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

日常睡眠-觉醒周期中的干扰是患有 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 骚乱对他们的生活质量以及照顾他们的家庭成员都有重大影响。 亨廷顿病(HD)是最常见的遗传决定的神经退行性疾病，我们有 在三种不同的小鼠模型中，昼夜节律在疾病进展的早期被打乱 高清。使用表达人类突变的HD小鼠模型(BACHD)，我们成功地 改善了行为和一些自主神经缺陷，使用了一种方案，限制每日食物摄入量到 动物活动阶段的6小时窗口，因此被命名为：限时喂养(TRF)。这 在BACHD模型中，疾病早期应用喂养/禁食周期可改善行为定义的睡眠 进步。据我们所知，这是第一次证明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。一个 我们知识中的关键差距是TRF是否具体改变了睡眠阶段、睡眠的时间模式 反映慢波活动的稳态或皮质上/下状态。这项提案将雇用 电生理和光学方法来弥合这一差距，并确定这种治疗是否有效 受雇于房地产业。考虑到共同的病理包括蛋白质聚集体的形成和细胞死亡， 在HD中被证明有效的治疗策略很可能在管理中广泛受益 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.