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.

日常睡眠-觉醒周期紊乱是患有此病的人所经历的一个共同特征 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。 亨廷顿舞蹈症 (HD) 是最常见的由基因决定的神经退行性疾病，我们有 记录了三种不同小鼠模型的昼夜节律在疾病进展早期被破坏 高清。使用表达人类突变（BACHD）的 HD 小鼠模型，我们成功地 使用限制每日食物摄入量的方案改善了行为和一些自主神经缺陷 动物活跃期的 6 小时窗口，因此被命名为：时间限制饲喂 (TRF)。这 在疾病早期应用时，进食/禁食周期可改善 BACHD 模型中行为定义的睡眠 进展。据我们所知，这是 TRF 可以改善小鼠睡眠参数的首次证明 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 是否专门改变睡眠阶段、睡眠的时间模式 反映慢波活动的稳态或皮质上/下状态。本提案将采用 电生理学和光学方法可以缩小这一差距并确定此类治疗是否有效 受雇于高清。鉴于共同的病理学，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 HD 的管理 神经退行性疾病。