Behavioral therapy reverses circadian deficits in a transgenic mouse model of Huntington's disease

• Circadian disruption is common in HD patients and HD mouse models.
• Disintegration of circadian rhythms in R6/2 mice can be prevented with bright light therapy and/or voluntary exercise.
• Behavioral therapies aimed at improving patterns of sleep-wake may be beneficial in HD patients.

Progressive disruption of circadian rhythmicity associated with disturbance of the sleep-wake cycle is one of the most insidious symptoms of Huntington's disease (HD) and represents a critical management issue for both patients and their care takers. The R6/2 mouse model of HD shows a progressive disruption of the circadian rhythmicity at both behavioral and molecular levels, although the intrinsic cellular machinery that drives circadian rhythmicity in individual cells appears to be fundamentally intact. Circadian rhythms are controlled by a master clock located in the suprachiasmatic nuclei (SCN) and can be synchronized by light and non-photic factors such as exercise. Here, we aimed to test whether or not stimulating the SCN directly could prevent the loss of circadian rhythmicity in R6/2 mice. We used combinations of bright light therapy and voluntary exercise as our treatment regimes. We found that all treatments had some beneficial effects, as measured by delayed disintegration of the rest-activity rhythm and improved behavioral synchronization to the light–dark cycle. The best effects were observed in mice treated with a combination of bright light therapy and restricted periods of voluntary exercise. Neither the cause nor the consequence of deteriorating sleep-wake activity in HD patients is known. Nevertheless, our findings can be translated immediately to human patients with little cost or risk, since both light therapy and restricted exercise regimes are non-pharmacological interventions that are relatively easy to schedule. Improved circadian rhythmicity is likely to have beneficial knock-on effects on mood and general health in HD patients. Until effective treatments are found for HD, strategies that reduce deleterious effects of disordered physiology should be part of HD patient treatment programs.