase, and was accompanied by a raise in body temperature, suggesting that it might be a characteristic of the Swiss background . A reduced amount of global activity has been described in nude mice from C57BL/6J background, compared with their WT controls . Unfortunately, due to differences in the sensitivity among infrared sensors, the absolute number of counts is not reliably comparable between different animals, therefore making it impossible to estimate a global activity mean that can be used to compare the nude and the WT strains.
Under conditions of continuous darkness (DD), circadian rhythms assume free-running periods that are close to 24 hours. Our data indicate a slightly larger period in nude and control mice with Swiss Webster background (23.86 and 23.88 h, respectively), compared with a previous report that showed a 23.3 h period in wheel running activity rhythms for the Swiss strain mice . However, it has been described that wheel-running can shorten the period of circadian rhythms in rodents [34–36], which might explain the longer period found in our work, where we measured general activity rhythms of mice without access to running wheels. Importantly, there were no differences between the free-running period or in the α in DD of nude and WT control mice (although the percentage of activity occurring within the α interval was lower in nude mice), suggesting that the Foxn1(Δ/Δ) mutation doesn’t affect the central pacemaker, at least regarding this particular behavioral output. In addition, our findings add substantial information regarding the circadian system of Swiss mice, a strain that has received relatively little attention in chronobiology.
Circadian entrainment to light–dark cycles is mediated through daily phase shifts induced by light on the pacemaker. We found no differences in the magnitude of the phase shifts (both at the early or late night) between WT Swiss mice and the nude mutant mice. Also, the ability to resynchronize to a 6-hour shift (both in delayed or advanced schedules) in the LD cycle did not differ between the two strains. This finding could be expected given the similarities in both the response to light pulses and the endogenous periods of each strain.
Alterations in the immune system can produce changes in circadian physiology. For example, mice mutant for the Galectin-1 gene, which regulates cytokine synthesis , show altered free-running periods and responses to early-night light pulses . Moreover, activation of the immune system can also modulate the circadian clock. Peripheral LPS administration or introcerebroventricular (icv) injection of TNF-α or IL-1β produced phase delays in wheel running activity [17, 39], and icv delivery of a proinflammatory cocktail also activated c-Fos expression in the SCN . In addition, clock gene expression can be altered by exposure to different proinflammatory factors [41–44]. Besides the lack of functional T cells, nude athymic mice show resistance to Bacillus anthracis, Listeria monocytogenes and Staphylococcus aureus infection [45, 46], reduced levels of circulating TNF-α, IL-6 and IFN-γ, in response to Pseudomonas aeruginosa exotoxin  and present a higher activation of macrophages . It should also be noted that the nude mice were found to have a reduced number of glial cells (oligodendrocytes, astrocytes, and microglia), with presence of hypertrophic astroglia in the adult brain , and glial cells have been suggested to modulate the circadian system [50–52]. However, given the results of this work, none of these characteristics (or other phenotypic changes) occurring in the Foxn1(Δ/Δ) mice results in a notable alteration in the circadian rhythm of activity.
The results of the present work show that the profound alterations in the immune system of the nude mice do not modify the circadian activity rhythms of these animals, suggesting that the lack of functional T-cell generation (or any other differential phenotype occurring in the athymic mice) does not produce changes in the circadian control of locomotor activity. Indeed, the effect of the Foxn1(Δ/Δ) (nude) mutation on other circadian rhythms remains to be established. These findings are relevant, both regarding the growing interest in the modulation of the circadian system by immune factors, as well as in the use of the immunodeficient nude mice in cancer research, particularly in approaches that rely in the alteration of normal circadian rhythmicity or in chronopharmacological treatment designs.
We thank the staff of the Animal Facilities of the National University of Quilmes. This work was supported by grants from the National University of Quilmes, the National Research Council (CONICET) and the National Agency for Promotion of Science and Technology (ANPCyT). MMF is a fellow from the National University of Quilmes, JMD is a fellow from the National Research Council of Argentina (CONICET) and NP and DAG are established researchers of the CONICET.
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