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Can mice outrun the deleterious impacts of radiation to the brain?

Kamila U. Szulc¹, Shannon Egan², Elizabeth A. de Guzman^2,3,4, Aidin Arbabi^2,3,4, Donald J. Mabbott^1,5, and Brian J. Nieman^2,3,4

¹Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada, ²Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada, ³Ontario Institute for Cancer Research, Toronto, ON, Canada, ⁴Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada, ⁵Department of Psychology, University of Toronto, Toronto, ON, Canada

Synopsis

Pediatric cancer patients who receive cranial radiation therapy (CRT) exhibit cognitive deficits later in life. These deficits are often accompanied by brain structure abnormalities, especially prevalent in the white matter and hippocampus. The objective of this study was to explore the potential of physical exercise to mitigate some of the deleterious effects of CRT on the brain, using a mouse model and high-resolution MRI as a measure of brain structure. We found that irradiated mice housed in cages with access to running wheels showed a remarkable recovery of a number of CRT-induced brain volume deficits, most notably in the hippocampus.

Introduction

Cranial radiation therapy (CRT) in pediatric cancer patients is associated with cognitive deficits later in life, commonly known as late effects^1-3. Imaging studies in both mice and humans have shown that CRT leads to impaired brain development, affecting both white and gray matter areas, particularly regions dependent on ongoing neurogenesis^4-8. Consequently, there is need for interventions that mitigate the deleterious effects of CRT on the brain. Previous work demonstrated that voluntary running can rescue decline in neurogenesis of adult mice following CRT⁹, and a recent study in long-term pediatric brain tumor survivors who had received CRT found positive brain changes after completion of an exercise training program¹⁰. We used in vivo anatomical MRI to assess exercise-induced neuroanatomical changes in young mice following CRT, applied at a stage approximately equivalent to early childhood. We showed that running ameliorated, previously well-characterized^4-6, post-CRT volume and growth deficits. There were particularly strong effects in the hippocampus, a brain region critical for long-term memory formation.

Methods

In vivo images were acquired using a T1-weighted gradient echo sequence (TE/TR=8/26 ms, FA=23°, FOV=25x22x22mm, NA=2, scan duration=59 min, “cylindrical” acquisition) with 75 μm isotropic resolution, acquired four mice at a time with 4 cryo-coils on a 7 T Bruker MRI. Female CD-1 mice were imaged at P14, then received a 7 Gy dose of radiation (or sham) at P16. Following another MRI scan at P23, the mice were housed in pairs in either standard cages or cages equipped with a running wheel for the remainder of the study. Subsequent MRI was performed at P42 and P63. Mice were anaesthetized using isoflurane and injected intraperitoneally with MnCl₂ (0.4 mmol/kg) 24h prior to each scan. Volume changes were computed using deformation-based morphometry (DBM) via a well-established registration pipeline^11-13. Images were analyzed voxel-wise and/or registered to a mouse brain atlas to perform structure-wise analysis. Multiple comparisons were corrected using the false discovery rate¹⁴.

Results

Mice housed in cages with running wheels displayed statistically significant hippocampal volume increases (Fig 1 and Fig 2) in both irradiated (IR/Run) and sham-irradiated groups (Run). IR-treated running mice also showed at least partial recovery of CRT-induced volume losses in the following regions: habenular commissure, stria medullaris, fimbria, stria terminalis, internal capsule, hypothalamus, cerebral aqueduct, third ventricle, fornix, olfactory bulbs, fasciculus retroflexus and mammillary bodies (Fig 2). Interestingly non-irradiated runners (Run) showed statistically significant volume decreases of amygdala and lateral olfactory tract.

Discussion

A recent study¹⁰ in children investigated the benefits of exercise to long-term pediatric brain tumor survivors. Their findings showed increases in hippocampal volume and improved MR metrics related to white matter health after completing a 3-month long exercise training program. In our mouse study, running also increased hippocampal volume in both irradiated and non-irradiated runners, in addition to decreased CRT-induced volume losses in a number of other regions. These results further strengthen the evidence for an important role of exercise in fostering recovery of structural deficits caused by CRT. In the next steps, MRI and measures of exercise “dose” will be combined to evaluate the relationship between running patterns and anatomical outcomes. In addition, transgenic mice will be used to further investigate mechanisms by which exercise exerts its beneficial effect on the irradiated brain.

Conclusion

While CRT increases survival rates, it also leads to long-term cognitive impairments and neurodegeneration. Unfortunately, there is no cure or standard of care for these treatment-related side effects. We conducted a controlled mouse study that demonstrates that running leads to at least partial mitigation of CRT-induced brain volume loss, with particularly strong benefits for the hippocampus. These results support the idea that exercise promotes neuro-rehabilitation^15-16. The potential of exercise for fostering neuro-recovery in children treated for brain tumors with radiation merits further investigation.

Acknowledgements

This work was supported by funding from Brain Canada, NeuroDevNet and CBMH Postdoctoral Fellowship (KS), Canadian Institutes for Health Research and Ontario Institute for Cancer Research (BN) and Ontario Institute for Cancer Research grants (BN).

References

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Figures

Restoration of CRT-induced volume loss in the dentate gyrus (DG) of the hippocampus. Plot illustrates absolute volume versus mouse age from a piecewise linear mixed effects model fit. DG exhibits volume decrease following irradiation, which is subsequently rescued in runners due to significantly increased growth rates observed after placing mice in cages equipped with running wheels.

Heat map of t-values from comparison of IR, Run and IR/Run groups with sedentary controls based on a linear mixed effect model. Regions with statistically significant differences are denoted by asterisks. Running resulted in improved volume outcomes after CRT, such that no regions were statistically smaller in the IR/Run group relative to controls. Increases in hippocampal volume were especially pronounced in running mice (IR or control).

Maps of volume increases (red) and decreases (blue) in experimental groups compared to controls, as evaluated at P42 using a simple linear model. t-statistic maps were overlaid on an average anatomical image. IR group shows widespread decreases, which are largely rescued in IR/Run mice. Running increases hippocampal volume in both irradiated and non-irradiated runners.

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)

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