Time restricted feeding rescues circadian and motor dysfunction in a mouse model of Huntington's disease

日常睡眠-觉醒周期的紊乱是患有以下疾病的个体经历的常见特征： 神经退行性疾病他们晚上很难入睡，白天也很难保持清醒。这些 干扰对他们的生活质量以及照顾他们的家庭成员产生重大影响。 亨廷顿氏病（HD）是最常见的遗传决定的神经退行性疾病， 在三种不同的小鼠模型中记录了昼夜节律在疾病进展的早期被破坏 HD的。使用表达人类突变（BACHD）的HD小鼠模型，我们成功地 改善了行为和一些自主神经缺陷，使用一种协议，限制每日食物摄入量， 在动物的活动期期间的6小时窗口，因此被命名为：时间限制喂养（TRF）。这 在疾病早期应用时，进食/禁食周期改善了BACHD模型中的行为定义睡眠 进展据我们所知，这是首次证明TRF可以改善小鼠的睡眠参数 尽管早期的研究表明，类似的时间表可以改善果蝇的行为睡眠模式。一 我们知识的关键缺口是TRF是否特别改变睡眠阶段的时间模式， 稳态或反映慢波活动的皮质上/下状态。该提案将采用 电生理学和光学方法来缩小这一差距，并确定这种治疗是否可以有效地 在HD工作。考虑到共同的病理学，包括蛋白质聚集体的形成和细胞死亡， 被证明对HD有效的治疗策略可能广泛有益于 神经退行性疾病

Disturbances in the daily sleep-wake cycle are a common feature experienced by individuals with neurodegenerative disorders. They have difficulty sleeping at night and staying awake during the day. These disturbances have a major impact on their quality of life as well as on the family members who care for them. Huntington's disease (HD) is the most common genetically determined neurodegenerative disease and we have documented that circadian rhythms are disrupted early in the disease progression in three distinct mouse models of HD. Using a mouse model of HD which expresses the human mutation (BACHD), we have successfully improved the behavioral and some of the autonomic deficits using a protocol that limits the daily food intake into a 6-hr window during the animal's active phase, and is thus named: time restricted feeding (TRF). This feeding/fasting cycle improved behaviorally defined sleep in the BACHD model when applied early in disease progression. To our knowledge, this is the first demonstration that TRF can improve sleep parameters in mice although earlier work has shown that a similar schedule can improve behavioral sleep patterns in Drosophila. A critical gap in our knowledge is whether TRF specifically alters the temporal pattern of sleep stages, sleep homeostasis or cortical up/down states reflecting slow wave activity. This proposal will employ electrophysiological and optical approaches to close this gap and determine if such treatments can be usefully employed in HD. Given the shared pathology including the formation of protein aggregates and cell death, treatment strategies that prove to be effective in HD are likely to be broadly beneficial in the management of neurodegenerative diseases.