Abstract
Rationale
Chemotherapy, used for the treatment of cancer, often produces cognitive impairment that has been related to suppression of neurogenesis. Physical exercise, which promotes neurogenesis, is known to improve cognitive function in neurologically challenged animals and humans. It is unknown whether exercise similarly protects against chemotherapy-induced cognitive impairment and whether recovery of neurogenesis is a critical factor.
Objective
The present study investigated the relationship between hippocampal neurogenesis and cognitive performance in chemotherapy-treated rats that engaged in different amounts of physical activity.
Methods
Groups of rats, housed individually in standard cages or in specially designed cages that allowed unlimited access to a running wheel, received three injections of the chemotherapeutic drugs methotrexate and 5-flourouracil, or equal volumes of saline. They were then administered the following cognitive tests in a water maze: (1) spatial memory (SM), (2) cued memory, (3) non-matching to sample (NMTS) rule learning; (4) delayed NMTS (DNMTS). Hippocampal neurogenesis was quantified by counting doublecortin-expressing cells in the dentate gyrus.
Results
Chemotherapy administered to rats in standard cages resulted in a significant reduction in hippocampal neurogenesis and impaired performance on the SM, NMTS, and DNMTS tasks. In rats receiving chemotherapy and housed in exercise cages, neurogenesis was not suppressed and cognitive performance was similar to controls.
Conclusions
Physical exercise can reduce cognitive deficits that result from chemotherapy and this effect is mediated, at least in part, by preventing suppression of drug-induced hippocampal neurogenesis. The results suggest benefits of exercise in preventing or treating cognitive impairment associated with chemotherapy.
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Notes
The shortest interval between sample and test trials was the same as in NMTS testing. In fact, while designated as 0 s, the actual interval was about 10 s, the time required to prepare the cues and platform for the test trial. This 10-s interval was consistently added to each of the four delay intervals.
The considerable variability in the SAL group was due primarily to 2 rats that inexplicably and consistently ran three times further than the mean for that group. Excluding the running scores of these rats from the analysis did not change the outcome and, on all behavioral and neurogenesis measures, their scores were unremarkable, relative to the rest of the group. Accordingly, it was decided to include them in all running analyses.
Abbreviations
- R:
-
Runners
- CHEMO:
-
Chemotherapy
- CON:
-
Control
- SM:
-
Spatial memory
- CM:
-
Cued memory
- NMTS:
-
Non-matching to sample
- DNMTS:
-
Delayed NMTS
References
Ahles TA, Saykin AJ (2007) Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 7(3):192–201
Briones TL, Woods J (2011) Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications. BMC Neurosci 12(1):124
Christie LA, Acharya MM, Parihar VK, Nguyen A, Martirosian V, Limoli CL (2012) Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin Cancer Res 18(7):1954–1965
Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11(5):339–350
Fardell JE, Vardy J, Johnston IN, Winocur G (2011) Chemotherapy and cognitive impairment: treatment options. Clin Pharmacol Ther 90(3):366–376
Heyn P, Abreu BC, Ottenbacher KJ (2004) The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 85(10):1694–1704
Hou JG, Xue JJ, Lee MR, Sun MQ, Zhao XH, Zheng YN, Sung CK (2013) Compound K is able to ameliorate the impaired cognitive function and hippocampal neurogenesis following chemotherapy treatment. Biochem Biophys Res Commun 436(1):104–109
Jones DG, Smith BJ (1980) The hippocampus and its response to differential environments. Prog Neurobiol 15(1):19–69
Kirk RE (1968) Experimental design: procedures for the behavioral sciences. Wadsworth, New York
Konat GW, Kraszpulski M, James I, Zhang HT, Abraham J (2008) Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats. Metab Brain Dis 23(3):325–333
Kramer AF, Bherer L, Colcombe SJ, Dong W, Greenough WT (2004) Environmental influences on cognitive and brain plasticity during aging. J Gerontol A Biol Sci Med Sci 59(9):M940–M957
