Brain Imaging and Behavior

, Volume 12, Issue 1, pp 87–95 | Cite as

In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction

  • Robert L. Barry
  • Nellie E. Byun
  • M. Noor Tantawy
  • Chase A. Mackey
  • George H. WilsonIII
  • Adam J. Stark
  • Michael P. Flom
  • Laura C. Gee
  • C. Chad Quarles
Original Research
  • 352 Downloads

Abstract

Adjuvant chemotherapy has been used for decades to treat cancer, and it is well known that disruptions in cognitive function and memory are common chemotherapeutic adverse effects. However, studies using neuropsychological metrics have also reported group differences in cognitive function and memory before or without chemotherapy, suggesting that complex factors obscure the true etiology of chemotherapy-induced cognitive dysfunction (CICD) in humans. Therefore, to better understand possible mechanisms of CICD, we explored the effects of CICD in rats through cognition testing using novel object recognition (NOR) and contextual fear conditioning (CFC), and through metabolic neuroimaging via [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Cancer-naïve, female Sprague-Dawley rats were administered either saline (1 mL/kg) or doxorubicin (DOX) (1 mg/kg in a volume of 1 mL/kg) weekly for five weeks (total dose = 5 mg/kg), and underwent cognition testing and PET imaging immediately following the treatment regime and 30 days post treatment. We did not observe significant differences with CFC testing post-treatment for either group. However, the chemotherapy group exhibited significantly decreased performance in the NOR test and decreased 18F-FDG uptake only in the prefrontal cortex 30 days post-treatment. These results suggest that long-term impairment within the prefrontal cortex is a plausible mechanism of CICD in this study, suggesting DOX-induced toxicity in the prefrontal cortex at the dose used.

Keywords

Chemotherapy Doxorubicin Chemobrain Chemotherapy-induced cognitive dysfunction Neurobehavioral testing Novel object recognition Contextual fear conditioning Neuroimaging [18F]fluorodeoxyglucose positron emission tomography 

Notes

Acknowledgments

This research was supported by the American Cancer Society (IRG-58-009-51 to C.C.Q.). The authors thank Dr. M. Scott Thompson at the Vanderbilt University Medical Center Oncology Pharmacy; Dr. Randy L. Smith Barrett at the Vanderbilt University School of Medicine Rat Neurobehavioral Core; and Fuxue Xin and Dr. Zou Yue at the Vanderbilt University Institute of Imaging Science Center for Small Animal Imaging. We also acknowledge Mackenzie Whitehurst for her assistance in analyzing the novel object recognition data and Tanner Liddy for his assistance in analyzing the contextual fear conditioning data. Finally, we thank Mrs. Joan M. Gee for asking the question “I wonder what chemotherapy will do to my brain?”; her personal experiences with breast cancer and chemotherapy in 2010 was the motivation for this study.

Author contributions

 Concept and study design: Barry, Byun, Gee, Quarles

Development of methodology: Barry, Byun, Tantawy, Wilson

Acquisition of data: Barry, Byun, Tantawy, Wilson, Gee

Analysis and interpretation of data: Barry, Byun, Tantawy, Mackey, Flom, Stark

Writing, reviewing, and revising manuscript: Barry, Byun, Tantawy, Quarles

Compliance with ethical standards

Competing financial interests

The authors declare no competing financial interests.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Robert L. Barry
    • 1
    • 2
    • 3
    • 4
  • Nellie E. Byun
    • 1
    • 5
    • 6
  • M. Noor Tantawy
    • 1
    • 2
  • Chase A. Mackey
    • 1
  • George H. WilsonIII
    • 1
  • Adam J. Stark
    • 1
    • 7
  • Michael P. Flom
    • 1
    • 7
  • Laura C. Gee
    • 8
  • C. Chad Quarles
    • 1
    • 2
    • 9
    • 10
    • 11
  1. 1.Vanderbilt University Institute of Imaging ScienceVanderbilt University Medical CenterNashvilleUSA
  2. 2.Department of Radiology and Radiological SciencesVanderbilt University Medical CenterNashvilleUSA
  3. 3.Athinoula A. Martinos Center for Biomedical Imaging, Department of RadiologyMassachusetts General HospitalCharlestownUSA
  4. 4.Department of RadiologyHarvard Medical SchoolBostonUSA
  5. 5.Vanderbilt Center for Neuroscience Drug DiscoveryVanderbilt University Medical CenterNashvilleUSA
  6. 6.Department of PharmacologyVanderbilt University Medical CenterNashvilleUSA
  7. 7.Neuroscience ProgramVanderbilt UniversityNashvilleUSA
  8. 8.Division of Animal CareVanderbilt University Medical CenterNashvilleUSA
  9. 9.Department of Cancer BiologyVanderbilt University Medical CenterNashvilleUSA
  10. 10.Department of Biomedical EngineeringVanderbilt UniversityNashvilleUSA
  11. 11.Barrow Neurological InstituteSt. Joseph’s Hospital and Medical CenterPhoenixUSA

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