Comment Cite this article: Mason G, Wu¨rbel H. 2016 What can be learnt from wheel-running by wild mice, and how can we identify when wheel-running is pathological? Proc. R. Soc. B 283: 20150738. http://dx.doi.org/10.1098/rspb.2015.0738
Received: 10 April 2015 Accepted: 10 July 2015
Author for correspondence: Georgia Mason e-mail: [email protected]
Comment to: Meijer JH, Robbers Y. 2014 Wheel running in the wild. Proc. R. Soc. B 281, 20140210. Electronic supplementary material is available at http://dx.doi.org/10.1098/rspb.2015.0738 or via http://rspb.royalsocietypublishing.org.
What can be learnt from wheel-running by wild mice, and how can we identify when wheel-running is pathological? Georgia Mason1 and Hanno Wu¨rbel2 1 2
Animal Biosciences, University of Guelph, Ontario, Canada N1G 2W1 Vetsuisse Faculty, University of Bern, Bern 3012, Switzerland
Meijer & Robbers recently reported wheel-running (WR) in wild mice . Arguing that because WR occurs in non-captive animals, with bout lengths resembling those from a laboratory study, this ‘falsifies one criterion for stereotypic behaviour’ [1, p. 1]. They suggest that this should reassure researchers who use WR to investigate exercise but are also concerned that it ‘merely signifies neurosis or stereotypy’ [1, p. 1]. However, concluding that this should ‘help alleviate the main concern regarding the use of running wheels in research on exercise’ [1, p. 1] is premature. Here, we propose better ways to assess whether WR is pathological, making three main points: observing WR in wild animals does not demonstrate that laboratory animals’ WR is normal, because abnormal behaviours often develop from normal ones (see text below and electronic supplementary material); how to distinguish stereotypic from non-stereotypic behaviour depends on the definitions used, but has never been based on bout length alone (see electronic supplementary material); and clear, useful objective methods exist for identifying behaviours that reflect underlying pathology (see text below). Stereotypic behaviours (SBs), such as repetitive pacing and object-biting, are common in captivity . Taxon-typical, they often develop from normal intention, redirected or displacement activities performed when highly motivated behaviour is thwarted. Repetition may be further sustained by changes in neural circuitry (e.g. in the basal ganglia) that mediate behavioural inhibition and cause perseveration (functionless repetition) [2–4]. As in humans (see below), SBs can be malfunctional: for example, stereotypic horses and mink are poor at winning food in tasks requiring flexibility [4,5], and stereotypic mink gain fewer copulations in mate choice tasks . Many have asked whether WR is stereotypic (e.g. [1,7–9]), not least because it can consume many hours a day and persist for weeks (see electronic supplementary material). Using the standard, descriptive definition of SB (repetitive, unvarying and apparently goalless ; see electronic supplementary material), WR clearly is [7,8], but this leaves unanswered the key question: can WR be pathological, too [1,8,9]? Current data suggest that WR is heterogeneous (e.g. [1,7,9]), occurring, respectively, in adaptive, maladaptive and malfunctional forms. Thus, as well as in nature, WR occurs in large, semi-natural enclosures . It is reinforcing, and may be stress-reducing [8,10]. Providing wheels can boost litter size  and reduce bar-mouthing [9,11], an SB shown by caged rodents highly motivated to escape . Together, this suggests that WR, even in laboratory environments, can represent normal, adaptive, intrinsically rewarding running. However, WR varies with circumstance, increasing as current environmental quality declines. It is thus higher in barren cages than enriched ones [12–16]; and in animals exposed to noise, rough handling, intra-specific aggression or predator cues [12,14,17–20], or deprived of food [8,21], mates  or alcohol (if addicted ). When elicited by sub-optimal circumstances like these, WR may represent thwarted, unsuccessful, and thence maladaptive attempts to relocate . Consistent with this, WR is also highest in environments eliciting the most bar-mouthing in hamsters , and can be reduced with anxiolytics . Could WR also reflect pathology? In humans, abnormal repetitive behaviours typify autism, and impulsive, obsessive-compulsive and stereotyped movement disorders [2– 4,23,24]. For WR to indicate malfunction (e.g. [1,9]),
& 2016 The Author(s) Published by the Royal Society. All rights reserved.
Authors’ contributions. G.M. and H.W. co-wrote the original submission. G.M. led revisions, with H.W. editing/commenting to improve the MS. Both approved the final submission. Competing interests. We declare we have no competing interests. Funding. G.M. thanks NSERC for funding. Acknowledgements. Thanks to Maria Diez-Leon, Mike Walker, Innes Cuthill and referees for helpful comments.
