Skip to main content

Advertisement

SpringerLink
Log in

Physical exercise prevents suppression of hippocampal neurogenesis and reduces cognitive impairment in chemotherapy-treated rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Notes

  1. 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.

  2. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Briones TL, Woods J (2011) Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications. BMC Neurosci 12(1):124

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fardell JE, Vardy J, Johnston IN, Winocur G (2011) Chemotherapy and cognitive impairment: treatment options. Clin Pharmacol Ther 90(3):366–376

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Jones DG, Smith BJ (1980) The hippocampus and its response to differential environments. Prog Neurobiol 15(1):19–69

    Article  CAS  PubMed  Google Scholar 

  • Kirk RE (1968) Experimental design: procedures for the behavioral sciences. Wadsworth, New York

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • McDonald HY, Wojtowicz JM (2005) Dynamics of neurogenesis in the dentate gyrus of adult rats. Neurosci Lett 385(1):70–75

    Article  CAS  PubMed  Google Scholar 

  • 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

    Chapter  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  Google Scholar 

  • Morris RGM, Garrud P, Rawlins JNP, O'Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297(5868):681–683

    Article  CAS  PubMed  Google Scholar 

  • 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

    Chapter  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7(9):697–709

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Seigers R, Fardell JE (2011) Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev 35(3):729–741

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Wefel JS, Schagen SB (2012) Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep 12(3):267–275

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Winocur G, Becker S, Luu P, Rosenzweig S, Wojtowicz M (2012a) Adult hippocampal neurogenesis and memory interference. Behav Brain Res 227(2):464–469

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Wojtowicz JM, Kee N (2006) BrdU assay for neurogenesis in rodents. Nat Protoc 1(3):1399–1405

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Baycrest Centre, Rotman Research Institute, 3560 Bathurst St, Toronto, Ontario, Canada, M6A 2E1

    Gordon Winocur

  2. Departments of Psychology and Psychiatry, University of Toronto, Toronto, Canada

    Gordon Winocur

  3. Department of Psychology, Trent University, Peterborough, Ontario, Canada

    Gordon Winocur

  4. Department of Physiology, University of Toronto, Toronto, Canada

    J. Martin Wojtowicz & Johnny Huang

  5. Divisions of Medical Oncology and Hematology, University of Toronto and Princess Margaret Hospital, Toronto, Ontario, Canada

    Ian F. Tannock

Authors
  1. Gordon Winocur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Martin Wojtowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johnny Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ian F. Tannock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gordon Winocur.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3394-0

Keywords

Search

Navigation