We describe a method using targeted peripheral irradiation to induce fatigue-like behavior in mice. The selected non-lethal irradiation dose leads to a week-long reduction in voluntary wheel-running activity.
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Method Article
A Mouse Model of Fatigue Induced by Peripheral Irradiation
In This Article
Summary
Abstract
Cancer-related fatigue (CRF) is a distressing and costly condition that often affects patients receiving cancer treatments, including radiation therapy. Here we describe a method using targeted peripheral irradiation to induce fatigue-like behavior in mice. With appropriate shielding, the irradiation targets the lower abdominal/pelvic region of the mouse, sparing the brain, in an effort to model radiation treatment received by individuals with pelvic cancers. We deliver an irradiation dose that is sufficient to induce fatigue-like behavior in mice, measured by voluntary wheel-running activity (VWRA), without causing obvious morbidity. Since wheel running is a normal, voluntary behavior in mice, its use should have little confounding effect on other behavioral tests or biological measures. Hence, wheel running can be used as a feasible outcome measure in understanding the behavioral and biological correlates of fatigue. CRF is a complex condition with frequent comorbidities, and likely has causes related both to cancer and its various treatments. The methods described in this paper are useful for investigating radiation-induced changes that contribute to the development of CRF and, more generally, to explore the biological networks that can explain the development and persistence of a peripherally-triggered but centrally-driven behavior like fatigue.
Introduction
Cancer-related fatigue (CRF) is a distressing and costly condition that often affects patients receiving cancer treatments1. The fatigue is neither proportional to recent activity nor alleviated by rest, and it is associated with a wide variety of disturbances related to mood, motivation, attention, and cognition2. The biological causes of CRF are unknown, though it has been shown in many cases to correlate with inflammation and cytokine levels, also in some cases with hemoglobin levels and the function of various hormone systems (see Saligan et al.3 for a review of biological studies of ....
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Protocol
Ethics Statement: This study was approved by the National Institutes of Health (NIH) Animal Care and Use Committee. All investigators taking part in animal handling and measurement of study outcomes were properly trained by the NIH Office of Animal Care and Use and the National Heart, Lung, and Blood Institute Murine Phenotyping Core. All aspects of animal testing, housing, and environmental conditions used in this study were in compliance with The Guide for the Care and Use of Laboratory Animals11.
1. Housing and Experimental Animals
NOTE: House male C57BL/6 mice (roughly five weeks old upo....
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Results
Three batches of mice were run through the protocol described above. There were a total of 16 sham and 20 irradiated (2,400 cGy, 3 x 800 cGy/day) mice. After three consecutive days of irradiation, the irradiated group showed significantly reduced VWRA compared to sham (mixed repeated measures ANOVA: main effect of irradiation treatment, F1,13 = 19.233, p < 0.001). The effect was significant for the first seven days after irradiation (simple main effects, p < 0.05 with Bon.......
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Discussion
We have described a protocol using targeted peripheral irradiation to induce a reduction of VWRA in mice without confounding morbidity or mortality. Importantly, a simple shielding device allows irradiation in this protocol to target a desired region consistently, mimicking the radiation treatments received by patients with pelvic cancer. In contrast to existing CRF models involving brain or total body irradiation8,9, this model explores how a peripherally-target.......
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Disclosures
This research was supported by the Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health.
Acknowledgements
The authors would like to thank Michele Allen of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) for generously sharing her expertise in murine phenotyping methods and for her ongoing technical assistance, as well as for Timothy Hunt of NHLBI for helping us develop the shielding device. This study is supported by the Division of Intramural Research of the National Institute of Nursing Research of the NIH, and part of the validation trial is supported by a grant from the Oncology Nursing Society Foundation.
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Materials
| Name | Company | Catalog Number | Comments |
|---|---|---|---|
| C57BL/6 Mice | Charles River | Strain code 027 (http://www.criver.com/products-services/basic-research/find-a-model/c57bl-6n-mouse) | |
| Ketamine HCl | Putney | 100 mg/mL stock solution | |
| Xylazine HCl | Lloyd Laboratories | 100 mg/mL stock solution | |
| Rodent Tattoo System | AIMS | ATS-3 | http://animalid.com/lab-animal-identification-systems/ats-3-general-rodent-tattoo-system |
| Lead Shielding Apparatus | (custom made) | One-inch thick lead shielding arranged as two boxes with a one-inch thick gap between them for targeted irradiation | |
| Plexiglass shielding container | (custom made) | Plexiglass container filled with styrofoam. Styrofoam cutouts hold the lead shielding in place. | |
| GammaCell 40 Exactor | Best Theratronics | http://www.theratronics.ca/product_gamma40.html | |
| RAD Disk Ultra | Best Theratronics | http://www.theratronics.ca/product_rad.html | |
| Mouse Single Activity Wheel Chamber | Lafayette Instrument Company | #80820 | http://www.lafayetteneuroscience.com/product_detail.asp?itemid=980 |
| Activity Wheel Counter for Computer Monitoring | Lafayette Instrument Company | #86061 | http://www.lafayetteneuroscience.com/product_detail.asp?itemid=1052 |
| Modular Cable for Wheel Counters | Lafayette Instrument Company | #86051-7 | http://www.lafayetteneuroscience.com/product_detail.asp?itemid=1046 |
| USB Computer Interface for Activity Wheel Counters | Lafayette Instrument Company | #86056A | http://www.lafayetteneuroscience.com/product_detail.asp?itemid=1047 |
| Activity Wheel Monitor Software | Lafayette Instrument Company | #86065 | http://www.lafayetteneuroscience.com/product_detail.asp?itemid=1053 |
References
- Minton, O., et al. Cancer-related fatigue and its impact on functioning. Cancer. 119, Suppl 11. 2124-2130 (2013).
- Bower, J. E. Cancer-related fatigue--mechanisms, risk factors, and treatments. Nat Rev Clin Oncol. 11 (10), 597-609 (2014).
- Saligan, L.....
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