Meijer JH, Robbers Y. 2014 Wheel running in the wild. Proc. R. Soc. B 281, 20140210. (doi:10.1098/ rspb.2014.0210) Mason G, Rushen, J (eds). 2006 Stereotypic animal behaviour: fundamentals and applications to welfare. Wallingford, UK: CABI. (doi:10.1079/ 9780851990040.0001) Garner JP, Thogerson CM, Dufour BD, Wu¨rbel H, Murray JD, Mench JA. 2011 Reverse-translational biomarker validation of abnormal repetitive behaviors in mice: an illustration of the 4Ps modeling approach. Behav. Brain Res. 219, 189–196. (doi:10.1016/j.bbr.2011.01.002) Campbell DLM, Dallaire JA, Mason GJ. 2013 Environmentally enriched rearing environments reduce repetitive perseveration in caged mink, but increase spontaneous alternation. Behav. Brain Res. 239, 177–187. (doi:10.1016/j.bbr. 2012.11.004) Hausberger M, Gautier E, Mu¨ller C, Jego P. 2007 Lower learning abilities in stereotypic horses. Appl. Anim. Behav. Sci. 107, 299–306. (doi:10.1016/j. applanim.2006.10.003) Dı´ez-Leo´n M et al. 2013 Environmentally enriched male mink gain more copulations than stereotypic, barren-reared competitors. PLoS ONE 8, e80494 (doi:10.1371/journal.pone.0080494) Latham N, Wu¨rbel H. 2006 Wheel-running: a common rodent stereotypy? In Stereotypic animal behaviour: fundamentals and applications to welfare
(eds G Mason, J Rushen), pp. 91 –92. Wallingford, UK: CABI. Sherwin CM. 1998 Voluntary wheel running: a review and novel interpretation. Anim. Behav. 56, 11 –27. (doi:10.1006/anbe.1998.0836) Richter SH, Gass P, Fuss J. 2014 Resting is rusting: a critical view on rodent wheel-running behaviour. The Neuroscientist 20, 313–325. (doi:10.1177/ 1073858413516798) Brene´ S, Bjørnebekk A, A˚ berg E, Mathe´ AA, Olson L, Werme M. 2007 Running is rewarding and antidepressive. Physiol. Behav. 92, 136 –140. (doi:10. 1016/j.physbeh.2007.05.015) Gebhardt-Henrich SG, Vonlanthen EM, Steiger A. 2005 How does the running wheel affect the behaviour and reproduction of golden hamsters kept as pets? Appl. Anim. Behav. Sci. 95, 199– 203. (doi:10.1016/j.applanim.2005.02.019) Uchiumi K, Aoki M, Kikusui T, Takeuchi Y, Mori Y. 2008 Wheel-running activity increases with social stress in male DBA mice. Physiol. Behav. 93, 1–7. (doi:10.1016/j.physbeh.2007.07.006) Kuhnen G. 2002 Comfortable quarters for hamsters in research institutions. In Comfortable quarters for laboratory animals (eds V Reinhardt, A Reinhardt), pp. 33– 37. Washington, DC: Animal Welfare Institute. Hauzenberger AR, Gebhardt-Henrich SG, Steiger A. 2006 The influence of bedding depth on behaviour in golden hamsters (Mesocricetus auratus). Appl.
