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Pathogenic mechanisms
B29 Voluntary exercise improves circadian function in a mouse model of Huntington's disease
  1. J Aungier,
  2. M Cuesta,
  3. AJ Morton
  1. Department of Pharmacology, University of Cambridge, Cambridge, UK

Abstract

Background The R6/2 mouse model of Huntington's disease exhibits many aspects of the human disease, including a progressively disrupted circadian rhythm. Previously we showed that restoring the circadian rhythm in R6/2 mice pharmacologically using alprazolam and modafinil prevented the cognitive decline seen in these mice. In addition we showed that the food-entrainable oscillator was intact in R6/2 mice whose circadian rhythms had broken down.

Aim To investigate whether or not voluntary, scheduled wheel running could be used to prevent circadian breakdown in R6/2 mice.

Methods We used four groups of R6/2 mice housed under LD (12:12). Control mice had fixed running wheels in their cage; “Free wheel” mice had unlimited access to wheels; “Restricted wheel” mice, could use their wheels for 6 h per day from lights off. The last group of mice had wheels that were “fixed” until they showed significant disintegration of their circadian rhythm. Then, for 4 weeks, their wheels were freed so they could be used for 3 h per day from lights off.

Results The rest-activity rhythm of control R6/2 mice disintegrated progressively from 12 weeks of age. Complete disintegration of their rhythm was seen by 14 weeks of age. By contrast, in the free wheel group breakdown of the rest-activity rhythm was delayed until 14–15 weeks. Their rhythm did not completely disintegrate until 18.6 weeks. Onset of disintegration of the rest-activity rhythm in the restricted wheel group was delayed until 15.5–16.5 weeks and did not disintegrate until shortly before their death at 20 weeks. When mice in the fourth group (with disintegerating rhythms) were given access to the wheel, their rest-activity rhythm was either improved, or no further disintegration was seen. If the wheel was fixed again so they could not run on it, the rest-activity rhythm improvements disappeared.

Conclusion Non-photic information from daily scheduled voluntary exercise prevented deterioration of circadian rhythms in R6/2 mice.

  • Circadian
  • R6/2
  • exercise
  • behavioural (circadian rhythm)

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