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

限时喂养可挽救亨廷顿病小鼠模型的昼夜节律和运动功能障碍

• 批准号: 10261774
• 负责人: CHRISTOPHER SCOTT COLWELL
• 金额: $ 12.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261774
• 关键词: Anatomy; Animals; Behavioral; Brain; Brain region; Calcium; Caring; Cell Death; Cells; Circadian Dysregulation; Circadian Rhythms; Corpus striatum structure; Development; Disease Management; Disease Progression; Drosophila genus; Drowsiness; Eating; Electrodes; Electroencephalography; Electrophysiology (science); Exhibits; Family member; Fasting; Frequencies; Gills; Head; Homeostasis; Human; Huntington Disease; Impaired cognition; Individual; Knowledge; Life; Measurement; Measures; Methods; Microscope; Modeling; Motor; Motor Cortex; Mus; Mutation; Names; Neurodegenerative Disorders; Neurons; Optics; Pathology; Patients; Pattern; Performance; Phase; Polysomnography; Process; Property; Protocols documentation; Quality of life; Recovery; Reporter; Schedule; Signal Transduction; Sleep; Sleep Deprivation; Sleep Stages; Sleep Wake Cycle; Sleep disturbances; Slow-Wave Sleep; Source; Specificity; Testing; Time-restricted feeding; Wakefulness; Work; awake; experience; experimental study; feeding; improved; motor disorder; mouse model; mutant; open source; protein aggregation; response; restoration; sleep behavior; sleep difficulty; sleep onset; sleep pattern; sleep quality; therapy design; tool; treatment strategy; vigilance

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.

每日睡眠觉醒周期中的骚乱是患有的人的共同特征 神经退行性疾病。他们很难在晚上睡觉，白天保持清醒。这些 干扰对他们的生活质量以及关心他们的家庭成员产生了重大影响。 亨廷顿氏病（HD）是最常见的遗传确定的神经退行性疾病，我们已经 记录在三种不同的小鼠模型中，昼夜节律在疾病进展的早期就被破坏 高清。使用表达人突变（BACHD）的HD的小鼠模型，我们已经成功 使用将日常食品摄入量限制为 在动物的活动阶段，一个6小时的窗口，因此被命名：时间限制喂养（TRF）。这 早期在疾病中应用喂养/禁食周期在BACHD模型中改善了行为定义的睡眠 进展。据我们所知，这是TRF可以改善小鼠睡眠参数的首次演示 尽管较早的工作表明，类似的时间表可以改善果蝇的行为睡眠方式。一个 我们知识上的关键差距是TRF是否专门改变了睡眠阶段的时间模式，睡眠 体内平衡或皮质上/下降状态反映了慢波活动。该建议将采用 电生理学和光学方法来缩小此差距并确定是否可以有用 雇用高清。鉴于共同的病理，包括形成蛋白质聚集体和细胞死亡， 被证明在HD中有效的治疗策略可能在管理方面具有广泛的好处 神经退行性疾病。