Anim. Behav. Sci. 100, 280 –294. (doi:10.1016/j. applanim.2005.11.012) Reebs SG, Maillet D. 2003 Effect of cage enrichment on the daily use of running wheels by Syrian hamsters. Chronobiol. Int. 1, 9 –20 (doi:10.1081/ CBI-120018329) Pham TM, Brene´ S, Baumans V. 2005 Behavioural assessment of intermittent wheel running and individual housing in mice in the laboratory. J. Appl. Anim. Welf. Sci. 8, 157–173. (doi:10.1207/s15327604jaws0803_1) Eberli P, Gebhardt-Henrich SG, Steiger A. 2011 The influence of handling and exposure to a ferret on body temperature and running wheel activity of golden hamsters (M. auratus). Appl. Anim. Behav. Sci. 131, 131–137. (doi:10.1016/j.applanim.2011.02.006) Mather JG. 1981 Wheel-running activity: a new interpretation. Mamm. Rev. 11, 41– 51. (doi:10. 1111/j.1365-2907.1981.tb00246.x) Fischer K, Gebhardt-Henrich SG, Steiger A. 2007 Behaviour of golden hamsters (M. auratus) kept in four different cage sizes. Anim. Welf. 16, 85 –93. Kock LL, Rohn I. 1971 Observations on the use of the exercise-wheel in relation to the social rank and hormonal conditions in the bank vole (Clethrionomys glareolus), and Norway lemming (Lemmus lemmus). Z. Tierpsychol. 29 180 –195. (doi:10.1111/j.1439-0310.1971.tb01732.x) Novak CM, Burghardt PR, Levine JA. 2012 The use of a running wheel to measure activity in rodents: relationship to energy balance, general activity, and
Proc. R. Soc. B 283: 20150738
how WR changes as malfunction increases, so yielding useful diagnostics for researchers keen to avoid forms caused by underlying pathology. Overall, WR in wild animals is fascinating. However, it should not be used to ‘explain away’ or normalize WR in laboratory rodents, because pathological activities often develop from normal ones. To identify whether WR reflects pathology, we advise using the objective methods that exist for identifying when repetitive behaviour patterns reflect underlying malfunction and for elucidating underlying mechanisms. These methods come from clinical practice and neuroscience, and have recently revolutionized the understanding of captive animals’ SBs [2–4]. They could do likewise for WR. Meanwhile, for researchers concerned that WR may not model normal exercise, we suggest either recognizing that findings may relate more to ‘exercise addicts’ than normal exercising humans, or, instead, using enriched, low-stress housing to minimize risks of frustration or brain malfunction.
it should therefore demonstrably reflect alterations in brain function that are disabling (e.g. that interfere with social, occupational or other important areas of functioning ). High WR rodents do show altered basal ganglia physiology (e.g. [7,25]). Genotypes prone to addiction (e.g. ) and neurological plaques  also perform more WR. As for impairment, WR may cause paw injuries, tail malformations or even lethal weight loss (e.g. [9,21,27]) and promote infanticide . Missing, however, is research systematically comparing how WR differs between normal subjects and those affected by brain malfunction. We therefore suggest raising genetically similar, individually identified rodents (see the electronic supplementary material) to adulthood in environments varying in quality (from large, semi-naturalistic and low-stress to small, barren and chronically stressful), to induce differential neurological development [2,23]. We predict that impoverished rearing will elevate WR, regardless of the test environment (WR thus not merely reflecting dispersal). This should covary with perseverative errors (e.g. during extinction/reversal learning) and basal ganglial changes (e.g. regional cytochrome oxidase activity ). Furthermore, the most affected subjects should be most impaired (e.g. poorest at maternal care or attracting mates, and/or in tasks requiring flexibility). Were these predictions confirmed, then WR’s fine details should be analysed (bout lengths; 24 h time budgets; inter-bout and day-to-day variation; fidelity of running direction). This would reveal
disorders, 5th edn. Arlington, VA: American Psychiatric Publishing. 25. Mathes WF, Nehrenberg DL, Gordon R, Hua K, Garland T, Pomp D. 2010 Dopaminergic dysregulation in mice selectively bred for excessive exercise or obesity. Behav. Brain Res. 210, 155 –163. (doi:10.1016/j.bbr.2010.02.016) 26. Werme M, Thore´n P, Olson L, Brene´ S. 1999 Addiction-prone Lewis but not Fischer rats develop compulsive running that coincides with downregulation of Nerve Growth Factor Inducible-B and
Neuron-Derived Orphan Receptor 1. J. Neurosci. 19, 6169– 6174. 27. Veillette M, Guitard J, Reebs SG. 2010 Cause and possible treatments of foot lesions in captive Syrian hamsters. Vet. Med. Int. 2010, 1–5. (doi:10.4061/ 2010/951708) 28. Petri I, Scherbarth F, Steinlechner S. 2010 Voluntary exercise at the expense of reproductive success in Djungarian hamsters (Phodopus sungorus). Naturwissenschaften 97, 837–843. (doi:10.1007/ s00114-010-0701-z)
reward. Neurosci. Biobehav. Rev. 36, 1001 –1014. (doi:10.1016/j.neubiorev.2011.12.012) 22. Ozbum AR, Harris RA, Blednov YA. 2008 Wheel running, voluntary ethanol consumption and hedonic substitution. Alcohol 42, 417–424. (doi:10. 1016/j.alcohol.2008.04.006) 23. Bechard A, Lewis M. 2012 Modeling restricted repetitive behaviour in animals. Autism S1, 1–7. (doi:10.4172/2165-7890.S1-006) 24. American Psychiatric Association. 2013 Diagnostic and statistical manual of mental
Proc. R. Soc. B 283: 20150738