Ouk Koliane, Aungier Juliet, Morton A Jennifer
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
Neurobiol Sleep Circadian Rhythms. 2016 Nov 30;2:27-38. doi: 10.1016/j.nbscr.2016.11.004. eCollection 2017 Jan.
The circadian disruption seen in patients of Huntington's disease (HD) is recapitulated in the R6/2 mouse model. As the disease progresses, the activity of R6/2 mice increases dramatically during the rest (light) period and decreases during the active (dark) period, eventually leading to a complete disintegration of rest-activity rhythms by the age of ~16 weeks. The suprachiasmatic nucleus controls circadian rhythms by entraining the rest-activity rhythms to the environmental light-dark cycle. Since R6/2 mice can shift their rest-activity rhythms in response to a jet-lag paradigm and also respond positively to bright light therapy (1000 lx), we investigated whether or not a prolonged day length exposure could reduce their daytime activity and improve their behavioural circadian rhythms. We found that a long-day photoperiod (16 h light/8 h dark cycle; 100 lx) significantly improved the survival of R6/2 female mice by 2.4 weeks, compared to mice kept under standard conditions (12 h light/12 h dark cycle). Furthermore, a long-day photoperiod improved the nocturnality of R6/2 female mice. Mice kept under long-day photoperiod also maintained acrophase in activity rhythms (a parameter of rhythmicity strength) in phase with that of WT mice, even if they were symptomatic. By contrast, a short-day photoperiod (8 h light/16 h dark cycle) was deleterious to R6/2 female mice and further reduced the survival by ~1 week. Together, our results support the idea that light therapy may be beneficial for improving circadian dysfunction in HD patients.
亨廷顿舞蹈症(HD)患者出现的昼夜节律紊乱在R6/2小鼠模型中得到了重现。随着疾病进展,R6/2小鼠在休息(光照)期的活动显著增加,而在活动(黑暗)期则减少,最终在约16周龄时导致休息-活动节律完全瓦解。视交叉上核通过使休息-活动节律与环境明暗周期同步来控制昼夜节律。由于R6/2小鼠能够根据时差模式改变其休息-活动节律,并且对强光疗法(1000勒克斯)也有积极反应,我们研究了延长日照时长是否能减少它们的白天活动并改善其行为昼夜节律。我们发现,与饲养在标准条件(12小时光照/12小时黑暗周期)下的小鼠相比,长日照光周期(16小时光照/8小时黑暗周期;100勒克斯)显著提高了R6/2雌性小鼠的存活率,延长了2.4周。此外,长日照光周期改善了R6/2雌性小鼠的夜行性。即使出现症状,饲养在长日照光周期下的小鼠在活动节律(节律强度参数)中的峰相位也与野生型小鼠保持一致。相比之下,短日照光周期(8小时光照/16小时黑暗周期)对R6/2雌性小鼠有害,并使存活率进一步降低了约1周。总之,我们的结果支持光疗法可能有助于改善HD患者昼夜节律功能障碍这一观点。