Lyons L, Elbeltagy M, Umka J, Markwick R, Startin C, Bennett G, Wigmore P (2011) Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy. Psychopharmacology (Berlin) 215(1):105–115
McDonald HY, Wojtowicz JM (2005) Dynamics of neurogenesis in the dentate gyrus of adult rats. Neurosci Lett 385(1):70–75
McDonald RA, Ergis A-M, Winocur G (1999) Functional dissociation of brain regions in learning and memory: evidence for multiple systems. In: Foster JK, Jelicic M (eds) Memory: systems, process or function. Oxford University Press, New York, pp 66–103
Monje M, Dietrich J (2012) Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis. Behav Brain Res 227(2):376–379
Morris RGM, Garrud P, Rawlins JNP, O'Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297(5868):681–683
Moscovitch M, Winocur G (2002) The frontal cortex and working with memory. In: Stuss DT, Knight RT (eds) Principles of frontal lobe function. Oxford University Press, London, pp 188–209
Mustafa S, Walker A, Bennett G, Wigmore PM (2008) 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 28(2):323–330
Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7(9):697–709
Nokia MS, Anderson ML, Shors TJ (2012) Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain. Eur J Neurosci 36(11):3521–3530
Olson AK, Eadie BD, Ernst C, Christie BR (2006) Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus 16(3):250–260
Seigers R, Fardell JE (2011) Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev 35(3):729–741
Seigers R, Schagen SB, Beerling W, Boogerd W, van Tellingen O, van Dam FS, Koolhass JM, Buwalda B (2008) Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav Brain Res 186(2):168–175
van Kesteren MT, Rijpkema M, Ruiter DJ, Fernandez G (2010) Retrieval of associative information congruent with prior knowledge is related to increased medial prefrontal activity and connectivity. J Neurosci 30(47):15888–15894
van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25(38):8680–8685
Vardy J, Rourke S, Tannock IF (2007) Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research. J Clin Oncol 25(17):2455–2463
Wefel JS, Schagen SB (2012) Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep 12(3):267–275
West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractinator. Anat Rec 231(4):482–497
Winocur G (1992) A comparison of normal old rats and young adult rats with lesions to the hippocampus or prefrontal cortex on a test of matching-to-sample. Neuropsychologia 30(9):769–781
Winocur G, Vardy J, Binns MA, Kerr L, Tannock IF (2006a) The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice. Pharmacol Biochem Behav 85(1):66–75
Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang S (2006b) Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 16(3):296–304
Winocur G, Binns MA, Tannock IF (2011) Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology 61(8):1222–1228
Winocur G, Becker S, Luu P, Rosenzweig S, Wojtowicz M (2012a) Adult hippocampal neurogenesis and memory interference. Behav Brain Res 227(2):464–469
Winocur G, Henkelman M, Wojtowicz JM, Zhang H, Binns MA, Tannock IF (2012b) The effects of chemotherapy on cognitive function in a mouse model: a prospective study. Clin Cancer Res 18(11):3112–3121
Wojtowicz JM, Kee N (2006) BrdU assay for neurogenesis in rodents. Nat Protoc 1(3):1399–1405
Wojtowicz JM, Askew ML, Winocur G (2008) The effects of running and of inhibiting adult neurogenesis on learning and memory in rats. Eur J Neurosci 27(6):1494–1502
Acknowledgments
The authors thank Dr. Malcolm Binns for his help with data analysis, and Dr. Melanie Sekeres for her critical reading of an earlier version of this paper. The technical assistance of Jeremy Audia, Yao Fang, and Nick Hoang is gratefully acknowledged. This research was supported by grants from the Canadian Institutes for Health Research (#MOP285993) and the Canadian Breast Cancer Foundation (#10470).
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Winocur, G., Wojtowicz, J.M., Huang, J. et al. Physical exercise prevents suppression of hippocampal neurogenesis and reduces cognitive impairment in chemotherapy-treated rats. Psychopharmacology 231, 2311–2320 (2014). https://doi.org/10.1007/s00213-013-3394-0
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DOI: https://doi.org/10.1007/s00213-013-3394-0